Unique lncRNA signatures mark the major T-ALL genetic subgroups

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SOX11 is a lineage-survival oncogene in neuroblastoma

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SOX11 is a lineage-survival oncogene in neuroblastoma

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The HBP1 tumor suppressor is a druggable ALK downregulated gene controlling MYCN activity

ALK is an important druggable target in ALK mutant neuroblastoma (NB). In this study, we sought novel vulnerable nodes downstream of ALK for combinatorial therapy. First, we identified a 79-gene signature that recapitulates the transcriptional response upon ALK inhibition based on transcriptome profiling of ALK wild type, ALKF1174L or ALKR1275Q mutant and ALK amplified NB cell lines following ALK inhibition using NVP-TAE684, LDK-378, X-396 and Crizotinib. This signature was validated in primary tumor samples and in the SK-N-AS cell line with regulated expression of ALK wild type, ALKF1174L and ALKR1275Q constructs. The majority of the mutant ALK dependent downstream signaling components were implicated in MAPK/ERK, PI3K/AKT/mTOR, MYC/MYCN and neuronal differentiation signaling. Bioinformatic analysis using the iRegulon Cytoscape plugin (http://ift.tt/1nlxfL5) resulted in the identification of the transcriptional repressor HBP1 as a hub gene, acting downstream of ALK. HPB1 is a known negative regulator of MYC/MYCN activity. Using MYCN and miR-17-92 inducible SHEP model systems, we established a MYCN/miR-17-92/HBP1 positive feedback regulatory loop in which MYCN represses the negative control of HBP1 through upregulation of miR-17-92 which targets the HBP1 3'UTR. Next, we showed that stable HBP1 overexpression inhibits growth and induces apoptosis of NB cells. Finally, we explored the effects of the green tea compound epigallocatechin gallate (EGCG) on HBP1 upregulation in NB cells. EGCG treatment induced HBP1 expression and had a strong negative effect on cell growth and survival. EGCG/ALK inhibitor combination treatment in a panel of cell lines showed clear additive effects. In conclusion, we identified HBP1 as a novel important ALK downregulated gene controlling MYCN activity, further stressing the important interconnection between oncogenic MYCN and ALK signaling. EGCG upregulates HBP1 levels and is a strong candidate for further in vivo testing for additive or synergistic effects with ALK inhibitors or MYCN targeting compounds such as JQ1.

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Phf6 plays a role in hematopoiesis and thymopoiesis in zebrafish

T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of thymocytes and affects both children and adults. In T-ALL, multiple genetic lesions in oncogenes and tumor suppressor genes cooperatively contribute to leukemogenesis. Recently, our research group identified inactivating mutations and deletions in the PHF6 gene in 16% of pediatric and 38% of adult T-ALL patients. Although these frequencies suggest an important role for PHF6 as a tumor suppressor in T-ALL, the role of PHF6 in normal and malignant T-cell development remains largely unknown. Whole mount in situ hybridization (WISH) revealed phf6 expression in developing zebrafish in hematopoietic regions and in the thymus. Upon morpholino-mediated knockdown of phf6, WISH experiments demonstrated a normal onset of primitive hematopoiesis at 15 somites, while increased expression of lmo2, a marker for primitive hematopoiesis and erythropoiesis at 24hpf (hours post fertilization) can be observed. Moreover, also c-myb expression, a marker for definitive hematopoiesis, is increased in the caudal hematopoietic tissue at 36hpf after phf6 knockdown. Rag1 and rag2 are useful markers for following the development of lymphoid tissues since they are expressed together exclusively in immature lymphocytes. Interestingly, a significant reduction in thymus development and size could be observed in phf6 morphants at 5dpf (days post fertilization) using the transgenic zebrafish line tg(Rag2:GFP). In line with these results, strongly reduced rag1 expression was evident upon performing WISH on 5dpf phf6 knockdown embryos, as compared to control embryos. All together, our data provide strong evidence for an important role of phf6 in primitive hematopoiesis and thymopoiesis. Further studies will include phf6 knockout zebrafish to assess long-term effects and susceptibility to T-ALL formation in vivo.

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Vitamin D Deficiency Is Associated with Rapid Decline in Exercise Capacity in Male Patients with Chronic Obstructive Pulmonary Disease

Background: Vitamin D is suggested to play a role in airway and systemic inflammation in chronic obstructive pulmonary disease (COPD). Low serum 25-hydroxyvitamin D (25-OHD) levels have been suggested to be associated with lower lung function and poorer exercise capacity in COPD. Objectives: The main purpose of this study was to investigate the effects of vitamin D deficiency on the change in exercise capacity in male COPD patients. Methods: A total of 156 male subjects were selected from the Korean Obstructive Lung Disease cohort. Vitamin D deficiency was subdivided into three subgroups: mild, moderate, and severe deficiency groups. Rapid decline was defined as an annual rate of change in exercise capacity ≥17 m. Exercise capacity was assessed by 6-minute walk distance (6MWD). Results: Significant differences were observed in the serum levels of 25-OHD, the number of patients with vitamin D sufficiency, and moderate-to-severe deficiency between rapid decliners (n = 40) and non-rapid decliners (n = 116). No differences were found between the groups for age, smoking status, lung function, and 6MWD. Multivariate analysis showed that vitamin D deficiency was independently related to rapid decline in exercise capacity (p = 0.028). A statistically significant difference was observed among the subgroups of vitamin D deficiency in terms of the change in exercise capacity (p Conclusion: This study shows that vitamin D deficiency is associated with rapid decline in exercise capacity in male patients with COPD.
Respiration

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Establishing a national paediatric radiology global outreach group recent developments in the British Society of Paediatric Radiology

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Extraskeletal myxoid chondrosarcoma of maxilla: A rare entity

Janardan B Garde, Sangeeta J Palaskar, Pargatsingh T Kathuriya

Journal of Oral and Maxillofacial Pathology 2016 20(1):151-153



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Message from IAOMP secretary

N Chaitanya Babu

Journal of Oral and Maxillofacial Pathology 2016 20(1):2-2



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Prions in dentistry: A need to be concerned and known

B Sushma, Sachin Gugwad, Rajdeep Pavaskar, Shambhvi A Malik

Journal of Oral and Maxillofacial Pathology 2016 20(1):111-114

Prion diseases were first discovered by Stanley B. Prusiner who defined prions as infectious, transmissible proteinaceous particles that lack nucleic acid and are composed exclusively of a modified isoform of the noninfectious cellular prion protein (PrPC). These are incurable neurodegenerative conditions affecting both animals and humans. They may be sporadic, infectious or inherited in origin. Human prion diseases include Creutzfeldt-Jakob desease (CJD), Gerstmann- Straussler-Scheinker disease, Kuru and Fatal familial insomnia. Prions resist the conventional sterilization procedures and hence the dentists must be aware of such diseases so as to opt standard methods of infection control and decontamination for such infectious agents. This review article divulge the dentists with a brief overview of the characteristics of prions, the risk of transmission and the implications for infection control in dentist.

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Message from IAOMP treasurer

P Nainani

Journal of Oral and Maxillofacial Pathology 2016 20(1):3-3



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Message from IAOMP president

K Ranganathan

Journal of Oral and Maxillofacial Pathology 2016 20(1):1-1



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From the Editor's desk

Radhika Manoj Bavle

Journal of Oral and Maxillofacial Pathology 2016 20(1):4-4



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Precursor B-cell lymphoblastic lymphoma of oral cavity: A case report with its diagnostic workup

Komal Ladharam Talreja, Suresh Ramchandra Barpande, Jyoti Dilip Bhavthankar, Mandakini S Mandale

Journal of Oral and Maxillofacial Pathology 2016 20(1):133-136

Lymphoblastic lymphoma (LBL), seen primarily in children or young adults, is a malignant neoplasia that originates from B or T lymphocyte precursors and rarely occurs in the oral cavity. In this localization, neither the clinical features nor the radiologic appearances are pathognomic and can pose significant diagnostic problems. Histopathologically, it presents as a round blue cell tumor. An early and accurate diagnosis of this entity is very important due to its high cure rate. We report a case of B-cell LBL involving oral cavity in a 10-year-old child. The purpose of this report is to explore the diagnostic workup.

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Cancer Conundrum

Radhika M Bavle, M Sudhakara

Journal of Oral and Maxillofacial Pathology 2016 20(1):5-8



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Unusual presentation of squamous cell carcinoma in young female patient: A case report and review of literature

Jasbir Kaur, Anantpreet Singh, Rohit Chopra

Journal of Oral and Maxillofacial Pathology 2016 20(1):163-163

Oral squamous cell carcinoma is the most common "malignant neoplasm" of epithelial origin usually affecting individuals over 50 years of age. It is rare in patients aged <40 years old. This report describes a case of squamous cell carcinoma involving anterior mandibular alveolar region in a 17-year-old female patient, with no history of deleterious habits. This report focuses on etiological factors, diagnosis and prognosis related to the case.

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Toto bodies

Kunal Sah

Journal of Oral and Maxillofacial Pathology 2016 20(1):9-10



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Pyruvic acid levels in serum and saliva: A new course for oral cancer screening?

Manohara A Bhat, K.V.V. Prasad, Dheeraj Trivedi, BR Rajeev, Hemanth Battur

Journal of Oral and Maxillofacial Pathology 2016 20(1):102-105

Objective: Cancerous cells show increased glycolysis rate. This will increase overall levels of pyruvate as it is one of the end products of glycolysis. The present on-going study is to estimate the levels of pyruvate in saliva and serum among healthy and oral cancer subjects. Settings and Design: Hospital-based cross-sectional comparative study. Methodology: A total of 50 subjects among healthy and oral cancer subjects were selected based on clinical and histological criteria. Saliva and serum samples were collected and subjected to pyruvate level estimation using biochemical analysis. Statistical Analysis: Descriptive analysis and Mann-Whitney test were used to find the statistical difference between the two independent groups. Results: Serum pyruvic acid levels of the healthy group were 1.09 ± 0.14 and for oral cancer, it was 2.95 ± 0.59 and salivary level were 3.49 ± 0.47 and 1.32 ± 0.10 respectively. Mann-Whitney test showed statistically significant difference in serum and salivary pyruvate level in between two groups (P < 0.000 respectively). Conclusion: The present study showed noticeable variation in the level of pyruvic acid among healthy and oral cancer subjects. This generates the hypothesis that estimation of the pyruvic acid can be a new tool to screening of the cancer.

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Do the presence of Barr bodies in male jail inmates indicates criminality: A pilot study

Mayuri K Kulkarni, Pradeep D Somannavar, Vijayalakshmi Kotrashetti, Ramakant Nayak, Jagadish Hosmani, Deepa Babji

Journal of Oral and Maxillofacial Pathology 2016 20(1):11-15

Background: Cytogenetic studies from past decades have shown that interphase cells of female cats contain a densely stained chromatin mass in their nuclei called as Barr bodies (BBs) named after the scientist Murray Barr. BBs are unique chromatin structures formed due to the condensation of the X-chromosome. Many psychopathic disorders originate from defective genes including the multiple X syndromes. Males with extra X-chromosome generally present with severe personality disorder. The present study was conducted to determine the presence of extra X-chromosome in male jail inmates through the detection of BB in peripheral blood and buccal smear. Materials and Methods: Study included 100 male subjects (fifty jail inmates and fifty controls), after obtaining the consent, peripheral blood smears (PBS) and buccal smears (BS) were prepared and stained using Leishman's and cresyl violet stain respectively. One hundred neutrophils in PBS and epithelial cells in BS were screened for detection of the BB; accumulated data were tabulated and statistically analyzed using t-test and Chi-square test. Results: 60% of cases in PBS and 36% in BS showed positivity for the presence of BB in jail inmates as compared to 14% of cases in PBS and none in BS were positive for BB in controls. Conclusion: Presence of BB in male suggests increased likelihood of criminal tendencies. Further studies are to be carried out to compare the results with karyotyping.

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Epigenetics: A possible answer to the undeciphered etiopathogenesis and behavior of oral lesions

Narendra Nath Singh, Aakanksha Peer, Sherin Nair, Rupesh K Chaturvedi

Journal of Oral and Maxillofacial Pathology 2016 20(1):122-128

Much controversy has existed over the etiopathogenesis and management of oral lesions, especially oral malignancies. The knowledge of genetic basis is proving to be inadequate in the light of emerging new mechanisms termed epigenetic phenomena. The present review article aims to understand the role of epigenetic mechanisms in oral lesions. Epigenetics is the study of acquired changes in chromatin structure that arise independently of a change in the underlying deoxyribonucleic acid (DNA) nucleotide sequence. Key components involved in epigenetic regulation are DNA methylation, histone modifications and modifications in micro ribonucleic acids (miRNA). Epigenetics is a reversible system that can be affected by various environmental factors such as diet, drugs, mental stress, physical activity and addictive substances such as tobacco, nicotine and alcohol. Epigenetics may also play a role in explaining the etiopathogenesis of developmental anomalies, genetic defects, cancer as well as substance addiction (tobacco, cigarette and alcohol). Epigenetic modifications may contribute to aberrant epigenetic mechanisms seen in oral precancers and cancers. In the near future, epigenetic variations found in oral dysplastic cells can act as a molecular fingerprint for malignancies. The literature in English language was searched and a structured scientific review and meta-analysis of scientific publications from the year 2000 to year 2015 was carried out from various journals. It was observed that epigenetic marks can prove to be novel markers for early diagnosis, prognosis and treatment of oral cancers as well as other oral diseases.

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Long-term effect of tobacco on unstimulated salivary pH

Neeraj Grover, Jyoti Sharma, Shamindra Sengupta, Sanjeet Singh, Nishant Singh, Harjeet Kaur

Journal of Oral and Maxillofacial Pathology 2016 20(1):16-19

Aims and Objectives: The aim of this study was to analyze and compare the effects of tobacco on salivary pH between tobacco chewers, smokers and controls. Materials and Methods: A total of 60 subjects (males and females) aged 25-40 years, were divided equally into three groups: Tobacco smokers (Group A), chewers (Group B) and controls (Group C). Saliva of each subject was collected under resting condition. Salivary pH was determined using the specific salivary pH meter. Results: The mean (±standard deviation) pH for Group A was 6.75 (±0.11), Group B was 6.5 (±0.29) and Group C was 7.00 (±0.28) after comparison. The significant results showed lower salivary pH in Groups A and B as compared to controls. Salivary pH was lowest in Group B compared to Group A and Group C. Conclusion : This study indicates that a lower (acidic) salivary pH was observed in tobacco users as compared with control. These alterations in pH due to the long-term effect of tobacco use can render oral mucosa vulnerable to various oral and dental diseases.

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Basal cell adenoma of maxillary sinus mimicking ameloblastoma

Priya Anil Bhagde, Suresh Ramchandra Barpande, Jyoti Dilip Bhavthankar, Jayanti G Humbe

Journal of Oral and Maxillofacial Pathology 2016 20(1):142-146

Basal cell adenoma (BCA) is a rare basaloid tumor, with only 20% of cases occurring in minor salivary glands. Histologically, BCA is characterized by the presence of basaloid cells and may frequently be mistaken with canalicular adenoma, basal cell adenocarcinoma, adenoid cystic carcinoma and basaloid squamous cell carcinoma. Immunohistochemistry may aid in arriving at a final diagnosis as in the present case. Reported here is a case of locally aggressive BCA. Histologically, the lesion mimicked ameloblastoma and other entities which posed a diagnostic challenge. There are no reports of BCA presenting as an aggressive lesion available in English literature so far; moreover, merely a single case of BCA of maxillary sinus has been previously reported to the best of our cognition. This case report highlights the rarity of this tumor with regards to its site of origin, clinical behavior and histopathological mimics.

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Mounting ground sections of teeth: Cyanoacrylate adhesive versus Canada balsam

Manogna R.L. Vangala, Amrutha Rudraraju, RV Subramanyam

Journal of Oral and Maxillofacial Pathology 2016 20(1):20-24

Introduction: Hard tissues can be studied by either decalcification or by preparing ground sections. Various mounting media have been tried and used for ground sections of teeth. However, there are very few studies on the use of cyanoacrylate adhesive as a mounting medium. Aims: The aim of our study was to evaluate the efficacy of cyanoacrylate adhesive (Fevikwik™) as a mounting medium for ground sections of teeth and to compare these ground sections with those mounted with Canada balsam. Materials and Methods: Ground sections were prepared from twenty extracted teeth. Each section was divided into two halves and mounted on one slide, one with cyanoacrylate adhesive (Fevikwik™) and the other with Canada balsam. Scoring for various features in the ground sections was done by two independent observers. Statistical Analysis Used: Statistical analysis using Student's t-test (unpaired) of average scores was performed for each feature observed. Results: No statistically significant difference was found between the two for most of the features. However, cyanoacrylate was found to be better than Canada balsam for observing striae of Retzius (P < 0.0205), enamel lamellae (P < 0.036), dentinal tubules (P < 0.0057), interglobular dentin (P < 0.0001), sclerotic dentin - transmitted light (P < 0.00001), sclerotic dentin - polarized light (P < 0.0002) and Sharpey's fibers (P < 0.0004). Conclusions: This initial study shows that cyanoacrylate is better than Canada balsam for observing certain features of ground sections of teeth. However, it remains to be seen whether it will be useful for studying undecalcified sections of carious teeth and for soft tissue sections.

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Compound composite odontoma

G Girish, Radhika M Bavle, Manish Kumar Singh, Sahana N Prasad

Journal of Oral and Maxillofacial Pathology 2016 20(1):162-162

The term odontoma has been used as a descriptor for any tumor of odontogenic origin. It is a growth in which both epithelial and mesenchymal cells exhibits complete differentiation. Odontomas are considered as hamartomas rather than true neoplasm. They are usually discovered on routine radiographic examination. Odontomas, according to the World Health Organization, are classified into complex odontoma and compound odontomas. The present paper reports a case of compound composite odontomas.

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A correlative study of the levels of salivary Streptococcus mutans lactobacilli and Actinomyces with dental caries experience in subjects with mixed and permanent dentition

Achala Chokshi, Pushpalatha Mahesh, P Sharada, Krunal Chokshi, S Anupriya, BK Ashwini

Journal of Oral and Maxillofacial Pathology 2016 20(1):25-28

Purpose: The aim of the study was to estimate the salivary levels of Streptococcus mutans, Lactobacilli and Actinomyces and to correlate it with dental caries experience in mixed and permanent dentition. Materials and Methods: The sample size comprised 110 subjects. The decayed, missing and filled teeth (DMFT) index of all the individuals participating in the study was calculated. Saliva samples were collected from patients and samples were inoculated on specific culture media and incubated for a period of 48 h. Based on colony characteristics, S. mutans, Lactobacilli and Actinomyces were identified. Results: A positive correlation exists between DMFT and S. mutans, Lactobacilli and Actinomyces in mixed dentition and permanent dentition group samples (P < 0.001). Conclusion: The conclusion from the results obtained was that S. Mutans, lactobacilli and Actinomyces which are the components of the normal microbial flora of the oral cavity play an important role in the pathogenesis of dental caries and increased number of microorganisms is associated with an increased caries frequency.

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Role of inflammation in developmental odontogenic pathosis

Sandeep S Gupta, Devi C Shetty, Aadithya B Urs, P Nainani

Journal of Oral and Maxillofacial Pathology 2016 20(1):164-164

Periapical infection in the primary tooth may lead to periapical abscess, granuloma, radicular cyst and even osteomyelitis. The infection in primary teeth can also affect the developing successor teeth leading to hypomineralization, hypoplasia, arrest of tooth development, regional odontodysplasia, delayed eruption etc. The purpose of this article is to report a case of malformed permanent tooth in relation to overlying infected deciduous teeth. The probable role of inflammation in pathogenesis of the present condition is also being discussed.

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Long term scar quality in burns with three distinct healing potentials: A multicenter prospective cohort study

Abstract

The laser Doppler imager is used in cases of indeterminate burn depth to accurately predict wound healing time at an early stage. The laser Doppler imager classifies burns into three estimated healing potentials as follows: high, <14 days; intermediate, 14-21 days; and low, >21 days. At this time, the relationship between these healing potentials and long-term scar quality is unknown. The objective of this study was to determine the long-term scar quality of burns with three distinct healing potentials. The secondary objectives were to compare treatment strategies in intermediate wounds, to study the effect of the timing of surgery on low healing potential wounds and to identify predictors of reduced scar quality. Hence, in a prospective cohort study, scar quality was determined in patients whose burns were assessed with laser Doppler imaging. Scar Quality was assessed with objective and subjective measurement tools, including overall scar quality (Patient Observer Scar Assessment Scale) as a primary outcome and color and elasticity parameters. A total of 141 patients (>19 months post-burn) with 216 scars were included. Wounds with high and intermediate healing potential did not significantly differ regarding scar quality. Wounds with a low healing potential had a significantly lower scar quality. Analysis of 76 surgically-treated low healing potential wounds showed no significant differences in the primary outcome regarding the timing of surgery (≤14 days versus >14). Predictors of reduced long term scar quality were darker skin type and multiple surgeries. In conclusion, scar quality was strongly related to the healing potential category. Scar quality was very similar in high and intermediate healing potential wounds. No positive effects were found on scar quality or on healing time in surgically-treated wounds with intermediate healing potential, advocating a conservative approach. Further studies should focus on the optimal timing of surgery in low healing potential wounds. This article is protected by copyright. All rights reserved.

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Altered ECM Deposition by Diabetic Foot Ulcer-Derived Fibroblasts Implicates Fibronectin in Chronic Wound Repair

Abstract

Current chronic wound treatments often fail to promote healing of diabetic foot ulcers (DFU), leading to amputation and increased patient morbidity. A critical mediator of proper wound healing is the production, assembly, and remodeling of the extracellular matrix (ECM) by fibroblasts. However, little is known about how these processes are altered in fibroblasts within the DFU microenvironment. Thus, we investigated the capacity of multiple, primary DFU-derived fibroblast strains to express, produce, and assemble ECM proteins compared to diabetic patient-derived fibroblasts and healthy donor-derived fibroblasts. Gene expression microarray analysis demonstrated differential expression of ECM and ECM-regulatory genes by DFU-derived fibroblasts which translated to functional differences in a 3D in vitro ECM tissue model. DFU-derived fibroblasts produced thin, fibronectin-rich matrices and responded abnormally when challenged with transforming growth factor-beta (TGF-β), a key regulator of matrix production during healing. These results provide novel evidence that DFU-derived fibroblasts contribute to the defective matrices of DFUs and chronic wound pathogenesis. This article is protected by copyright. All rights reserved.

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EGFR inhibitors Identified as a Potential Treatment for Chordoma in a Focused Compound Screen

Abstract

Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on 3 well-characterised chordoma cell lines. 154 compounds were selected from the single concentration screen (1 μM) based on their growth inhibitory effect. Their half-maximal effective concentration (EC₅₀) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of 7 chordoma cell lines, 4/7 of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream-pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4- position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in 2 xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplification (EGFR, ERBB2, MET), nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-) EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo.

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Septicemia with Streptococcus pseudopneumoniae: report of three cases with an apparent hepatic or bile duct association

10.3109/23744235.2016.1157896<br/>Kurt Fuursted

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Cancers Vol. 8 Pages 46: A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian Fallopian Tube or Peritoneal Cancer in First Remission

We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient's pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.

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Combinatorial epigenetic deregulation by Helicobacter pylori and Epstein-Barr virus infections in gastric tumorigenesis

Abstract

Epigenetic mechanisms including DNA methylation, histone modifications, chromatin remodeling and microRNAs convert environmental signals to transcriptional outputs but are commonly hijacked by pathogenic microorganisms. Recent advances in cancer epigenomics have shed new light on the importance of epigenetic deregulation in Helicobacter pylori- and Epstein-Barr virus (EBV)-driven gastric tumorigenesis. Moreover, it is becoming apparent that epigenetic mechanisms interact through crosstalk and feedback loops, which modify global gene expression patterns. The SWI/SNF remodeling complexes are commonly involved in gastric cancers associated with H. pylori or EBV through different mechanisms including microRNA-mediated deregulation and genetic mutations. While H. pylori causes epigenetic silencing of tumor-suppressor genes to deregulate cellular pathways, EBV-positive tumors exhibit a widespread and distinctive DNA hypermethylation profile. Given the early successes of epigenetic drugs in hematologic malignancies, further studies are mandated to enrich and translate our understanding of combinatorial epigenetic deregulation in gastric cancers into interventional strategies in the clinic.

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The role of aging body mass index and estrogen on symptomatic lumbar osteoarthritis in post-menopausal women

2016-04-22T03-02-18Z
Source: International Journal of Research in Medical Sciences
I Ketut Suyasa, I G. N. Yudhi Setiawan.
Background: Low back pain is a common complaint which is always found in old age due to degeneration process. Degeneration process of spine, especially in the lumbar region is called lumbar osteoarthritis (OA). Various factors are thought to be the cause of lumbar OA, including primarily due to hormonal changes of estrogen and increase of age and body mass index in postmenopausal women. Methods: The purpose of this study is to determine the role of hormonal changes pathogenesis in lumbar osteoarthritis in postmenopausal women and its correlation with age and body mass index. Cross sectional analytic method had been conducted to determine the role of age, body mass index and estrogen for lumbar OA in postmenopausal women. The study was conducted in Sanglah General Hospital from October 2015 until March 2016 by anthropometric measures and blood samples. Results: From 196 samples showed that the estrogen deficiency in postmenopausal women have a correlation with the symptomatic lumbar OA (r=0.252, p = 0.000). While age and the body mass index in postmenopausal women has a correlation with symptomatic lumbar OA (r = 0.150 and 0.198, p = 0.000 and 0.013). Conclusions: The aging process, body mass index and estrogen deficiency correlated with the symptomatic OA lumbar in post-menopausal women.


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Clinical Features of Food Allergy during the 1st Year of Life: The ADAPAR Birth Cohort Study

Background: Although food allergies (FAs) occur most commonly during the 1st year of life, there is limited information available regarding the epidemiology of FAs. In this study, we investigated the incidence of FA and the associated risk factors during the 1st year of life in southeast Turkey. Methods: This study is a prospective evaluation of 1,377 infants born at the Balcalı Hospital (Çukurova University) and includes four routine follow-up assessments until the age of 1 year. At birth, a physical examination was performed, cord blood samples were taken, and parents completed a baseline questionnaire. Follow-up visits were scheduled at 3, 6 and 12 months and included the infants' physical examination and a follow-up questionnaire. A skin prick test (SPT) was performed and food-specific IgE levels were measured at 6 and 12 months. Telephone interviews were conducted when the infants were 9 months of age, and the questionnaire was administered. The diagnosis of FA was based on food-specific IgE levels, positive SPT results, associated clinical findings and an oral food challenge (OFC) test. Results: Patient histories, physical examinations and laboratory results indicated a possible FA in 90 infants (6.5%) during the 1st year of life. All of them underwent OFC testing with the suspected foods, and FA was confirmed in 33 cases (2.4%). Cow's milk allergy was the major cause of FA. Skin reactions were major clinical findings in FA. A family history of atopy was identified as the major risk factor for FA. Conclusions: The prevalence and risk factors of FA in our region are consistent with those reported in the literature.
Int Arch Allergy Immunol 2016;169:171-180

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Nevus count associations with pigmentary phenotype histopathological melanoma characteristics and survival from melanoma

Abstract

Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment, and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics, and we assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis and inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features. This article is protected by copyright. All rights reserved.

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Stillbirth and neonatal death among female cancer survivors: A national cohort study

Abstract

The number of cancer survivors continues to increase worldwide. Many of these survivors have had children of their own. It is less well-known whether radiation therapy or chemotherapy could affect the risk of stillbirth and neonatal death for these children. To explore this research questions, we identified all women diagnosed with cancer between 1958 and 2012 from the Swedish Cancer Register and they were further linked to the Swedish Medical Birth Register to identify their subsequent child birth between 1973 and 2012. Multivariate logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between stillbirth and neonatal death and maternal cancer diagnosis. As compared to the children without maternal cancer, the risk of stillbirth was significantly higher among children of female cancer survivors born within three years after cancer diagnosis with an OR of 1.92 (95%CI 1.03-3.57). The incidence of neonatal death did not show a significant change. For women with more than one pregnancy after cancer diagnosis, the risk of stillbirth and neonatal death was lower for the second child birth compared to the first child birth. Our study suggested that the risk of stillbirth was negatively associated with the time after cancer diagnosis, providing evidence that the adverse effect associated with cancer treatment may diminish with time. This article is protected by copyright. All rights reserved.

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Detecting 5-Methylcytosine Using an Enzyme-free DNA Strand Exchange Reaction Without Pretreatment Under Physiological Conditions

Chem. Commun., 2016, Accepted Manuscript
DOI: 10.1039/C6CC03138B, Communication

Xiang Zhou, Chen Xu, Jinjun Wu, wenting liu, Tingting Hong, Tianlu Wang, Xiaoe Zhang, Boshi Fu, Fan Wu, Zhiguo Wu
We present here a novel and efficient method for 5mC detection using a DNA strand exchange reaction (SER) strategy. This enzyme-free method needs no pre-treatment of target DNAs and can...
The content of this RSS Feed (c) The Royal Society of Chemistry

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Isolation and genotyping of Acanthamoeba strains (T4 T9 and T11) from amoebic keratitis patients in Iran

Abstract

The continuous increase in Acanthamoeba keratitis, a severe corneal infection, worldwide is mainly due to the increase in the number of soft contact lens users. In the present study, which involves a 5-year study, a total of 138 corneal scraps and contact lenses together with their paraphernalias were obtained from suspected amoebic keratitis patients. All samples were cultured using culture-enrichment method. Pathogenic assay, using thermotolerance and osmotolerance tests were also performed on the positive strains. Sequencing of the isolated strains was done by targeting the DF3 region of 18s rRNA gene. The results revealed that 18 (13 %) of patients were infected with Acanthamoeba spp. As expected, T4 genotype was the most common genotype among the clinical samples; however, in three cases, Acanthamoeba belonging to T11 and T9 were detected. Interestingly, T9 genotype, commonly classified as non-pathogenic amoebae, was identified as a causal agent of a patient with amoebic keratitis. From the pathogenic assay, four strains belonging to T4 genotypes were highly pathogenic. This is the first report of Acanthamoeba T9 genotypes isolated in Iran and the first report of T9 type occurring in amoebic keratitis patients worldwide. Due to the increasing trend of amoebic keratitis (AK) and the identification of new genotypes, such as T9 as the causative agent of AK, more researches in this field are necessary in the region and the world at large.

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Stereotypes override grammar: Social knowledge in sentence comprehension

Publication date: April–May 2016
Source:Brain and Language, Volumes 155–156
Author(s): Nicola Molinaro, Jui-Ju Su, Manuel Carreiras
Many studies have provided evidence for the automaticity and immediacy with which stereotypical knowledge affects our behavior. However, less is known about how such social knowledge interacts with linguistic cues during comprehension. In this ERP sentence processing study we took advantage of the rich grammatical gender morphology of Spanish to explore the processing of role nouns in which stereotype and grammatical cues were simultaneously manipulated, in a factorial design. We show that stereotypical knowledge overrides syntactic cues, highlighting the immediacy with which stereotype knowledge is activated during language comprehension and supporting proposals claiming that social knowledge impacts on language processing differently from other forms of semantics.



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Infiltration of the basal ganglia by brain tumors is associated with the development of co-dominant language function on fMRI

Publication date: April–May 2016
Source:Brain and Language, Volumes 155–156
Author(s): Katharina Shaw, Nicole Brennan, Kaitlin Woo, Zhigang Zhang, Robert Young, Kyung Peck, Andrei Holodny
Studies have shown that some patients with left-hemispheric brain tumors have an increased propensity for developing right-sided language support. However, the precise trigger for establishing co-dominant language function in brain tumor patients remains unknown. We analyzed the MR scans of patients with left-hemispheric tumors and either co-dominant (n=35) or left-hemisphere dominant (n=35) language function on fMRI to investigate anatomical factors influencing hemispheric language dominance. Of eleven neuroanatomical areas evaluated for tumor involvement, the basal ganglia was significantly correlated with co-dominant language function (p<0.001). Moreover, among patients whose tumors invaded the basal ganglia, those with language co-dominance performed significantly better on the Boston Naming Test, a clinical measure of aphasia, compared to their left-lateralized counterparts (56.5 versus 36.5, p=0.025). While further studies are needed to elucidate the role of the basal ganglia in establishing co-dominance, our results suggest that reactive co-dominance may afford a behavioral advantage to patients with left-hemispheric tumors.



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The critical state of initial teacher education (ITE) in Pakistan: need for urgent reforms

The current research study investigates the perceived adoption of didactical strategies and how this adoption is related to student teachers' cognitions; i.e. student teachers' pedagogical beliefs and self-efficacy beliefs. A sample of 250 student teachers enrolled in masters in education from two largest universities of Pakistan participated in the study. The respondents filled out survey instruments related to their perceived adoption of didactical strategies, pedagogical beliefs and self-efficacy beliefs. The main findings of the study includes (i) an overall weak adoption of the different types of didactical strategies by student teachers, and (ii) a significant positive relationship found in the perceived adoption of didactical strategies and student teachers' cognitions. The results suggest a critical need for the continuous professional development of teacher educators in ITE institutes in Pakistan. Also, there are clear recommendations for the curriculum developers and educational policy makers to put forward benchmarking exercises on regular basis.

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The interplay between cognitive risk and resilience factors in remitted depression: a network analysis

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The relationship between perceived promotion of autonomy/dependence and pain-related disability in older adults with chronic pain: The mediating role of self-reported physical functioning.

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A counterpoint reading of the MoussemCities@Tunis festival

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The logic of the database and responsive social work

Over the last decade, western child welfare and protection has been subjected to many reforms. This is no different in Flanders - the Dutch speaking part of Belgium - where child welfare and protection has been reconstructed by integrating the various child welfare and protection services into one shared organisational framework. This reform has been defined as a way forward to a more emancipatory and needs-driven instead of supply-driven youth care system and even has been called a Copernican Revolution towards more responsive social work, stressing the welfare logic above the protectionistic logic. In order to realize this Copernican Revolution, the Flemish government invested to a great extent in the enhanced introduction of more and better information and registration tools to better capture and respond to the needs of children and families. In this presentation we draw on preliminary results of an empirical study where we performed 1) a conventional qualitative content analysis of policy documents relating to the subject of information and registration tools in child welfare and protection and 2) qualitative semi-structured interviews with key policy actors in the field of Flemish child welfare and protection in order to gain insight into the governmental logics and goals for installing information and registration tools. These results show that there are various "underlying" governmental logics regarding the use and installation of these information and registration tools. In this oral presentation, we will argue that these various underlying logics raise severe questions concerning the development a Copernican revolution towards responsive social work, as these instruments are mainly driven by a protectionistic logic rather than child welfare logic.

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CRISPR/Cas9-mediated genome editing in primed versus naïve human embryonic stem cells

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Validity of the oxygen uptake efficiency slope (OUES) as a parameter of maximal and submaximal exercise testing in children with mild CF

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Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

BACKGROUND: Necrotizing enterocolitis (NEC), an intestinal inflammatory disease affecting premature infants, is associated with low regulatory T (Treg) to effector T (Teff) cell ratios. We recently demonstrated that heme oxygenase-1 (HO-1) deficiency leads to increased NEC development. Here, we investigated the effects of HO-1 on T-cell proportions in a murine NEC-like injury model. METHODS: Intestinal injury was induced in 7-d-old wildtype (WT) or HO-1 heterozygous (HO-1 Het) pups by formula-feeding every 4h for 24-78h by oral gavage and exposures to 5%O-2. Controls remained breastfed. HO-1 was induced in WT pups by administering heme preinjury induction. Lamina propria T cells were identified by flow cytometry. For adoptive transfer studies, WT splenic/thymic Tregs were injected intraperitoneally into HO-1 Het pups 12-24 h preinduction. Results: Het mice showed increased intestinal injury and decreased Treg/Teff ratios. Genes for pattern recognition (Toll-like receptor-4, C-reactive protein, MyD88) and neutrophil recruitment increased in Het pups after NEC induction. Inducing intestinal HO-1 decreased NEC scores and incidence, and increased Treg/Teff ratios. Moreover, adoptive transfer of Tregs from WT to HO-1 Het pups decreased NEC scores and incidence and restored Treg/Teff ratios. Conclusion: HO-1 can change Treg proportions in the lamina propria of young mice under inflammatory conditions, which might, in part, confer intestinal protection.

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The Logic of the Database: In Search of Responsive Social Work

Over the last decades, youth care has been subjected to many reforms. Also in Flanders -the Dutch speaking part of Belgium- a reform is currently taking place. A new policy framework, named Integrated Youth Care (IYC), integrates different youth care sectors in order to install a more coordinated instead of fragmented youth care system. The Flemish government invested in more and better information and registration tools in order to achieve this reform. Policy papers point out that these tools will serve as instruments for reflection since they will be able to capture the needs of children, the case trajectories of all clients, the balance between supply and demand as well as the effectiveness of youth care organizations. It is the contention of this doctoral research to question this underling logic of reflection in relation to the use of information and registration tools. Especially because the use of these tools as an instrument for reflection does not remain uncontested. For example, research shows the emergence of decontextualisation, a process by which children are disconnected from their social and relational context (e.g. Aas, 2004; Parton, 2008). Consequently, the client's situation is split into a series of data, which tend to break up the holistic view (Aas, 2004) and which results in a social work based on the logic of the database (Parton, 2008). The aim of the research is to denude the logics behind the installation of these tools at three levels: the governmental, organisational and frontline level. Moreover, the research aims to discuss the installation and use of these tools in relation to the realisation of the right for care and support as well as to the development of responsive social work.

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Antitumoural activity of a cytotoxic peptide of Lactobacillus casei peptidoglycan and its interaction with mitochondrial-bound hexokinase.

In a previous study, we reported the cytotoxic activity against various tumour cells of the peptidoglycan of Lactobacillus casei. To isolate the most active components, we performed column-chromatography separation of the peptidoglycan complex and tested the related fractions for their cytotoxic activity. The most active fractions were then lyophilized and the residue was analysed by gas chromatography for its amino acid content and composition. On the basis of the known chemical formula of the basic peptidic component of the peptidoglycan complex of L. casei, a peptide was then synthesized [Europ. (CH-DE-FR-GB) Patent number 1217005; IT number 01320177] and its cytotoxicity was tested against tumoural and normal cells. The synthetic peptide was found to impair the entire metabolism of cultured tumour cells and to restore the apoptotic process. By contrast, normal cells appeared to be stimulated rather than inhibited by the peptide, whereas primary mouse embryo fibroblasts behaved similarly to tumour cells. On the basis of these results, L. casei peptidoglycan fragments and their constituent basic peptide might be applicable as potent antitumour agents. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://ift.tt/1hexVwJ Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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