The term "primary intraosseous squamous cell carcinoma" was introduced in 2005 by the World Health Organization with three subcategories. Squamous cell carcinoma arising from the lining of an odontogenic cyst ...
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Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Πέμπτη 30 Νοεμβρίου 2017
Squamous cell carcinoma arising from a keratocystic odontogenic tumor: a case report
Evidence of the efficacy and safety of house dust mite subcutaneous immunotherapy in elderly allergic rhinitis patients: a randomized, double-blind placebo-controlled trial
Allergen specific immunotherapy (AIT) in elderly patients is controversial, and there is still little evidence supporting the safety and efficacy of this treatment in this population. The study objective was t...
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Analysis of the relationship between prescribed dose and dosimetric advantage of real-time intraoperatively built custom-linked seeds in iodine-125 prostate brachytherapy
The purpose of this study was to investigate the differences in the dosimetric advantage of using intraoperatively built custom-linked (IBCL) seeds between permanent iodine-125 (I-125) seed implantation (PI) a...
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The effectiveness of vibrational stimulus to accelerate orthodontic tooth movement: a systematic review
Abstract
Background
In recent years, it has been a hot research topic to accelerate orthodontic tooth movement (OTM) through vibration. This review was therefore aimed to systematically evaluate the available evidences on the efficacy of vibrational stimulus to accelerate OTM.
Methods
Randomized controlled trials and controlled clinical trials that evaluated the efficacy of vibration on OTM acceleration were searched through electronic and manual search. Two review authors independently conducted the study inclusion, quality assessment and data extraction. The quality of synthesized evidence was assessed according to GRADE system.
Results
Eight clinical trials were included in this systematic review. Four studies found that vibration did not enhance the rate of OTM during alignment phase. Two studies revealed that the use of vibratory stimulation accelerated canine retraction. No deleterious effects including pain perceptions and root resorptions were reported.
Conclusions
Within the limitations of this review, weak evidence indicates that vibrational stimulus is effective for accelerating canine retraction but not for alignment. The effects of vibration on pain intensity and root resorption during orthodontic treatment are inconclusive. Future high-quality clinical trials are needed before warranting recommendations to clinical application.
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Modeling Cytostatic and Cytotoxic Responses to New Treatment Regimens for Ovarian Cancer
The margin for optimizing polychemotherapy is wide, but a quantitative comparison of current and new protocols is rare even in preclinical settings. In silico reconstruction of the proliferation process and the main perturbations induced by treatment provides insight into the complexity of drug response and grounds for a more objective rationale to treatment schemes. We analyzed 12 treatment groups in trial on an ovarian cancer xenograft, reproducing current therapeutic options for this cancer including one-, two-, and three-drug schemes of cisplatin (DDP), bevacizumab (BEV), and paclitaxel (PTX) with conventional and two levels ("equi" and "high") of dose-dense schedules. All individual tumor growth curves were decoded via separate measurements of cell death and other antiproliferative effects, gaining fresh insight into the differences between treatment options. Single drug treatments were cytostatic, but only DDP and PTX were also cytotoxic. After treatment, regrowth stabilized with increased propensity to quiescence, particularly with BEV. More cells were killed by PTX dose-dense-equi than with PTX conventional, but with the addition of DDP, cytotoxicity was similar and considerably less than expected from that of individual drugs. In the DDP/PTX dose-dense-high scheme, both cell death and regrowth impairment were intensified enough to achieve complete remission, and addition of BEV increased cell death in all schemes. The results support the option for dose-dense PTX chemotherapy with active single doses, showing the relative additional contribution of BEV, but also indicate negative drug interactions in concomitant DDP/PTX treatments, suggesting that sequential schedules could improve antitumor efficacy. Cancer Res; 77(23); 6759–69. ©2017 AACR.
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Oral Microbiome Composition Reflects Prospective Risk for Esophageal Cancers
Bacteria may play a role in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although evidence is limited to cross-sectional studies. In this study, we examined the relationship of oral microbiota with EAC and ESCC risk in a prospective study nested in two cohorts. Oral bacteria were assessed using 16S rRNA gene sequencing in prediagnostic mouthwash samples from n = 81/160 EAC and n = 25/50 ESCC cases/matched controls. Findings were largely consistent across both cohorts. Metagenome content was predicted using PiCRUST. We examined associations between centered log-ratio transformed taxon or functional pathway abundances and risk using conditional logistic regression adjusting for BMI, smoking, and alcohol. We found the periodontal pathogen Tannerella forsythia to be associated with higher risk of EAC. Furthermore, we found that depletion of the commensal genus Neisseria and the species Streptococcus pneumoniae was associated with lower EAC risk. Bacterial biosynthesis of carotenoids was also associated with protection against EAC. Finally, the abundance of the periodontal pathogen Porphyromonas gingivalis trended with higher risk of ESCC. Overall, our findings have potential implications for the early detection and prevention of EAC and ESCC. Cancer Res; 77(23); 6777–87. ©2017 AACR.
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Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging
Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared with adjacent normal tissue and the contralateral kidney. Upon glutaminase inhibition with CB-839 or BPTES, the RCC cell lines SN12PM-6-1 (SN12) and 786-O exhibited decreased survival and pronounced apoptosis associated with a decreased GSH/GSSG ratio, augmented nuclear factor erythroid-related factor 2, and increased 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of DNA damage. SN12 tumor xenografts showed decreased growth when treated with CB-839. Furthermore, PET imaging confirmed that ccRCC tumors exhibited increased tumoral uptake of 18F-(2S,4R)4-fluoroglutamine compared with the kidney in the orthotopic mouse model. This technique can be utilized to follow changes in ccRCC metabolism in vivo. Further development of these paradigms will lead to new treatment options with glutaminase inhibitors and the utility of PET to identify and manage patients with ccRCC who are likely to respond to glutaminase inhibitors in the clinic. Cancer Res; 77(23); 6746–58. ©2017 AACR.
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SMYD5 Controls Heterochromatin and Chromosome Integrity during Embryonic Stem Cell Differentiation
Epigenetic regulation of chromatin states is thought to control gene expression programs during lineage specification. However, the roles of repressive histone modifications, such as trimethylated histone lysine 20 (H4K20me3), in development and genome stability are largely unknown. Here, we show that depletion of SET and MYND domain–containing protein 5 (SMYD5), which mediates H4K20me3, leads to genome-wide decreases in H4K20me3 and H3K9me3 levels and derepression of endogenous LTR- and LINE-repetitive DNA elements during differentiation of mouse embryonic stem cells. SMYD5 depletion resulted in chromosomal aberrations and the formation of transformed cells that exhibited decreased H4K20me3 and H3K9me3 levels and an expression signature consistent with multiple human cancers. Moreover, dysregulated gene expression in SMYD5 cancer cells was associated with LTR and endogenous retrovirus elements and decreased H4K20me3. In addition, depletion of SMYD5 in human colon and lung cancer cells results in increased tumor growth and upregulation of genes overexpressed in colon and lung cancers, respectively. These findings implicate an important role for SMYD5 in maintaining chromosome integrity by regulating heterochromatin and repressing endogenous repetitive DNA elements during differentiation. Cancer Res; 77(23); 6729–45. ©2017 AACR.
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Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target
Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression. Cancer Res; 77(23); 6679–91. ©2017 AACR.
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Integrated Analysis of Whole-Genome ChIP-Seq and RNA-Seq Data of Primary Head and Neck Tumor Samples Associates HPV Integration Sites with Open Chromatin Marks
Chromatin alterations mediate mutations and gene expression changes in cancer. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been utilized to study genome-wide chromatin structure in human cancer cell lines, yet numerous technical challenges limit comparable analyses in primary tumors. Here we have developed a new whole-genome analytic pipeline to optimize ChIP-Seq protocols on patient-derived xenografts from human papillomavirus–related (HPV+) head and neck squamous cell carcinoma (HNSCC) samples. We further associated chromatin aberrations with gene expression changes from a larger cohort of the tumor and normal samples with RNA-Seq data. We detect differential histone enrichment associated with tumor-specific gene expression variation, sites of HPV integration in the human genome, and HPV-associated histone enrichment sites upstream of cancer driver genes, which play central roles in cancer-associated pathways. These comprehensive analyses enable unprecedented characterization of the complex network of molecular changes resulting from chromatin alterations that drive HPV-related tumorigenesis. Cancer Res; 77(23); 6538–50. ©2017 AACR.
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Clonality, Heterogeneity, and Evolution of Synchronous Bilateral Ovarian Cancer
Synchronous bilateral ovarian cancer (SBOC) represents a relatively frequent occurrence and clinically relevant diagnostic dilemma. Delineation of its clonal architecture, genetic heterogeneity, and evolutionary trajectories may have important implications for prognosis and management of patients with SBOC. Here, we describe the results of next-generation whole-exome or whole-genome sequencing of specimens from 12 SBOC cases and report that bilateral tumors from each individual display a comparable number of genomic abnormalities and similar mutational signatures of single-nucleotide variations. Clonality indices based on tumor-specific alterations supported monoclonal origins of SBOC. Each of the ovarian lesions was nevertheless oligoclonal, with inferred metastatic tumors harboring more subclones than their primary counterparts. The phylogenetic structure of SBOC indicated that most cancer cell dissemination occurred early, when the primary carcinoma was still relatively small (<100 million cells). Accordingly, the mutation spectra and mutational signatures of somatic variants exhibited pronounced spatiotemporal differences in each patient. Overall, these findings suggest that SBOCs are clonally related and form through pelvic spread rather than independent multifocal oncogenesis. Metastatic dissemination is often an early event, with dynamic mutational processes leading to divergent evolution and intratumor and intertumor heterogeneity, ultimately contributing substantially to phenotypic plasticity and diverse clinical course in SBOC. Cancer Res; 77(23); 6551–61. ©2017 AACR.
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EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming
Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle–regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease. Cancer Res; 77(23); 6651–66. ©2017 AACR.
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Mesenchymal Stem Cells Promote Hepatocarcinogenesis via lncRNA-MUF Interaction with ANXA2 and miR-34a
Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial–mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA–MUF (MSC-upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA–MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA–MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA–MUF bound Annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA-mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting. Cancer Res; 77(23); 6704–16. ©2017 AACR.
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DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer
Deregulation of the Wnt/β-catenin signaling pathway drives the development of colorectal cancer, but understanding of this pathway remains incomplete. Here, we report that the damage-specific DNA-binding protein DDB2 is critical for β-catenin–mediated activation of RNF43, which restricts Wnt signaling by removing Wnt receptors from the cell surface. Reduced expression of DDB2 and RNF43 was observed in human hyperplastic colonic foci. DDB2 recruited EZH2 and β-catenin at an upstream site in the Rnf43 gene, enabling functional interaction with distant TCF4/β-catenin–binding sites in the intron of Rnf43. This novel activity of DDB2 was required for RNF43 function as a negative feedback regulator of Wnt signaling. Mice genetically deficient in DDB2 exhibited increased susceptibility to colon tumor development in a manner associated with higher abundance of the Wnt receptor–expressing cells and greater activation of the downstream Wnt pathway. Our results identify DDB2 as both a partner and regulator of Wnt signaling, with an important role in suppressing colon cancer development. Cancer Res; 77(23); 6562–75. ©2017 AACR.
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Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors
Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis–associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance. Cancer Res; 77(23); 6576–88. ©2017 AACR.
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MYC Inhibition Depletes Cancer Stem-like Cells in Triple-Negative Breast Cancer
There is mounting evidence that cancer stem-like cells (CSC) are selectively enriched in residual tumors after anticancer therapies, which may account for tumor recurrence and metastasis by regenerating new tumors. Thus, there is a critical need to develop new therapeutic agents that can effectively eliminate drug-resistant CSCs and improve the efficacy of cancer therapy. Here, we report that Triptolide (C1572), a small-molecule natural product, selectively depletes CSCs in a dose-dependent fashion in human triple-negative breast cancer (TNBC) cell lines. Nanomolar concentrations of C1572 markedly reduced c-MYC (MYC) protein levels via a proteasome-dependent mechanism. Silencing MYC expression phenocopied the CSC depletion effects of C1572 and induced senescence in TNBC cells. Limited dilution assays revealed that ex vivo treatment of TNBC cells with C1572 reduced CSC levels by 28-fold. In mouse xenograft models of human TNBC, administration of C1572 suppressed tumor growth and depleted CSCs in a manner correlated with diminished MYC expression in residual tumor tissues. Together, these new findings provide a preclinical proof of concept defining C1572 as a promising therapeutic agent to eradicate CSCs for drug-resistant TNBC treatment. Cancer Res; 77(23); 6641–50. ©2017 AACR.
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R-Spondin1/LGR5 Activates TGF{beta} Signaling and Suppresses Colon Cancer Metastasis
Leucine-rich repeat containing G-protein–coupled receptor 5 (LGR5), an intestinal stem cell marker, is known to exhibit tumor suppressor activity in colon cancer, the mechanism of which is not understood. Here we show that R-spondin 1 (RSPO1)/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFβ signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFβ receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFβ activation in colon cancer. Our study uncovers a novel cross-talk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis. Cancer Res; 77(23); 6589–602. ©2017 AACR.
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IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer
Ligation of programmed cell death-1 (PD-1) in the tumor microenvironment is known to inhibit effective adaptive antitumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow–derived dendritic cells (DC) with IL10 led to increased PD-1 expression. Both groups of DCs also responded to PD-1 blockade by increasing production of IL10. Similarly, treatment of ovarian tumor–bearing mice with PD-1 blocking antibody resulted in an increase in IL10 levels in both serum and ascites. While PD-1 blockade or IL10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented antitumor T- and B-cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti–PD-1 (or anti–PD-L1) monotherapies and prompt further studies aimed at identifying such resistance mechanisms. Cancer Res; 77(23); 6667–78. ©2017 AACR.
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Administering xCT Inhibitors Based on Circadian Clock Improves Antitumor Effects
Clock genes encoding transcription factors that regulate circadian rhythms may inform chronomodulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here, we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects and that the Clock gene itself induces xCT expression and regulates its circadian rhythm. Our findings highlight the clinical potential of chronomodulated chemotherapy and the importance of xCT-mediated transcriptional regulation in the utility of such strategies. Cancer Res; 77(23); 6603–13. ©2017 AACR.
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Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion
Astrocytes, the most abundant type of glial cells in the brain, play critical roles in supporting neuronal development and brain function. Although astrocytes have been frequently detected in brain tumors, including medulloblastoma (MB), their functions in tumorigenesis are not clear. Here, we demonstrate that astrocytes are essential components of the MB tumor microenvironment. Tumor-associated astrocytes (TAA) secrete the ligand sonic hedgehog (Shh), which is required for maintaining MB cell proliferation despite the absence of its primary receptor Patched-1 (Ptch1). Shh drives expression of Nestin in MB cells through a smoothened-dependent, but Gli1-independent mechanism. Ablation of TAA dramatically suppresses Nestin expression and blocks tumor growth. These findings demonstrate an indispensable role for astrocytes in MB tumorigenesis and reveal a novel Ptch1-independent Shh pathway involved in MB progression. Cancer Res; 77(23); 6692–703. ©2017 AACR.
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Complete heart block as the presenting feature in subarachnoid haemorrhage
Cardiac manifestations of subarachnoid haemorrhage (SAH) are well-documented phenomena that can complicate the treatment of this devastating condition. Here, we present a case of SAH presenting as complete heart block on initial assessment, an extremely rare event.
A 53-year-old woman presented with a witnessed fall, sustaining a mild head injury. She denied any symptoms of SAH. Initial ECG revealed complete heart block, for which the patient was accepted under the cardiology team. For completion, a CT head scan was requested, this demonstrated significant SAH blood load in an aneurysmal rather than traumatic pattern. CT angiogram and subsequent digital subtraction angiography confirmed a posterior communicating artery aneurysm as the cause of the SAH. This case highlights the importance of considering neurological diagnoses in patients with collapse even with concomitant cardiac abnormalities, as the two are often inextricably linked.
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Ringed telangiectasias: an unusual presentation of telangiectasia macularis eruptiva perstans
Telangiectasia macularis eruptiva perstans (TMEP) is a rare form of cutaneous mastocytosis. While most cutaneous mastocytoses occur in children and are asymptomatic, TMEP occurs predominantly in adults and is associated with systemic manifestations, requiring medical management. TMEP is typically characterised by scattered red-brown macules on the trunk and extremities, but must be differentiated from other telangiectatic conditions such as scleroderma, hereditary haemorrhagic telangiectasia and telangiectasias secondary to cirrhosis. Practitioners must be aware that variants to the classic presentation of TMEP exist, such as the ringed telangiectasias we describe. Diagnostic workup including tissue biopsy must be considered in such patients after a thorough history and physical have been performed and other telangiectatic processes have been ruled out. The treatment of cutaneous mastocytosis aims at controlling symptoms and preventing mast cell degranulation. Cosmetic treatment includes the use ofPsoralen and ultraviolet A (PUVA) therapy, total skin electron beam radiation and flashlamp pulsed-dye laser treatment.
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Fine-scale population genetic structure of arctic foxes (Vulpes lagopus) in the High Arctic
The arctic fox (Vulpes lagopus) is a circumpolar species inhabiting all accessible Arctic tundra habitats. The species forms a panmictic population over areas connected by sea ice, but recently, kin clustering an...
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Type IV dual left anterior descending coronary artery: a case report
Dual left anterior descending (LAD) artery or duplication of LAD is a rarely reported coronary anomaly, consisting of two branches supplying the usual distribution of the LAD. Type IV dual LAD, in which a shor...
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Involuntary protection against dermatosis: A preliminary observation on trypophobia
Trypophobia refers to the intense negative emotions evoked by exposure to repeated visual patterns like a honeycomb. We propose a cognitive mechanism that can explain why such negative emotions are triggered b...
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Performance of MTBDRplus assay in detecting multidrug resistant tuberculosis at hospital level
Multidrug-resistant tuberculosis (MDR-TB) case finding progressively increased in Ethiopia mainly as a result of the utilization of World Health Organization (WHO)-endorsed rapid technologies including MTBDRplus ...
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“#akademiuppropet is a unique opportunity for change”
2,400 women have signed the academic community's #metoo – #akademiuppropet, the University Call to Action, as having been subjected to sexual harassment or other forms of violations of personal integrity based on their gender. Stories also come from the staff and students at the Karolinska Institutet. The Call to Action is now seen as an opportunity to transform the academic community at its foundation. "Karolinska Institutet takes these testimonies presented in the Call to Action extremely seriously. KI must be an organisation where neither the staff nor its students are subjected to or subject another to violations of personal integrity of the kind that those in the academic community are now talking about," says Karin Dahlman-Wright, Pro-Vice-Chancellor and responsible for gender mainstreaming issues and work environment at Karolinska Institutet, and continues: "KI must be prepared to investigate suspected cases and to provide the victim with adequate support and assistance. A part of this, is that leaders at all levels are alert, responsive and act forcefully when suspicions of sexual harassment arise." KI actively works to combat discrimination, including via regular educational efforts and workshops for both employees and students. Equal treatment and equal opportunities is also an element of various leadership courses and courses related to academic supervision, as well as the courses and educational programs for students. Plus, in addition to support for students and staff, KI funds a student ombudsman and a graduate student ombudsman where undergraduate and graduate students can turn to. Surveys do not provide the whole picture In order to measure the extent of the problem of sexual harassment and other discrimination at KI, questionnaire surveys have been conducted regularly among staff and students. However Caroline Olsson, who has been the coordinator for equal opportunity and broadening recruitment at KI for many years, is of the view that these are blunt instruments, and that staff surveys and actual complaints filed do not provide an accurate picture of how substantial and complex the problem really is. "#akademiuppropet shows that violations of personal integrity in the academic world have been normalised. Some women haven't even verbalised either to themselves or someone else that they have been subjected to such an incident. Only now do they begin to think about what happened and recall the events, which is now described as violations of personal integrity. On the other hand, in some cases it is very clear to both those who have been the victim and to those who have been the perpetrator – and many in the immediate environment know very well what is going on," says Caroline Olsson. Sexual harassment has many nuances Elisa Floriddia, Chair of the KI Postdoctoral Association at KI thinks #akademiuppropet strikingly illustrates both the extent and the many nuances of sexual harassment that exists. "I would really hope that the most extreme cases of sexual harassment get reported; but I'm really not so sure. Many are too afraid to put their job at risk, especially as many postdocs only have temporary contracts. In addition, it is sometimes difficult to promptly recognize signs of harassment, as we all grew up in in a gender biased/discriminatory society," she says. The Junior Faculty's Chair Emma Andersson thinks that #akademiuppropet reveals the inequalities, how unequal the power relationships between men and women are in the professional world, something that is a particularly hard burden for young female academics. "I truly hope that now more attention will be devoted to microaggression, inappropriate behaviour and unconscious prejudices at all levels of academia. At the same time, I hope that the campaign does not eat away at the trust and the great progress we are making in terms of good cooperation and mentoring between men and women or non-binary* individuals," she says. Many simply do not know where to turn to In a survey that Junior Faculty made of its members in 2017, nine percent (approximately 400 of those responding) stated that they had been a victim of discrimination in one way or another. Of these, 72 percent had not sought assistance or support at all; and 80 percent of those who sought help had not received adequate support. 52 percent did not know to whom, or where, they could turn to if they were subjected to such an incident. Therefore, despite KI's systematic efforts to combat discrimination, the problem is difficult to solve as it is rooted in power imbalances, situations of dependency and structural problems in the competitiveness of the academic world. "The problem persists in the entire academic research community, not only at KI. This often involves a power relationship, and many choose not to take the matter further, perhaps for fear that they will suffer negative consequences," Caroline Olsson says. So how can we address the problem? Caroline Olsson describes a kind of "culture of silence" that exists within academic institutions throughout the world, a normalisation of discrimination. It may be that many in a group keep quiet, even though they know that someone is being subjected to abuse. "#akademiuppropet is a way to break this silence. This is a unique opportunity for the academic community in general and KI in particular to change the culture that has for so long maintained power imbalances between the genders. The evidence testifies to that this is a structural problem, not simply individual individuals who 'were treated poorly' or 'got into trouble'," she comments. Elisa Floriddia thinks it's primarily about education, that everyone at KI should know how to best deal with sexual harassment and whom to contact for assistance and information, anonymously. Secondly, it is about continuing the efforts to implement a culture of mutual respect and gender equality. "Sexual harassment stems from discrimination and, in turn, from prejudice. The KI Postdoc Association thinks that in addition to explicit prejudices, we should become be even more aware of our unconscious prejudices, and find tools to neutralise them," she says. Emma Andersson has hopes that KI will implement a course on unconscious prejudices for everyone who reviews and makes decisions regarding the approving of applications for funding or the hiring for employment. "The Junior Faculty also thinks that increased transparency and policies concerning prejudices should be incorporated into in all decision-making and evaluation processes, as subjectivity has proven to be a common cause for discrimination. Increased gender equality and diversity among members of the boards, departments, workgroups and dissertation defence committees is also needed. This will ultimately lead to a meritocracy* where the best academic researchers, irrespective of gender, get promoted," she remarks. KI must raise the level of ambition Both Elisa Floriddia and Emma Andersson emphasize that KI must have an organisation which takes a very strong stand against discrimination and sexual harassment. Department heads and the senior management need to show that this is wrong. It must also be clear, where one can and should turn to. "It is important that complaints of sexual harassment are handled properly and taken seriously. Perpetrators must suffer the consequences of their actions," stresses Elisa Floriddia. Since the 1 January 2017 when the provisions of the Swedish Anti-Discrimination Act were made more stringent, KI has imposed upon itself the requirement to analyse the risks that are present for discrimination and sexual harassment to arise in the institution. "After that, we must then analyse what the risks are due to and then work on both prevention and promotion. KI must raise its level of ambition in this work and with this, the leadership in the academic community has a vital role. Ultimately, it is us at the management level who have the responsibility for combating the kind of abuses and violations of personal integrity that women testify to in #akademiuppropet," stresses Karin Dahlman-Wright. * Meritocracy is a social order in which individuals are ranked in a hierarchy and the distribution of social rewards is according to ability and merits, usually measured by educational attainment and qualifications. Source: NE * "Non-binary" is what the person who identifies as between or beyond the female-male division of gender might call themselves. Source: RFSL Text: Helena Mayer Facts The legislation is clear: sexual harassment is illegal and suspected cases must be investigated. Anyone who has been found guilty risks, as an employee, being dismissed from their job, or suffering a reduction in salary; or as a student, being expelled from the educational programme.
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Treatment of meningioma and glioma with protons and carbon ions
Abstract
The rapid rise of particle therapy across the world necessitates evidence to justify its ever-increasing utilization. This narrative review summarizes the current status of these technologies on treatment of both meningiomas and gliomas, the most common benign and malignant primary brain tumors, respectively. Proton beam therapy (PBT) for meningiomas displays high rates of long-term local control, low rates of symptomatic deterioration, along with the potential for safe dose-escalation in select (but not necessarily routine) cases. PBT is also associated with low adverse events and maintenance of functional outcomes, which have implications for quality of life and cost-effectiveness measures going forward. Data on carbon ion radiation therapy (CIRT) are limited; existing series describe virtually no high-grade toxicities and high local control. Regarding the few available data on low-grade gliomas, PBT provides opportunities to dose-escalate while affording no increase of severe toxicities, along with maintaining appropriate quality of life. Although dose-escalation for low-grade disease has been less frequently performed than for glioblastoma, PBT and CIRT continue to be utilized for the latter, and also have potential for safer re-irradiation of high-grade gliomas. For both neoplasms, the impact of superior dosimetric profiles with endpoints such as neurocognitive decline and neurologic funcionality, are also discussed to the extent of requiring more data to support the utility of particle therapy. Caveats to these data are also described, such as the largely retrospective nature of the available studies, patient selection, and heterogeneity in patient population as well as treatment (including mixed photon/particle treatment). Nevertheless, multiple prospective trials (which may partially attenuate those concerns) are also discussed. In light of the low quantity and quality of available data, major questions remain regarding economic concerns as well.
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A Novel Notch-YAP Circuit Drives Stemness and Tumorigenesis in Embryonal Rhabdomyosarcoma
Rhabdomyosarcoma (RMS), a cancer characterized by skeletal muscle features, is the most common soft-tissue sarcoma of childhood. While low- and intermediate-risk groups have seen improved outcomes, high-risk patients still face a 5-year survival rate of <30%, a statistic that has not changed in over 40 years. Understanding the biologic underpinnings of RMS is critical. The developmental pathways of Notch and YAP have been identified as potent but independent oncogenic signals that support the embryonal variant of RMS (eRMS). Here, the cross-talk between these pathways and the impact on eRMS tumorigenesis is reported. Using human eRMS cells grown as three-dimensional (3D) rhabdospheres, which enriches in stem cells, it was found that Notch signaling transcriptionally upregulates YAP1 gene expression and YAP activity. Reciprocally, YAP transcriptionally upregulates the Notch ligand genes JAG1 and DLL1 and the core Notch transcription factor RBPJ. This bidirectional circuit boosts expression of key stem cell genes, including SOX2, which is functionally required for eRMS spheres. Silencing this circuit for therapeutic purposes may be challenging, because the inhibition of one node (e.g., pharmacologic Notch blockade) can be rescued by upregulation of another (constitutive YAP expression). Instead, dual inhibition of Notch and YAP is necessary. Finally, supporting the existence of this circuit beyond a model system, nuclear Notch and YAP protein expression are correlated in human eRMS tumors, and YAP suppression in vivo decreases Notch signaling and SOX2 expression.
Implications: This study identifies a novel oncogenic signaling circuit driving eRMS stemness and tumorigenesis, and provides evidence and rationale for combination therapies co-targeting Notch and YAP. Mol Cancer Res; 15(12); 1777–91. ©2017 AACR.
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The Influential Role of BCL2 Family Members in Synovial Sarcomagenesis
Synovial sarcomas are deadly soft tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Furthermore, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database. Conditional genetic disruption of Bcl2 in mice also led to reduced sarcomagenesis. Pharmacologic inhibition specific to BCL2 had no demonstrable efficacy against human synovial sarcoma cell lines or mouse tumors. However, targeting BCLxL in human and mouse synovial sarcoma with the small molecule BH3 domain inhibitor, BXI-72, achieved significant cytoreduction and increased apoptotic signaling. Thus, the contributory role of BCL2 in synovial sarcomagenesis does not appear to render it as a therapeutic target, but mitochondrial antiapoptotic BCL2 family members may be.
Implications: The association of BCL2 expression with synovial sarcoma is found to fit with a subtle, but significant, impact of its enhanced presence or absence during early tumorigenesis. However, specific pharmacologic inhibition of BCL2 does not demonstrate a persistent dependence in fully developed tumors. Conversely, inhibition of the BCL2 family member BCLxL resulted in nanomolar potency against human synovial sarcoma cell lines and 50% tumor reduction in a genetically engineered mouse model. Mol Cancer Res; 15(12); 1733–40. ©2017 AACR.
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The MiTF/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation
The microphthalmia family (MITF, TFEB, TFE3, and TFEC) of transcription factors is emerging as global regulators of cancer cell survival and energy metabolism, both through the promotion of lysosomal genes as well as newly characterized targets, such as oxidative metabolism and the oxidative stress response. In addition, MiT/TFE factors can regulate lysosomal signaling, which includes the mTORC1 and Wnt/β-catenin pathways, which are both substantial contributors to oncogenic signaling. This review describes recent discoveries in MiT/TFE research and how they impact multiple cancer subtypes. Furthermore, the literature relating to TFE-fusion proteins in cancers and the potential mechanisms through which these genomic rearrangements promote tumorigenesis is reviewed. Likewise, the emerging function of the Folliculin (FLCN) tumor suppressor in negatively regulating the MiT/TFE family and how loss of this pathway promotes cancer is examined. Recent reports are also presented that relate to the role of MiT/TFE–driven lysosomal biogenesis in sustaining cancer cell metabolism and signaling in nutrient-limiting conditions. Finally, a discussion is provided on the future directions and unanswered questions in the field. In summary, the research surrounding the MiT/TFE family indicates that these transcription factors are promising therapeutic targets and biomarkers for cancers that thrive in stressful niches. Mol Cancer Res; 15(12); 1637–43. ©2017 AACR.
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Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow
Clinical observations have identified an association between psychologic stress and cancer relapse, suggesting that the sympathetic nervous system/norepinephrine (NE) plays a role in reactivation of dormant disseminated tumor cells (DTC) in the bone marrow niche. Here, the mechanism by which NE regulates prostate cancer DTCs in the marrow is explored. NE directly stimulated prostate cancer cell proliferation through β2-adrenergic receptors (ADRB2). NE also altered prostate cancer proliferation in the marrow niche by indirectly downregulating the secretion of the dormancy inducing molecule growth arrest specific-6 (GAS6) expressed by osteoblasts. These observations were confirmed in cocultures of prostate cancer cells expressing the fluorescent ubiquitination-based cell-cycle reporters (FUCCI) and osteoblasts isolated from GAS6-deficient (GAS6–/–) animals. A novel ex vivo model system, using femurs harvested from GAS6+/+ or GAS6–/– mice, was used to confirm these results. As in coculture, when prostate cancer cells were injected into the marrow cavities of GAS6+/+ femurs, NE altered the prostate cancer cell cycle. However, NE had less of an impact on prostate cancer cells in femur explants isolated from GAS6–/– mice. Together, this study demonstrates that NE reactivates prostate cancer cell cycling through both a direct action on prostate cancer cells and indirectly on adjacent niche cells.
Implications: Identification of mechanisms that target DTCs may provide novel therapeutic approaches to prevent or treat cancer metastases more effectively. Mol Cancer Res; 15(12); 1644–55. ©2017 AACR.
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YAP Expression and Activity Are Suppressed by S100A7 via p65/NF{kappa}B-mediated Repression of {Delta}Np63
In several squamous cell carcinoma (SCC) cells, it has been previously observed that induction of the S100 calcium-binding protein A7 (S100A7) is repressed by YAP via the Hippo pathway. This report now demonstrates that S100A7 also represses YAP expression and activity by Np63 in cancer cells. Stable overexpression of S100A7 activates the NFB pathway and inhibits the expression of Np63. Caffeic acid phenethyl ester (CAPE), as a specific inhibitor of NFB, counteracts the inhibitory effect of S100A7 on the expression of Np63 and its target genes. Depletion of S100A7 significantly promotes Np63 expression. These data indicate that S100A7 acts as a suppressor of Np63. Mechanistic examination finds that Np63 not only directly binds to the region of YAP promoter and induces its expression, but also inhibits the Hippo pathway and enhances YAP activity. Importantly, either the positive correlation between S100A7 and YAP phosphorylation at S127 or the negative correlation between S100A7 and Np63 is also observed in skin SCC tissues. Chemosensitivity analysis reveals that S100A7 enhances cancer cells' resistance by inhibition of YAP expression and activity. These results demonstrate that S100A7 is an upstream modulator of the Hippo pathway and extend our understanding of S100A7 functions in cancer.
Implications: S100A7 is a new upstream regulator of the Hippo signaling pathway and reduces chemosensitivity of SCC cells through inhibitions of YAP expression and activity. Mol Cancer Res; 15(12); 1752–63. ©2017 AACR.
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Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells
Metastases are a major cause of cancer mortality. AXL, a receptor tyrosine kinase aberrantly expressed in many tumors, is a potent oncogenic driver of metastatic cell motility and has been identified as broadly relevant in cancer drug resistance. Despite its frequent association with changes in cancer phenotypes, the precise mechanism leading to AXL activation is incompletely understood. In addition to its ligand growth arrest specific-6 (Gas6), activation of AXL requires the lipid moiety phosphatidylserine (PS). Phosphatidylserine is only available to mediate AXL activation when it is externalized on cell membranes, an event that occurs during certain physiologic processes such as apoptosis. Here, it is reported that exposure of cancer cells to phosphatidylserine-containing vesicles, including synthetic liposomes and apoptotic bodies, contributes to enhanced migration of tumor cells via a PS–Gas6–AXL signaling axis. These findings suggest that anticancer treatments that induce fractional cell killing enhance the motility of surviving cells in AXL-expressing tumors, which may explain the widespread role of AXL in limiting therapeutic efficacy.
Implications: This study demonstrates that motility behavior of AXL-expressing tumor cells can be elicited by Gas6-bearing apoptotic bodies generated from tumor treatment with therapeutics that produce killing of a portion of the tumor cells present but not all, hence generating potentially problematic invasive and metastatic behavior of the surviving tumor cells. Mol Cancer Res; 15(12); 1656–66. ©2017 AACR.
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Syngeneic Mouse Models of Oral Cancer Are Effectively Targeted by Anti-CD44-Based NIR-PIT
Oral cavity squamous cell carcinoma (OSCC) is considered one of the most aggressive subtypes of cancer. Anti-CD44 monoclonal antibodies (mAb) are a potential therapy against CD44 expressing OSCC; however, to date the therapeutic effects have been disappointing. Here, a new cancer treatment is described, near-infrared photoimmunotherapy (NIR-PIT), that uses anti-CD44 mAbs conjugated to the photoabsorber IR700DX. This conjugate is injected into mice harboring one of three CD44 expressing syngeneic murine oral cancer cell (MOC) lines, MOC1 (immunogenic), MOC2 mKate2 (moderately immunogenic), and MOC2-luc (poorly immunogenic). Binding of the anti-CD44–IR700 conjugate was shown to be specific and cell-specific cytotoxicity was observed after exposure of the cells to NIR light in vitro. The anti-CD44–IR700 conjugate, when assessed in vivo, demonstrated deposition within the tumor with a high tumor-to-background ratio. Tumor-bearing mice were separated into four cohorts: no treatment; 100 μg of anti-CD44–IR700 i.v. only; NIR light exposure only; and 100 μg of anti-CD44–IR700 i.v. with NIR light exposure. NIR-PIT therapy, compared with the other groups, significantly inhibited tumor growth and prolonged survival in all three cell model systems. In conclusion, these data reveal that anti-CD44 antibodies are suitable as mAb–photoabsorber conjugates for NIR-PIT in MOC cells.
Implications: This study using syngeneic mouse models, which better model the disease in humans than conventional xenografts, suggests that NIR-PIT with anti-CD44–IR700 is a potential candidate for the treatment of OSCC. Mol Cancer Res; 15(12); 1667–77. ©2017 AACR.
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Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes
Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 (CDKN2A) locus and mutations in NF-B pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFβ pathway activation signature.
Implications: This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease. Mol Cancer Res; 15(12); 1722–32. ©2017 AACR.
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FOXD3 Regulates CSC Marker, DCLK1-S, and Invasive Potential: Prognostic Implications in Colon Cancer
The 5' (α)-promoter of the human doublecortin-like kinase 1 (DCLK1) gene becomes epigenetically silenced during colon carcinogenesis, resulting in loss of expression of the canonical long(L)-isoform1 (DCLK1-L) in human colon adenocarcinomas (hCRCs). Instead, hCRCs express a short(S)-isoform2 (DCLK1-S) from an alternate (β)-promoter of DCLK1. The current study, examined if the transcriptional activity of the (β)-promoter is suppressed in normal versus cancerous cells. On the basis of in silico and molecular approaches, it was discovered that FOXD3 potently inhibits the transcriptional activity of the (β)-promoter. FOXD3 becomes methylated in human colon cancer cells (hCCC), with loss of FOXD3 expression, allowing expression of the DCLK1(S) variant in hCCCs/hCRCs. Relative levels of FOXD3/DCLK1(S/L) were measured in a cohort of CRC patient specimens (n = 92), in relation to overall survival (OS). Patients expressing high DCLK1(S), with or without low FOXD3, had significantly worse OS compared with patients expressing low DCLK1(S). The relative levels of DCLK1-L did not correlate with OS. In a pilot retrospective study, colon adenomas from high-risk patients (who developed CRCs in <15 years) demonstrated significantly higher staining for DCLK1(S) + significantly lower staining for FOXD3, compared with adenomas from low-risk patients (who remained free of CRCs). Latter results strongly suggest a prognostic value of measuring DCLK1(S)/FOXD3 in adenomas. Overexpression of DCLK1(S), but not DCLK1(L), caused a significant increase in the invasive potential of hCCCs, which may explain worse outcomes for patients with high DCLK1-S–expressing tumors. On the basis of these data, FOXD3 is a potent repressor of DCLK1-S expression in normal cells; loss of FOXD3 in hCCCs/hCRCs allows upregulation of DCLK1-S, imparting a potent invasive potential to the cells. Mol Cancer Res; 15(12); 1678–91. ©2017 AACR.
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Alternative Polyadenylation of PRELID1 Regulates Mitochondrial ROS Signaling and Cancer Outcomes
Disruption of posttranscriptional gene regulation is a critical step in oncogenesis that can be difficult to observe using traditional molecular techniques. To overcome this limitation, a modified polyadenylation site sequencing (PAS-seq) protocol was used to generate a genome-wide map of alternative polyadenylation (APA) events in human primary breast tumor specimens and matched normal tissue. This approach identified an APA event in the PRELID1 mRNA that enhances its steady-state level and translational efficiency, and is a strong breast cancer subtype-dependent predictor of patient clinical outcomes. Furthermore, it has been demonstrated that PRELID1 regulates stress response and mitochondrial reactive oxygen species (ROS) production in a cell type–specific manner. Modulation of PRELID1 expression, including its posttranscriptional control, appears to be a common stress response across different cancer types. These data reveal that PRELID1 mRNA processing is an important regulator of cell type–specific responses to stress used by multiple cancers and is associated with patient outcomes.
Implications: This study suggests that the regulation of PRELID1 expression, by APA and other mechanisms, plays a role in mitochondrial ROS signaling and represents a novel prognostic factor and therapeutic target in cancer. Mol Cancer Res; 15(12); 1741–51. ©2017 AACR.
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B-cell Receptor Signaling Regulates Metabolism in Chronic Lymphocytic Leukemia
Peripheral blood chronic lymphocytic leukemia (CLL) cells are quiescent but have active transcription and translation processes, suggesting that these lymphocytes are metabolically active. Based on this premise, the metabolic phenotype of CLL lymphocytes was investigated by evaluating the two intracellular ATP-generating pathways. Metabolic flux was assessed by measuring glycolysis as extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation as oxygen consumption rate (OCR) and then correlated with prognostic factors. Further, the impact of B-cell receptor signaling (BCR) on metabolism was determined by genetic ablation and pharmacological inhibitors. Compared with proliferative B-cell lines, metabolic fluxes of oxygen and lactate were low in CLL cells. ECAR was consistently low, but OCR varied considerably in human patient samples (n = 45). Higher OCR was associated with poor prognostic factors such as ZAP 70 positivity, unmutated IGHV, high β2M levels, and higher Rai stage. Consistent with the association of ZAP 70 and IGHV unmutated status with active BCR signaling, genetic ablation of BCR mitigated OCR in malignant B cells. Similarly, knocking out PI3K, a critical component of the BCR pathway, decreased OCR and ECAR. In concert, PI3K pathway inhibitors dramatically reduced OCR and ECAR. In harmony with a decline in metabolic activity, the ribonucleotide pools in CLL cells were reduced with duvelisib treatment. Collectively, these data demonstrate that CLL metabolism, especially OCR, is linked to prognostic factors and is curbed by BCR and PI3K pathway inhibition.
Implications: This study identifies a relationship between oxidative phosphorylation in CLL and prognostic factors providing a rationale to therapeutically target these processes. Mol Cancer Res; 15(12); 1692–703. ©2017 AACR.
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A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer
TWIST1, an epithelial–mesenchymal transition (EMT) transcription factor, is critical for oncogene-driven non–small cell lung cancer (NSCLC) tumorigenesis. Given the potential of TWIST1 as a therapeutic target, a chemical–bioinformatic approach using connectivity mapping (CMAP) analysis was used to identify TWIST1 inhibitors. Characterization of the top ranked candidates from the unbiased screen revealed that harmine, a harmala alkaloid, inhibited multiple TWIST1 functions, including single-cell dissemination, suppression of normal branching in 3D epithelial culture, and proliferation of oncogene driver-defined NSCLC cells. Harmine treatment phenocopied genetic loss of TWIST1 by inducing oncogene-induced senescence or apoptosis. Mechanistic investigation revealed that harmine targeted the TWIST1 pathway through its promotion of TWIST1 protein degradation. As dimerization is critical for TWIST1 function and stability, the effect of harmine on specific TWIST1 dimers was examined. TWIST1 and its dimer partners, the E2A proteins, which were found to be required for TWIST1-mediated functions, regulated the stability of the other heterodimeric partner posttranslationally. Harmine preferentially promoted degradation of the TWIST1-E2A heterodimer compared with the TWIST-TWIST1 homodimer, and targeting the TWIST1-E2A heterodimer was required for harmine cytotoxicity. Finally, harmine had activity in both transgenic and patient-derived xenograft mouse models of KRAS-mutant NSCLC. These studies identified harmine as a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC including EGFR mutant, KRAS mutant and MET altered NSCLC.
Implications: TWIST1 is required for oncogene-driven NSCLC tumorigenesis and EMT; thus, harmine and its analogues/derivatives represent a novel therapeutic strategy to treat oncogene-driven NSCLC as well as other solid tumor malignancies. Mol Cancer Res; 15(12); 1764–76. ©2017 AACR.
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Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin
Obesity is associated with poorer outcome for many cancers. Previously, we observed that adipocytes protect acute lymphoblastic leukemia (ALL) cells from the anthracycline, daunorubicin. In this study, it is determined whether adipocytes clear daunorubicin from the tumor microenvironment (TME). Intracellular daunorubicin concentrations were evaluated using fluorescence. Daunorubicin and its largely inactive metabolite, daunorubicinol, were analytically measured in media, cells, and tissues using liquid chromatography/mass spectrometry (LC/MS). Expression of daunorubicin-metabolizing enzymes, aldo-keto reductases (AKR1A1, AKR1B1, AKR1C1, AKR1C2, AKR1C3, and AKR7A2) and carbonyl reductases (CBR1, CBR3), in human adipose tissue, were queried using public databases and directly measured by quantitative PCR (qPCR) and immunoblot. Adipose tissue AKR activity was measured by colorimetric assay. Adipocytes absorbed and efficiently metabolized daunorubicin to daunorubicinol, reducing its antileukemia effect in the local microenvironment. Murine studies confirmed adipose tissue conversion of daunorubicin to daunorubicinol in vivo. Adipocytes expressed high levels of AKR and CBR isoenzymes that deactivate anthracyclines. Indeed, adipocyte protein levels of AKR1C1, AKR1C2, and AKR1C3 are higher than all other human noncancerous cell types. To our knowledge, this is the first demonstration that adipocytes metabolize and inactivate a therapeutic drug. Adipocyte-mediated daunorubicin metabolism reduces active drug concentration in the TME. These results could be clinically important for adipocyte-rich cancer microenvironments such as omentum, breast, and marrow. As AKR and CBR enzymes metabolize several drugs, and can be expressed at higher levels in obese individuals, this proof-of-principle finding has important implications across many diseases.
Implications: Adipocyte absorption and metabolism of chemotherapies can reduce cytotoxicity in cancer microenvironments, potentially contributing to poorer survival outcomes. Mol Cancer Res; 15(12); 1704–13. ©2017 AACR.
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Paradoxic eczema in infants after heart transplantation
Abstract
New-onset psoriasis in patients receiving tumor necrosis factor inhibitors is well recognized in children and adults. We describe three children who underwent cardiac transplantation and developed an analogous form of paradoxic eczema occurring 2-48 months after starting systemic tacrolimus, a drug widely used topically to treat eczema. Anecdotal reports and our experience suggest that tacrolimus taper with alternative systemic antirejection immunosuppressant may lead to skin clearance. Pending additional insight, treatment should include optimizing skin barrier function, minimizing microbial and allergic triggers, and coordinating care to choose the best-tolerated systemic immunosuppressant regimen at the lowest effective dose.
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Diaphragm and Intercostal Muscle Activity after Mid-Cervical Spinal Cord Contusion in the Rat
Journal of Neurotrauma , Vol. 0, No. 0.
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Diaphragm and Intercostal Muscle Activity after Mid-Cervical Spinal Cord Contusion in the Rat
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Editorial Board
Source:Dental Materials, Volume 33, Issue 12
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Preoperative detection of pleural adhesions by respiratory dynamic computed tomography
Abstract
Background
Video-assisted thoracic surgery (VATS) plays an important role in thoracic surgery because it is less invasive. However, the existence of severe pleural adhesions may make VATS difficult and complicated. The aim of this study was to assess the utility of inspiration and expiration computed tomography (respiratory dynamic CT (RD-CT)) in evaluation of pleural adhesions preoperatively.
Methods
RD-CT was performed on 107 patients undergoing thoracotomies (both VATS and open). We assessed synchronous motion during respiration on RD-CT. Comparing the results of RD-CT and intraoperative findings, we assessed the utility of preoperative evaluation.
Results
A negative correlation between sliding score and adhesion grade was revealed. Sliding score in adhesion negative patients was significantly higher than that in adhesion positive patients (P < 0.0001). The sensitivity of RD-CT was 63.6%, specificity was 74.1%, and accuracy was 72%. Among 62 patients with a CT-Respiration Ratio of less than 0.65, the sensitivity of RD-CT was 77.8%, specificity was 86.8%, and accuracy was 85.5%.
Conclusions
RD-CT may be clinically useful for detecting the presence of pleural adhesions. It can be adopted as one of the criteria for deciding the surgical approach.
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Detection of Bacteria Colonizing Titanium Spinal Implants in Children
Surgical Infections , Vol. 0, No. 0.
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The optimal treatment of metastatic hormone-naive prostate cancer: abiraterone acetate or docetaxel?
Future Oncology, Ahead of Print.
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Steroid-induced mental disorders in cancer patients: a systematic review
Future Oncology, Ahead of Print.
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Perurethral transvesical route for oocytes retrieval: an old technique for a new indication in oncofertility
Future Oncology, Ahead of Print.
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Clinical significance of preoperative liver stiffness measurements in primary HBV-positive hepatocellular carcinoma
Future Oncology, Ahead of Print.
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Human Mesenchymal Stem Cells Pretreated with Interleukin-1β and Stimulated with Bone Morphogenetic Growth Factor-3 Enhance Chondrogenesis
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Articular Cartilage Repair with Mesenchymal Stem Cells After Chondrogenic Priming: A Pilot Study
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Thymus-Derived Mesenchymal Stem Cells for Tissue Engineering Clinical-Grade Cardiovascular Grafts
Tissue Engineering Part A , Vol. 0, No. 0.
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Retention of the Structure and Function of Heparan Sulfate Biomaterials After Gamma Irradiation
Tissue Engineering Part A , Vol. 0, No. 0.
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Immunohistochemistry defined subtypes of breast cancer in 678 Sudanese and Eritrean women; hospitals based case series
Abstract
Background
Breast cancer is the most common malignancy accounting for 25% of all cancers in females. In Africa, breast cancer prevalence and mortality are steadily increasing. Knowledge of hormone receptors and human epidermal growth factor receptor-2 (HER-2) expressions are vital for breast cancer management plans and decision making. There is wide regional variation in the proportion of these biomarkers, especially in African countries. Hormone receptors positivity in indigenous African and African American women is considered to be low and triple negative breast cancer is a dominant phenotype. There is paucity of data regarding hormone receptors (ER and PR) and HER2 expressions in North-eastern Africa (Eritrea and Sudan). The purpose of this study was to evaluate the expression of ER, PR and HER2 in Eritrean and Sudanese case series and correlate these biomarkers with the clinicopathological profile.
Method
Clinicopathologic data of patients were collected from clinical records. Immunohistochemistry biomarkers (ER, PR, and HER2) were assessed in consecutive female patients who had been diagnosed with invasive breast cancer from 2011 to 2015 in Gezira University Pathology Laboratory, the Sudan and National Health laboratory, Asmara, Eritrea.
Results
There were 678 cases involved in this study. The mean age was 48.8 years with ±0.53 standard error of the mean. Two-thirds of the case were ≤50 years. Invasive ductal carcinoma, no special type was the most dominant histologic type (86%) in both study groups. The majority of cases (70%) had tumour stage pT2 and pT3 and about 50% had lymph node involvement. Less than 5% of the cases had well-differentiated tumours. The ER, PR and HER2 positive rates were 45%, 32%, and 29%, respectively. The proportion of luminal-A like, luminal-B like, HER2 enriched and TNBC were 37%, 13%, 16% and 34%, respectively. Fisher extract analysis showed age (p = .015), tumour size (p = .041), and histologic grade (p = .000) were significantly associated with intrinsic subtypes. Furthermore, Logistic regression analysis stratified by origin, age, tumour size, lymph-node metastasis and grade indicated that younger women age (≤50 years) and grade III tumours were more likely to be diagnosed with ER negative breast cancer.
Conclusion
Most of Sudanese and Eritrean women were diagnosed at younger age and with unfavourable prognostic clinicopathologic prognostic markers. TNBC is more frequent in this cohort study; patients with grade III tumours and young age are more likely to be hormone receptors negative. Therefore, routine determination of hormone receptors is warranted for appropriate targeted therapy.
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MicroRNA profile in HBV-induced infection and hepatocellular carcinoma
Abstract
Background
MicroRNAs (miRNAs) exhibit essential regulatory functions related to cell growth, apoptosis, development and differentiation. Dysregulated expression of miRNAs is associated with a wide variety of human diseases. As such miRNA signatures are valuable as biomarkers for disease and for making treatment decisions. Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). Here we screened for miRNAs in chronic HBV associated HCC.
Methods
To determine the miRNAs in HCC occurrence associated with HBV infection, we analyzed global miRNA expression profiles in 12 pairs of HCC and adjacent matched non-HCC tissues from HBV-positive and HBV-negative patients using microarray analyses. The microarray result was validated by real-time PCR in 32 HBV-positive and 24 HBV-negative patient HCC samples. The potential candidate target genes of the miRNAs were predicted by miRWalk software. Genes simultaneously predicted as targets by two or more miRNAs were subjected to GO and KEGG pathway analysis. The miRNA regulatory network analysis was performed using the Ingenuity Pathway Analysis (IPA) software.
Results
Eight miRNAs (miR-223, miR-98, miR-15b, miR-199a-5p, miR-19b, miR-22, miR-451, and miR-101) were involved in HBV-unrelated HCC, 5 miRNAs (miR-98, miR-375, miR-335, miR-199a-5p, and miR-22) were involved in HBV infection, and 7 miRNAs (miR-150, miR-342-3p, miR-663, miR-20b, miR-92a-3p, miR-376c-3p and miR-92b) were specifically altered in HBV-related HCC. Gene Ontology and KEGG analyses predict that these HBV-related HCC miRNAs are involved in the regulation of: transcription, RNA polymerase II promoter, phosphorylation of proteins through MAPK signaling pathway, focal adhesion, and actin cytoskeleton. IPA analysis also suggest that these miRNAs act on AGO2, TP53, CCND1, and 11 other genes that significantly influence HCC occurrence and HBV infection.
Conclusion
Our data indicates that the unique 7 miRNAs expression signature could be involved in the development HBV- related HCC.
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Nonlinear Tracking Control of a Conductive Supercoiled Polymer Actuator
Soft Robotics , Vol. 0, No. 0.
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Characterization of Whooper Swan (Cygnus cygnus) Interferon α: Prokaryotic Expression, Biological Activities, and Physicochemical Characteristics
Journal of Interferon & Cytokine Research , Vol. 0, No. 0.
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Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer
Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer
Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive <i>EGFR</i>-mutant non-small cell lung cancer, Published online: 30 November 2017; doi:10.1038/bjc.2017.394
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Tumour budding in oral squamous cell carcinoma: a meta-analysis
Tumour budding in oral squamous cell carcinoma: a meta-analysis
Tumour budding in oral squamous cell carcinoma: a meta-analysis, Published online: 30 November 2017; doi:10.1038/bjc.2017.425
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Lymphographic-Like Technique for the Treatment of Microcystic Lymphatic Malformation Components of <3 mm [HEAD & NECK]
BACKGROUND AND PURPOSE:
The treatment of microcystic lymphatic malformations remains challenging. Our aim was to describe the lymphographic-like technique, a new technique of slow bleomycin infusion for the treatment of microcyst components of <3 mm, performed at our institution.
MATERIALS AND METHODS:A retrospective analysis of a prospectively collected lymphatic malformation data base was performed. Patients with at least 1 microcystic lymphatic malformation component demonstrated on MR imaging treated by lymphographic-like technique bleomycin infusion were included in the study. Patient interviews and MR imaging were performed to assess subjective and objective (microcystic lymphatic malformation size decrease of >30%) clinical improvement, respectively. Patients were reviewed 3 months after each sclerotherapy session. Lymphographic-like technique safety and efficacy were assessed.
RESULTS:Between January 2012 and July 2016, sixteen patients (5 males, 11 females; mean age, 15 years; range, 1–47 years) underwent the bleomycin lymphographic-like technique for microcystic lymphatic malformations. Sixty sclerotherapy sessions were performed, with a mean of 4 sessions per patient (range, 1–8 sessions) and a mean follow-up of 26 months (range, 5–58 months). We observed no major and 3 minor complications: 1 eyelid infection, 1 case of severe postprocedural nausea and vomiting, and 1 case of skin discoloration. One patient was lost to follow-up. Overall MR imaging objective improvement was observed in 5/16 (31%) patients; overall improvement of clinical symptoms was obtained in 93% of treated patients.
CONCLUSIONS:The bleomycin lymphographic-like technique for microcystic lymphatic malformations is safe and feasible with objective improvement in about one-third of patients. MR signal intensity changes after the lymphographic-like technique are associated with subjective improvement of the patient's symptoms.
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CT Attenuation Analysis of Carotid Intraplaque Hemorrhage [EXTRACRANIAL VASCULAR]
BACKGROUND AND PURPOSE:
Intraplaque hemorrhage is considered a leading parameter of carotid plaque vulnerability. Our purpose was to assess the CT characteristics of intraplaque hemorrhage with histopathologic correlation to identify features that allow for confirming or ruling out the intraplaque hemorrhage.
MATERIALS AND METHODS:This retrospective study included 91 patients (67 men; median age, 65 ± 7 years; age range, 41–83 years) who underwent CT angiography and carotid endarterectomy from March 2010 to May 2013. Histopathologic analysis was performed for the tissue characterization and identification of intraplaque hemorrhage. Two observers assessed the plaque's attenuation values by using an ROI (≥ 1 and ≤2 mm2). Receiver operating characteristic curve, Mann-Whitney, and Wilcoxon analyses were performed.
RESULTS:A total of 169 slices were assessed (59 intraplaque hemorrhage, 63 lipid-rich necrotic core, and 47 fibrous); the average values of the intraplaque hemorrhage, lipid-rich necrotic core, and fibrous tissue were 17.475 Hounsfield units (HU) and 18.407 HU, 39.476 HU and 48.048 HU, and 91.66 HU and 93.128 HU, respectively, before and after the administration of contrast medium. The Mann-Whitney test showed a statistically significant difference of HU values both in basal and after the administration of contrast material phase. Receiver operating characteristic analysis showed a statistical association between intraplaque hemorrhage and low HU values, and a threshold of 25 HU demonstrated the presence of intraplaque hemorrhage with a sensitivity and specificity of 93.22% and 92.73%, respectively. The Wilcoxon test showed that the attenuation of the plaque before and after administration of contrast material is different (intraplaque hemorrhage, lipid-rich necrotic core, and fibrous tissue had P values of .006, .0001, and .018, respectively).
CONCLUSIONS:The results of this preliminary study suggest that CT can be used to identify the presence of intraplaque hemorrhage according to the attenuation. A threshold of 25 HU in the volume acquired after the administration of contrast medium is associated with an optimal sensitivity and specificity. Special care should be given to the correct identification of the ROI.
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John Nash and the Organization of Stroke Care [PRACTICE PERSPECTIVES]
SUMMARY:
The concept of Nash equilibrium, developed by John Forbes Nash Jr, states that an equilibrium in noncooperative games is reached when each player takes the best action for himself or herself, taking into account the actions of the other players. We apply this concept to the provision of endovascular thrombectomy in the treatment of acute ischemic stroke and suggest that collaboration among hospitals in a health care jurisdiction could result in practices such as shared call pools for neurointervention teams, leading to better patient care through streamlined systems.
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Influences for Gender Disparity in Academic Neuroradiology [ACADEMIC PERSPECTIVES]
BACKGROUND AND PURPOSE:
There has been extensive interest in promoting gender equality within radiology, a predominately male field. In this study, our aim was to quantify gender representation in neuroradiology faculty rankings and determine any related factors that may contribute to any such disparity.
MATERIALS AND METHODS:We evaluated the academic and administrative faculty members of neuroradiology divisions for all on-line listed programs in the US and Canada. After excluding programs that did not fulfill our selection criteria, we generated a short list of 85 US and 8 Canadian programs. We found 465 faculty members who met the inclusion criteria for our study. We used Elsevier's SCOPUS for gathering the data pertaining to the publications, H-index, citations, and tenure of the productivity of each faculty member.
RESULTS:Gender disparity was insignificant when analyzing academic ranks. There are more men working in neuroimaging relative to women (2 = 0.46; P = .79). However, gender disparity was highly significant for leadership positions in neuroradiology (2 = 6.76; P = .009). The median H-index was higher among male faculty members (17.5) versus female faculty members (9). Female faculty members have odds of 0.84 compared with male faculty members of having a higher H-index, adjusting for publications, citations, academic ranks, leadership ranks, and interaction between gender and publications and gender and citations (9).
CONCLUSIONS:Neuroradiology faculty members follow the same male predominance seen in many other specialties of medicine. In this study, issues such as mentoring, role models, opportunities to engage in leadership/research activities, funding opportunities, and mindfulness regarding research productivity are explored.
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Alphabet Soup: Sagittal Balance Correction Osteotomies of the Spine--What Radiologists Should Know [REVIEW ARTICLE]
SUMMARY:
Global sagittal malalignment has been demonstrated to have correlation with clinical symptoms and is a key component to be restored in adult spinal deformity. In this article, various types of sagittal balance-correction osteotomies are reviewed primarily on the basis of the 3 most commonly used procedures: Smith-Petersen osteotomy, pedicle subtraction osteotomy, and vertebral column resection. Familiarity with the expected imaging appearance and commonly encountered complications seen on postoperative imaging studies following correction osteotomies is crucial for accurate image interpretation.
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Reproducibility of Deep Gray Matter Atrophy Rate Measurement in a Large Multicenter Dataset [ADULT BRAIN]
BACKGROUND AND PURPOSE:
Precise in vivo measurement of deep GM volume change is a highly demanded prerequisite for an adequate evaluation of disease progression and new treatments. However, quantitative data on the reproducibility of deep GM structure volumetry are not yet available. In this paper we aim to investigate this reproducibility using a large multicenter dataset.
MATERIALS AND METHODS:We have assessed the reproducibility of 2 automated segmentation software packages (FreeSurfer and the FMRIB Integrated Registration and Segmentation Tool) by quantifying the volume changes of deep GM structures by using back-to-back MR imaging scans from the Alzheimer Disease Neuroimaging Initiative's multicenter dataset. Five hundred sixty-two subjects with scans at baseline and 1 year were included. Reproducibility was investigated in the bilateral caudate nucleus, putamen, amygdala, globus pallidus, and thalamus by carrying out descriptives as well as multilevel and variance component analysis.
RESULTS:Median absolute back-to-back differences varied between GM structures, ranging from 59.6–156.4 μL for volume change, and 1.26%–8.63% for percentage volume change. FreeSurfer had a better performance for the outcome of longitudinal volume change for the bilateral amygdala, putamen, left caudate nucleus (P < .005), and right thalamus (P < .001). For longitudinal percentage volume change, Freesurfer performed better for the left amygdala, bilateral caudate nucleus, and left putamen (P < .001). Smaller limits of agreement were found for FreeSurfer for both outcomes for all GM structures except the globus pallidus. Our results showed that back-to-back differences in 1-year percentage volume change were approximately 1.5–3.5 times larger than the mean measured 1-year volume change of those structures.
CONCLUSIONS:Longitudinal deep GM atrophy measures should be interpreted with caution. Furthermore, deep GM atrophy measurement techniques require substantially improved reproducibility, specifically when aiming for personalized medicine.
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Time for a Time Window Extension: Insights from Late Presenters in the ESCAPE Trial [INTERVENTIONAL]
BACKGROUND AND PURPOSE:
The safety and efficacy of endovascular therapy for large-artery stroke in the extended time window is not yet well-established. We performed a subgroup analysis on subjects enrolled within an extended time window in the Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) trial.
MATERIALS AND METHODS:Fifty-nine of 315 subjects (33 in the intervention group and 26 in the control group) were randomized in the ESCAPE trial between 5.5 and 12 hours after last seen healthy (likely to have groin puncture administered 6 hours after that). Treatment effect sizes for all relevant outcomes (90-day mRS shift, mRS 0–2, mRS 0–1, and 24-hour NIHSS scores and intracerebral hemorrhage) were reported using unadjusted and adjusted analyses.
RESULTS:There was no evidence of treatment heterogeneity between subjects in the early and late windows. Treatment effect favoring intervention was seen across all clinical outcomes in the extended time window (absolute risk difference of 19.3% for mRS 0–2 at 90 days). There were more asymptomatic intracerebral hemorrhage events within the intervention arm (48.5% versus 11.5%, P = .004) but no difference in symptomatic intracerebral hemorrhage.
CONCLUSIONS:Patients with an extended time window could potentially benefit from endovascular treatment. Ongoing randomized controlled trials using imaging to identify late presenters with favorable brain physiology will help cement the paradigm of using time windows to select the population for acute imaging and imaging to select individual patients for therapy.
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Efficacy of Rebamipide in Organic and Functional Dyspepsia: A Systematic Review and Meta-Analysis
Abstract
Objective
The role of gastritis in dyspepsia remains controversial. We aimed to examine the efficacy of rebamipide, a gastric mucosal protective agent, in both organic and functional dyspepsia.
Design
A systematic review and meta-analysis was performed. The following databases were searched using the keywords ("rebamipide" OR "gastroprotective agent*" OR "mucosta") AND ("dyspepsia" OR "indigestion" OR "gastrointestinal symptoms"): PubMed, Wed of Science, Embase, CINAHL, Cochrane Clinical Trials Register. The primary outcome was dyspepsia or upper GI symptom score improvement. Pooled analysis of the main outcome data were presented as risk ratio (RR) for dichotomous data and standardized mean difference (SMD) for continuous data.
Results
From an initial 248 records, 17 randomised controlled trial (RCT) publications involving 2170 subjects (1224 rebamipide, 946 placebo/control) were included in the final analysis. Twelve RCTs were conducted in subjects with organic dyspepsia (peptic ulcer disease, reflux esophagitis or NSAID-induced gastropathy) and five RCTs were conducted in patients with functional dyspepsia (FD). Overall, dyspepsia symptom improvement was significantly better with rebamipide compared to placebo/control drug (RR 0.77, 95% CI = 0.64–0.93; SMD −0.46, 95% CI = −0.83 to −0.09). Significant symptom improvement was observed both in pooled RR and SMD in subjects with organic dyspepsia (RR 0.72, 95% CI = 0.61–0.86; SMD −0.23, 95% CI = −0.4 to −0.07), while symptom improvement in FD was observed in pooled SMD but not RR (SMD −0.62, 95% CI = −1.16 to −0.08; RR 1.01, 95% CI = 0.71–1.45).
Conclusion
Rebamipide is effective in organic dyspepsia and may improve symptoms in functional dyspepsia.
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Impact of Bacterial Translocation on Hepatopulmonary Syndrome: A Prospective Observational Study
Abstract
Background/Aims
Hepatopulmonary syndrome (HPS) is characterized by a defect in oxygenation induced by pulmonary vascular dilatation in cirrhosis. While severe HPS is responsible for a high rate of mortality, the prevalence and pathophysiology of HPS are not fully elucidated. We evaluated the prevalence and pathophysiology of HPS in patients with cirrhosis.
Methods
A total of 142 patients with cirrhosis who underwent saline-agitated contrast echocardiography were enrolled in this prospective observational study. HPS was defined by positive findings on contrast echocardiography, cirrhosis, and the presence of an oxygenation defect (alveolar–arterial oxygen gradient > 15 mmHg). HPS grades from 0 to 3 were assigned based on the density and spatial distribution of microbubbles in the left ventricle. The primary endpoint was the prevalence of HPS. The secondary endpoints included clinical characteristics and levels of lipopolysaccharide (LPS), LPS-binding protein (LBP), nitric oxide, and endothelin-1 in HPS.
Results
Fifty-nine patients (41.5%) were diagnosed with HPS (grade 1: 24, grade 2: 23, and grade 3: 12 patients). The mean levels of LPS (0.36 ± 0.02, 1.02 ± 0.18, 2.86 ± 0.77, and 6.56 ± 1.46 EU/mL, p < 0.001) and LBP (7026 ± 3336, 11,445 ± 1247, 11,947 ± 1164, and 13,791 ± 2032 ng/mL, p = 0.045) were found to be increased according to HPS grade (negative, grade 1–3). Endothelin-1 levels were significantly elevated according to HPS grade (1.83 ± 0.17, 2.62 ± 0.22, 3.69 ± 0.28, and 4.29 ± 0.34 pg/mL, p < 0.001), demonstrating a significant difference between each grade (p < 0.05).
Conclusions
HPS is a common complication with a prevalence of 41.5% in patients with cirrhosis. Bacterial translocation and portal pulmonary vascular dilatation are key mechanism involved in the progression of HPS.
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Effect of Intraoral Mechanical Cleaning Techniques on Bond Strength of Cast Crowns to Metal Cores
Abstract
Purpose
To evaluate the effect of cleaning of metal cores from provisional cement, using an intraoral airborne-particle abrasion method, on the bond strength of permanent resin cement with cast crowns to cores.
Materials and Methods
Thirty stainless steel models of a standard complete crown tooth preparation were fabricated. Thirty Type III gold crowns were fabricated. Each cast crown corresponded to one stainless steel crown preparation model. All crowns were cemented with noneugenol zinc oxide cement and stored for 7 days at 37°C. All crowns were debonded, and the cement was cleaned with airborne-particle abrasion using 50 μm aluminum oxide at 4.1 bar (0.41 MPa) followed by ultrasonic cleaning. Based on the mechanical cleaning technique of the remaining provisional cement on surfaces of cast cores, specimens were equally divided into 3 groups: hand cleaning (HC) with a dental excavator, hand cleaning followed by polishing using a brush and pumice (BP), and hand cleaning followed by intraoral airborne-particle abrasion (APA). All crowns were then cemented to their corresponding cores using universal resin cement. All crowns were stored for 7 days at 37°C. An Instron universal testing machine was used to record the bond strength of crowns.
Results
Airborne-particle abrasion method for intraoral mechanical cleaning revealed a statistically significantly higher bond strength compared to the other two methods.
Conclusions
When comparing the three methods of provisional cement cleaning from metal cores, airborne-particle abrasion resulted in the highest bond strength for cast crowns.
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A Digital Approach to Retrofitting a Post and Core Restoration to an Existing Crown
Abstract
One problem that may arise in full-coverage restorations is clinical crown fracture. Fracture of an endodontically treated and crowned tooth in the esthetic zone may be embarrassing to both the patient and clinician. If a completely sound margin and at least 2 mm of coronal structure remain, a fractured tooth may possibly be retreated by a repair. Several methods have been introduced to reproduce the original contour of the tooth for retrofitting an existing crown. If an existing crown is used as a template, excessive core material may remain over the margin, as loading the proper amount of core material is difficult, and making vent holes on the existing crown is not feasible. This article presents a repair technique to reuse an existing crown with computer-aided design and computer-aided manufacturing (CAD/CAM) technology. By using a milled poly(methylmethacrylate) matrix, the mentioned limitations are eliminated, and the original contour of the tooth can be effectively restored with minimal intervention. As an existing crown is reused, the issues of additional time and cost for repreparation, reimpression, and new crown are eliminated.
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Marginal and Internal Fit of CAD/CAM Crowns Fabricated Over Reverse Tapered Preparations
Abstract
Purpose
Intraoral digital scanning can accurately record single abutment tooth preparations despite their geometry, and the algorithms of the CAD software can be set to manage different abutment forms. The purpose of this in vitro study was to evaluate the marginal and internal fit of CAD/CAM zirconia crowns fabricated over conventional and reverse-tapered preparations.
Materials and Methods
Crown preparations with known total occlusal convergence (TOC) angles (–8°, –4°, 0°, 8°, 12°, 16°, and 22°) were digitally created from a maxillary left central incisor and printed in acrylic resin. Next, casts were scanned with a TRIOS intraoral scanner, and crowns were designed with KaVo multiCAD software using default parameters (50 μm cement space) on abutments with positive TOC angles, whereas reverse-tapered abutments (negative TOC angles) were digitally blocked out at 0° and had an extra mesiodistal gap set to 50 μm. Then, zirconia crowns were fabricated, and their marginal and internal discrepancies were recorded with the silicone replica technique. All replicas were examined under a stereomicroscope at 50× magnification. Collected data were analyzed with one-way ANOVA and post hoc Tukey test for marginal fit. For the axial and incisal fit, measured values did not follow a normal distribution; therefore, the Kruskal-Wallis and the Dunn/Bonferroni multiple comparison tests were applied (p = 0.05).
Results
The mean marginal fit of –8° crowns (58.2 ± 6.0 μm) was statistically different (p < 0.0001) from all the remaining crowns (range 42.1-47.3 μm). Also, the internal fit was statistically significant when comparing crowns fabricated over abutments with positive and negative TOC angles (p < 0.0001). The largest median axial discrepancies were found in the –8° (165.5 μm) and –4° (130.8 μm) groups; however, when evaluating the incisal fit, they showed the smallest discrepancies (67.3 and 81.8 μm, respectively).
Conclusions
Under the conditions of this study, the marginal and internal fit of zirconia crowns fabricated over inverse-tapered preparations is within clinically accepted values.
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