[A Case of Squamous Cell Carcinoma of the Breast].

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[A Case of Squamous Cell Carcinoma of the Breast].

Gan To Kagaku Ryoho. 2016 Jun;43(6):749-52

Authors: Terasawa R, Iwamoto M, Tanaka S, Kimura K, Takahashi Y, Fujioka H, Sato N, Kawaguchi K, Ikari A, Maezawa S, Tominaga T, Matsuda J, Umezaki N, Uchiyama K

Abstract
Squamous cell carcinoma(SCC)of the breast is a rare disease. We encountered a case of SCC of the breast that relapsed in the early postoperative period and rapidly progressed thereafter. A 38-year-old woman visited our hospital presenting with a tumor in the left breast consisting of a 5-cm mass with an irregularly sharped wall. Fine needle biopsy examination showed squamous cell carcinoma. A modified radical mastectomy by Auchincloss's method was performed on the left breast. SCC was confirmed by histological examination. Two months later, local recurrence on the chest wall was found during adjuvant chemotherapy. Thereafter, the disease rapidly progressed, and finally, the patient died of respiratory failure caused by lung metastasis. The prognosis of SCC of the breast is recognized as being more unfavorable than that of invasive ductal carcinoma. We should develop an effective chemotherapeutic strategy for this disease.

PMID: 27306813 [PubMed - indexed for MEDLINE]

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Adrenal Insufficiency Associated with Small Cell Lung Cancer: A Case Report and Literature Review.

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Adrenal Insufficiency Associated with Small Cell Lung Cancer: A Case Report and Literature Review.

J UOEH. 2016 Jun 1;38(2):155-62

Authors: Noguchi S, Torii R, Shimabukuro I, Yamasaki K, Kido T, Yoshii C, Mukae H, Yatera K

Abstract
A 78-year-old Japanese man with fatigue, appetite loss, skin hyperpigmentation, hypotension and hypoglycemia, visited our hospital to evaluate an abnormal chest X-ray and adrenal gland swelling in echography in February 2015. Chest computed tomography showed a mass lesion in the right lower lobe and bilateral adrenal swellings, and small cell lung cancer (SCLC) with bilateral adrenal metastasis was diagnosed after bronchoscopy. According to low levels of serum cortisol, elevated adrenocorticotropic hormone (ACTH) and rapid ACTH test, the diagnosis of adrenal insufficiency associated with SCLC was made. Treatment with hydrocortisone (20 mg/day) was started in addition to systemic chemotherapy with carboplatin and etoposide. The patient's symptoms were slightly improved, however, systemic chemotherapy was discontinued according to the patient's request after 1 course of chemotherapy. Thereafter, he received only supportive care, and his general condition gradually worsened and he ultimately died in August 2015. Adrenal insufficiency associated with SCLC, which is caused by tissue destruction more than 90% of the adrenal glands, is rare although adrenal metastasis is not rare in patients with lung cancer. The findings such as general fatigue, appetite loss, hypotension, and hyponatremia are often got follow up as findings of advanced cancer, but appropriate therapy for adrenal insufficiency, supplement of the adrenal corticosteroid hormone, may lead to a significant improvement in the symptoms and quality of life in clinical practice of lung cancer. Therefore, physicians must consider potential adrenal insufficiency in lung cancer patients with bilateral adrenal metastasis.

PMID: 27302729 [PubMed - indexed for MEDLINE]

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Histiocytic necrotising lymphadenitis in mediastinum mimicking thymoma or lymphoma - case presentation and literature review of Kikuchi Fujimoto disease.

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Histiocytic necrotising lymphadenitis in mediastinum mimicking thymoma or lymphoma - case presentation and literature review of Kikuchi Fujimoto disease.

Pol J Pathol. 2016 Mar;67(1):91-5; quiz 96

Authors: Błasiak P, Jeleń M, Rzechonek A, Marciniak M, Pawełczyk K, Cianciara J, Kołodziej J, Muszczyńska-Bernhard B

Abstract
Kikuchi Fujimoto disease (KFD) as a rare self-limiting lymphadenopathy of short and benign course concerns most frequently the lymph nodes of the neck. The most common symptoms are painfulness of the diseased area, fever and night sweating. The etiology is not well understood, but in the role of pathogenesis viral, autoimmune and genetic factors are taken into account. In the presented case of 37-year-old female it was necessary to exclude diseases such as lymphoma or thymoma because of atypical mediastinal location of Kikuchi Fujimoto disease. After multidisciplinary consultation the lymph node was resected from the mediastinum with videothoracoscopic approach. The diagnosis was difficult for the pathologist because of the large percentage of necrosis of the lymph node but the image was typical for histiocytic necrotizing lymphadenitis. Two cases of patients with KFD limited to the mediastinum have been previously reported in the literature. This article presents the world's first reported case of this disease in the topographic location of the thymus. Furthermore, a review of current literature was made.

PMID: 27179280 [PubMed - indexed for MEDLINE]

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Giant cribriform adenocarcinoma of the tongue showing PRKD3 rearrangement.

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Giant cribriform adenocarcinoma of the tongue showing PRKD3 rearrangement.

Pol J Pathol. 2016 Mar;67(1):84-90

Authors: Majewska H, Skálová A, Weinreb I, Stodulski D, Hyrcza M, Stankiewicz C, Biernat W

Abstract
Cribriform adenocarcinoma of the tongue and minor salivary glands (CAMSG) was first described 16 years ago. It typically presents as a mass at the base of the tongue with early spread to lymph nodes, but without potential for distant metastases. In the 2005 World Health Organization Classification of Tumors the entity was classified as a possible variant of polymorphous low-grade adenocarcinoma (PLGA). Since then, more than 40 cases have been described in the English literature. Recently, PRKD1-3 translocation was found in more than 80% of CAMSGs. In some of those cases ARID1A or DDX3X was the translocation partner. We reviewed 183 primary carcinomas of major and minor salivary glands, resected at the Medical University of Gdańsk, Poland, in the period 1992-2012, and identified only one case of CAMSG. A giant tumor developed at the base of the tongue in a 76-year-old man. The primary tumor was resected with multiple bilateral cervical lymph node metastases. The patient received radiotherapy but died 10 months after the surgery due to causes not related to the primary cancer. The tumor presented PRKD3 rearrangement as confirmed by FISH. As the tumor is extremely rare (it represented only 0.5% of salivary gland tumors in our series), the controversy on its nosological status is still unresolved. This is the first report in the world literature of a patient who died in the course of CAMSG.

PMID: 27179279 [PubMed - indexed for MEDLINE]

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Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma.

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Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma.

PLoS One. 2016;11(3):e0152820

Authors: Lian YF, Yuan J, Cui Q, Feng QS, Xu M, Bei JX, Zeng YX, Feng L

Abstract
Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.

PMID: 27030985 [PubMed - indexed for MEDLINE]

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[Gene mutations connected to Waldenstöm macroglobulinemia].

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[Gene mutations connected to Waldenstöm macroglobulinemia].

Vnitr Lek. 2016 Jan;62(1):40-3

Authors: Kutálková K, Sedlaříková L, Adam Z, Ševčíková S

Abstract
Waldenstöm macroglobulinemia (WM) is a rare lymphoproliferative disorder, currently classified as a monoclonal gammopathy, with incidence rate of 3 per million. The disease is characterized by presence of clonal B lymphocytes in the bone marrow and by presence of monoclonal immunoglobulin IgM in serum. It is mostly an indolent disorder, with median overall survival 6 years. Molecular pathogenesis of WM remains unclear, but deletion of 6q and 13q, trisomy of chromosomes 4 and 8 seem to be typical. Mutations of MYD88(L265P) and CXCR4(WHIM) are very common for WM and affect growth and survival of malignant cells. This work is aimed at the current knowledge of chromosomal aberrations and gene mutations connected to the pathophysiology of WM.

PMID: 26967235 [PubMed - indexed for MEDLINE]

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[Changes in the prognosis and treatment of Waldenström macroglobulinemia. Literature overview and own experience].

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[Changes in the prognosis and treatment of Waldenström macroglobulinemia. Literature overview and own experience].

Vnitr Lek. 2016 Jan;62(1):25-39

Authors: Adam Z, Pour L, Krejčí M, Ševčíková S, Pourová E, Ševčíková E, Král Z, Mayer J

Abstract
Waldenström macroglobulinemia is defined by the presence of monoclonal immunoglobulin IgM type (M-IgM) and evidence of lymphoplasmacytic bone marrow infiltration. The disease has an indolent course, the treatment is only initiated when the disease has begun to damage its carrier. The following symptoms are regarded as proven indications for initiating therapy: B symptoms, symptomatic lymphadenopathy, splenomegaly, anemia with hemoglobin below 100 g / l or thrombocytopenia < 100 × 10(9)/l, caused by lymphoplasmacytic bone marrow infiltration. Frequent indications for initiating treatment include clinical evidence of hyperviscosity or cryoglobulinemia. M-IgM tends to have a character of autoantibody reaching up to 50 %, which may harm the organism, and therefore any proven damage to the organism by an autoimmune activity of M-IgM is also an indication for treatment. The text includes an overview of rare and very rare types of damage to the organism by M-IgM autoimmune activity. A combination of rituximab, cyclophosphamide and dexamethasone (RCD) is recommended for the initial treatment, possibly extended to R-CHOP regimen (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In our cohort of 43 patients the therapy involving a combination of R-CHOP achieved 3 (8.1 %) complete remissions and 31 (83.8 %) partial remissions. The remission in 75 % of the patients lasted more than 3 years. In case of recurrence after > 2 years, the same therapy can be used, in case of a relapse within a shorter period of time different treatment schedules are recommended. High-dose chemotherapy with an autologous transplant of stem cells obtained from peripheral blood is only recommended after the first recurrence for people under 65 years of age without contraindications. The text analyses the benefits of the new drugs for the treatment of Waldenström macroglobulinemia (bendamustine, thalidomide, lenalidomide, ibrutinib and high-dose chemotherapy).

PMID: 26967234 [PubMed - indexed for MEDLINE]

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Pleural myelomatous involvement in multiple myeloma: five cases.

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Pleural myelomatous involvement in multiple myeloma: five cases.

Ann Saudi Med. 2015 Jul-Aug;35(4):327-30

Authors: Ghorbel IB, Feki NB, Lamloum M, Hamzaoui A, Khanfir M, Salem TB, Said F, Romdhane NB, Houman MH

Abstract
Pleural myelomatous involvement in multiple myeloma (MM) is rare, occurring in less than 1% of cases. We retrospectively studied five cases of patients with MM who developed myelomatous pleural effusions. Three men and 2 women with a mean age of 61 years presented with myelomatous pleural effusion. The pleural fluid electrophoresis revealed a peak of IgG in three cases, of IgA in one case, and of lambda light chains in one case, which were identical to that in the sera of the patients. Detection of typical plasma cells in pleural fluid cytology was contributive, and histologic confirmation by pleural biopsy was positive in four cases. Treatment consisted of chemotherapy. The clinical outcome was initially good, but relapses occurred in all cases early and were complicated by fatal infections. Myelomatous pleural effusion is a rare affection. It is usually a late complication associated with poor prognosis.

PMID: 26497716 [PubMed - indexed for MEDLINE]

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Bacterial brain abscess formation in post-irradiated patients: What is the possible pathogenesis?

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Bacterial brain abscess formation in post-irradiated patients: What is the possible pathogenesis?

Clin Neurol Neurosurg. 2015 Sep;136:132-8

Authors: Chuang JM, Lin WC, Fang FM, Huang YJ, Ho JT, Lu CH

Abstract
BACKGROUND: Until recently, post-radiotherapy brain abscess was considered rare, but it has become an increasingly important aetiology. Discussions of the relationship between bacterial brain abscess and radiotherapy (RT) are rare in the literature. Our clinical study was conducted to analyse the role of RT in the pathogenesis of bacterial brain abscess.
METHODS: For our retrospective study, 146 patients with bacterial brain abscess were recruited. Ten patients with a history of RT before brain abscess formation were reviewed.
RESULTS: Eight of these patients underwent RT treatment for nasopharyngeal carcinoma, one for olfactory neuroblastoma, and another for nasal plasmacytoma. Three showed presence of temporal lobe radiation necrosis neighbouring abscess. Eight patients were shown to have the evidence of tumour invasion. Seven had evidence of nasal infection or otitis media. Statistically significant differences between the RT and non-RT patients were observed for radionecrosis, bone defects between the middle fossa/sphenoid sinus, and the presence of nasal infection/otitis media. The mortality rate was 30%.
CONCLUSION: This study shows possible pathogenesis of bacterial brain abscess formation in post-irradiated patients, which is complicated by both radiation effects and tumour effects. Skull base deficits (either from tumour erosion or osteonecrosis) and nasal/ear infection were significantly different in patients who received radiation vs. those who did not. Radiation-related temporal lobe necrosis was also a predisposing factor. Further study based on a proper patient cohort is warranted.

PMID: 26099700 [PubMed - indexed for MEDLINE]

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Extradural transcavernous approach to cavernous sinus cavernous hemangiomas.

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Extradural transcavernous approach to cavernous sinus cavernous hemangiomas.

Clin Neurol Neurosurg. 2015 Sep;136:110-5

Authors: Li MH, Zhao JL, Li YY, Zeng CH, Xu GS, Hong T

Abstract
OBJECTIVE: Cavernous sinus cavernous hemangioma (CSCH) is a rare extra-axial vascular lesion and is difficult to be removed due to their location, propensity for profuse bleeding during surgery, and relationship to complex neurovascular structures. The purpose of this study is to report our experience of the removal of CSCHs through a completely extradural transcavernous approach.
METHODS: Twelve patients with CSCH, who were operated through a purely extradural approach, were retrospectively studied. Clinical symptoms and signs, radiographic characteristics, operative techniques and outcomes of these patients were analyzed.
RESULTS: Headache and visual impairment were the most common clinical symptoms, followed by facial hypesthesia and ptosis. Radiographically, CSCHs have a characteristic pattern. On computed tomography (CT) scans, CSCHs are isodense or minimally hyperdense, with an intense homogenous contrast administration. Magnetic resonance image (MRI) scans revealed well-demarcated and hypo- to isointense lesions on T1-weighted images and characteristically, markedly hyperintense lesions on T2-weighted images. The T2-weighted images showed a marked homogeneous and an intense enhancement after contrast administration. All CSCHs were treated by a completely extradural transcavernous approach. Gross total excision was achieved in all 12 patients. Post-operative complication included transient cranial nerve dysfunction for 2-3 months in eight patients, and three patients developed a permanent VI nerve palsy. The follow-up period ranged from 4 to 117 months (mean 62 months), and no patient had experienced tumor recurrence.
CONCLUSION: CSCHs are rare and challenging skull base tumors. The microsurgical resection, using an extradural transcavernous approach which allows complete tumor resection with an acceptable intraoperative and postoperative complications, should be considered as a favorable choice among all treatments.

PMID: 26093228 [PubMed - indexed for MEDLINE]

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Transfer Effect of Speech-sound Learning on Auditory-motor Processing of Perceived Vocal Pitch Errors.

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Transfer Effect of Speech-sound Learning on Auditory-motor Processing of Perceived Vocal Pitch Errors.

Sci Rep. 2015;5:13134

Authors: Chen Z, Wong FC, Jones JA, Li W, Liu P, Chen X, Liu H

Abstract
Speech perception and production are intimately linked. There is evidence that speech motor learning results in changes to auditory processing of speech. Whether speech motor control benefits from perceptual learning in speech, however, remains unclear. This event-related potential study investigated whether speech-sound learning can modulate the processing of feedback errors during vocal pitch regulation. Mandarin speakers were trained to perceive five Thai lexical tones while learning to associate pictures with spoken words over 5 days. Before and after training, participants produced sustained vowel sounds while they heard their vocal pitch feedback unexpectedly perturbed. As compared to the pre-training session, the magnitude of vocal compensation significantly decreased for the control group, but remained consistent for the trained group at the post-training session. However, the trained group had smaller and faster N1 responses to pitch perturbations and exhibited enhanced P2 responses that correlated significantly with their learning performance. These findings indicate that the cortical processing of vocal pitch regulation can be shaped by learning new speech-sound associations, suggesting that perceptual learning in speech can produce transfer effects to facilitating the neural mechanisms underlying the online monitoring of auditory feedback regarding vocal production.

PMID: 26278337 [PubMed - indexed for MEDLINE]

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Clinical features of delayed endolymphatic hydrops and intralabyrinthine schwannoma : An imaging-confirmed comparative case series. English version.

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Clinical features of delayed endolymphatic hydrops and intralabyrinthine schwannoma : An imaging-confirmed comparative case series. English version.

HNO. 2016 Aug 4;

Authors: Jerin C, Krause E, Ertl-Wagner B, Gürkov R

Abstract
BACKGROUND: The aim of this study was to compare the clinical history and audiovestibular function test results of patients suffering from intralabyrinthine schwannoma or delayed endolymphatic hydrops (DEH).
PATIENTS AND METHODS: Five patients diagnosed with intralabyrinthine schwannoma by magnetic resonance imaging (MRI) and five patients diagnosed with DEH by locally enhanced inner ear MRI (LEIM) were retrospectively studied.
RESULTS: All patients with intralabyrinthine schwannoma or DEH initially presented with hearing loss. Vertigo occurred in two patients with intralabyrinthine schwannoma and in all patients with DEH. While audiometry achieved poorer results for patients with intralabyrinthine schwannomas, vestibular function tests revealed normal results in about half of the patients in both groups.
CONCLUSION: Patients with intralabyrinthine schwannomas may present with clinical symptoms similar to patients suffering from other inner ear disorders such as delayed endolymphatic hydrops and they may obtain similar findings in audiovestibular function tests. High-resolution magnetic resonance imaging with locally applied contrast agent may provide evidence of both underlying pathologies.

PMID: 27492473 [PubMed - as supplied by publisher]

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[Clinical features of delayed endolymphatic hydrops and intralabyrinthine schwannoma : An imaging-confirmed comparative case series. German version].

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[Clinical features of delayed endolymphatic hydrops and intralabyrinthine schwannoma : An imaging-confirmed comparative case series. German version].

HNO. 2016 Aug 4;

Authors: Jerin C, Krause E, Ertl-Wagner B, Gürkov R

Abstract
BACKGROUND: The aim of this study was to compare the clinical history and the findings in audiovestibular function tests in patients suffering from intralabyrinthine schwannoma or delayed endolymphatic hydrops (DEH).
PATIENTS AND METHODS: Five patients diagnosed with intralabyrinthine schwannoma by magnetic resonance imaging (MRI) and five patients diagnosed with DEH by locally enhanced inner ear MRI (LEIM) were retrospectively studied.
RESULTS: All patients with intralabyrinthine schwannoma or DEH initially presented with hearing loss. Vertigo occurred in two patients with intralabyrinthine schwannoma and in all patients with DEH. While audiometry achieved poorer results for patients with intralabyrinthine schwannomas, vestibular function tests revealed normal results in about half of the patients in both groups.
CONCLUSION: Patients with intralabyrinthine schwannomas may present with clinical symptoms similar to patients suffering from other inner ear disorders like delayed endolymphatic hydrops and may obtain similar findings in audiovestibular function tests. High-resolution MR imaging with locally applied contrast agent may provide evidence of both underlying pathologies.

PMID: 27492472 [PubMed - as supplied by publisher]

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Celiac Disease Presenting as Profound Diarrhea and Weight Loss - A Celiac Crisis.

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Celiac Disease Presenting as Profound Diarrhea and Weight Loss - A Celiac Crisis.

Am J Case Rep. 2016;17:559-561

Authors: Bul V, Sleesman B, Boulay B

Abstract
BACKGROUND Celiac disease is a hypersensitivity enteropathy that can have various presentations in adults. Rarely, patients can present with severe lab abnormalities, dehydration and weight loss caused by celiac disease - a celiac crisis. CASE REPORT A 46-year-old male with a past medical history significant for diabetes mellitus, type 2 (DM2) and recently treated Bell's Palsy presented to the emergency room complaining of weakness, diarrhea and lightheadedness. On presentation, the patient had a systolic blood pressure (SBP) of 60 mm Hg and a lactic acidosis with pH of 7.28. Infectious etiologies of diarrhea were ruled out. The patient had an EGD which showed erythema of the duodenal bulb. Serum anti-gliadin and anti-TTG IgA were both elevated suggesting Celiac disease. Biopsies showed histopathology consistent with celiac disease. The patient's diarrhea resolved after initiation of a gluten free diet. He gained 25 kilograms after discharge and did not require further hospitalizations for diarrhea. CONCLUSIONS Celiac crisis is a very rare presentation of celiac disease in adults but nonetheless should be considered in patients with marked metabolic derangements in the setting of osmotic diarrhea. Treatment consists of a gluten free diet and may require management with steroids and total parenteral nutrition (TPN).

PMID: 27492679 [PubMed - as supplied by publisher]

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BRAF and MEK inhibitors in pediatric glioma: new therapeutic strategies, new toxicities.

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BRAF and MEK inhibitors in pediatric glioma: new therapeutic strategies, new toxicities.

Expert Opin Drug Metab Toxicol. 2016 Aug 5;:1-9

Authors: Rizzo D, Ruggiero A, Amato M, Maurizi P, Riccardi R

Abstract
INTRODUCTION: BRAF mutation was initially reported in metastatic melanomas, and more recently in a variety of human cancers. BRAF acts as a down-stream effector of growth factor signaling leading to cell cycle progression, proliferation and survival. Development of selective inhibitors of BRAF has improved the survival of patients with melanoma and offers potential new therapeutic strategy in children with BRAF-mutant glioma.
AREAS COVERED: Mechanisms of resistance to BRAF inhibitors have recently been described as due to the paradoxical activation of the MAPK pathway. Combination therapy with BRAF and MEK inhibition has proved capable of overcoming the resistance with effective results in patients with melanoma. Prospective studies in pediatric glioma are warranted. Combination therapy has a different toxicity profile compared to BRAF inhibitor alone. Herein we review the state-of-the-art of toxicities associated with these agents, with a special focus on children.
EXPERT OPINION: Some toxicities appear more specific to adults, due to a combination of factors, such as patient age and predisposing risk factors. Moreover, it is recommended that the co-administration of BRAF inhibitors and drugs metabolized by the cytochrome P450 system in the liver be avoided, as this can lead to significant complications secondary to pharmacological interactions.

PMID: 27494648 [PubMed - as supplied by publisher]

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The efficacy and safety of teriflunomide based therapy in patients with relapsing multiple sclerosis: A meta-analysis of randomized controlled trials.

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The efficacy and safety of teriflunomide based therapy in patients with relapsing multiple sclerosis: A meta-analysis of randomized controlled trials.

J Clin Neurosci. 2016 Aug 1;

Authors: Xu M, Lu X, Fang J, Zhu X, Wang J

Abstract
The aim of this study was to evaluate the efficacy and safety of teriflunomide in reducing the frequency of relapses and progression of physical disability in patients with relapsing multiple sclerosis (RMS). Literatures were searched in Pubmed, Medline and Embase to screen citations from January 1990 to April 2015. Studies of parallel group design comparing teriflunomide and placebo for RMS were screened. After independent review of 234 citations by two authors, seven studies were identified as meeting the inclusion criteria. The results showed teriflunomide (7 and 14mg) could significantly reduce annualized relapse rate and teriflunomide at the higher dose could also decrease the disability progression (risk ratio (RR)=0.69, 95% confidence interval (CI): 0.55-0.87). And teriflunomide significantly reduce annualized rates of relapses with sequelae-EDSS/FS, relapses leading to hospitalization, and relapses requiring IV corticosteroids. Patients treated with teriflunomide 14mg have a lower annualized rate of relapses with sequelae-investigator (RR=0.37, 95% CI: 0.26-0.52). Teriflunomide 7mg has a higher incidence of diarrhea (RR=1.73, 95% CI: 1.32-2.26) and hair thinning (RR=1.99, 95% CI: 1.4-2.81), while teriflunomide 14mg has a higher incidence of diarrhea (RR=1.71, 95% CI: 1.34-2.18), hair thinning (RR=2.81, 95% CI: 2.02-3.91) and nausea (RR=1.65, 95% CI: 1.03-2.31) compared with placebo. The incidence of elevated alanine aminotransferase levels was also higher with teriflunomide than with placebo. However, the incidence of serious adverse events was similar across groups. In conclusion, teriflunomide significantly reduces annualized relapse rates and disability progression with a similar safety and tolerability profile to placebo.

PMID: 27492048 [PubMed - as supplied by publisher]

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Pituitary dysfunction after aneurysmal subarachnoid hemorrhage in Japanese patients.

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Pituitary dysfunction after aneurysmal subarachnoid hemorrhage in Japanese patients.

J Clin Neurosci. 2016 Aug 1;

Authors: Goto Y, Oshino S, Nishino A, Fujinaka T, Nakamura H, Yuguchi T, Mori S, Yoshimine T, Saitoh Y

Abstract
To elucidate the pituitary function of Japanese patients after aneurysmal subarachnoid hemorrhage (aSAH) and implicative factors related to growth hormone deficiency (GHD) after aSAH. We evaluated basal pituitary hormone levels among 59 consecutive aSAH patients with a modified Rankin Scale (mRS) ⩽4 at 3months after aSAH onset. Patients with low insulin-like growth factor 1 (IGF-1) SD score (SDS) or who seemed to develop pituitary dysfunction underwent provocative endocrine testing during a period of 3-36months after SAH onset. The relationship between IGF-1 SDS and clinical factors of the patients such as severity of SAH, aneurysm location, and treatment modalities, were assessed. Six patients (10.2%) demonstrated their IGF-1 SDS less than -2. Multiple logistic regression analyses revealed that patients who underwent surgical clipping had a significantly lower IGF-1 SDS (<-1SD) than patients who underwent endovascular embolization with an odds ratio of 5.83 (p=0.032). Thirty-three patients took provocative tests and five (15.6%) patients were identified as having GHD. The mean IGF-1 SDS of these five GHD patients was 0.08 SD. The aneurysms in all GHD patients were located in internal carotid artery (ICA) or anterior cerebral artery (ACA). To the best of our knowledge, this is the first report describing the prevalence of GHD in Japanese patients after aSAH, and it was not as high as that of previous European studies. We recommend that screening pituitary dysfunction for aSAH survivors with their aneurysms located in ICA or ACA.

PMID: 27492047 [PubMed - as supplied by publisher]

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Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

Publication date: October 2016
Source:Free Radical Biology and Medicine, Volume 99
Author(s): Zhilei Liu, Yadong Hu, Yiyi Gong, Wenhao Zhang, Chongdong Liu, Qingtao Wang, Haiteng Deng
Isoform 1 of uracil-DNA glycosylase (UNG1) is the major protein for initiating base-excision repair in mitochondria and is in close proximity to the respiratory chain that generates reactive oxygen species (ROS). Effects of ROS on the stability of UNG1 have not been well characterized. In the present study, we found that overexpression of UNG1 enhanced cells' resistance to oxidative stress and protected mitochondrial DNA (mtDNA) from oxidation. Proteomics analysis showed that UNG1 bound to eight proteins in the mitochondria, including PAPSS2, CD70 antigen, and AGR2 under normal growth conditions, whereas UNG1 mainly bound to Peroxiredoxin 3 (PRDX3) via a disulfide linkage under oxidative stress. We further demonstrated that the UNG1-PRDX3 interaction protected UNG1 from ROS-mediated degradation and prevented mtDNA oxidation. Moreover, our results show that ROS-mediated UNG1 degradation was Lon protease 1 (LonP1)-dependent and mitochondrial UNG1 degradation was aggravated by knockdown of PRDX3 expression. Taken together, these results reveal a novel function of UNG1 in the recruitment of PRDX3 to mtDNA under oxidative stress, enabling protection of UNG1 and UNG1-bound DNA from ROS damage and enhancing cell resistance to oxidative stress.

Graphical abstract

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4-Hydroxyhexenal and 4-hydroxynonenal are mediators of the anti-cachectic effect of n-3 and n-6 polyunsaturated fatty acids on human lung cancer cells

Publication date: October 2016
Source:Free Radical Biology and Medicine, Volume 99
Author(s): G. Muzio, M. Ricci, N. Traverso, F. Monacelli, M. Oraldi, M. Maggiora, R.A. Canuto
Cachexia, the most severe paraneoplastic syndrome, occurs in about 80% of patients with advanced cancer; it cannot be reverted by conventional, enteral, or parenteral nutrition. For this reason, nutritional interventions must be based on the use of substances possessing, alongside nutritional and energetic properties, the ability to modulate production of the pro-inflammatory factors responsible for the metabolic changes characterising cancer cachexia. In light of their nutritional and anti-inflammatory properties, polyunsaturated fatty acids (PUFAs), and in particular n-3, have been investigated for treating cachexia; however, the results have been contradictory.Since both n-3 and n-6 PUFAs can affect cell functions in several ways, this research investigated the possibility that the effects of both n-3 and n-6 PUFAs could be mediated by their major aldehydic products of lipid peroxidation, 4-hydroxyhexenal (HHE) and 4-hydroxynonenal (HNE), and by their anti-inflammatory properties. An "in vitro" cancer cachexia model, consisting of human lung cancer cells (A427) and murine myoblasts (C2C12), was used.The results showed that: 1) both n-3 and n-6 PUFAs reduced the growth of lung cancer cells without causing cell death, increased lipid peroxidation and Peroxisome Proliferator-Activated Receptor (PPAR)α, and decreased TNFα; 2) culture medium conditioned by A427 cells grown in the absence of PUFAs blocked myosin production and the differentiation of C2C12 muscle cells; conversely, muscle cells grown in culture medium conditioned by the same cells in the presence of PUFAs showed myosin expression and formed myotubes; 3) adding HHE or HNE directly to C2C12 cells maintained in culture medium conditioned by A427 cells in the absence of PUFAs stimulated myosin production and myotube formation; 4) putative consensus sequences for (PPARs) have been found in genes encoding fast isoforms of myosin heavy chain, by a bioinformatics approach.The overall results show, first, the ability of both n-3 and n-6 PUFAs and their lipid peroxidation products to prevent the blocking of myosin expression and myotube formation caused in C2C12 cells by medium conditioned by human lung tumour cells. The C2C12 cell differentiation can be due to direct effect of lipid peroxidation products, as evidenced by treating C2C12 cells with HHE and HNE, and to the decrease of pro-inflammatory TNFα in A427 cell culture medium. The presence of consensus sequences for PPARs in genes encoding the fast isoforms of myosin heavy chain suggests that the effects of PUFAs, HHE, and HNE are PPAR-mediated.

Graphical abstract

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Quercetin reduces manic-like behavior and brain oxidative stress induced by paradoxical sleep deprivation in mice

Publication date: October 2016
Source:Free Radical Biology and Medicine, Volume 99
Author(s): Luiz K.S. Kanazawa, Débora D. Vecchia, Etiéli M. Wendler, Palloma de A.S. Hocayen, Francislaine A. dos Reis Lívero, Maria Carolina Stipp, Inara M.R. Barcaro, Alexandra Acco, Roberto Andreatini
Quercetin is a known antioxidant and protein kinase C (PKC) inhibitor. Previous studies have shown that mania involves oxidative stress and an increase in PKC activity. We hypothesized that quercetin affects manic symptoms. In the present study, manic-like behavior (hyperlocomotion) and oxidative stress were induced by 24h paradoxical sleep deprivation (PSD) in male Swiss mice. Both 10 and 40mg/kg quercetin prevented PSD-induced hyperlocomotion. Quercetin reversed the PSD-induced decrease in glutathione (GSH) levels in the prefrontal cortex (PFC) and striatum. Quercetin also reversed the PSD-induced increase in lipid peroxidation (LPO) in the PFC, hippocampus, and striatum. Pearson's correlation analysis revealed a negative correlation between locomotor activity and GSH in the PFC in sleep-deprived mice and a positive correlation between locomotor activity and LPO in the PFC and striatum in sleep-deprived mice. These results suggest that quercetin exerts an antimanic-like effect at doses that do not impair spontaneous locomotor activity, and the antioxidant action of quercetin might contribute to its antimanic-like effects.



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Swallowing function and chronic respiratory diseases: Systematic review.

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Swallowing function and chronic respiratory diseases: Systematic review.

Respir Med. 2016 Aug;117:54-64

Authors: Ghannouchi I, Speyer R, Doma K, Cordier R, Verin E

Abstract
BACKGROUND: The precise coordination between breathing and swallowing is an important mechanism to prevent pulmonary aspiration. Factors that alter breathing patterns and ventilation, such as chronic respiratory diseases, may influence that precise coordination of breathing and swallowing.
PURPOSE: The purpose of this systematic literature review is to examine the effects of chronic respiratory diseases on swallowing function.
METHOD: Literature searches were performed using the electronic databases PubMed and Embase. All articles meeting the eligibility criteria up to March 2016 were included.
RESULTS: All articles included studied Chronic Obstructive Pulmonary Diseases (COPD) or Obstructive Sleep Apnea (OSA); no studies involving other respiratory diseases were found. A total of 1069 abstracts were retrieved, of which twenty-six studies met the inclusion criteria; eleven studies dealt with OSA and fifteen studies dealt with COPD.
CONCLUSION: The outcome data indicate that chronic respiratory diseases increase the prevalence of oropharyngeal dysphagia (OD) in patients. However, the relative small number of studies, differences in selection criteria, definitions and assessment techniques used for diagnosing OSA, COPD, and OD point to the need for further research.

PMID: 27492514 [PubMed - in process]

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Comparison of functional change in parotid gland after surgical excision of pleomorphic adenoma by two different types of parotidectomy.

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Comparison of functional change in parotid gland after surgical excision of pleomorphic adenoma by two different types of parotidectomy.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Apr 7;

Authors: Liu H, Pei J, He Y, Lan X, Sun R, Deng T, Xu Y, Zhu G, Wang W, Duan Y, Ma H, Wang S, Fan J, Li C

Abstract
OBJECTIVE: To compare the functional changes in parotid gland after surgical excision of pleomorphic adenoma by partial superficial parotidectomy (PSP), or conventional superficial parotidectomy (CSP).
STUDY DESIGN: A prospective study including 117 patients undergoing CSP or PSP was performed. The uptake rate (UR) and excretion fraction (EF) of the parotid gland were measured by salivary gland scintigraphy before the surgery, as well as at months 3, 6, and 12 after the surgery; ΔUR and ΔEF, defined as the UR and EF differences between the contralateral side and the operated side, were also calculated.
RESULTS: Either UR or EF of the operated side was lower than that in the contralateral side after surgery (P < .05). ΔEF and ΔUR values at months 6 and 12 were significantly smaller in the PSP group than those in the CSP group.
CONCLUSIONS: PSP is preferable for preservation of the functions of the parotid gland.

PMID: 27492567 [PubMed - as supplied by publisher]

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Tooth autotransplantation in the anterior maxilla and mandible: retrospective results in young patients.

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Tooth autotransplantation in the anterior maxilla and mandible: retrospective results in young patients.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Jun 29;

Authors: Gilijamse M, Baart JA, Wolff J, Sándor GK, Forouzanfar T

Abstract
OBJECTIVE: This retrospective study evaluated survival rates, prognosis, and overall success of autotransplanted teeth in young patients missing anterior teeth as a result of trauma, agenesis, or developmental disturbances.
STUDY DESIGN: Retrospective data were collected from the medical records of patients who had undergone tooth autotransplantations to anterior sites between January 2001 and December 2012. Clinical variables, such as gender, age, surgical indications, donor and recipient sites, type of anesthetics, bone augmentation, and complications during follow-up, were assessed.
RESULTS: A total of 59 donor teeth in 46 patients (30 boys and 16 girls; average age 12.15 years) were autotransplanted to the anterior region of the maxilla and mandible. After a mean follow-up period of 17.35 months (range 10-61 months), all of the transplanted teeth remained in situ with no complications.
CONCLUSIONS: This study supports the autotransplantation of teeth to the anterior alveolus as a viable option suitable in growing patients with missing anterior teeth.

PMID: 27492566 [PubMed - as supplied by publisher]

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AAOM Clinical Practice Statement: Oral lichen planus and oral cancer.

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AAOM Clinical Practice Statement: Subject: Oral lichen planus and oral cancer.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Jul 5;

Authors: Greenberg MS

PMID: 27492565 [PubMed - as supplied by publisher]

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Agonistic analogs of growth hormone releasing hormone (GHRH) promote wound healing by stimulating the proliferation and survival of human dermal fibroblasts through ERK and AKT pathways.

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Agonistic analogs of growth hormone releasing hormone (GHRH) promote wound healing by stimulating the proliferation and survival of human dermal fibroblasts through ERK and AKT pathways.

Oncotarget. 2016 Aug 2;

Authors: Cui T, Jimenez JJ, Block NL, Badiavas EV, Rodriguez-Menocal L, Vila Granda A, Cai R, Sha W, Zarandi M, Perez R, Schally AV

Abstract
Decreased or impaired proliferation capability of dermal fibroblasts interferes with successful wound healing. Several growth factors tested failed to fully restore the growth of fibroblasts, possibly due to their rapid degradation by proteases. It is therefore critical to find new agents which have stimulatory effects on fibroblasts while being highly resistant to degradation. In such a scenario, the activities of two agonistic analogs of growth hormone releasing hormone (GHRH), MR-409 and MR-502, were evaluated for their impact on proliferation and survival of primary human dermal fibroblasts. In vitro, both analogs significantly stimulated cell growth by more than 50%. Under serum-depletion induced stress, fibroblasts treated with MR-409 or MR-502 demonstrated better survival rates than control. These effects can be inhibited by either PD98059 or wortmannin. Signaling through MEK/ERK1/2 and PI3K/AKT in an IGF-1 receptor-independent manner is required. In vivo, MR-409 promoted wound closure. Animals treated topically with MR-409 healed earlier than controls in a dose-dependent manner. Histologic examination revealed better wound contraction and less fibrosis in treated groups. In conclusion, MR-409 is a potent mitogenic and anti-apoptotic factor for primary human dermal fibroblasts. Its beneficial effects on wound healing make it a promising agent for future development.

PMID: 27494841 [PubMed - as supplied by publisher]

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Radiotherapy for Colorectal Cancer: Current Standards and Future Perspectives.

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Radiotherapy for Colorectal Cancer: Current Standards and Future Perspectives.

Visc Med. 2016 Jun;32(3):172-7

Authors: Häfner MF, Debus J

Abstract
BACKGROUND: Multimodal treatment approaches are indispensable for patients with advanced-stage colorectal cancer. Radiotherapy has been established as essential part of perioperative concepts and was introduced as an option to face challenges such as local relapse or oligometastases.
METHODS: A literature review was performed to summarize evidence and current standards of radiotherapeutic concepts in the treatment of colorectal cancer.
RESULTS: For stage II/III rectal cancer, neoadjuvant radiotherapy is superior to adjuvant treatment. Two preoperative regimens have been established and are commonly used with different objectives: short-course radiotherapy (SC-RT) and long-course chemoradiotherapy (LC-CRT). Both reduce the risk of local relapse. Additionally, LC-CRT aims at downsizing the tumor to potentially reduce radicalness of surgery. There is increasing evidence that not all stage II/III rectal cancer patients need neoadjuvant irradiation but also that in some cases surgery might be omitted. Stereotactic body radiotherapy (SBRT) of the liver shows high rates of local control in oligometastatic patients. Intraoperative and particle radiotherapy extend the spectrum of treatment options for locally recurrent patients.
CONCLUSION: Radiotherapeutic concepts are crucial for the primary management of locally advanced colorectal cancer and can essentially contribute to treatment approaches in locally recurrent, oligometastatic or palliative patients.

PMID: 27493944 [PubMed]

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Personalized Clinical Trials in Hepatocellular Carcinoma Based on Biomarker Selection.

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Personalized Clinical Trials in Hepatocellular Carcinoma Based on Biomarker Selection.

Liver Cancer. 2016 Jul;5(3):221-32

Authors: Zhang B, Finn RS

Abstract
BACKGROUND: Since the approval of sorafenib there have been numerous failures of new agents in Phase III studies for treatment of advanced hepatocellular carcinoma (HCC). These studies have generally ignored the molecular heterogeneity of HCC and they have not enrolled patients based on predictive markers of response. The development of molecular targeted therapeutics in HCC needs to model the approach that has been taken with great success in other solid tumors, to decrease the likelihood of failure in future studies.
SUMMARY: Here we review the paradigm taken with novel targeted agents in other solid tumors and highlight ongoing studies in HCC that are incorporating biomarkers in clinical development.
KEY MESSAGES: With the appreciation of the molecular diversity of HCC, clinical development of new agents in HCC will need to be targeted towards those patients who are most likely to benefit. This strategy, based on biomarkers for patient selection, is more likely to yield positive results and mitigate the risk of continued negative Phase III studies.

PMID: 27493897 [PubMed]

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Consensus for Radiotherapy in Hepatocellular Carcinoma from The 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014): Current Practice and Future Clinical Trials.

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Consensus for Radiotherapy in Hepatocellular Carcinoma from The 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014): Current Practice and Future Clinical Trials.

Liver Cancer. 2016 Jul;5(3):162-74

Authors: Park HC, Yu JI, Cheng JC, Zeng ZC, Hong JH, Wang ML, Kim MS, Chi KH, Liang PC, Lee RC, Lau WY, Han KH, Chow PK, Seong J

Abstract
A consensus meeting to develop practice guidelines and to recommend future clinical trials for radiation therapy (RT), including external beam RT (EBRT), and selective internal RT (SIRT) in hepatocellular carcinoma (HCC) was held at the 5th annual meeting of the Asia-Pacific Primary Liver Cancer Expert consortium. Although there is no randomized phase III trial evidence, the efficacy and safety of RT in HCC has been shown by prospective and retrospective studies using modern RT techniques. Based on these results, the committee came to a consensus on the utility and efficacy of RT in the management of HCC according to each disease stage as follows: in early and intermediate stage HCC, if standard treatment is not compatible, RT, including EBRT and SIRT can be considered. In locally advanced stage HCC, combined EBRT with transarterial chemoembolization or hepatic arterial infusion chemotherapy, and SIRT can be considered. In terminal stage HCC, EBRT can be considered for palliation of symptoms and reduction of morbidity caused by the primary tumor or its metastases. Despite the currently reported benefits of RT in HCC, the committee agreed that there is a compelling need for large prospective studies, including randomized phase III trial evidence evaluating the role of RT. Specifically studies evaluating the efficacy and safety of sequential combination of EBRT and SIRT are strongly recommended.

PMID: 27493892 [PubMed]

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Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer.

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Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer.

Breast Care (Basel). 2016 Jun;11(3):167-73

Authors: Barroso-Sousa R, Shapiro GI, Tolaney SM

Abstract
Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.

PMID: 27493615 [PubMed]

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Experiences of posttraumatic growth in siblings of children with cancer.

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Experiences of posttraumatic growth in siblings of children with cancer.

Clin Child Psychol Psychiatry. 2016 Aug 4;

Authors: D'Urso A, Mastroyannopoulou K, Kirby A

Abstract
As survival rates continue to improve for children diagnosed with cancer, strides in achieving better psychosocial outcomes for both children with cancer and their families have been accentuated. The current study aimed to explore the experiences of siblings of children diagnosed with cancer and attempted to overcome some of the limitations described in previous research. Primarily, the study considered the theoretical framework of posttraumatic growth (PTG) in the project design and analysis. Semi-structured interviews were completed with six siblings. Thematic analysis was employed to identify themes within the data set as a whole. The data revealed that siblings experienced a range of difficult emotions throughout the cancer trajectory as well as experiencing remarkable changes in their lives. This included both positive and negative changes. These changes included increased empathy and resilience, improved family relationships, disrupted routine, increased responsibility and perceived changes in the ill child. Siblings described factors which they found helpful and unhelpful in adjusting to these changes. The report ends with a discussion of the themes and their clinical and theoretical implications. The report also highlights the research limitations and areas for future investigation.

PMID: 27493233 [PubMed - as supplied by publisher]

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Efficacy of tip cryotherapy in the treatment of Idiopathic guttate hypomelanosis (IGH): a randomized, controlled, evaluator-blinded study.

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Efficacy of tip cryotherapy in the treatment of Idiopathic guttate hypomelanosis (IGH): a randomized, controlled, evaluator-blinded study.

J Dermatolog Treat. 2016 Aug 5;:1-19

Authors: Laosakul K, Juntongjin P

Abstract
BACKGROUND: Idiopathic guttate hypomelanosis (IGH) is a common hypopigmentation affecting a large amount of older population. However, there is no standard treatment. Cryotherapy has been reported as an alternative therapy for years; nevertheless, there is no randomized controlled study to determine its efficacy.
OBJECTIVES: To evaluate the efficacy and side effects of tip cryotherapy in IGH treatment Material and methods: Total 101 lesions were included. 43 lesions were treated with cryotherapy and 58 lesions were assigned as control. A single session of tip cryotherapy was delivered and remained for 5 seconds. Colorimeter was used to measure lesional luminosity at baseline and then monthly until 4 months. Digital photographs were evaluated by two blinded dermatologists. In addition, patients' assessments and side effects were assessed.
RESULTS: Mean luminosity scale gradually decreased from baseline. Also, the score of the treated lesions has been significantly lower than that of the control lesions since week 8 (P = 0.005). At 4 months, dermatologists' assessment revealed that 82.3% of the treated lesions comparing to only 2% of the control showed more than 75% improvement (P < 0.001). Burning sensation was the most common side effect.
CONCLUSION: Tip cryotherapy appears to be an effective therapy with minimal adverse effect for IGH.

PMID: 27494272 [PubMed - as supplied by publisher]

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MiR-146a-5p inhibits cell proliferation and cell cycle progression in NSCLC cell lines by targeting CCND1 and CCND2.

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MiR-146a-5p inhibits cell proliferation and cell cycle progression in NSCLC cell lines by targeting CCND1 and CCND2.

Oncotarget. 2016 Aug 3;

Authors: Li YL, Wang J, Zhang CY, Shen YQ, Wang HM, Ding L, Gu YC, Lou JT, Zhao XT, Ma ZL, Jin YX

Abstract
Previous studies have indicated that miR-146a-5p acts as an oncogene in several types of cancer, yet a tumor suppressor gene in others. In non-small cell lung cancer (NSCLC), one report showed that it was downregulated and played the role of tumor suppressor. However, another study showed that miR-146a-5p was overexpressed in the serum of NSCLC patients compared to healthy controls. Therefore, it is obvious that further study of the function of miR-146a-5p in NSCLC is necessary to fully understand its importance. Herein, we have verified that miR- 146a- 5p acts as a tumor suppressor in NSCLC. Our data revealed that the expression level of miR-146a-5p was significantly decreased in several human NSCLC cell lines, and also less abundant in human NSCLC tissues, when compared with controls. Moreover, we observed that miR-146a-5p could suppress cell proliferation, both in vitro and in vivo. Our results also showed that miR-146a-5p directly targeted the 3'-UTR of CCND1 and CCND2 mRNAs as well as decreased their expression at both mRNA and protein levels, causing cell cycle arrest at the G0/G1 phase. Furthermore, siRNA-mediated downregulation of CCND1 or CCND2 yielded the same effects on proliferation and cell cycle arrest as miR-146a-5p upregulation did in the NSCLC cell lines. We confirmed that the expression of miR-146a-5p had negative relationship with CCND1 or CCND2. Besides, we also found that miR-146a-5p could inhibit tumor growth in xengroft mouse models, and CCND1 and CCND2 were downregulated in miR-146a-5p overexpressed xengroft tumor tissues. In summary, our results demonstrated that miR-146a-5p could suppress the proliferation and cell cycle progression in NSCLC cells by inhibiting the expression of CCND1 and CCND2.

PMID: 27494902 [PubMed - as supplied by publisher]

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Advanced new strategies for metastatic cancer treatment by therapeutic stem cells and oncolytic virotherapy.

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Advanced new strategies for metastatic cancer treatment by therapeutic stem cells and oncolytic virotherapy.

Oncotarget. 2016 Aug 2;

Authors: Park GT, Choi KC

Abstract
The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field.

PMID: 27494901 [PubMed - as supplied by publisher]

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Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis.

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Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis.

Oncotarget. 2016 Aug 2;

Authors: Roth B, Jayaratna I, Sundi D, Cheng T, Melquist J, Choi W, Porten S, Nitti G, Navai N, Wszolek M, Guo C, Czerniak B, McConkey D, Dinney C

Abstract
Epithelial-to-mesenchymal transition (EMT) has been implicated in the progression of bladder cancer. To study its contribution to bladder cancer metastasis, we established new xenograft models derived from human bladder cancer cell lines utilizing an orthotopic "recycling" technique that allowed us to isolate and examine the primary tumor and its corresponding circulating tumor cells (CTC's) and metastatic lesions. Using whole genome mRNA expression profiling, we found that a reversible epithelial-to-mesenchymal transition (EMT) characterized by TGFβ pathway activation and SNAIL expression was associated with the accumulation of CTCs. Finally, we observed that conditional silencing of SNAIL completely blocked CTC production and regional/distant metastasis. Using this unique bladder cancer xenograft model, we conclude that metastasis is dependent on a reversible EMT mediated by SNAIL.

PMID: 27494900 [PubMed - as supplied by publisher]

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miR-513a-5p regulates radiosensitivity of osteosarcoma by targeting human apurinic/apyrimidinic endonuclease.

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miR-513a-5p regulates radiosensitivity of osteosarcoma by targeting human apurinic/apyrimidinic endonuclease.

Oncotarget. 2016 Aug 2;

Authors: Dai N, Qing Y, Cun Y, Zhong Z, Li C, Zhang S, Shan J, Yang X, Dai X, Cheng Y, Xiao H, Xu C, Li M, Wang D

Abstract
Radiotherapy in osteosarcoma patients is problematic due to radioresistance; therefore, understanding the mechanism of radioresistance is integral to providing effective radiotherapeutic regimens for osteosarcoma. We now report the activity of an miRNA, miR-513a-5p, in stimulating radiosensitivity of osteosarcoma cells in vitro and in vivo. MiR-513a-5p expression is decreased in osteosarcoma tissue from patients and cultured osteosarcoma cell lines. However, exogenous re-expression of this miRNA in osteosarcoma cell lines, including HOS, U2OS and 9901, can induce sensitization to ionizing radiation. We also confirm that miR-513a-5p suppresses APE1 expression, and that both the redox and DNA repair activity of APE1 were decreased in miR-513a-5p expressing cell lines. By suppressing APE1, miR-513a-5p induces the DNA damage response which stimulates apoptosis after irradiation. Our report establishes miR-513a-5p as a radiosensitizing miRNA and identifies its activity in the suppression of APE1, which could directly lead to radiosensitization.

PMID: 27494899 [PubMed - as supplied by publisher]

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Distribution of lymph node metastasis from lymphoepithelial-like carcinoma of the parotid.

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Distribution of lymph node metastasis from lymphoepithelial-like carcinoma of the parotid.

Oncotarget. 2016 Aug 2;

Authors: Yin L, Huang X, Liu X, Zhang Y, Wang X

Abstract
PURPOSE: To explore the distribution of node spread from lymphoepithelial-like carcinoma (LELC) of the parotid gland based on the 2013 updated guidelines for neck node levels.
RESULTS: 42 (58.3%) cases had metastatic nodes, all were localized at the ipsilateral neck. The detailed distribution was: level Ia 0, level Ib 6(14.3%), level II 34 (80.1%), level III 16 (38.1%), level IV 9 (21.4%), level V 7 (16.7%), level VI 0, level VII 0, level VIII 37 (88.1%), level IX 0, level Xa 2 (4.8%), and level Xb 0. Lymphadenopathy in level Ib, V and Xa was always accompanied with level II or level VIII nodal metastasis. No statistical significance was found in the incidence of nodal involvement between T1-2 and T3-4 tumors (57.4% versus 61.1%, p = 0.78).
METHODS: We retrospectively reviewed the surgical and imaging documents of 72 cases of LELC from the parotid gland between January 2004 and November 2015. All patients received contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Parotid metastasis from nasopharyngeal cancer (NPC) was excluded. Nodal status and distribution was evaluated by both pathologic reports and imaging studies.
CONCLUSIONS: This is the first description of topography of cervical nodal metastases from LELC of the parotid gland. Incidence of nodal involvement is high. Nodes at ipsilateral level VIII and II were most frequently involved, followed by level III, IV, V and Ib. Nodes in level Ia, VI and level VII were rarely seen.

PMID: 27494898 [PubMed - as supplied by publisher]

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MicroRNA-891b is an independent prognostic factor of pancreatic cancer by targeting Cbl-b to suppress the growth of pancreatic cancer cells.

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MicroRNA-891b is an independent prognostic factor of pancreatic cancer by targeting Cbl-b to suppress the growth of pancreatic cancer cells.

Oncotarget. 2016 Aug 2;

Authors: Dong Q, Li C, Che X, Qu J, Fan Y, Li X, Li Y, Wang Q, Liu Y, Yang X, Qu X

Abstract
Growing evidence has revealed that microRNAs could regulate the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells and predict the prognosis of PDAC. Here the comparative microRNA expression profiles of the good and poor prognosis groups were performed by microRNA microarray. MicroRNA-891b (miR-891b) was screened and validated to be a prognostic predictor of PDAC in the initial group and further evaluated to be an independent predictor for the overall survival of resectable PDACs in an independent cohort. By a series of cellular and animal experiments, as well as clinical specimen analyses, miR-891b was confirmed to target the Cbl-b gene, promot the expression of tumor suppressor p21 protein and inhibit the proliferation of PDAC cells. The results provide a theoretical basis for the study of miR-891b as an independent prognostic predictor of PDAC and the role of miR-891b/Cbl-b pathway in this prediction, as well as the identification of new targets for PDAC.

PMID: 27494897 [PubMed - as supplied by publisher]

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MicroRNA 10b promotes abnormal expression of the protooncogene c-Jun in metastatic breast cancer cells.

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MicroRNA 10b promotes abnormal expression of the protooncogene c-Jun in metastatic breast cancer cells.

Oncotarget. 2016 Aug 2;

Authors: Knirsh R, Ben Dror I, Modai S, Shomron N, Vardimon L

Abstract
MicroRNAs have been shown to act as oncogenes or tumor suppressers via various cellular pathways. Specifically, in breast cancer, upregulation of miR-10b is positively associated with aggressiveness of tumors. However, the mechanism by which miR-10b contributes to cell malignancy is largely unknown. Here we show that at the receiving end of the miR-10b pathway is the proto-oncogene c-Jun, a transcription factor that plays a critical role in stimulation of cell proliferation and tumor progression. c-Jun is known to be translationally activated by loss of cell contacts or restructuring of the cytoskeleton. A comprehensive analysis of miRNA expression exhibited a significant increase in miR-10b expression. This was supported by analysis of breast cancer cells, which showed that loss of E-cadherin in metastatic cells is accompanied by elevation of miR-10b and interestingly, by a marked increase in accumulation of c-Jun. Silencing miR-10b in metastatic breast cancer cells leads to a decline in c-Jun expression, whereas overexpression of miR-10b in HaCaT cells is sufficient to elevate the accumulation of c-Jun. The increase in c-Jun protein accumulation in metastatic cells is not accompanied by an increase in c-Jun mRNA and is not dependent on MAPK activity. Knockdown and overexpression experiments revealed that the increase is mediated by NF1 and RhoC, downstream targets of miR-10b that affect cytoskeletal dynamics through the ROCK pathway. Overall, we show the ability of miR-10b to activate the expression of c-Jun through RhoC and NF1, which represents a novel pathway for promoting migration and invasion of human cancer cells.

PMID: 27494896 [PubMed - as supplied by publisher]

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Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation.

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Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation.

Oncotarget. 2016 Aug 1;

Authors: Gallo C, Dallaglio K, Bassani B, Rossi T, Rossello A, Noonan DM, D'Uva G, Bruno A, Albini A

Abstract
Angiogenesis, a process characterized by the formation of new blood vessels from pre-existing ones, is a crucial step in tumor growth and dissemination. Recently, increased attention has been addressed to the ability of flavonoids to prevent cancer by suppressing angiogenesis, strategy that we named "angioprevention". Several natural compounds exert their anti-tumor properties by activating 5' adenosine monophosphate-activated protein kinase (AMPK), a key regulator of metabolism in cancer cells. Drugs with angiopreventive activities, in particular metformin, regulate AMPK in endothelial cells. Here we investigated the involvement of AMPK in the anti-angiogenic effects of xanthohumol (XN), the major prenylated flavonoid of the hop plant, and mechanisms of action. The anti-angiogenic activity of XN was more potent than epigallocatechin-3-gallate (EGCG). Treatment of endothelial cells with XN led to increased AMPK phosphorylation and activity. Functional studies using biochemical approaches confirmed that AMPK mediates XN anti-angiogenic activity. AMPK activation by XN was mediated by CAMMKβ, but not LKB1. Analysis of the downstream mechanisms showed that XN-induced AMPK activation reduced nitric oxide (NO) levels in endothelial cells by decreasing eNOS phosphorylation. Finally, AKT pathway was inactivated by XN as part of its anti-angiogenic activity, but independently from AMPK, suggesting that these two signaling pathways proceed autonomously. Our study dissects the molecular mechanism by which XN exerts its potent anti-angiogenic activity, pointing out AMPK as a crucial signal transducer.

PMID: 27494895 [PubMed - as supplied by publisher]

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Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes.

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Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes.

Oncotarget. 2016 Aug 1;

Authors: Tseng YY, Su CH, Yang ST, Huang YC, Lee WH, Wang YC, Liu SC, Liu SJ

Abstract
Glioblastoma multiforme (GBM), the most prevalent and malignant form of a primary brain tumour, is resistant to chemotherapy. In this study, we concurrently loaded three chemotherapeutic agents [bis-chloroethylnitrosourea, irinotecan, and cisplatin; BIC] into 50:50 poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibres and an antiangiogenic agent (combretastatin) into 75:25 PLGA nanofibres [BIC and combretastatin (BICC)/PLGA]. The BICC/PLGA nanofibrous membranes were surgically implanted onto the brain surfaces of healthy rats for conducting pharmacodynamic studies and onto C6 glioma-bearing rats for estimating the therapeutic efficacy.The chemotherapeutic agents were rapidly released from the 50:50 PLGA nanofibres after implantation, followed by the release of combretastatin (approximately 2 weeks later) from the 75:25 PLGA nanofibres. All drug concentrations remained higher in brain tissues than in the blood for more than 8 weeks. The experimental results, including attenuated malignancy, retarded tumour growth, and prolonged survival in tumour-bearing rats, demonstrated the efficacy of the BICC/PLGA nanofibrous membranes. Furthermore, the efficacy of BIC/PLGA and BICC/PLGA nanofibrous membranes was compared. The BICC/PLGA nanofibrous membranes more efficiently retarded the tumour growth and attenuated the malignancy of C6 glioma-bearing rats. Moreover, the addition of combretastatin did not significantly change the drug release behaviour of the BIC/PLGA nanofibrous membranes. The present advanced and novel interstitial chemotherapy and targeted treatment provide a potential strategy and regimen for treating GBM.

PMID: 27494894 [PubMed - as supplied by publisher]

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Blood concentration of cyclosporine during early post-transplant period may have influence on the occurrence of chronic graft versus host disease in patients who received allogeneic hematopoietic stem cell transplantation.

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Blood concentration of cyclosporine during early post-transplant period may have influence on the occurrence of chronic graft versus host disease in patients who received allogeneic hematopoietic stem cell transplantation.

Oncotarget. 2016 Aug 1;

Authors: Park S, Kim K, Jang JH, Kim SJ, Kim WS, Jung CW

Abstract
INTRODUCTION: It has rarely been studied that how the blood level of CsA affect the incidence of chronic GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
METHODS: A total of 183 patients who underwent allo-HSCT from an HLA-matched or haplo matched family donors between 2006 and 2014 were reviewed.
RESULTS: The average monthly CsA blood concentration (CsAavr ,ng/ml) was calculated in each patient: 0-1, 1-2, and 2-3 months after allo-HSCT. CsAavr at the first month showed significant association with the occurrence of moderate to severe cGVHD in multivariate analysis adjusted for gender, age, total body irradiation, anti-thymocyte globulin, acute GVHD ≥ grade 2 and CsAavr levels of other periods. The risk of cGVHD development was lowest in patients with CsAavr of 200-250 ng/ml when compared to those with CsAavr of ≥ 250 or < 200 ng/ml (p=0.003).
CONCLUSIONS: CsA level between 200 and 250 mg/ml during the first month after transplantation was significantly associated with the decreased risk of moderate to severe cGVHD.

PMID: 27494893 [PubMed - as supplied by publisher]

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Sirtuin1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions.

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Sirtuin1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions.

Oncotarget. 2016 Aug 2;

Authors: Pinho AV, Mawson A, Gill A, Arshi M, Warmerdam M, Giry-Laterriere M, Eling N, Lie T, Kuster E, Camargo S, Biankin AV, Wu J, Rooman I

Abstract
Metabolic reprogramming is a feature of neoplasia and tumor growth. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators such as p53. SIRT1 regulates metaplasia in the pancreas. Nevertheless, it is unclear if SIRT1 affects the development of neoplastic lesions and whether metabolic gene expression is altered.To assess neoplastic lesion development, mice with a pancreas-specific loss of Sirt1 (Pdx1-Cre;Sirt1-lox) were bred into a KrasG12D mutant background (KC) that predisposes to the development of pancreatic intra-epithelial neoplasia (PanIN) and ductal adenocarcinoma (PDAC). Similar grade PanIN lesions developed in KC and KC;Sirt1-lox mice but specifically early mucinous PanINs occupied 40% less area in the KC;Sirt1-lox line, attributed to reduced proliferation. This was accompanied by reduced expression of proteins in the glycolysis pathway, such as GLUT1 and GAPDH.The stimulatory effect of SIRT1 on proliferation and glycolysis gene expression was confirmed in a human PDAC cell line. In resected PDAC samples, higher proliferation and expression of glycolysis genes correlated with poor patient survival. SIRT1 expression per se was not prognostic but low expression of Cell Cycle and Apoptosis Regulator 2 (CCAR2), a reported SIRT1 inhibitor, corresponded to poor patient survival.These findings open perspectives for novel targeted therapies in pancreatic cancer.

PMID: 27494892 [PubMed - as supplied by publisher]

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Analysis of the chemotherapeutic effects of a propadiene compound on malignant ovarian cancer cells.

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Analysis of the chemotherapeutic effects of a propadiene compound on malignant ovarian cancer cells.

Oncotarget. 2016 Aug 2;

Authors: Li S, Yang L, Wang J, Liang F, Chang B, Gu H, Wang H, Yang G, Chen Y

Abstract
Epithelial ovarian cancer is most lethal in female reproductive carcinomas owing to the high chemoresistance and metastasis, so more efficient therapeutic agents are terribly needed. A propadiene compound: 1-phenylpropadienyl phosphine oxide (PHPO), was employed to test the chemotherapeutic efficacy against ovarian cancer cell lines. MTT assay showed that PHPO displayed a much lower IC50 than cisplatin and paclitaxel, while combination treatment of cells with PHPO + cisplatin induced more apoptosis than with PHPO + paclitaxel or with cisplatin + paclitaxel (p < 0.05). Animal assays demonstrated that subcutaneous tumor growth was highly inhibited by PHPO + cisplatin, compared with that inhibited by PHPO or by cisplatin treatment alone, indicating PHPO and cisplatin may have synergistic effects against ovarian cancer growth. We also found that PHPO induced few side effects on animals, compared with cisplatin. Mechanistic studies suggested that treatment of cells with PHPO or with PHPO + cisplatin differentially inhibited the PI3K/Akt, MAPK and ATM/Chk2 pathways, which consequently suppressed the anti-apoptotic factors Bcl-xL, Bcl-2 and XIAP, but activated the pro-apoptotic factors Bad, Bax, p53, caspase 9, caspase 8, caspase 7 and PARP. Taken together, PHPO may induce cell apoptosis through multiple signal pathways, especially when used along with cisplatin. Therefore, PHPO may be explored as a prospective agent to effectively treat ovarian cancer.

PMID: 27494891 [PubMed - as supplied by publisher]

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Decreased TCL6 expression is associated with poor prognosis in patients with clear cell renal cell carcinoma.

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Decreased TCL6 expression is associated with poor prognosis in patients with clear cell renal cell carcinoma.

Oncotarget. 2016 Aug 2;

Authors: Su H, Sun T, Wang H, Shi G, Zhang H, Sun F, Ye D

Abstract
One-third of clear cell renal cell carcinoma (ccRCC) patients present with metastasis at the time of diagnosis. The prognosis of these patients is poor. To identify potential prognostic biomarkers and therapeutic targets for ccRCC, we re-evaluated published long non-coding RNA (lncRNA) expression profiling data from the Gene Expression Omnibus and ArrayExpress database. We found that five lncRNAs were differentially expressed in ccRCC and adjacent tissues. These lncRNAs were assessed in an independent cohort of 71 paired patient samples using real-time PCR. Differences in expression of three of the lncRNAs (ENSG00000177133, TCL6, and ENSG00000244020) were validated in this analysis. Kaplan-Meier analysis indicated that low expression of ENSG00000177133 and TCL6 was associated with a poor prognosis. Univariate and multivariate regression analyses demonstrated that TCL6 but not ENSG00000177133 expression was an independent predictor of ccRCC aggressiveness and had hazard ratios predictive of clinical outcome. TCL6 expression was negatively correlated with pTNM stage. Overexpression of TCL6 in 786-O and Caki-1 ccRCC cells decreased proliferation and increased apoptosis compared to controls. Our results indicate that lncRNA expression is altered in ccRCC and that decreased TCL6 expression may be an independent adverse prognostic factor in ccRCC patients.

PMID: 27494890 [PubMed - as supplied by publisher]

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Stathmin overexpression is associated with growth, invasion and metastasis of lung adenocarcinoma.

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Stathmin overexpression is associated with growth, invasion and metastasis of lung adenocarcinoma.

Oncotarget. 2016 Aug 2;

Authors: Yurong L, Biaoxue R, Wei L, Zongjuan M, Hongyang S, Ping F, Wenlong G, Shuanying Y, Zongfang L

Abstract
Stathmin has been investigated as a tumor biomarker because it appear to be associated with tumorigenesis; however, the effect of stathmin in lung adenocarcinoma (LAC) remains poorly understood. The purpose of this study was to examine the expression of stathmin in lung adenocarcinoma, and to disclose the relationship between them. The expression of stathmin was examined by RT-PCR, IHC and Western blot. Furthermore, small interfering RNA (shRNA)-mediated silencing of stathmin was employed in LAC cells to investigate cell proliferation, invasion and apoptosis. In this study, we showed that overexpression of stathmin was significantly associated with poorly differentiated, lymph node metastasis and advance TNM stages of lung adenocarcinoma. And silencing of stathmin expression inhibited the proliferation, migration and invasion of lung adenocarcinoma PC-9 cells, and retarded the growth of PC-9 cells xenografts in nude mice. Additionally, the anticarcinogenic efficacy of stathmin silencing might be involved in P38 and MMP2 signaling pathways. In conclusion, these results showed that stathmin expression was significantly up-regulated in LAC, which may act as a biomarker for LAC. Furthermore, silence of stathmin inhibiting LAC cell growth indicated that stathmin may be a promising molecular target for LAC therapy.

PMID: 27494889 [PubMed - as supplied by publisher]

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The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition.

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The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition.

Oncotarget. 2016 Aug 2;

Authors: Ivanova H, Ritane A, Wagner L, Luyten T, Shapovalov G, Welkenhuyzen K, Seitaj B, Monaco G, De Smedt H, Prevarskaya N, Yule DI, Parys JB, Bultynck G

Abstract
The anti-apoptotic Bcl-2 protein is emerging as an efficient inhibitor of IP3R function, contributing to its oncogenic properties. Yet, the underlying molecular mechanisms remain not fully understood. Using mutations or pharmacological inhibition to antagonize Bcl-2's hydrophobic cleft, we excluded this functional domain as responsible for Bcl-2-mediated IP3Rs inhibition. In contrast, the deletion of the C-terminus, containing the trans-membrane domain, which is only present in Bcl-2α, but not in Bcl-2β, led to impaired inhibition of IP3R-mediated Ca2+ release and staurosporine-induced apoptosis. Strikingly, the trans-membrane domain was sufficient for IP3R binding and inhibition. We therefore propose a novel model, in which the Bcl-2's C-terminus serves as a functional anchor, which beyond mere ER-membrane targeting, underlies efficient IP3R inhibition by (i) positioning the BH4 domain in the close proximity of its binding site on IP3R, thus facilitating their interaction; (ii) inhibiting IP3R-channel openings through a direct interaction with the C-terminal region of the channel downstream of the channel-pore. Finally, since the hydrophobic cleft of Bcl-2 was not involved in IP3R suppression, our findings indicate that ABT-199 does not interfere with IP3R regulation by Bcl-2 and its mechanism of action as a cell-death therapeutic in cancer cells likely does not involve Ca2+ signaling.

PMID: 27494888 [PubMed - as supplied by publisher]

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Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia.

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Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia.

Oncotarget. 2016 Aug 1;

Authors: Alameen AA, Simioni C, Martelli AM, Zauli G, Ultimo S, McCubrey JA, Gonelli A, Marisi G, Ulivi P, Capitani S, Neri LM

Abstract
An attractive molecular target for novel anti-cancer therapies is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway which is commonly deregulated in many types of cancer. Nevertheless, the effects of PI3K/Akt/mTOR inhibitors on T lymphocytes, a key component of immune responses, have been seldom explored. In this study we investigated the effects on human CD4+ T-cells of a panel of PI3K/Akt/mTOR inhibitors: BGT226, Torin-2, MK-2206, and ZSTK474. We also assessed their efficacy against two acute leukemia T cell lines. T lymphocytes were stimulated with phytohemagglutinin. Inhibitor effects on cell cycle and apoptosis were analyzed by flow cytometry, while cytotoxicity was assessed by MTT assays. In addition, the activation status of the pathway as well as induction of autophagy were analyzed by Western blotting.Quiescent healthy T lymphocytes were unaffected by the drugs whereas mitogen-stimulated lymphocytes as well as leukemic cell lines displayed a cell cycle block, caspase-dependent apoptosis, and dephosphorylation of key components of the signaling pathway. Autophagy was also induced in proliferating lymphocytes and in JURKAT and MOLT-4 cell lines. When autophagy was inhibited by 3-methyladenine or Bafilomycin A1, drug cytotoxicity was increased, indicating that autophagy is a protective mechanism.Therefore, our findings suggest that PI3K/Akt/mTOR inhibitors preserve lymphocyte viability. This is a valuable result to be taken into account when selecting drugs for targeted cancer therapy in order to minimize detrimental effects on immune function.

PMID: 27494886 [PubMed - as supplied by publisher]

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Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism.

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Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism.

Oncotarget. 2016 Aug 1;

Authors: La SH, Kim SJ, Kang HG, Lee HW, Chun KH

Abstract
The human Telomerase Reverse Transcriptase (hTERT) gene encodes a rate-limiting catalytic subunit of telomerase that maintains genomic integrity. Suppression of hTERT expression could induce cellular senescence and is considered a potent approach for gastric cancer therapy. However, control of hTERT expression and function remains poorly understood in gastric cancer. In this study, we demonstrated that high expression levels of hTERT in malignant tissues are correlated with poor survival probability in gastric cancer patients. Knockdown of hTERT expression retarded cell proliferation and cellular senescence, which was confirmed by increased protein expression levels of p21cip1 and p27kip1, and decreased phosphorylation of Rb. In contrast, overexpression of hTERT increased cell proliferation and decreased cellular senescence. Remarkably, the down-regulation of hTERT expression was detected in lgals3-/- mouse embryo fibroblasts (MEFs). Knockdown of galectin-3 decreased the expression of hTERT in gastric cancer cells. Galectin-3 ablation-induced cellular senescence was rescued by concomitant overexpression of hTERT. hTERT ablation-induced cellular senescence and p21cip1 and p27kip1 expression was rescued by concomitant overexpression of galectin-3. The size of tumor burdens was increased in hTERT-overexpressed gastric cancer cells xenografted mice, whereas it was repressed by concomitant depletion of galectin-3. Additionally, we determined that the N-terminal domain of galectin-3 directly interacted with hTERT. The telomeric activity of hTERT was also decreased by galectin-3 ablation. Taken together, ablation of hTERT induces cellular senescence and inhibits the growth of gastric cancer cells, suggesting that it could be a potent target in gastric cancer therapy. We also propose that galectin-3 is an important regulator of hTERT expression and telomeric activity in gastric tumorigenesis.

PMID: 27494887 [PubMed - as supplied by publisher]

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Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma.

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Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma.

Oncotarget. 2016 Aug 1;

Authors: Gaudio E, Tarantelli C, Ponzoni M, Odore E, Rezai K, Bernasconi E, Cascione L, Rinaldi A, Stathis A, Riveiro E, Cvitkovic E, Zucca E, Bertoni F

Abstract
The bromodomain inhibitor OTX015 (MK-8628) has shown anti-lymphoma activity as a single agent in both the preclinical and clinical settings, as well as in vitro synergism with several anticancer agents. Here, we report in vivo data for OTX015 in combination with the histone deacetylase inhibitor vorinostat, the Bruton's tyrosine kinase inhibitor ibrutinib, the anti-CD20 monoclonal antibody rituximab, and the mTOR inhibitor everolimus in a diffuse large B cell lymphoma model. The antitumor effect of OTX015-containing combinations in SU-DHL-2 xenografts in mice was much stronger than the activity of the corresponding single agents with almost complete tumor eradication for all four combinations. Pharmacokinetic analyses showed similar OTX015 levels in plasma and tumor samples of approximately 1.5 μM, which is equivalent to the concentration showing strong in vitro activity. For all four combinations, mean terminal levels of the bromodomain inhibitor differed from those in mice exposed to single agent OTX015, indicating a need for thorough pharmacokinetic investigations in phase I combination studies. In conclusion, our results provide a strong rationale to explore OTX015-containing combinations in the clinical lymphoma setting.

PMID: 27494885 [PubMed - as supplied by publisher]

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A seven-gene signature predicts overall survival of patients with colorectal cancer.

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A seven-gene signature predicts overall survival of patients with colorectal cancer.

Oncotarget. 2016 Aug 1;

Authors: Chen H, Sun X, Ge W, Qian Y, Bai R, Zheng S

Abstract
Colorectal cancer (CRC) is a major cause of global cancer mortality. Gene expression profiles can help predict prognosis of patients with CRC. In most of previous studies, disease recurrence was analyzed as the survival endpoint. Thus we aim to build a robust gene signature for prediction of overall survival (OS) in patients with CRC. Fresh frozen CRC tissues from 64 patients were analyzed using Affymetrix HG-U133plus 2.0 gene arrays. By performing univariate survival analysis, 6487 genes were found to be associated with the OS in our cohort. KEGG analysis revealed that these genes were mainly involved in pathways such as endocytosis, axon guidance, spliceosome, Wnt signalling and ubiquitin mediated proteolysis. A seven-gene signature was further selected by a robust likelihood-based survival modelling approach. The prognostic model of seven-gene signature (NHLRC3, ZDHHC21, PRR14L, CCBL1, PTPRB, PNPO, and PPIP5K2) was constructed and weighted by regression coefficient, which divided patients into high- and low-risk groups. The OS for patients in high-risk group was significantly poorer compared with patients in low-risk group. Moreover, all seven genes were found to be differentially expressed in CRC tissues as compared with adjacent normal tissues, indicating their potential role in CRC initiation and progression. This seven-gene signature was further validated as an independent prognostic marker for OS prediction in patients with CRC in other two independent cohorts. In short, we developed a robust seven-gene signature that can predict the OS for CRC patients, providing new insights into identification of CRC patients with high risk of mortality.

PMID: 27494884 [PubMed - as supplied by publisher]

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