Incremental improvement in osteosarcoma chemotherapy?

Osteosarcoma is one of the first solid cancers for which a survival benefit from adjuvant chemotherapy was established [1, 2]. After decades of clinical research to improve on results obtained in the 1980s, the long-standing chemotherapy regimen of doxorubicin and cisplatin with or without methotrexate remains a standard treatment of osteosarcoma, resulting in a 5-year survival rate of more than 60% in patients with localized disease [3, 4]. In patients with metastatic osteosarcoma at diagnosis, or with distant disease relapse after treatment of localized disease, the long-term survival rate is <20%, and new therapies are much needed for this group of patients [5]. Neither the intensification of chemotherapy by adding ifosfamide and etoposide nor the use of muramyl tripeptide or traztuzumab has improved the survival of patients with metastatic osteosarcoma [6–8]. However, cure can be achieved in patients with metastatic osteosarcoma who undergo metastasectomy [5, 9].

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Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer

Abstract

Background

Incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing. There is interest in identifying healthy individuals most at risk for development of oropharyngeal cancer to inform screening strategies.

Patients and methods

All data are from 2009 to 2014, including 13 089 people ages 20–69 in the National Health and Nutrition Examination Survey (NHANES), oropharyngeal cancer cases from the Surveillance, Epidemiology, and End Results (SEER 18) registries (representing ∼28% of the US population), and oropharyngeal cancer mortality from National Center for Health Statistics (NCHS). Primary study outcomes are (i) prevalence of oncogenic HPV DNA in an oral rinse and gargle sample, and (ii) incident oropharyngeal squamous cell cancer.

Results

Oncogenic oral HPV DNA is detected in 3.5% of all adults age 20–69 years; however, the lifetime risk of oropharyngeal cancer is low (37 per 10 000). Among men 50–59 years old, 8.1% have an oncogenic oral HPV infection, 2.1% have an oral HPV16 infection, yet only 0.7% will 'ever' develop oropharyngeal cancer in their lifetime. Oncogenic oral HPV prevalence was higher in men than women, and increased with number of lifetime oral sexual partners and tobacco use. Men who currently smoked and had ≥5 lifetime oral sexual partners had 'elevated risk' (prevalence = 14.9%). Men with only one of these risk factors (i.e. either smoked and had 2–4 partners or did not smoke and had ≥5 partners) had 'medium risk' (7.3%). Regardless of what other risk factors participants had, oncogenic oral HPV prevalence was 'low' among those with only ≤1 lifetime oral sexual partner (women = 0.7% and men = 1.7%).

Conclusions

Screening based upon oncogenic oral HPV detection would be challenging. Most groups have low oncogenic oral HPV prevalence. In addition to the large numbers of individuals who would need to be screened to identify prevalent oncogenic oral HPV, the lifetime risk of developing oropharyngeal caner among those with infection remains low.

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Emerging treatment paradigms for brain metastasis in non-small-cell lung cancer: an overview of the current landscape and challenges ahead

Abstract

Advances in the last decade in genomic profiling and the identification of druggable targets amenable to biological agents have transformed the management and survival of a subgroup of patients with brain metastasis in non-small-cell lung cancer. In parallel, clinicians have reevaluated the role of whole brain radiotherapy in selected patients with brain metastases to reduce neurocognitive toxicity. Continual progress in this understudied field is required: optimization of the sequence of schedules for therapies in patients with brain metastases of differing genomic profiles, focusing on new strategies to overcome mechanisms of biological resistance and increasing drug penetrability into the central nervous system. This review summarizes the field to date and possible treatment strategies based on current evidence.

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Refractory or relapsed aggressive B-cell lymphoma failing (R)-CHOP: an analysis of patients treated on the RICOVER-60 trial

Abstract

Background

The prognosis of elderly patients with aggressive B-non-Hodgkin's lymphoma after first lymphoma-related treatment failure (TF-L) is not well described.

Methods

We analysed patient characteristics including the presence of MYC rearrangements and MYC-expression immunohistochemistry (IHC) at diagnosis and modalities of salvage therapy and their impact on the prognosis of patients between 61 and 80 years who had been treated on the RICOVER-60 trial.

Results

TF-L occurred in 301 of the 1222 (24.6%) patients; 297 patients could be analysed. Prognosis was extremely poor in patients with primary progressive disease or early relapse (≤12 months) with median survivals of 3.3 and 6.4 months. Survival after TF-L was significantly lower in patients pretreated with R-CHOP compared with CHOP (23.0% versus 36.4% at 2 years, P = 0.016). In patients with MYC translocation at diagnosis Rituximab reduced the risk of TF-L from 58.8% to 26.3%. Survival after TF-L was significant longer for patients after CHOP without MYC translocations (31.8% versus 0% at 2 years, P < 0.001) or negative MYC-IHC (41.0% versus 16.8% at 2 years, P = 0.017) but not after R-CHOP. 224 patients (75.4%) received salvage therapy. Rituximab was part of salvage therapy in 57.4% and improved 2-year survival rate from 20.7% to 46.8% (P < 0.001). The benefit of R was significant after first-line CHOP [2-year overall survival (OS) 49.6% versus 19.1%, P < 0.001] as well as after R-CHOP (2-year OS 33.1% and 22.5%, P = 0.034). For patients pretreated with R-CHOP long-term survival was below 15% regardless of the treatment chosen.

Conclusion

MYC rearrangement and IHC are adverse prognostic factors after TF-L for CHOP treated patients, rituximab as part of first-line therapy reduced the effects of MYC-break. Rituximab improves results of any type of salvage therapy; however, survival after progression/relapse of aggressive B-cell lymphoma in elderly patients pretreated with (R)-CHOP is poor regardless of treatment chosen.

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DPYD genotype-guided fluoropyrimidines dose: is it ready for prime time?

For over 50 years, fluoropyrimidines have been the cornerstone of anticancer drugs for various types of solid cancers. Treatment with these drugs—5-fluorouracil (FU) and its oral prodrugs, capecitabine and tegafur—is generally well-tolerated, except in a small proportion of patients who develop severe and life-threatening early toxicity. This toxicity is mainly associated with a deficiency of the primary fluoropyrimidine detoxifying enzyme, dihydropryrimidine dehydrogenase (DPD) [1]. The drug labels of FU and capecitabine state DPD deficiency as a contraindication, but they give no warning for the 3%–8% of the population who are partially DPD deficient.

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SELECT-2: a phase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer

Abstract

Background

Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC.

Patients and methods

Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m² (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m² (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations.

Results

A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified.

Conclusion

The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported.

Trial identifier

Clinicaltrials.gov NCT01750281.

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Gougerot-Sjogren-like syndrome under PD-1 inhibitor treatment

A 36-year-old female patient with no significant medical history except hypothyroidism was diagnosed with left parotid acinic cell carcinoma that was treated by radical parotidectomy followed by adjuvant radiotherapy (50 Gy) in 2004. Seven years after the initial diagnosis, the patient developed histologically confirmed metastases on the left adrenal gland and the lung, for which systemic therapy was indicated. The patient participated in two successive studies and received lapatinib and then an EZH-2 inhibitor. In March 2016, the patient's adrenal lesion progressed, and she started treatment with pembrolizumab, 200 mg, every 3 weeks. At the time of the 11th injection, the patient experienced a retinal detachment that was linked to her myopia. The detachment was treated by surgery and amoxicillin for 7 days. Subsequently, the patient developed an oral candidiasis that was treated with systemic fungizone. At the time of the 13th injection, in December 2016, the patient experienced a debilitating grade 2 dry-eye syndrome that was associated with grade 1 conjunctival hyperemia, grade 2 xerostomia, and grade 1 skin rash on both hands. Therefore, serum protein electrophoresis (SPEP) and determination of antinuclear antibodies (ANA) [particularly Sjogren's syndrome A/Sjogren's syndrome B (SSA/SSB)] were carried out. A salivary gland biopsy could not be conducted because of the patient's radiation history. The SPEP and the ANA were normal. Concomitantly, the CT-scan showed a stable disease using the RECIST criteria v1.1.

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Molecular Tumor Boards: current practice and future needs

Abstract

Background

Due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as whole-exome and whole-genome sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date.

Methods

Based on literature review, a survey among hospitals in The Netherlands, and our own experience with the establishment of a nationally operating MTB, this article evaluates current knowledge and unmet needs and lays out a strategy for successful MTB implementation.

Results

Having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, <50% of hospitals and only 5% of nonacademic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools, and workflow. This may not only lead to variation in quality of care but also hinders data sharing and thus creation of an effective learning community.

Conclusions

This article acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning but also improve general interpretation and application of genomics-guided cancer care.

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Clinical and molecular characterization of patients with cancer of unknown primary in the modern era

Abstract

Background

On the basis of historical data, patients with cancer of unknown primary (CUP) are generally assumed to have a dismal prognosis with overall survival of less than 1 year. Treatment is typically cytotoxic chemotherapy guided by histologic features and the pattern of metastatic spread. The purpose of this study was to provide a clinical and pathologic description of patients with CUP in the modern era, to define the frequency of clinically actionable molecular alterations in this population, to determine how molecular testing can alter therapeutic decisions, and to investigate novel uses of next-generation sequencing in the evaluation and treatment of patients with CUP.

Patients and methods

Under Institutional Review Board approval, we identified all CUP patients evaluated at our institution over a recent 2-year period. We documented demographic information, clinical outcomes, pathologic evaluations, next-generation sequencing of available tumor tissue, use of targeted therapies, and clinical trial enrollment.

Results

We identified 333 patients with a diagnosis of CUP evaluated at our institution from 1 January 2014 through 30 June 2016. Of these patients, 150 had targeted next-generation sequencing carried out on available tissue. Median overall survival in this cohort was 13 months. Forty-five of 150 (30%) patients had potentially targetable genomic alterations identified by tumor molecular profiling, and 15 of 150 (10%) received targeted therapies. Dominant mutation signatures were identified in 21 of 150 (14%), largely implicating exogenous mutagen exposures such as ultraviolet radiation and tobacco.

Conclusions

Patients with CUP represent a heterogeneous population, harboring a variety of potentially targetable alterations. Next-generation sequencing may provide an opportunity for CUP patients to benefit from novel personalized therapies.

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Clinical benefit of systemic treatment in patients with advanced pancreatic and gastrointestinal neuroendocrine tumours according to ESMO-MCBS and ASCO framework

Abstract

Background

Assessment of clinical benefit of systemic treatments of rare diseases including gastroenteropancreatic neuroendocrine tumours (GEP-NET) is challenging. Recently several tools have been developed to grade the clinical benefit of cancer drugs. The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). The American Society of Clinical Oncology (ASCO) has developed and revised the ASCO framework consisting of the Net Health Benefit (NHB) score juxtaposed against the costs of the treatment. In this review, we graded systemic treatments for GEP-NET patients with both frameworks.

Methods

The electronic databases (PubMed and EMBASE) were searched for papers reporting comparative trials, conducted in adult GEP-NET patients in the English language. Papers were assessed according to the ESMO-MCBS and the NHB part of the ASCO revised Framework (NHB-ASCO-F) by four independent assessors, and discrepancies were discussed.

Results

The search yielded 32 trials of which 6 were eligible for grading with the ESMO-MCBS resulting in scores of 2 or 3. Eight trials were eligible for grading with the NHB-ASCO-F, resulting in scores between 37.6 and 57.4. Trials that were not primary assessable by the tools were analysed separately. Consensus between assessors was reached in 68% of trials with the ESMO-MCBS and in 23% of trials with the NHB-ASCO-F.

Conclusion

The currently used systemic treatments for GEP-NET patients had low scores according to the NHB-ASCO-F and none could be graded as meaningful clinical beneficial according to the ESMO-MCBS. Despite the low incidence, the heterogeneous patient population and relatively long natural course of NET, future studies on new treatment modalities should aim for high clinical benefit outcomes.

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Gemcitabine plus sirolimus for relapsed and progressing osteosarcoma patients after standard chemotherapy: a multicenter, single-arm phase II trial of Spanish Group for Research on Sarcoma (GEIS)

Abstract

Background

Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients.

Patients and methods

A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome.

Results

Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3–4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival.

Conclusion

Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.

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LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors

Abstract

Background

Novel immune checkpoint blockade strategies are being evaluated in clinical trials and include targeting the lymphocyte activation gene 3 (LAG-3) checkpoint, alone or in combination with PD-1/PD-L1 blockade. We investigated LAG-3 expression and its prognostic value in a large series of breast cancer patients, and correlated LAG-3 expression with key biomarkers including PD-1 and PD-L1.

Experimental design

LAG-3 expression was evaluated by immunohistochemistry on two tissue microarray series incorporating 4322 breast cancer primary excision specimens (N = 330 in the training and N= 3992 in the validation set) linked to detailed clinicopathologic, biomarker and long-term clinical outcome data. PD-1 and PD-L1 expressions were also evaluated by immunohistochemistry. Stromal or intra-epithelial tumor infiltrating lymphocytes (sTILs or iTILs) expressing LAG-3 or PD-1 were assessed by absolute count. PD-L1 expression was evaluated as the percentage of positive carcinoma cells per core. Kaplan–Meier curves and Cox proportional hazard models were used for survival analyses.

Results

After locking down interpretation cut-offs on the training set, LAG-3+ iTILs were found in 11% of cases in the validation set. In both sets, LAG-3+ iTILs were significantly associated with negative prognostic factors: young age, large tumor size, high proliferation, HER2E and basal-like breast cancer subtypes. In multivariate analyses, breast cancer patients with LAG-3+ iTILs had a significantly improved breast cancer-specific survival [hazard ratio (HR): 0.71, 95% CI 0.56–0.90], particularly among estrogen receptor-negative patients (HR: 0.50, 95% CI 0.36–0.69). Furthermore, we found that 53% of PD-L1+ and 61% of PD-1+ cases were also positive for LAG-3+ iTILs. Concurrent infiltration of LAG-3+ and CD8+ iTILs was significantly associated with increased breast cancer-specific survival (HR: 0.49, 95% CI 0.32–0.74).

Conclusion

LAG-3+ iTILs are enriched in estrogen receptor-negative breast cancers and represent an independent favorable prognostic factor. In addition, a high proportion of PD-1/PD-L1+ tumors are co-infiltrated with LAG-3+ TILs, supporting potential immune checkpoint blockade combination strategies as a treatment option for breast cancer patients.

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The antibody–drug conjugate target landscape across a broad range of tumour types

Abstract

Background

Antibody–drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Because ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours.

Materials and methods

PubMed and ClinicalTrials.gov were searched for ADCs that are or were evaluated in clinical trials. Gene expression profiles of 18 055 patient-derived tumour samples representing 60 tumour (sub)types and 3520 healthy tissue samples were collected from the public domain. Next, we applied Functional Genomic mRNA-profiling to predict per tumour type the overexpression rate at the protein level of ADC targets with healthy tissue samples as a reference.

Results

We identified 87 ADCs directed against 59 unique targets. A predicted overexpression rate of ≥ 10% of samples for multiple ADC targets was observed for high-incidence tumour types like breast cancer (n = 31 with n = 23 in triple negative breast cancer), colorectal cancer (n = 18), lung adenocarcinoma (n = 18), squamous cell lung cancer (n = 16) and prostate cancer (n = 5). In rare tumour types we observed, amongst others, a predicted overexpression rate of 55% of samples for CD22 and 55% for ENPP3 in adrenocortical carcinomas, 81% for CD74 and 81% for FGFR3 in osteosarcomas, and 95% for c-MET in uveal melanomas.

Conclusion

This study provides a data-driven prioritization of clinically available ADCs directed against 59 unique targets across 60 tumour (sub)types. This comprehensive ADC target landscape can guide clinicians and drug developers which ADC is of potential interest for further evaluation in which tumour (sub)type.

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Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case–control study

Abstract

Background

Refining the selection of metastatic colorectal cancer patients candidates for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signalling pathways, have been suggested by preclinical and retrospective studies.

Patients and methods

We conducted this multicentre, prospective, case–control study to demonstrate the negative predictive impact of a panel of rare genomic alterations [PRESSING (PRimary rESiStance IN RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-eGfr monoclonal antibodies) panel], including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions and PIK3CA mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with two-sided α and β errors of 0.05 and 0.20, 47 patients per group were needed.

Results

Forty-seven patients per group were included. PRESSING panel alterations were significantly more frequent in resistant (24 out of 47, 51.1%) than in sensitive (1 out of 47, 2.1%) patients (P < 0.001) and in right- (12 out of 29, 41.4%) than left-sided (13 out of 65, 20.0%) tumours (P = 0.03). The predictive accuracy of PRESSING panel and sidedness was 75.3% and 70.2%, respectively. Among hyper-selected patients, right-sidedness was still associated with resistance (P = 0.002). The predictive accuracy of the combined evaluation of PRESSING panel and sidedness was 80.4%. As a secondary analysis, 8 (17.0%) resistant and 0 sensitive patients showed microsatellite instability (P < 0.001).

Conclusion

The investigated panel of genomic alterations allows refining the selection of RAS and BRAF wild-type metastatic colorectal cancer patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary tumour sidedness.

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Response to ‘Survival advantage for etoposide/cisplatin over paclitaxel/carboplatin concurrent chemoradiation in patients with inoperable stage III NSCLC: a subgroup analysis for ECOG 2 patients would be of great interest’

We thank Farkhad Manapov and Chukwuka Eze [1] for their interest in our phase III trial of etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small-cell lung cancer [2]. We have addressed here, and hope to clarify, a few points that they raised in their letter.

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Trastuzumab use in patients with durable complete response in HER2-amplified metastatic breast cancer: to continue or not to continue

Exceptional response to trastuzumab, a monoclonal antibody against human epidermal growth factor receptor-2 (HER2/ERBB2), as manifested by prolonged absence of radiographic evidence of disease (durable complete response, DCR) is uncommon.

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Role of adjuvant chemotherapy in early-stage endometrioid and clear-cell ovarian cancer

With more than 200 000 new cases annually worldwide [1], ovarian cancer represents the sixth most common cancer among women and the most lethal gynecologic malignancy.

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Epigenetics in Clinical Management of Children and Adolescents with Brain Tumors

Central nervous system (CNS) tumors represent the second most prevalent group of cancers in children and adolescents, yet account for the majority of childhood cancer-related deaths and considerable morbidity among survivors, due to high-intensity non-selective standard therapies delivered to immature nervous system structures undergoing development. These tumors arise at different ages –not infrequently very early in life-, in different locations and cellular contexts, have varied cell types of origin, and have heterogeneous responses to the "classic" current therapeutic approaches. Demographic, radiologic and morphological characterization have several limitations, putting into the "classic boxes" heterogeneous tumors that are diverse in their genetic and epigenetic background and that will likely behave biologically different. Given that, epigenetic disruption (i.e. DNA methylation, histone modification and chromatin remodeling) is a common feature identified more and more frequently in pediatric cancer, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore tumor biology, evolution and treatment of these tumors. An integrated approach that incorporates traditional features complemented with genetic and epigenenetic specific markers offers tremendous promise to "risk-group" stratification and better prognostication. Also, it will help unveil the key driver pathways for tumor formation and for the discovery of targeted therapy for neoplasms that appear in the developing brain, facilitating early identification of therapy responders and track accurately disease progression. In this paper, we reviewed the most representative pediatric brain tumors where epigenetic alterations have been identified as initiating or driving events in tumor development, maintenance or progression.

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Preface

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Meet Our Editorial Board Member

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Editorial: Cancer Epigenetics

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Epigenetic Regulation of EMT in Non-Small Cell Lung Cancer

Lung cancer remains the most diagnosed cancer in the world, with a high mortality rate and fewer therapeutic options. The most common lung cancer is non-small cell, consisting of adenocarcinoma, squamous cell carcinoma and large cell lung carcinoma. As per all solid tumours, the changes that occur for the initiation and metastasis of lung cancer can be described using the EMT (epithelial mesenchymal transition). Cells progressing through EMT lose their epithelial cell characteristics, expressing more mesenchymal markers and are phenotypically different. The transition can be controlled by changes in various pathways, such as TGF-β, PI3K, MAPK, Hedgehog and Wnt. The changes in those pathways can be controlled epigenetically, via DNA methylation, histone modifications or changes in small/non-coding RNA. We will describe the epigenetic changes that occur in these pathways and how we can consider novel methods to generate a synthetic lethality target in an epigenetically regulated pathway in EMT.

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Multimodal HDAC Inhibitors with Improved Anticancer Activity

Histone deacetylases (HDACs) play a significant role in the proliferation and dissemination of cancer and represent promising epigenetic drug targets. The HDAC inhibitor vorinostat featuring a zinc-binding hydroxamate fragment was already clinically approved. However, HDAC inhibitors containing hydroxamic acids are often hampered by acquired or intrinsic drug resistance and may lead to enhanced tumor aggressiveness. In order to overcome these drawbacks of hydroxamate HDAC inhibitors, a series of multimodal derivatives of this compound class, including such with different zinc-binding groups, was recently developed and showed promising anticancer activity. This review provides an overview of the chemistry and pleiotropic anticancer modes of action of these conceptually new HDAC inhibitors.

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Lung Cancer Stem Cells: An Epigenetic Perspective

Lung cancer remains the major cause of human mortality among all the cancer types despite the colossal amount of efforts to prevent the cancer onset and to provide the appropriate cure. Recent reports have identified that important contributors of lung cancer-related mortality are the drug resistance and aggressive tumor relapse, the characteristics contributed by the presence of lung cancer stem cells (CSCs). The identification of lung CSCs is inherently complex due to the quiescent nature of lung epithelium, which makes the distinction between the normal lung epithelium and lung CSCs difficult. Recently, multiple researches have helped in the identification of lung CSCs based on the presence or absence of certain specific types of stem cell markers. Maintenance of lung CSCs is chiefly mediated through the epigenetic modifications of their genome. In this review, we will discuss about the origin of lung CSCs and the role of epigenetic modifications in their maintenance. We will also discuss in brief the major lung CSC markers and the therapeutic approaches to selectively target this population of cells.

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Outlook on Epigenetic Therapeutic Approaches for Treatment of Gastric Cancer

The incidence of gastric cancer has been declining globally in the last decades. Despite the improvements in the diagnostic procedures, most cases are still detected at advanced stages due to lack of specific symptoms associated with early phases of tumour development. Consequently, gastric cancer poses a major health burden worldwide due to high mortality rates. Continuing advances in high-throughput technologies are revealing an intricate network of genetic and epigenetic changes associated with carcinogenesis. In addition, several risk factors, both environmental and genetic, have been recognized, which promote accumulation of diverse alterations affecting the expression of oncogenes, tumour suppressor genes, DNA repair genes, and other genes, implicated in normal gastric cell functions. A plethora of aberrant molecular events found in patients with this disease and intragenic heterogeneity of tumours from individuals are delaying the development of targeted biological therapies. Frequent occurrence of characteristic CpG island methylator phenotypes (CIMP phenotypes) in gastric cancers, particularly in association with Helicobacter pylori or EBV infection, could lead to introduction of epigenetic modulators into standard treatment regimens used against early and advanced forms of adenocarcinomas. This review highlights aberrant DNA methylation events in the development of gastric tumours and addresses the different aspects associated with the application of therapeutic epigenetic modulation in the management of the disease.

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Transforming Cancer Epigenetics Using Nutritive Approaches and Noncoding RNAs

Cancer is considered one of the leading causes of death in the United States. Although preventive strategies, early detection, and improved treatment options have been developed, novel targets and therapeutics are still needed. Since concluding that cancer is mediated by genetic and epigenetic alterations of the cell, many research groups are now focusing on other means of prevention and therapy via nutrition, epigenetic mechanisms, and non-coding RNAs which have been shown to control gene expression and have many different functions at the cellular level. With the advent of high-throughput sequencing in human cancer, the potential to identify novel biomarkers and therapeutic targets of disease has increased tremendously and led to the identification of many non-coding RNAs that are dysregulated in various cancers. Gene expression and regulation is important in maintaining the homeostasis of normal tissues and cells. Not uncommonly, up- or down-regulation of particular genes are associated with cancer as a result of increased or decreased expression of transcriptional targets. This review focuses on the role of nutrition in cancer and the dysregulation of non-coding RNAs with particular emphasis on long non-coding RNAs and microRNAs in different cancer types.

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Mechanisms for the Inhibition of Colon Cancer Cells by Sulforaphane through Epigenetic Modulation of MicroRNA-21 and Human Telomerase Reverse Transcriptase (hTERT) Down-regulation

Background: Epigenetic modulations such as histone modifications are becoming increasingly valued for their ability to modify genes without altering the DNA sequence. Many bioactive compounds have been shown to alter genetic and epigenetic profiles in various cancers. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables such as kale, cabbage and broccoli sprouts, is one of the most potent histone deacetylase inhibitors (HDACis) to date. Recently, it has been identified that HDACis may play a vital role in regulating microRNAs (miRs) and human telomerase reverse transcriptase (hTERT).

Objective: The aim of our study was to identify if aberrant HDAC, hTERT and miR levels could be regulated through novel dietary-based approaches in colorectal cancer (CRC) cells.

Methods: We evaluated the in vitro epigenetic effects of SFN on CRC cells by MTT assay, cellular density assay, real-time reverse transcriptase-polymerase chain reaction (RT-PCR), cell cycle analysis, western-blot assay, HDAC activity assay and teloTAGGG telomerase PCR Elisa assay.

Results: We demonstrated the inhibitory effects of physiologically relevant concentrations of SFN in both HCT116 and RKO CRC cells, and showed for the first time that SFN treatment decreased cell density, significantly inhibited cell viability and induced apoptosis in CRC cells. We also found that practical doses of SFN significantly down-regulated oncogenic miR-21, HDAC and hTERT mRNA, protein and enzymatic levels in CRC cells.

Conclusion: Our studies suggest that the regulation of HDAC, hTERT and miR-21 is a promising approach for delaying and/or preventing CRC and may be accomplished via the consumption of SFN in cruciferous vegetables.

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Erratum

http://ift.tt/2yQGX3H

Issue Information

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An in vivo 11C-PK PET study of microglia activation in Fatal Familial Insomnia

Abstract

Objective

Postmortem studies reported significant microglia activation in association with neuronal apoptosis in Fatal Familial Insomnia (FFI), indicating a specific glial response, but negative evidence also exists. An in vivo study of local immune responses over FFI natural course may contribute to the understanding of the underlying pathogenesis.

Methods

We included eight presymptomatic subjects (mean ± SD age:44.13 ± 3.83 years) carrying the pathogenic D178N-129^met FFI mutation, one symptomatic patient (male, 45 yrs. old), and nine healthy controls (HC) (mean ± SD age: 44.00 ± 11.10 years.) for comparisons. ¹¹C-(R)-PK11195 PET allowed the measurement of Translocator Protein (TSPO) overexpression, indexing microglia activation. A clustering algorithm was adopted to define subject-specific reference regions. Voxel-wise statistical analyses were performed on ¹¹C-(R)-PK11195 binding potential (BP) images both at the group and individual level.

Results

The D178N-129^met/val FFI patient showed significant ¹¹C-(R)-PK11195 BP increases in the midbrain, cerebellum, anterior thalamus, anterior cingulate cortex, orbitofrontal cortex, and anterior insula, bilaterally. Similar TSPO increases, but limited to limbic structures, were observed in four out of eight presymptomatic carriers. The only carrier with the codon 129^met/val polymorphism was the only one showing an additional TSPO increase in the anterior thalamus.

Interpretation

In comparison to nonprion neurodegenerative diseases, the observed lack of a diffuse brain TSPO overexpression in preclinical and the clinical FFI cases suggests the presence of a different microglia response. The involvement of limbic structures might indicate a role for microglia activation in these key pathologic regions, known to show the most significant neuronal loss and functional deafferentation in FFI.

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PI3K in cancer: its structure, activation modes and role in shaping tumor microenvironment

Future Oncology, Ahead of Print.


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Can we predict the response to therapy in soft tissue sarcoma?

Future Oncology, Ahead of Print.


http://ift.tt/2A4W87D

Therapy sequencing strategies in multiple myeloma: who, what and why?

Future Oncology, Ahead of Print.


http://ift.tt/2AIVQob

Osteoblast-like cells in human cancers: new cell type and reliable markers for bone metastasis

Future Oncology, Ahead of Print.


http://ift.tt/2A5Eh0k

Nonprogression with avelumab treatment associated with gains in quality of life in metastatic Merkel cell carcinoma

Future Oncology, Ahead of Print.


http://ift.tt/2AGoczq

NFS1 Expression Protects Lung Tumor Cells from Ferroptosis [Research Watch]

NFS1 activity is essential for maintenance of iron–sulfur cluster biosynthesis in response to oxidative stress.

http://ift.tt/2yQHFON

Mutant IDH1R132H Induces Transcriptional and Epigenomic Reprogramming [Research Watch]

A fraction of the chromatin state and DNA methylation changes induced by IDH1^R132H are irreversible.

http://ift.tt/2y9wSeO

Osteoblasts Promote Release of Tumor-Promoting SiglecFhi Neutrophils [Research Watch]

Lung tumors activate OCN⁺ osteoblasts in distant bone stroma to supply tumor-infiltrating neutrophils.

http://ift.tt/2yQCGxo

Loss of DNA Repair Drives Neoantigen Renewal and Inhibits Tumor Growth [Research Watch]

DNA mismatch repair in tumors promotes enhanced immune surveillance.

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MYC Induces Immune Suppression to Promote Lung Tumorigenesis [Research Watch]

MYC promotes angiogenesis, inflammation, and immune suppression to accelerate KRAS^G12D tumor growth.

http://ift.tt/2yQxppt

Effect of abutment height on interproximal implant bone level in the early healing: A randomized clinical trial

Abstract

Objective

The aim of this randomized clinical trial was to compare the effect on the interproximal implant bone loss (IBL) of two different heights (1 and 3 mm) of definitive abutments placed at bone level implants with a platform switched design.

Material and methods

Twenty-two patients received forty-four implants (6.5–10 mm length and 3.5–4 mm diameter) to replace at least two adjacent missing teeth, one bridge set to each patient—two implants per bridge. Patients were randomly allocated, and two different abutment heights, 1 and 3 mm using only one abutment height per bridge, were used. Clinical and radiological measurements were performed at 3 and 6 months after surgery. Interproximal bone level changes were compared between treatment groups. The association between IBL and categorical variables (history of periodontitis, smoking, implant location, implant diameter, implant length, insertion torque, width of keratinized mucosa, bone density, gingival biotype and antagonist) was also performed.

Results

At 3 months, implants with a 1-mm abutment had significantly greater IBL (0.83 ± 0.19 mm) compared to implants with a 3-mm abutment (0.14 ± 0.08 mm). At 6 months, a greater IBL was observed at implants with 1-mm abutments compared to implants with 3-mm abutments (0.91 ± 0.19 vs. 0.11 ± 0.09 mm). The analysis of the relation between patient characteristics and clinical variables with IBL revealed no significant differences at any moment except for smoking.

Conclusions

Abutment height is an important factor to maintain interproximal implant bone level in early healing. Short abutments led to a greater interproximal bone loss in comparison with long abutments after 6 months. Other variables except smoking showed no relation with interproximal bone loss in early healing.

http://ift.tt/2AoJ29u

Novel in vitro cancer models for optimizing anti-EGFR therapies

Pre-clinical models, that are able to recapitulate the biology and pathology of the original individual cancer, are needed to better investigate mechanisms of response and resistance to anticancer therapies. In this respect, novel in vitro models for metastatic colorectal cancer could be of high value.

http://ift.tt/2nKVSZO

Dual Inhibition of PIK3C3 and FGFR as a New Therapeutic Approach to Treat Bladder Cancer

Purpose: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms. Experimental Design: Autophagy flux, morphology and intracellular organelles were evaluated by western blotting, transmission electron microscope and fluorescence microscope. Molecular docking, surface plasmon resonance assay were performed to identify drug-protein interaction. Lentiviral delivery of cDNA or shRNA, and CRISPR/Cas9-mediated genome editing were used to modulate gene expression. Mitochondrial oxygen consumption rate was measured by a Seahorse XFe24 extracellular flux analyzer, and ROS level was measured by flow cytometry. Results: MPT0L145 persistently increased incomplete autophagy and phase-lucent vacuoles at the peri-nuclear region, which were identified as enlarged and alkalinized late-endosomes. Screening of a panel of lipid kinases revealed that MPT0L145 strongly inhibits PIK3C3 with a KD value of 0.53 nmol/L. Ectopic expression of PIK3C3 reversed MPT0L145-increased cell death and incomplete autophagy. Four residues (Y670, F684, I760, D761) at the ATP-binding site of PIK3C3 are important for the binding of MPT0L145. Additionally, MPT0L145 promotes mitochondrial dysfunction, ROS production and DNA damage, which may in part, contribute to cell death. ATG5-knockout rescued MPT0L145-induced cell death, suggesting simultaneous induction of autophagy is crucial to its anticancer activity. Lastly, our data demonstrated that MPT0L145 is able to overcome cisplatin resistance in bladder cancer cells. Conclusions: MPT0L145 is a first-in-class PIK3C3/FGFR inhibitor, providing an innovative strategy to design new compounds that increase autophagy, but simultaneously perturb its process to promote bladder cancer cell death.

http://ift.tt/2AoVdTS

NKG2D-based CAR-T cells and radiotherapy exert synergistic efficacy in glioblastoma

Chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapy against several malignancies including glioblastoma, the most common and most aggressive malignant primary brain tumor in adults. The challenges in solid tumor immunotherapy comprise heterogenously expressed tumor target antigens and restricted trafficking of CAR T cells to and impaired long-term persistence at the tumor site, as well as the unaddressed integration of CAR T cell therapy into conventional anti-cancer treatments. We addressed these questions using a NKG2D-based chimeric antigen receptor construct (chNKG2D) in fully immunocompetent orthotopic glioblastoma mouse models. ChNKG2D T cells demonstrated high IFN-γ production and cytolytic activity in vitro. Upon systemic administration in vivo, chNKG2D T cells migrated to the tumor site in the brain, did not induce adverse events, prolonged survival, and cured a fraction of glioma-bearing mice. Surviving mice were protected long-term against tumor re-challenge. Mechanistically, this was not solely the result of a classical immune memory response, but rather involved local persistence of chNKG2D T cells. A subtherapeutic dose of local radiotherapy in combination with chNKG2D T cell treatment resulted in synergistic activity in 2 independent syngeneic mouse glioma models by promoting migration of CAR T cells to the tumor site and increased effector functions. We thus provide preclinical proof-of-concept of NKG2D CAR T cell activity in mouse glioma models and demonstrate efficacy, long-term persistence, and synergistic activity in combination with radiotherapy, providing a rationale to translate this immunotherapeutic strategy to human glioma patients.

http://ift.tt/2kbtD1o

Elevated levels of the antimicrobial peptide LL-37 in hidradenitis suppurativa are associated with a Th1/Th17 immune response

Summary

Hidradenitis suppurativa (HS) is an inflammatory skin disease with poorly understood immunopathogenic mechanisms. LL-37 is an antimicrobial peptide, which is transcribed from the CAMP (cathelicidin antimicrobial peptide) gene. Previous reports showed upregulated levels of CAMP and LL-37 in HS lesions and therefore the aim of this study was to compare levels of LL-37 in HS to other inflammatory skin diseases and to establish immunomodulatory functions of LL-37 in HS. We confirm an upregulation of the LL-37 peptide in lesional HS skin with comparable levels as in psoriasis patients and are able to positively correlate the presence of LL-37 in HS with the presence of T cells, macrophages, neutrophils, IFNγ, IL-17, IL-23, TNFα, IL-32 and IL-1β. Mechanistically, LL-37 boosts the proliferation of unspecifically activated CD4⁺ T cells via an increased calcium signalling independent of antigen presenting cells. Targeting LL-37 may therefore represent a new therapeutic option for the treatment of this recalcitrant disease, but it has to be kept in mind that LL-37 also has an antimicrobial function.

This article is protected by copyright. All rights reserved.

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Synthesis of Novel Norsufentanil Analogues via a Four-component Ugi Reaction and in Vivo, Docking, and QSAR Studies of their Analgesic Activity

Abstract

Novel substituted amino acid tethered norsufentanil derivatives were synthesized by the four-component Ugi reaction. Norsufentanil was reacted with succinic anhydride to produce the corresponding carboxylic acid. The resulting carboxylic acid has undergone a multicomponent reaction with different aldehydes, amines, and isocyanides to produce a library of the desired compounds. In all cases, amide bond rotation was observed in the NMR spectra. In vivo analgesic activity of the synthesized compounds was evaluated by a tail flick test. Very encouraging results were obtained for a number of the synthesized products. Some of the synthesized compounds such as 5a, 5b, 5h, 5j and 5r were found to be more potent than sufentanil, sufentanil citrate, and norsufentanil. Binding modes between the compounds and mu and delta opioid receptors were studied by molecular docking method. The relationship between the molecular structural features and the analgesic activity was investigated by a quantitative structure-activity relationship (QSAR) model. The results of the molecular modeling studies and the in vivo analgesic activity suggested that the majority of the synthesized compounds were more potent than sufentanil, and norsufentanil.

This article is protected by copyright. All rights reserved.

In this study eighteen novel bivalent opioid ligands were prepared by a multicomponent reaction. The in vivo evaluation of the synthesized compounds showed that many of them were most potent than sufentanil as a commercial analgesic drug. The experimental data were supported by the QSAR and docking studies.

http://ift.tt/2nLq8UA

Is Low-Dose Ketamine an Effective Alternative to Opioids for the Treatment of Acute Pain in the Emergency Department?

The search identified 1,396 articles, of which 44 were deemed eligible for full-text review. Of these, a total of 8 articles (n=609 patients) were included in the final qualitative analysis. The review included 6 randomized controlled trials and 2 observational studies. Five studies were conducted in the United States, with the remainder conducted in France, India, and Iran. Most of the randomized controlled trials used low-dose ketamine, with doses ranging from 0.1 to 0.5 mg/kg given intravenously; however, one study followed the initial intravenous dose with a subcutaneous infusion at 0.1 mg/kg per hour.

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Risk of complications in coeliac patients depends on age at diagnosis and type of clinical presentation

Coeliac disease is characterised by an increased mortality mostly due to its complications.

http://ift.tt/2jw6300

Gastric Emptying Time, Esophageal pH-Impedance Parameters, Quality of Life, and Gastrointestinal Comorbidity in Obese Children and Adolescents

To provide further evidence regarding the relationship between obesity and gastroesophageal reflux disease (GERD) in children, through the use of 13C-octanoic acid breath test for gastric emptying time (GET) assessment and esophageal multichannel intraluminal impedance pH-testing (MII-pH).

http://ift.tt/2iJ3B5o

Efficacy of Human Botulism Immune Globulin for the Treatment of Infant Botulism: The First 12 Years Post Licensure

To report the efficacy of Human Botulism Immune Globulin Intravenous (BIG-IV) in the first 12 years following its licensure in 2003 and to characterize its use nationwide in treating patients with infant botulism.

http://ift.tt/2kDz4dj

More Clinical Mimics of Infant Botulism

To ascertain the actual diagnoses of 76 patients (2005-2015) whose clinical presentations so closely resembled infant botulism that the patients were treated with Human Botulism Immune Globulin Intravenous (BIG-IV; BabyBIG), but whose illnesses subsequently were not laboratory confirmed as infant botulism ("clinical mimics" of infant botulism).

http://ift.tt/2iGqiag

Long-Term Patient-Reported Outcomes in Older Breast Cancer Survivors: A Population-Based Survey Study

For older women with breast cancer, local therapy options may include lumpectomy plus whole breast irradiation (Lump+WBI), lumpectomy plus brachytherapy (Lump+Brachy), lumpectomy alone (Lump alone), mastectomy without radiation (Mast alone), and mastectomy plus radiation (Mast+RT). We surveyed a population-based cohort of older breast cancer survivors to assess the association of local therapy with long-term quality of life (QOL) outcomes.

http://ift.tt/2iGARdn

Earlier initiation of community-based palliative care is associated with fewer unplanned hospitalisations and emergency department presentations in the final months of life: a population-based study amongst cancer decedents

While community-based palliative care (CPC) is associated with decreased acute care use in the lead up to death, it is unclear how the timing of CPC initiation affects this association.

http://ift.tt/2AoqGFC

Doctors’ Attitudes to Palliation and Palliative Care in Patients with Advanced Chronic Obstructive Pulmonary Disease

Patients with severe Chronic obstructive pulmonary disease (COPD) may experience distressing symptoms and reduced quality of life, therefore many international COPD guidelines recommend palliative care and advance care planning (ACP) together with disease-directed care [1, 2]. However, COPD patients rarely discuss ACP and infrequently access any specialist palliative care, with doctors' attitudes and poor communication reported as barriers [3-6]. Junior doctors working in tertiary medical care commonly manage, under consultant supervision, COPD patients who are approaching the end of life, and it is therefore essential they understand the importance of ACP and palliative care for these patients.

http://ift.tt/2nJU7fp

Effect of sleep on overnight CSF amyloid-β kinetics

Abstract

Sleep disturbances are associated with future risk of Alzheimer's disease. Disrupted sleep increases soluble amyloid-β, suggesting a mechanism for sleep disturbances to increase Alzheimer's disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with ¹³C₆-leucine to measure amyloid-β kinetics. We found that sleep deprivation increased overnight amyloid-β-38, amyloid-β-40, and amyloid-β-42 levels by 25-30% via increased overnight amyloid-β production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer's disease risk via increased amyloid-β production. This article is protected by copyright. All rights reserved.

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Tai Chi and Qigong for cancer-related symptoms and quality of life: a systematic review and meta-analysis

Abstract

Purpose

This study aims to summarize and critically evaluate the effects of Tai Chi and Qigong (TCQ) mind–body exercises on symptoms and quality of life (QOL) in cancer survivors.

Methods

A systematic search in four electronic databases targeted randomized and non-randomized clinical studies evaluating TCQ for fatigue, sleep difficulty, depression, pain, and QOL in cancer patients, published through August 2016. Meta-analysis was used to estimate effect sizes (ES, Hedges' g) and publication bias for randomized controlled trials (RCTs). Methodological bias in RCTs was assessed.

Results

Our search identified 22 studies, including 15 RCTs that evaluated 1283 participants in total, 75% women. RCTs evaluated breast (n = 7), prostate (n = 2), lymphoma (n = 1), lung (n = 1), or combined (n = 4) cancers. RCT comparison groups included active intervention (n = 7), usual care (n = 5), or both (n = 3). Duration of TCQ training ranged from 3 to 12 weeks. Methodological bias was low in 12 studies and high in 3 studies. TCQ was associated with significant improvement in fatigue (ES = − 0.53, p < 0.001), sleep difficulty (ES = − 0.49, p = 0.018), depression (ES = − 0.27, p = 0.001), and overall QOL (ES = 0.33, p = 0.004); a statistically non-significant trend was observed for pain (ES = − 0.38, p = 0.136). Random effects models were used for meta-analysis based on Q test and I ² criteria. Funnel plots suggest some degree of publication bias. Findings in non-randomized studies largely paralleled meta-analysis results.

Conclusions

Larger and methodologically sound trials with longer follow-up periods and appropriate comparison groups are needed before definitive conclusions can be drawn, and cancer- and symptom-specific recommendations can be made.

Implications for Cancer Survivors

TCQ shows promise in addressing cancer-related symptoms and QOL in cancer survivors.

http://ift.tt/2BWPxNU

Healthcare system barriers to long-term follow-up for adult survivors of childhood cancer in British Columbia, Canada: a qualitative study

Abstract

Purpose

Risk-stratified life-long follow-up care is recommended for adult childhood cancer survivors (CCS) to ensure appropriate prevention, screening, and management of late effects. The identification of barriers to long-term follow-up (LTFU), particularly in varying healthcare service contexts, is essential to develop and refine services that are responsive to survivor needs. We aimed to explore CCS and healthcare professionals (HCP) perspectives of healthcare system factors that function as barriers to LTFU in British Columbia, Canada.

Methods

We analyzed data from 43 in-depth interviews, 30 with CCS and 13 with HCP, using qualitative thematic analysis and constant comparative methods.

Results

Barriers to accessible, comprehensive, quality LTFU were associated with the following: (1) the difficult and abrupt transition from pediatric to adult health services, (2) inconvenient and under-resourced health services, (3) shifting patient-HCP relationships, (4) family doctor inadequate experience with late effects management, and (5) overdue and insufficient late effects communication with CCS.

Conclusions

Structural, informational, and interpersonal/relational healthcare system factors often prevent CCS from initially accessing LTFU after discharge from pediatric oncology programs as well as adversely affecting engagement in ongoing screening, surveillance, and management of late effects.

Implications for Cancer Survivors

Understanding the issues faced by adult CCS will provide insight necessary to developing patient-centered healthcare solutions that are key to accessible, acceptable, appropriate, and effective healthcare.

http://ift.tt/2BOt4C2

New hydrazide-hydrazones of isonicotinic acid: synthesis, lipophilicity and in vitro antimicrobial screening

Abstract

This paper describes the synthesis, lipophilicity and in vitro antimicrobial assays of 15 new hydrazide-hydrazones of isonicotinic acid. New derivatives were obtained on the basis of the condensation reaction of isonicotinic acid hydrazide with different aromatic aldehydes. The chemical structure of synthesized compounds was confirmed by spectral methods. Experimental lipophilicity of new isonicotinic acid derivatives was determined using reversed-phase thin-layer chromatography. All synthesized compounds were subjected to in vitro antimicrobial assays against reference strains of Gram-positive bacteria, Gram-negative bacteria and fungi belonging to Candida spp. Some of synthesized hydrazide-hydrazones proved to be significant antibacterial compounds and more potent than commonly used chemotherapeutic agents.

This article is protected by copyright. All rights reserved.

This paper describes the synthesis, lipophilicity and in vitro antimicrobial assays of 15 new hydrazide-hydrazones of isonicotinic acid. New derivatives were obtained on the basis of the condensation reaction of isonicotinic acid hydrazide with different aromatic aldehydes. The chemical structure of synthesized compounds was confirmed by spectral methods. Experimental lipophilicity of new isonicotinic acid derivatives was determined using reversed-phase thin-layer chromatography. All synthesized compounds were subjected to in vitro antimicrobial assays against reference strains of Gram-positive bacteria, Gram-negative bacteria and fungi belonging to Candida spp. Some of synthesized hydrazide-hydrazones proved to be significant antibacterial compounds and more potent than commonly used chemotherapeutic agents.

http://ift.tt/2kFoEKa

Texas fire department welcomes first female firefighter-paramedic in its 141 years

By Drew Smith Herald Democrat DENISON, Texas — Denison Fire Rescue crews welcomed Hanna Lindemuth to their team last week as not only one of the department's newest employees but as the first female firefighter and paramedic in the department's 141-year history. "We're happy she's here and we're proud of her at the same time," Assistant Fire Chief Mark Escamilla said ...

http://ift.tt/2jbWdDg

TAR cloning and integrated overexpression of 6-demethylchlortetracycline biosynthetic gene cluster in Streptomyces aureofaciens

Abstract

6-Demethylchlortetracycline (6-DCT), a tetracycline antibiotic produced by Streptomyces aureofaciens, is a crucial precursor employed for the semi-synthesis of tigecycline, minocycline, and amadacyclin (PTK 0796). In this study, the 6-DCT biosynthetic gene cluster (BGC) was cloned from genomic DNA of a high 6-DCT-producing strain, S. aureofaciens DM-1, using the transformation-associated recombination method. An extra copy of the 6-DCT BGC was introduced and integrated into the chromosome of S. aureofaciens DM-1. Duplication of the 6-DCT BGC resulted in a maximum increase of the 6-DCT titer by 34%.

http://ift.tt/2iDUm6y

Oestrogen receptor β ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis

Abstract

Oestrogen treatments are neuroprotective in a variety of neurodegenerative disease models. Selective oestrogen receptor modifiers are needed to optimize beneficial effects while minimizing adverse effects to achieve neuroprotection in chronic diseases. Oestrogen receptor beta (ERβ) ligands are potential candidates. In the multiple sclerosis model chronic experimental autoimmune encephalomyelitis, ERβ-ligand treatment is neuroprotective, but mechanisms underlying this neuroprotection remain unclear. Specifically, whether there are direct effects of ERβ-ligand on CD11c⁺ microglia, myeloid dendritic cells or macrophages in vivo during disease is unknown. Here, we generated mice with ERβ deleted from CD11c⁺ cells to show direct effects of ERβ-ligand treatment in vivo on these cells to mediate neuroprotection during experimental autoimmune encephalomyelitis. Further, we use bone marrow chimeras to show that ERβ in peripherally derived myeloid cells, not resident microglia, are the CD11c⁺ cells mediating this protection. CD11c⁺ dendritic cell and macrophages isolated from the central nervous system of wild-type experimental autoimmune encephalomyelitis mice treated with ERβ-ligand expressed less iNOS and T-bet, but more IL-10, and this treatment effect was lost in mice with specific deletion of ERβ in CD11c⁺ cells. Also, we extend previous reports of ERβ-ligand's ability to enhance remyelination through a direct effect on oligodendrocytes by showing that the immunomodulatory effect of ERβ-ligand acting on CD11c⁺ cells is necessary to permit the maturation of oligodendrocytes. Together these results demonstrate that targeting ERβ signalling pathways in CD11c⁺ myeloid cells is a novel strategy for regulation of the innate immune system in neurodegenerative diseases. To our knowledge, this is the first report showing how direct effects of a candidate neuroprotective treatment on two distinct cell lineages (bone marrow derived myeloid cells and oligodendrocytes) can have complementary neuroprotective effects in vivo.

http://ift.tt/2jc68ZR

DGUOK recessive mutations in patients with CPEO, mitochondrial myopathy, parkinsonism and mtDNA deletions

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Reply: DGUOK recessive mutations in patients with CPEO, mitochondrial myopathy, parkinsonism and mtDNA deletions

Sir,

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Structural connectivity of right frontal hyperactive areas scales with stuttering severity

Abstract

A neuronal sign of persistent developmental stuttering is the magnified coactivation of right frontal brain regions during speech production. Whether and how stuttering severity relates to the connection strength of these hyperactive right frontal areas to other brain areas is an open question. Scrutinizing such brain–behaviour and structure–function relationships aims at disentangling suspected underlying neuronal mechanisms of stuttering. Here, we acquired diffusion-weighted and functional images from 31 adults who stutter and 34 matched control participants. Using a newly developed structural connectivity measure, we calculated voxel-wise correlations between connection strength and stuttering severity within tract volumes that originated from functionally hyperactive right frontal regions. Correlation analyses revealed that with increasing speech motor deficits the connection strength increased in the right frontal aslant tract, the right anterior thalamic radiation, and in U-shaped projections underneath the right precentral sulcus. In contrast, with decreasing speech motor deficits connection strength increased in the right uncinate fasciculus. Additional group comparisons of whole-brain white matter skeletons replicated the previously reported reduction of fractional anisotropy in the left and right superior longitudinal fasciculus as well as at the junction of right frontal aslant tract and right superior longitudinal fasciculus in adults who stutter compared to control participants. Overall, our investigation suggests that right fronto-temporal networks play a compensatory role as a fluency enhancing mechanism. In contrast, the increased connection strength within subcortical-cortical pathways may be implied in an overly active global response suppression mechanism in stuttering. Altogether, this combined functional MRI–diffusion tensor imaging study disentangles different networks involved in the neuronal underpinnings of the speech motor deficit in persistent developmental stuttering.

http://ift.tt/2j8WyXD

Asymmetry of post-mortem neuropathology in behavioural-variant frontotemporal dementia

Abstract

Antemortem behavioural and anatomic abnormalities have largely been associated with right hemisphere disease in behavioural-variant frontotemporal dementia, but post-mortem neuropathological examination of bilateral hemispheres remains to be defined. Here we measured the severity of post-mortem pathology in both grey and white matter using a validated digital image analysis method in four cortical regions sampled from each hemisphere in 26 patients with behavioural-variant frontotemporal dementia, including those with frontotemporal degeneration (i.e. tau = 9, TDP-43 = 14, or FUS = 1 proteinopathy) or Alzheimer's pathology (n = 2). We calculated an asymmetry index based on the difference in measured pathology from each left-right sample pair. Analysis of the absolute value of the asymmetry index (i.e. degree of asymmetry independent of direction) revealed asymmetric pathology for both grey and white matter in all four regions sampled in frontototemporal degeneration patients with tau or TDP-43 pathology (P ≤ 0.01). Direct interhemispheric comparisons of regional pathology measurements within-subjects in the combined tauopathy and TDP-43 proteinopathy group found higher pathology in the right orbitofrontal grey matter compared to the left (P < 0.01) and increased pathology in ventrolateral temporal lobe grey matter of the left hemisphere compared to the right (P < 0.02). Preliminary group-wise comparisons between tauopathy and TDP-43 proteinopathy groups found differences in patterns of interhemispheric burden of grey and white matter regional pathology, with greater relative white matter pathology in tauopathies. To test the association of pathology measurement with ante-mortem observations, we performed exploratory analyses in the subset of patients with imaging data (n = 15) and found a direct association for increasing pathologic burden with decreasing cortical thickness in frontotemporal regions on ante-mortem imaging in tauopathy (P = 0.001) and a trend for TDP-43 proteinopathy (P = 0.06). Exploratory clinicopathological correlations demonstrated an association of socially-inappropriate behaviours with asymmetric right orbitofrontal grey matter pathology, and reduced semantically-guided category naming fluency was associated asymmetric white matter pathology in the left ventrolateral temporal region. We conclude that pathologic disease burden is distributed asymmetrically in behavioural-variant frontotemporal dementia, although not universally in the right hemisphere, and this asymmetry contributes to the clinical heterogeneity of the disorder. The basis for this asymmetric profile is enigmatic but may reflect distinct species or strains of tau and TDP-43 pathologies with propensities to spread by distinct cell- and region-specific mechanisms. Patterns of region-specific pathology in the right hemisphere as well as the left hemisphere may play a role in antemortem clinical observations, and these observations may contribute to antemortem identification of molecular pathology in frontotemporal degeneration.

http://ift.tt/2B3wunB

Obligatory and facultative brain regions for voice-identity recognition

Abstract

Recognizing the identity of others by their voice is an important skill for social interactions. To date, it remains controversial which parts of the brain are critical structures for this skill. Based on neuroimaging findings, standard models of person-identity recognition suggest that the right temporal lobe is the hub for voice-identity recognition. Neuropsychological case studies, however, reported selective deficits of voice-identity recognition in patients predominantly with right inferior parietal lobe lesions. Here, our aim was to work towards resolving the discrepancy between neuroimaging studies and neuropsychological case studies to find out which brain structures are critical for voice-identity recognition in humans. We performed a voxel-based lesion-behaviour mapping study in a cohort of patients (n = 58) with unilateral focal brain lesions. The study included a comprehensive behavioural test battery on voice-identity recognition of newly learned (voice-name, voice-face association learning) and familiar voices (famous voice recognition) as well as visual (face-identity recognition) and acoustic control tests (vocal-pitch and vocal-timbre discrimination). The study also comprised clinically established tests (neuropsychological assessment, audiometry) and high-resolution structural brain images. The three key findings were: (i) a strong association between voice-identity recognition performance and right posterior/mid temporal and right inferior parietal lobe lesions; (ii) a selective association between right posterior/mid temporal lobe lesions and voice-identity recognition performance when face-identity recognition performance was factored out; and (iii) an association of right inferior parietal lobe lesions with tasks requiring the association between voices and faces but not voices and names. The results imply that the right posterior/mid temporal lobe is an obligatory structure for voice-identity recognition, while the inferior parietal lobe is only a facultative component of voice-identity recognition in situations where additional face-identity processing is required.

http://ift.tt/2jbNAZq

Widespread brain tau and its association with ageing, Braak stage and Alzheimer’s dementia

Abstract

Autopsy data have proposed that a topographical pattern of tauopathy occurs in the brain with the development of dementia due to Alzheimer's disease. We evaluated the findings of tau-PET to better understand neurofibrillary tangle development as it is seen in cognitively unimpaired and impaired individuals. The evolution of Alzheimer's disease tauopathy in cognitively unimpaired individuals needs to be examined to better understand disease pathogenesis. Tau-PET was performed in 86 cognitively impaired individuals who all had abnormal amyloid levels and 601 cognitively unimpaired individuals. Tau-PET findings were assessed for relationships with clinical diagnosis, age, and regional uptake patterns relative to Braak stage. Regional and voxel-wise analyses were performed. Topographical findings from tau-PET were characterized using hierarchical clustering and clinical characteristic-based subcategorization. In older cognitively unimpaired individuals (≥50 years), widespread, age-related elevated tau signal was seen among those with normal or abnormal amyloid status as compared to younger cognitively unimpaired individuals (30–49 years). More frequent regional tau signal elevation throughout the brain was seen in cognitively unimpaired individuals with abnormal versus normal amyloid. Elevated tau signal was seen in regions that are considered high Braak Stage in cognitively unimpaired and cognitively impaired individuals. Hierarchical clustering and clinical characteristic-based categorizations both showed different patterns of tau signal between groups such as greater tau signal in frontal regions in younger onset Alzheimer's disease dementia participants (most of whom had a dysexecutive clinical presentation). Tau-PET signal increases modestly with age throughout the brain in cognitively unimpaired individuals and elevated tau is seen more often when amyloid brain accumulation is present. Tau signal patterns in cognitively unimpaired correspond to early Braak stage but also suggest tangle involvement in extra-medial temporal and extra-temporal regions that are considered more advanced in the Braak scheme even when amyloid negative. Our findings also suggest the possibility of widespread development of early tangle pathology rather than a pattern defined exclusively by adjacent, region-to-region spread, prior to onset of clinical symptoms. Distinct patterns of neurofibrillary tangle deposition in younger-onset Alzheimer's disease dementia versus older-onset Alzheimer's disease dementia provide evidence for variability in regional tangle deposition patterns and demonstrate that different disease phenotypes have different patterns of tauopathy. Pathological correlation with imaging is needed to assess the implications of these observations.

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Longitudinal structural and molecular neuroimaging in agrammatic primary progressive aphasia

Abstract

The agrammatic variant of primary progressive aphasia affects normal grammatical language production, often occurs with apraxia of speech, and is associated with left frontal abnormalities on cross-sectional neuroimaging studies. We aimed to perform a detailed assessment of longitudinal change on structural and molecular neuroimaging to provide a complete picture of neurodegeneration in these patients, and to determine how patterns of progression compare to patients with isolated apraxia of speech (primary progressive apraxia of speech). We assessed longitudinal structural MRI, diffusion tensor imaging and ¹⁸F-fluorodeoxyglucose PET in 11 agrammatic aphasia subjects, 20 primary progressive apraxia of speech subjects, and 62 age and gender-matched controls with two serial assessments. Rates of change in grey matter volume and hypometabolism, and white matter fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity were assessed at the voxel-level and for numerous regions of interest. The greatest rates of grey matter atrophy in agrammatic aphasia were observed in inferior, middle, and superior frontal gyri, premotor and motor cortices, as well as medial temporal lobe, insula, basal ganglia, and brainstem compared to controls. Longitudinal decline in metabolism was observed in the same regions, with additional findings in medial and lateral parietal lobe. Diffusion tensor imaging changes were prominent bilaterally in inferior and middle frontal white matter and superior longitudinal fasciculus, as well as right inferior fronto-occipital fasciculus, superior frontal and precentral white matter. More focal patterns of degeneration of motor and premotor cortex were observed in primary progressive apraxia of speech. Agrammatic aphasia showed greater rates of grey matter atrophy, decline in metabolism, and white matter degeneration compared to primary progressive apraxia of speech in the left frontal lobe, predominantly inferior and middle frontal grey and white matter. Correlations were also assessed between rates of change on neuroimaging and rates of clinical decline. Progression of aphasia correlated with rates of degeneration in frontal and temporal regions within the language network, while progression of parkinsonism and limb apraxia correlated with degeneration of motor cortex and brainstem. These findings demonstrate that disease progression in agrammatic aphasia is associated with widespread neurodegeneration throughout regions of the language network, as well as connecting white matter tracts, but also with progression to regions outside of the language network that are responsible for the development of motor symptoms. The fact that patterns of progression differed from primary progressive apraxia of speech supports the clinical distinction of these syndromes.

http://ift.tt/2jaaQag

Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5

Abstract

The hereditary spastic paraplegias are an expanding and heterogeneous group of disorders characterized by spasticity in the lower limbs. Plasma biomarkers are needed to guide the genetic testing of spastic paraplegia. Spastic paraplegia type 5 (SPG5) is an autosomal recessive spastic paraplegia due to mutations in CYP7B1, which encodes a cytochrome P450 7α-hydroxylase implicated in cholesterol and bile acids metabolism. We developed a method based on ultra-performance liquid chromatography electrospray tandem mass spectrometry to validate two plasma 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27-OHC) as diagnostic biomarkers in a cohort of 21 patients with SPG5. For 14 patients, SPG5 was initially suspected on the basis of genetic analysis, and then confirmed by increased plasma 25-OHC, 27-OHC and their ratio to total cholesterol. For seven patients, the diagnosis was initially based on elevated plasma oxysterol levels and confirmed by the identification of two causal CYP7B1 mutations. The receiver operating characteristic curves analysis showed that 25-OHC, 27-OHC and their ratio to total cholesterol discriminated between SPG5 patients and healthy controls with 100% sensitivity and specificity. Taking advantage of the robustness of these plasma oxysterols, we then conducted a phase II therapeutic trial in 12 patients and tested whether candidate molecules (atorvastatin, chenodeoxycholic acid and resveratrol) can lower plasma oxysterols and improve bile acids profile. The trial consisted of a three-period, three-treatment crossover study and the six different sequences of three treatments were randomized. Using a linear mixed effect regression model with a random intercept, we observed that atorvastatin decreased moderately plasma 27-OHC (∼30%, P < 0.001) but did not change 27-OHC to total cholesterol ratio or 25-OHC levels. We also found an abnormal bile acids profile in SPG5 patients, with significantly decreased total serum bile acids associated with a relative decrease of ursodeoxycholic and lithocholic acids compared to deoxycholic acid. Treatment with chenodeoxycholic acid restored bile acids profile in SPG5 patients. Therefore, the combination of atorvastatin and chenodeoxycholic acid may be worth considering for the treatment of SPG5 patients but the neurological benefit of these metabolic interventions remains to be evaluated in phase III therapeutic trials using clinical, imaging and/or electrophysiological outcome measures with sufficient effect sizes. Overall, our study indicates that plasma 25-OHC and 27-OHC are robust diagnostic biomarkers of SPG5 and shall be used as first-line investigations in any patient with unexplained spastic paraplegia.

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Structure and function analysis of Polygonatum cyrtonema lectin by site-directed mutagenesis

Abstract

The crystal structure of mature Polygonatum cyrtonema lectin (PCL) showed three similar carbohydrate-binding sites (CBS I, CBS II, and CBS III). The Gln58 and Asp60 residues of CBS II are substituted with His58 and Asn60. To establish the relationship between the key amino acid residues and structure or activity of PCL, we constructed four recombinant mutants in CBS I, CBS II, and CBS III. The experimental results indicate that CBS I, CBS III and the disulfide bond play vital roles in the binding with mannose. Furthermore, molecular dynamics simulations and binding free energy calculation illustrate that CBS I has a direct and strong relationship with the activity of PCL. CBS II does not play a critical role in the model for mannose binding by PCL. Although CBS III does not enhance the activity, it helps to maintain the activity and 3D structure. These results suggest that the carbohydrate-binding site of PCL may be in a hydrophilic environment, and Asn and Tyr are the key amino acids involved in its binding with sugar, but Gln and Asp are not necessary to maintain its activity.

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Time-dependent glucocorticoid administration differently affects peripheral circadian rhythm in rats

Abstract

There is a growing recognition that glucocorticoid (GC) acts as an internal timing signal for peripheral circadian oscillators. However, the transcription process of GC-related clock gene in the peripheral tissues is not fully understood. The present study was designed to explore the potential role of clock genes in the GC-induced peripheral circadian gene expression in vivo. Real-time RT-PCR analysis indicated that the transcript levels of Per1 and Dec1 were rapidly up-regulated within 0.5 and 1 h in the heart and kidney respectively after stimulation with dexamethasone (Dex). These results suggest that Per1 and Dec1 serve as the primary and secondary responsers respectively in initiating the GC-induced peripheral circadian gene expression. By comparing the effects of the different GC administration schedules on the circadian rhythm of clock genes in peripheral tissues in rats, we found that the circadian phases of Bmal1 and Per1 were shifted more in the ZT0 (endogenous valley time) Dex stimulation group than in the ZT12 (endogenous peak time) Dex stimulation group in heart and kidney under the normal LD cycle. Under the jet lag condition, the circadian phases of Bmal1 and Per1 were also shifted more in the ZT0 Dex stimulation group than in the ZT12 Dex stimulation group. Therefore, the GC stimulation in the endogenous valley time caused circadian disorder in the normal LD cycle, but it might benefit the circadian resetting of peripheral clocks under the LD reversal condition.

http://ift.tt/2iF8dJJ

Antimicrobial activity and mechanism of Larch bark procyanidins against Staphylococcus aureus

Abstract

Larch bark procyanidins (LBPCs) have not only antioxidant and antitumor properties, but also strong bacteriostatic effects. However, it is not clear about the antibacterial mechanisms of LBPC. In this work, the antibacterial effects and mechanisms of LBPC on Staphylococcus aureus were studied in the aspects of morphological structure, cell wall and membrane, essential proteins, and genetic material. The results showed that LBPC effectively inhibited bacterial growth at a minimum inhibitory concentration of 1.75 mg/ml. Bacterial morphology was significantly altered by LBPC treatment, with the cell walls and membranes being destroyed. Extracellular alkaline phosphatase content, bacterial fluid conductivity, and Na⁺/K⁺-ATPase and Ca²⁺-ATPase activities in the membrane system were all increased. In the energy metabolic systems, the activities of succinate dehydrogenase, malate dehydrogenase, and adenosine triphosphatase (ATPase) were all decreased, resulting in a slowdown of metabolism and bacterial growth inhibition. Changes of protein content and composition in the bacteria suggested that the protein expression system was affected. In addition, LBPC was found to bind to DNA grooves to form complexes. Thus, LBPC has a very strong inhibitory effect on S. aureus and can kill S. aureus by destroying the integrity and permeability of the cell wall and cell membrane, affecting protein synthesis, and binding to DNA.

http://ift.tt/2kbUuu9

Effects of high-intensity focused ultrasound on cisplatin-resistant human lung adenocarcinoma in vitro and in vivo

Abstract

It is widely accepted that high-intensity focused ultrasound (HIFU) is a minimally invasive treatment option for different tumors, but its roles and the corresponding mechanism in cisplatin (DDP) chemoresistance in lung adenocarcinoma (LA) remain unclear. In this study, we investigated the response of DDP-resistant LA cells to HIFU and its underlying molecular mechanisms using molecular biology techniques. It was found that HIFU exposure inhibited the proliferation of DDP-resistant A549 (A549/DDP) cells through arresting cell cycle at the G1/G0 phase via the Cyclin-dependent pathway and promoting apoptosis in a Bcl-2-dependent manner. Furthermore, the results also showed that HIFU exposure could down-regulate the expressions of MDR1, MRP1, and LRP mRNAs, as well as P-gp, MRP1, and LRP proteins related to drug resistance in A549/DDP cells. In vivo experiments also demonstrated that HIFU could reduce the size and mass of subcutaneously transplanted tumors produced by A549/DDP cells through mediating Cyclin-dependent and Bcl-2-dependent pathways. These results suggested that HIFU treatment could inhibit the proliferation of DDP-resistant lung cancer cells and might be a novel therapeutic method for patients with DDP resistance.

http://ift.tt/2kaQoCM

miR-219a-5p inhibits breast cancer cell migration and epithelial-mesenchymal transition by targeting myocardin-related transcription factor A

Abstract

Although many miRNAs are reported to be involved in tumor formation and progression, the effect of miR-219a-5p on breast cancer metastasis is not well-known. The aim of this study is to investigate the effect of miR-219a-5p on the migratory ability and epithelial-mesenchymal transition (EMT) of breast cancer cells. First, miR-219a-5p was found to be highly expressed in low-invasive breast cancer MCF-7 cells, but lowly expressed in high-invasive breast cancer MDA-MB-231 cells. Wound scratch assay and transwell assay showed that miR-219a-5p inhibited the migratory ability of MDA-MB-231 cells. miR-219a-5p also suppressed the cellular EMT, confirmed by suppressing the expression of mesenchymal markers vimentin and N-cadherin and increasing the expression of epithelial marker E-cadherin. Using the epithelial-mesenchymal-epithelial model in MCF-7 cells, we confirmed that the level of miR-219a-5p was highly expressed in epithelial-type cells and lowly expressed in mesenchymal-type cells. Importantly, we identified myocardin-related transcription factor A (MRTF-A) as a novel potential target gene of miR-219a-5p. Overexpression of miR-219a-5p in MDA-MB-231 cells could inhibit the expression of MRTF-A as revealed by real-time PCR and western blot analysis. miR-219a-5p inhibited the transcription of MRTF-A by targeting the 3′UTR of MRTF-A, which was confirmed by wild-type or mutant MRTF-A 3′UTR luciferase reporter system. Furthermore, knockdown of MRTF-A using siRNA for MRTF-A could depress breast cell migration. In conclusion, our present study revealed the tumor suppressive role of miR-219a-5p in regulating breast cancer migration by targeting MRTF-A, suggesting that miR-219a-5p might be a therapeutic target in breast cancer through regulating EMT.

http://ift.tt/2iFebdz

Gene expression profiling reveals heterogeneity of perivascular adipose tissues surrounding coronary and internal thoracic arteries

Abstract

The internal thoracic artery (ITA) that differs from coronary artery (CA), rarely develops atherosclerosis. Understanding the mechanism underlying such a difference will help to pave a new way to the prevention and treatment of the disease. We hypothesize herein that the difference in susceptibility to atherosclerosis between CA and ITA is attributable to the heterogeneity of perivascular adipose tissues (PVATs) surrounding these two kinds of arteries, i.e. PVAT-CA and PVAT-ITA. We isolated PVAT from eight patients of coronary heart disease (CHD) and four non-CHD patients. Gene expression patterns were analyzed by using Agilent whole gene expression profile chips. By comparison between PVAT-CA and PVAT-ITA, we identified 2053 differentially expressed genes, of which 1042 were up-regulated and 1011 were down-regulated, respectively, in CHD group. KEGG pathway and gene ontology (GO) analysis revealed that those differentially expressed genes related to inflammation, lipid metabolism and myocardial processes were particularly noted in the CHD group, but not in non-CHD. Several selected genes, including interleukin-1β (IL-1β), interleukin-6 (IL-6), Toll-like receptor 2 (TLR2), Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), serum amyloid A2 (SAA2), and Leptin were validated by real-time PCR analysis. The results showed that the expression levels of IL-1β, IL-6, and Leptin were significantly higher in PVAT-CA than in PVAT-ITA (P = 0.016, 0.021, and 0.018) in CHD patients. Levels of TLR2, TIRAP, and SAA2 expression were also higher in PVAT-CA, however no significant difference was observed (P = 0.054, 0.092, and 0.058). In conclusion, our findings demonstrate differential gene expression patterns between PVAT-CA and PVAT-ITA, revealing a high heterogeneity in PVAT. Particularly, those genes related to inflammation, lipid metabolism and myocardial processes are differentially expressed in PVAT-CA and PVAT-ITA in CHD patients, suggesting an important role of PVAT in the development of coronary atherosclerosis.

http://ift.tt/2kdc0yj

Role of the Akt/mTOR signaling pathway in human papillomavirus-associated nasal and sinonasal inverted papilloma

Abstract

Nasal and sinonasal inverted papilloma (NSIP) is a benign tumor in which surface epithelial cells grow downward into the underlying supportive tissue with varying degrees of metaplasia. Human papillomavirus (HPV) has been proposed as the causal agent in the pathogenesis of this disease. Many studies have shown that HPV can activate the Akt/mechanistic target of rapamycin (mTOR) signaling pathway, but the role of this pathway in HPV-associated NSIP is largely unknown. In this study, we enrolled 40 control tissue samples and 80 NSIP tissue samples. HPV genotyping showed that 47 of the 80 examined cases of NSIP were HPV-positive (58.8%), and the most common subtype was HPV11 (20/53, 37.7%). The immunohistochemistry showed statistically significant differences in phosphorylated Akt and phosphorylated S6 ribosomal protein staining among control samples, HPV-positive NSIP and HPV-negative NSIP. The HPV11 L1-L2 plasmid increased the proliferation of normal human nasopharyngeal epithelial NP69-SV40T cells and human nasopharyngeal cancer CNE1 cells. Meanwhile, rapamycin, an mTOR inhibitor, reversed the increased cell proliferation induced by the HPV11 L1-L2 plasmid. Western blot analysis showed that Akt/mTOR/S6 were overexpressed in NP69-SV40T cells and CNE1 cells infected with the HPV11 L1-L2 plasmid. These data demonstrate that HPV promotes cell proliferation through the Akt/mTOR signaling pathway in NSIP.

http://ift.tt/2iG2sLV

β-Cypermethrin and its metabolite 3-phenoxybenzoic acid exhibit immunotoxicity in murine macrophages

Abstract

β-Cypermethrin (β-CYP), one of most important pyrethroids, is widely used to control insects, and has been detected in organisms, including human. Pyrethroids have been shown to pose neurotoxicity, hepatotoxicity, endocrine disruption and reproductive risks in mammals. However, research in immunotoxicity of pyrethroids, especially their metabolites, is limited. A common metabolite of pyrethroids is 3-phenoxybenzoic acid (3-PBA) in mammals. Thus, in this study, we evaluated the immunotoxicity of β-CYP and 3-PBA in mouse macrophages, RAW 264.7 cells. MTT assays showed that both β-CYP and 3-PBA reduced cell viability in a concentration- and time-dependent manner. Flow cytometry with Annexin-V/PI staining demonstrated that both β-CYP and 3-PBA induced RAW 264.7 cell apoptosis. Furthermore, our results also showed that N-acetylcysteine partially blocked β-CYP- and 3-PBA-induced cytotoxicity and apoptosis. Intrinsic apoptotic pathway was stimulated by both β-CYP and 3-PBA exposure. In addition, we found that β-CYP and 3-PBA inhibited mRNA levels of pro-inflammatory cytokines with or without LPS stimulation. Phagocytosis assay showed that both β-CYP and 3-PBA inhibited phagocytic ability of macrophages. Moreover, it was also found that both β-CYP and 3-PBA increased reactive oxygen species (ROS) levels in RAW 264.7 cells. Accordingly, both β-CYP and 3-PBA were found to regulate the mRNA levels of oxidative stress-related genes in RAW 264.7 cells. Taken together, the results obtained in this study demonstrated that β-CYP and 3-PBA may have immunotoxic effect on macrophages and that elevated ROS may underlie the mechanism. The present study will help to understand the health risks caused by β-CYP and other pyrethroids.

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The ACC/AHA 2017 Hypertension Guidelines: Both Too Much and Not Enough of a Good Thing?

The most notable recommendation in the 2017 American College of Cardiology and American Heart Association hypertension guidelines is the reduced threshold for the diagnosis of hypertension, from ≥140/90 mm Hg to ≥130/80 mm Hg in the general population. This commentary discusses the guidelines and why they create as many questions as they answer.

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Whole-Exome Sequencing in Adults With Chronic Kidney Disease A Pilot Study

Background:

The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown.

Objective:

To study the diagnostic utility of WES in a selected referral population of adults with CKD.

Design:

Observational cohort.

Setting:

A major academic medical center.

Patients:

92 adults with CKD of unknown cause or familial nephropathy or hypertension.

Measurements:

The diagnostic yield of WES and its potential effect on clinical management.

Results:

Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most solved cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy.

Limitation:

The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.

Conclusion:

Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted.

Primary Funding Source:

New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.

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Trends in U.S. Drug Overdose Deaths in Non-Hispanic Black, Hispanic, and Non-Hispanic White Persons, 2000–2015

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Readmissions After Revascularization Procedures for Peripheral Arterial Disease A Nationwide Cohort Study

Background:

Limited data suggest high rates of unplanned rehospitalization after endovascular and surgical revascularization for peripheral arterial disease. However, the overall burden of readmissions has not been comprehensively explored.

Objective:

To evaluate nationwide readmissions after peripheral arterial revascularization for peripheral arterial disease and to assess whether readmission risk varies among hospitals.

Design:

Retrospective cohort study.

Setting:

1085 U.S. acute care hospitals participating in the Nationwide Readmissions Database.

Patients:

61 969 unweighted hospitalizations of patients with peripheral arterial disease who had peripheral arterial revascularization and were discharged alive between 1 January and 30 November 2014.

Measurements:

Thirty-day readmission rates, causes, and costs of unplanned rehospitalizations after peripheral arterial revascularization; 30-day risk-standardized readmission rates (RSRRs), calculated using hierarchical logistic regression, to assess for heterogeneity of readmission risk between hospitals.

Results:

Among 61 969 hospitalizations of patients with peripheral arterial disease who were discharged alive after peripheral arterial revascularization, the 30-day nonelective readmission rate was 17.6%. The most common cause of readmission was procedural complications (28.0%), followed by sepsis (8.3%) and complications due to diabetes mellitus (7.5%). Among rehospitalized patients, 21.0% underwent a subsequent peripheral arterial revascularization or lower extremity amputation, 4.6% died, and the median cost of a readmission was $11 013. Thirty-day RSRRs varied from 10.0% to 27.3% (interquartile range, 16.6% to 18.8%).

Limitation:

Inability to distinguish out-of-hospital deaths after discharge and potential misclassification bias due to use of billing codes to ascertain diagnoses and interventions.

Conclusion:

More than 1 in 6 patients with peripheral arterial disease who undergo peripheral arterial revascularization have unplanned readmission within 30 days, with high associated mortality risks and costs. Procedure- and patient-related factors were the primary reasons for readmission. Readmission rates varied moderately between institutions after hospital case mix was accounted for, suggesting that differences in hospital quality may only partially account for readmission.

Primary Funding Source:

Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center.

http://ift.tt/2j9YKxY