Bisphosphonate-loaded Bone Cement as a Local Adjuvant Therapy for Giant Cell Tumor of Bone: A 1 to 12-Year Follow-up Study

Background: Historically, nontargeted adjuvant therapies such as liquid nitrogen, phenol, argon beam, and alcohol have been applied locally after curettage of giant cell tumors (GCT) in the extremities. Systemic bisphosphonates (BP) and denosumab have emerged as osteoclast-targeting therapies because osteoclast-like giant cells, responsible for aggressive bone resorption, are susceptible to BP or denosumab. However, such drugs may cause systemic side effects. We examined the effects of an alternative intraoperative local delivery of BP on GCTs. Materials and Methods: In total, 17 patients with GCTs underwent extended surgical curettage procedures consisting of high-speed burring, traditional adjuvant therapy, and application of BP-loaded polymethylmethacrylate bone cement. Clinical data and follow-up radiographs were reviewed to investigate local recurrence (LR) rate and complications in a retrospective manner. Results: There were 6 males and 11 females (mean age, 33.7 y). There were no cases of pulmonary metastases. Patient follow-up ranged from 1 to 12 years. There was 1 LR during the follow-up period for an LR rate of 5.9%. The mean final Musculoskeletal Tumor Society (MSTS) score was 29. There were no systemic or localized avascular necrosis or atypical fractures related to BPs noted. Conclusions: BP-loaded polymethylmethacrylate is a targeted local adjuvant therapy that is feasible, safe, and may reduce LRs while alleviating the risk of systemic side effects of BPs such as avascular necrosis of jaw and atypical femur fractures. Future prospective randomized clinical trials will strengthen the level of evidence of this proposed targeted therapy. Level of Evidence: Therapeutic level IV—see instructions for authors for a complete description of evidence.

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Survival Implications of De Novo Versus Recurrent Metastatic Non–Small Cell Lung Cancer

Objectives: Metastatic non–small cell lung cancer (NSCLC) has a poor prognosis. Most patients present with stage IV, and many patients treated curatively with stage I to III develop recurrent metastatic disease. It is unknown whether the natural history differs between patients with recurrent versus de novo metastatic NSCLC. We hypothesized that de novo metastatic status is associated with decreased overall survival compared with recurrent metastatic disease. Materials and Methods: A retrospective review was completed of all patients with NSCLC referred to BC Cancer from 2005 to 2012. Two cohorts were created; de novo metastatic disease and patients treated with curative intent (surgery or radiotherapy) that developed recurrent, metastatic disease. Information was collected on known prognostic and predictive factors. Overall survival was calculated from the date of diagnosis of metastatic disease. Results: A total of 9651 patients were evaluated, 5782 (60%) with de novo stage IV disease, and 3869 (40%) with stage I to III disease. Of the 1658 patients who received curative therapy for stage I to III disease, 757 (46%) developed metastases. Patients in the de novo cohort versus recurrent cohort were more likely male (52% vs. 48%), have poorer performance status (Eastern Cooperative Oncology Group≥2 50% vs. 44%), and receive no palliative systemic therapy (67% vs. 61%). The median overall survival in the de novo cohort was 4.7 versus 6.9 m in the recurrent cohort (P

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Extraskeletal Osteosarcomas: A Case Made for Combined Modality Local Therapy With Radiation and Surgery

Objective: We evaluated our experience treating patients with extraskeletal osteosarcoma (ESOS) using combined modality local therapy, including surgery and radiation therapy (RT), to investigate local control (LC) and other survival endpoints. Methods: We reviewed the records of 21 consecutive patients with nonmetastatic, ESOS treated with RT in combination with surgery at our institution from 1984 to 2015. Postoperative RT was used for 10 patients (48%) to a median dose of 60 Gy (range, 60 to 68 Gy). The other 11 patients (52%) received 50 Gy preoperatively. Seven patients (33%) were treated with neoadjuvant or adjuvant chemotherapy. Among the patients who received chemotherapy, all were treated with doxorubicin and ifosfamide for a median of 6 cycles (range, 4 to 6). Results: Median follow-up time was 120 months (range, 6 to 200 mo). Larger tumor size (>5 cm) was associated with chemotherapy use (P=0.046). The 5-year LC, distant metastatic free survival, and disease-specific survival rates were 93%, 53%, and 62%, respectively. Only 1 patient (5%) had a local recurrence at 22 months. Nine patients (43%) developed distant metastases at a median time of 9 months (range, 1 to 30 mo) without any significant factors for reduced distant metastatic free survival. Following disease relapse, there were 2 patients who were ultimately salvaged, both of whom were treated with chemotherapy and surgery. Conclusions: RT in combination with surgery provides favorable LC for patients with ESOS. However, patients have a high rate of distant metastases with limited salvage.

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Metformin Use and Kidney Cancer Survival Outcomes: A Systematic Review and Meta-Analysis

Objectives: Metformin has been associated with improved survival outcomes in various malignancies. However, studies in kidney cancer are conflicting. We performed a systematic review and meta-analysis to evaluate the association between metformin and kidney cancer survival. Materials and Methods: We searched Medline and EMBASE databases from inception to June 2017 to identify studies evaluating the association between metformin use and kidney cancer survival outcomes. We evaluated risk of bias with the Newcastle-Ottawa scale. We pooled hazard ratios (HRs) for recurrence-free, progression-free, cancer-specific, and overall survival using random effects models, and explored heterogeneity with metaregression. We evaluated publication bias through Begg's and Egger's tests, and the trim and fill procedure. Results: We identified 9 studies meeting inclusion criteria, collectively involving 7426 patients. Five studies were at low risk of bias. The direction of association for metformin use was toward benefit for recurrence-free survival (HR, 0.99; 95% confidence interval [CI], 0.36-2.74), progression-free survival (pooled HR, 0.84; 95% CI, 0.66-1.07), cancer-specific (pooled HR, 0.72; 95% CI, 0.48-1.09), and overall survival (pooled HR, 0.73; 95% CI, 0.50-1.09), though none reached statistical significance. Metaregression found no study-level characteristic to be associated with the effect size, and there was no strong evidence of publication bias for any outcome. Conclusions: There is no evidence of a statistically significant association between metformin use and any survival outcome in kidney cancer. We discuss the potential for bias in chemoprevention studies and provide recommendations to reduce bias in future studies evaluating metformin in kidney cancer.

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Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma With the Introduction of New Chemotherapeutic Drugs: 10-Year Experience of a Single NCI-designated Comprehensive Cancer Center

Objectives: Adenocarcinoma of the pancreas represents the third leading cause of cancer-related death in the United States. Drug combinations, FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) and gemcitabine/nab-paclitaxel, showed a clinically meaningful benefit when compared with single-agent gemcitabine in phase III trials. The goal of this study was to investigate whether there was an increase in overall survival (OS) for patients treated for metastatic pancreatic cancer after the introduction of the above regimens. Materials and Methods: Patients were grouped into 2 treatment eras that were before and after the introduction of these newer chemotherapeutic regimens; 2006-2010 and 2011-2015, respectively. Baseline demographics and disease-related variables were collected from metastatic pancreatic cancer treated at the Barbara Ann Karmanos Cancer Institute in Detroit, MI. Results: When stratified by treatment era, the later era had an improvement in survival (hazard ratio for death of 0.61; P=0.005). Median OS was 8.97 and 9.95 months for the earlier (n=59) versus latter era (n=99), respectively. There was an increase from 28.3% to 38.9% at 12 months between the earlier and later era, an improvement of 37.4%. African Americans had a worse outcome with a hazard ratio of 1.63 (P=0.02) for death. When comparing the eras, Caucasians had a longer median OS in each era in addition to having a greater improvement in median OS between eras. Conclusions: There was a modest improvement in median OS between 2006-2010 and 2011-2015 with the introduction of newer chemotherapeutic regimens. However, there has been no significant improvement in outcomes for African Americans or in short-term survival.

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Challenges and Opportunities for High-grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangement (Double-hit Lymphoma)

The most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma, is cured in approximately two thirds of patients after initial therapy. The remaining one-third of patients who suffer relapse or become refractory have very poor survival outcomes despite salvage chemotherapy with or without stem cell transplantation. A considerable proportion of relapsed or refractory large B cells belong to the WHO subtype known as high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and/or BCL6, also known as double-hit lymphoma (DHL). Most DHL patients present with Ann Arbor's stage III/IV, a comparatively higher rate of extranodal involvement including bone marrow and central nervous system infiltration, high levels of lactate dehydrogenase, and an elevated Ki67 expression in the tumor cells. Newer therapeutic approaches, including targeted therapy against BCL2, MYC, or other associated pathways, are needed. In addition, recent therapies that harness the immune system, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, are changing the paradigm of treatment for non-Hodgkin lymphoma and could impact the outcome of DHL.

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Pattern of Marginal Local Failure in a Phase II Trial of Neoadjuvant Chemotherapy and Stereotactic Body Radiation Therapy for Resectable and Borderline Resectable Pancreas Cancer

Objectives: The main objectives of this study were to prospectively evaluate the safety and efficacy of stereotactic body radiation therapy (SBRT) in the neoadjuvant setting for resectable or borderline resectable pancreatic cancer. Materials and Methods: Eighteen patients were enrolled from November 2014 to June 2017. Following 3 cycles of chemotherapy, SBRT was delivered to the tumor and abutting vessel and a 3 mm planning target volume (PTV) margin to 33 Gy (6.6 Gy×5) with an optional elective PTV to 25 Gy (5 Gy×5) customized to the nodal space and mesenteric vessels. The primary endpoint is ≥grade 3 acute and late gastrointestinal toxicity. Results: Fifteen patients had borderline resectable tumors due to arterial abutment (n=7) or superior mesenteric vein encasement (n=8); 3 patients had resectable tumors. There were no ≥grade 3 acute or late gastrointestinal events. Following SBRT, surgery was performed in 12 patients (67%) with 11 (92%) R0 resections. The median overall survival and progression-free survival was 21 months (95% CI: 18-29) and 11 months (95% CI: 8.4-16). Progression occurred in 83% (10/12) of resected patients (distant [n=4, 40%], local-only [n=4, 40%], and local and distant [n=2, 20%]). The cumulative incidence of local failure (LF) at 12 months from resection was 50% (95% CI: 20-80). All LF were outside to the PTV33. Conclusions: Neoadjuvant SBRT was well tolerated, however LFs were predominantly observed outside the PTV33 volume that would have been covered with conventional RT volumes. The durability of local control after SBRT in the neoadjuvant setting merits examination relative to chemoradiation before incorporation into routine practice.

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Effect of Neutropenic Diet on Infection Rates in Cancer Patients With Neutropenia: A Meta-analysis of Randomized Controlled Trials

Introduction: Neutropenic diets are commonly prescribed to cancer patients with neutropenia with the intention of reducing rates of infection. These diets are restrictive and are associated with lower patient satisfaction and possibly malnutrition. Further, it is unclear if these restrictive diets are effective in reducing infection. We performed a meta-analysis on the rates of infection reported in trials comparing the neutropenic diet to unrestricted diets in cancer patients with neutropenia. Methods and Materials: A comprehensive database search for all published randomized controlled trials comparing infection rates in cancer patients receiving a neutropenic diet versus an unrestricted diet was performed for all publications in English language from database's inception until September 12, 2017. The search strategy, study selection, and subsequent analysis adhered to PRISMA guidelines. Random effects modeling was used to obtain pooled relative risks. The primary outcome measure was the rate of infection. Results: Five randomized controlled trials with a total of 388 patients were included in the final analysis. Patients mostly had acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or sarcoma. Infection was noted in 53.7% patients in the neutropenic diet group, as compared with 50% in the unrestricted diet group. No significant difference in infection rate was observed between the neutropenic diet versus unrestricted diet groups, pooled risk ratio (RR) 1.13 (95% CI, 0.98-1.30; P=0.10). Conclusions: This meta-analysis of randomized controlled trials suggests that the use of neutropenic diet was not associated with decreased risk of infection in neutropenic cancer patients. The continued use of neutropenic diets should be questioned.

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Concurrent Radiosurgery and Immune Checkpoint Inhibition: Improving Regional Intracranial Control for Patients With Metastatic Melanoma

Objectives: The anti-CTLA-4 and antiprogrammed cell death-1 (PD-1) therapies have significantly improved survival of patients with metastatic melanoma. However, there is limited data regarding the interaction between immunotherapy (IT) and stereotactic radiosurgery (SRS) in patients with brain metastasis, particularly how combination therapy may affect toxicity and intracranial tumor control. Methods: We retrospectively reviewed 26 patients with metastatic melanoma who received immune check point inhibitors and SRS for brain metastasis from 2011 to 2017. We evaluated lesions receiving SRS concurrently (within 30 days) and sequentially with IT. Overall survival (OS), local control (LC), and regional progression free survival (RPFS) were determined. Results: In total, 26 patients and 90 lesions were treated using pembrolizumab, nivolumab and/or ipilimumab, sequentially, or concurrently with SRS. Median follow-up was 18.9 months (range, 4.9 to 62.3 mo). Median overall survival was 26.1 months. There were 3 local failures, but no significant difference between the 2 groups. Following concurrent SRS and immunotherapy, patients had a significantly longer period of intracranial progression free survival than those treated with nonconcurrent therapy, 19 months versus 3.4 months (P

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A Phase II Study Evaluating Bone Marrow-Sparing, Image-guided Pelvic Intensity-Modulated Radiotherapy (IMRT) With Cesium-131 Brachytherapy Boost, Adjuvant Chemotherapy, and Long-Term Hormonal Ablation in Patients With High Risk, Nonmetastatic Prostate Cancer

Purpose/Objective(s): Management of localized high-risk prostate cancer remains challenging. At our institution we performed a prospective phase II study of 2 years of androgen deprivation therapy (ADT), pelvic radiation, Cesium (Cs)-131 brachytherapy boost, and adjuvant docetaxel in high risk, localized prostate cancer with a primary endpoint of 3-year disease-free survival. Materials/Methods: Acute/chronic hematologic, gastrointestinal (GI) and genitourinary (GU) toxicities were scored based on the CTCAE v3.0/RTOG-EORTC criteria, respectively. Actuarial biochemical recurrence free survival (bRFS), bRFSdisease free survival (DFS) and overall survival (OS) were calculated. Patients had a median age of 62 years (range, 45 to 82), median Gleason score 8 (74% Gleason 8-10), median PSA of 11.2 (range, 2.8 to 96), and 47% cT2-T3a stage disease. Androgen deprivation was given for 2 years, 45 Gy whole-pelvis IMRT was followed by an 85 Gy Cs-131 boost to the prostate gland, and adjuvant docetaxel was given for 4 cycles. Results: In total 38 patients enrolled from 2006 to 2014, with 82% completing protocol specified treatment, and 84.2% completing 4 cycles of docetaxel. Median follow-up for the entire and alive cohorts were 44 months and 58 months (range, 3.4 to 118), respectively. Acute grade ≥2 GI and GU toxicity rates were 18.4% and 23.7%, respectively. Chronic grade ≥2 GI and GU toxicity rates were 2.6% and 2.6%, respectively. Twelve patients (31.6%) developed grade 4 hematologic toxicity, with no grade 5 toxicity. The 5-year DFS, bRFS and OS rates were 74.1%, 86.0%, and 80.3%, respectively. Conclusions: This aggressive pilot multimodal approach appears to be safe and well-tolerated, providing disease control in a significant proportion of patients with particularly high-risk prostate cancer.

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Sequencing of Chemotherapy and Radiotherapy for Newly Diagnosed Anaplastic Oligodendroglioma and Oligoastrocytoma

Introduction: Adjuvant management of anaplastic oligodendrogliomas (AOs) and anaplastic oligoastrocytomas (AOAs) is guided by 2 seminal phase III trials, one of which utilized radiotherapy (RT) followed by chemotherapy (CT) (RT-CT), and the other in which CT was followed by RT (CT-RT). Both paradigms are endorsed by the National Comprehensive Cancer Network because no direct comparison in the first-line (nonprogressive) setting has been performed to date. This study of a contemporary national database sought to evaluate practice patterns and outcomes between both approaches. Materials and Methods: The National Cancer Database (NCDB) was queried for newly diagnosed AO/AOA treated with postoperative sequential CT-RT or RT-CT. Multivariable logistic regression ascertained factors independently associated with delivery of a particular paradigm. Overall survival (OS) between cohorts was compared using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazards modeling evaluated factors associated with OS. Results: Of 225 patients, 19 (8.4%) received CT-RT and 206 (91.6%) underwent RT-CT. Groups were well-balanced, although CT-RT was more often administered to men (P=0.009) and AOs (P=0.037). Median follow-up was 58 months. Median OS in the CT-RT cohort was 93 months (95% confidence interval, 37-150 mo), and 107 months (95% confidence interval, 72-142 mo) in the RT-CT group (P=0.709). Therapy sequence was not associated with OS on univariate (P=0.709) or multivariate (P=0.257) assessment. Conclusions: In the United States, most AO/AOA patients receiving sequential therapy undergo RT followed by CT. No differences in survival were observed with either approach; this addresses a knowledge gap and confirms that both paradigms are appropriate in the first-line setting.

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Impact of Primary Care Access on Mortality of Lung Cancer Patients in an Underserved Community

Background: Lack of access to primary care physicians (PCPs) may be an important contributor to mortality differences attributed to race/ethnicity. This study examined the effects of primary care access on mortality of lung cancer patients in an underserved community. Methods: Medical records of all newly diagnosed patients with primary lung cancer from 2012 to 2016 at a National Cancer Institute (NCI)-designated center in Bronx, New York were reviewed. Demographic data, PCP status, and residence in primary care shortage areas (PCSAs) were collected. Survival data from time of first imaging to death or the end of follow-up on January 1, 2018 were recorded. Survival analysis was performed using Kaplan-Meier and Cox hazards modeling. Results: Among 1062 patients, 874 (82%) were PCSA residents, 314 (30%) were Hispanic, and 445 (42%) were African American. PCSA residents were likely Hispanics (P

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Factors Influencing Clinical and Setting Pathways After Discharge From an Acute Palliative/Supportive Care Unit

Aim: The aim of this study was to assess the factors which influence the care pathway after discharge from an acute palliative supportive care unit (APSCU). Methods: Patients' demographics, indications for admission, kind of admission, the presence of a caregiver, awareness of prognosis, data on anticancer treatments in the last 30 days, ongoing treatment (on/off or uncertain), the previous care setting, analgesic consumption, and duration of admission were recorded. The Edmonton Symptom Assessment Scale (ESAS) at admission and at time of discharge (or the day before death), CAGE (cut down, annoy, guilt, eye-opener), and the Memorial Delirium Assessment Scale (MDAS), were used. At time of discharge, the subsequent referral to other care settings (death, home, home care, hospice, oncology), and the pathway of oncologic treatment were reconsidered (on/off, uncertain). Results: A total of 314 consecutive cancer patients admitted to the APSCU were surveyed. Factors independently associated with on-therapy were the lack of a caregiver, home discharge, and short hospital admission, in comparison with off-treatment, and less admission for other symptoms, shorter hospital admission, discharge at home, and better well-being, when compared with "uncertain." Similarly, many factors were associated with discharge setting, but the only factor independently associated with discharge home was being "on-therapy." Conclusions: The finding of this study is consistent with an appropriate selection of patients after being discharged by an APSCU, that works as a bridge between active treatments and supportive/palliative care, according the concept of early and simultaneous care.

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Novel Immunotherapeutic Agents for the Treatment of Multiple Myeloma

Multiple myeloma (MM) is a B-cell malignancy characterized by the abnormal proliferation of clonal plasma cells in the bone marrow leading to end-organ manifestations. Despite the advancement in the therapy and care of patients with MM, relapse and resistance to standard therapy remain significant. The development of immunotherapy as a treatment modality for many types of cancers has led investigators to explore its use in MM in order to elicit myeloma-targeted immune responses, especially given that immune dysregulation is an underlying feature in the pathogenesis and progression of MM. In this concise review, we discuss the different advances in the immune-based therapy of MM, from immunomodulation, vaccines, to monoclonal antibodies, checkpoint inhibitors, adoptive T-cell therapies, and future promising therapies under investigation.

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How does cilium length affect beating?

The effects of cilium length on the dynamics of cilia motion were investigated by high-speed video microscopy of uniciliated mutants of the swimming alga, Chlamydomonas reinhardtii. Cells with short cilia were obtained by deciliating cells via pH shock and allowing cilia to reassemble for limited times. The frequency of cilia beating was estimated from motion of the cell body and of the cilium. Key features of the ciliary waveform were quantified from polynomial curves fitted to the cilium in each image frame.

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Biophysics and structure-function relationships of LRRC8-formed volume-regulated anion channels (VRACs)

Volume-regulated anion channels (VRACs) are key players in regulatory volume decrease of vertebrate cells by mediating the extrusion of chloride and organic osmolytes. They play additional roles in various physiological processes beyond their role in osmotic volume regulation. VRACs are formed by heteromers of LRRC8 proteins; LRRC8A (also called SWELL1) is an essential subunit that combines with any of its paralogs, LRRC8B-E, to form hexameric VRAC complexes. The subunit composition of VRACs determines electrophysiological characteristics of their anion transport such as single-channel conductance, outward rectification and depolarization-dependent inactivation kinetics.

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Membrane Morphologies Induced by Arc-Shaped Scaffolds are Determined by Arc Angle and Coverage

The intricate shapes of biological membranes such as tubules and membrane stacks are induced by proteins. In this article, we systematically investigate the membrane shapes induced by arc-shaped scaffolds such as proteins and protein complexes with coarse-grained modeling and simulations. We find that arc-shaped scaffolds induce membrane tubules at membrane coverages larger than a threshold of about 40%, irrespective of their arc angle. The membrane morphologies at intermediate coverages below this tubulation threshold, in contrast, strongly depend on the arc angle.

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Structural characterization of N-WASP domain V using MD simulations with NMR and SAXS data

Due to their large conformational heterogeneity, structural characterization of intrinsically disordered proteins (IDPs) is very challenging using classical experimental methods alone. In the present study, we use nuclear magnetic resonance (NMR) and small-angle X-ray scattering (SAXS) data with multiple molecular dynamics (MD) simulations to describe the conformational ensemble of the fully disordered verprolin homology domain (V) of the Neural Wiskott-Aldrick Syndrome Protein (N-WASP) involved in the regulation of actin polymerization.

https://ift.tt/2VpTu6Z

Ab initio derivation of the FRET equations resolves old puzzles and suggests measurement strategies

Quantitative FRET-based imaging methods rely on the determination of an apparent FRET efficiency (Eapp) as well as donor and acceptor concentrations, in order to uncover the identity and relative abundance of the supramolecular (or quaternary) structures of associating macromolecules. Theoretical work has provided "structure-based" relationships between Eapp distributions and the quaternary structure models that underlie them. By contrast, the body of work that predicates the "signal-based" dependence of Eapp on directly measurable quantities (i.e., fluorescence emission of donors and acceptors) relies largely on plausibility arguments, one of which is the seemingly obvious assumption that the fraction of fluorescent molecules in the ground state pretty nearly equals the total concentration of molecules.

https://ift.tt/2Ewu16a

Hyaluronan disrupts cardiomyocyte organization within 3D fibrin-based hydrogels

The extracellular matrix in vivo contains variable but often large amounts of glycosaminoglycans that influence cell and tissue function. Hyaluronan (HA) is an abundant glycosaminoglycan within the extracellular matrix of the myocardium during early development and in the aftermath of a myocardial infarction. Its flexible anionic structure has a strong influence on mechanical response and interstitial fluid flow within the matrix. Additionally, HA has a direct, biochemical effect on cells through an array of cell-surface receptors including CD44, RHAMM/CD168, and other surface-exposed structures.

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A non-dimensional model reveals alterations in nuclear mechanics upon Hepatitis C Virus replication

Aberrations in nuclear morphology and cytoskeleton are indicative of abnormalities in cells. We discuss the case of Hepatitis C Virus (HCV) affecting nuclear and cytoskeletal mechanics in liver cells. We found that lamin-A,C present in the nuclear envelope is down-regulated while actin is up-regulated in liver cells expressing HCV proteins. A mechanical outcome of this is that the elastic stiffness of the nuclear envelope decreases and pre-tension in cortical actin increases. A morphological consequence is that nuclear volume and surface area increase. The interplay among aforesaid protein expression, mechanical response, and morphology is explained using a two-parameter analytical and computational model. The highlight of the work is that by merely measuring nuclear morphology, we extract relative changes in mechanical parameters.

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Neural Regeneration Research (Neural Regen Res)

Bridging larger gaps in peripheral nerves using neural prosthetics and physical therapeutic agents Muhammad Sana Ullah Sahar, Matthew Barton, Geoffrey Douglas Tansley Neural Regeneration Research 2019 14(7):1109-1115 Peripheral nerve injuries are relatively common and can be caused by a variety of traumatic events such as motor vehicle accidents. They can lead to long-term disability, pain, and financial burden, and contribute to poor quality of life. In this review, we systematically analyze the contemporary literature on peripheral nerve gap management using nerve prostheses in conjunction with physical therapeutic agents. The use of nerve prostheses to assist nerve regeneration across large gaps (> 30 mm) has revolutionized neural surgery. The materials used for nerve prostheses have been greatly refined, making them suitable for repairing large nerve gaps. However, research on peripheral nerve gap management using nerve prostheses reports inconsistent functional outcomes, especially when prostheses are integrated with physical therapeutic agents, and thus warrants careful investigation. This review explores the effectiveness of nerve prostheses for bridging large nerve gaps and then addresses their use in combination with physical therapeutic agents.

Magnesium: Pathophysiological mechanisms and potential therapeutic roles in intracerebral hemorrhage Jason J Chang, Rocco Armonda, Nitin Goyal, Adam S Arthur Neural Regeneration Research 2019 14(7):1116-1121 Intracerebral hemorrhage (ICH) remains the second-most common form of stroke with high morbidity and mortality. ICH can be divided into two pathophysiological stages: an acute primary phase, including hematoma volume expansion, and a subacute secondary phase consisting of blood-brain barrier disruption and perihematomal edema expansion. To date, all major trials for ICH have targeted the primary phase with therapies designed to reduce hematoma expansion through blood pressure control, surgical evacuation, and hemostasis. However, none of these trials has resulted in improved clinical outcomes. Magnesium is a ubiquitous element that also plays roles in vasodilation, hemostasis, and blood-brain barrier preservation. Animal models have highlighted potential therapeutic roles for magnesium in neurological diseases specifically targeting these pathophysiological mechanisms. Retrospective studies have also demonstrated inverse associations between admission magnesium levels and hematoma volume, hematoma expansion, and clinical outcome in patients with ICH. These associations, coupled with the multifactorial role of magnesium that targets both primary and secondary phases of ICH, suggest that magnesium may be a viable target of study in future ICH studies.

Network-centric medicine for peripheral nerve injury: Treating the whole to boost endogenous mechanisms of neuroprotection and regeneration David Romeo-Guitart, Caty Casas Neural Regeneration Research 2019 14(7):1122-1128 Peripheral nerve injuries caused by accidents may lead to paralysis, sensory disturbances, anaesthesia, and lack of autonomic functions. Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors: motoneuronal soma viability, proper axonal sprouting across inhibitory zones and elongation toward specific muscle, effective synapse contact rebuilding, and prevention of muscle atrophy. Therapies, such as adjuvant drugs with pleiotropic effects, that promote functional recovery after peripheral nerve injury are needed. Toward this aim, we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools. Our focus is on boosting intrinsic capabilities of neurons for neuroprotection; this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition. Using our workflow, we discovered neuroheal, a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection, is anti-inflammatory, enhances axonal regeneration after axotomy, and reduces muscle atrophy. This drug discovery workflow has thus yielded a therapy that is close to its clinical application.

Exogenous neural stem cell transplantation for cerebral ischemia Ling-Yi Liao, Benson Wui-Man Lau, Dalinda Isabel Sánchez-Vidaña, Qiang Gao Neural Regeneration Research 2019 14(7):1129-1137 Cerebral ischemic injury is the main manifestation of stroke, and its incidence in stroke patients is 70–80%. Although ischemic stroke can be treated with tissue-type plasminogen activator, its time window of effectiveness is narrow. Therefore, the incidence of paralysis, hypoesthesia, aphasia, dysphagia, and cognitive impairment caused by cerebral ischemia is high. Nerve tissue regeneration can promote the recovery of the aforementioned dysfunction. Neural stem cells can participate in the reconstruction of the damaged nervous system and promote the recovery of nervous function during self-repair of damaged brain tissue. Neural stem cell transplantation for ischemic stroke has been a hot topic for more than 10 years. This review discusses the treatment of ischemic stroke with neural stem cells, as well as the mechanisms of their involvement in stroke treatment.

Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage Hideki Kanamaru, Hidenori Suzuki Neural Regeneration Research 2019 14(7):1138-1143 Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities. Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure, followed by global cerebral ischemia. Post-subarachnoid hemorrhage ischemia, tissue injuries as well as extravasated blood components and the breakdown products activate microglia, astrocytes and Toll-like receptor 4, and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades. Once blood-brain barrier is disrupted, brain tissues are directly exposed to harmful blood contents and immune cells, which aggravate brain injuries furthermore. Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins. Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage, but the exact mechanisms remain unclear. Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage. This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.

Choroid plexus tumor necrosis factor receptor 1: A new neuroinflammatory piece of the complex Alzheimer's disease puzzle Sophie Steeland, Roosmarijn E Vandenbroucke Neural Regeneration Research 2019 14(7):1144-1147 Due to the aging of the population and despite the enormous scientific effort, Alzheimer’s disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer’s disease. Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer’s disease led to inconclusive results, partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1, but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer’s disease patients, signaling via tumor necrosis factor receptor 1. In agreement with this, choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer’s disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer’s disease-associated inflammation, choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in (early) Alzheimer’s disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer’s disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer’s disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer’s disease and prevent the irreversible neurodegeneration and resulting memory decline.

Transcriptional dysregulation in neurodegenerative diseases: Who tipped the balance of Yin Yang 1 in the brain? Zhefan Stephen Chen, Ho Yin Edwin Chan Neural Regeneration Research 2019 14(7):1148-1151 Yin Yang 1 (YY1) is a multi-functional transcription factor that regulates gene expression in a range of cell types, including neurons. It controls neuronal differentiation, as well as neuronal specification and migration during the development of the mammalian nervous system. Besides, YY1 also mediates the transcription of genes that are required for neuronal survival. An impairment of the transcriptional function of YY1 causes neuronal death. This review summarizes recent research findings that unveil the dysfunction of YY1 in multiple neurodegenerative disorders. The expression of disease proteins perturbs the function of YY1 via distinct molecular mechanisms, including recruitment to protein aggregates, protein degradation and aberrant nuclear/cytoplasmic shuttling. Understanding the pathogenic roles of YY1 will further broaden our knowledge of the disease mechanisms in distinct neurodegenerative disorders.

Effects of Ginkgo biloba extract EGb761 on neural differentiation of stem cells offer new hope for neurological disease treatment Chao Ren, Yong-Qiang Ji, Hong Liu, Zhe Wang, Jia-Hui Wang, Cai-Yi Zhang, Li-Na Guan, Pei-Yuan Yin Neural Regeneration Research 2019 14(7):1152-1157 Stem cell transplantation has brought new hope for the treatment of neurological diseases. The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells. Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors, the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located. Accordingly, the optimal microenvironment for inducing stem cell differentiation is a hot topic. EGb761 is extracted from the leaves of the Ginkgo biloba tree. It is used worldwide and is becoming one of the focuses of stem cell research. Studies have shown that EGb761 can antagonize oxygen free radicals, stabilize cell membranes, promote neurogenesis and synaptogenesis, increase the level of brain-derived neurotrophic factors, and replicate the environment required during the differentiation of stem cells into nerve cells. This offers the possibility of using EGb761 to induce the differentiation of stem cells, facilitating stem cell transplantation. To provide a comprehensive reference for the future application of EGb761 in stem cell therapy, we reviewed studies investigating the influence of EGb761 on stem cells. These started with the composition and neuropharmacology of EGb761, and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.

Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease Bridget Martinez, Philip V Peplow Neural Regeneration Research 2019 14(7):1158-1176 The most common age-related neurodegenerative disease is Alzheimer’s disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation.

Precision medicine in pantothenate kinase-associated neurodegeneration Mónica Alvarez-Cordoba, Marina Villanueva-Paz, Irene Villalón-García, Suleva Povea-Cabello, Juan M Suárez-Rivero, Marta Talaverón-Rey, Javier Abril-Jaramillo, Ana Belén Vintimilla-Tosi, José A Sánchez-Alcázar Neural Regeneration Research 2019 14(7):1177-1185 Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson’s disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate. The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available, and monitoring its effect on the pathophysiological changes, can help for a better therapeutic strategy. In addition, these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.

Mediterranean diet, alkaline water may be as effective as PPIs for laryngopharyngeal reflux

Alkaline water is water that's less acidic than regular tap water. This means it is rich in alkalizing compounds, including calcium, silica, potassium, magnesium, and bicarbonate.https://www.precisionnutrition.com/alkaline-water-legit-or-hoax

Seeing little relief with PPIs for patients, study author looked to dietary treatment for LPR

Treatment of laryngopharyngeal reflux (LPR) with alkaline water and the Mediterranean diet may be as effective as treatment with proton-pump inhibitors (PPIs), according to research published online in JAMA Otolaryngology–Head & Neck Surgery in September. Like gastroesophageal reflux disease, a similar condition, LPR occurs when acidic gastric juices in the stomach back up into the esophagus, but in LPR, the gastric juices reach the throat, resulting in symptoms such as hoarseness, sore throat, cough, and excessive mucous. 

In the study, researchers conducted a retrospective medical c­hart review comparing the change in Reflux Symptom Index (RSI) in two groups of patients, those treated between 2010 and 2012 with PPIs and standard reflux precautions and those treated between 2013 and 2015 with a plant-based Mediterranean diet and alkaline water that had a pH of at least 8. The team found that 54.1% of patients in the PPI group achieved a clinically meaningful reduction of at least 6 points, but 62.5% in the dietary group achieved similar results. Furthermore, those in the dietary group achieved a greater reduction in RSI: 39.8% compared with 27.2% in the PPI group.

"It's pretty clear that this data suggests that we, as health care professionals, need to start getting patients educated so they understand how important a role diet plays," said study lead author Craig H. Zalvan, MD, FACS, chief of otolaryngology and medical director at The Institute for Voice and Swallowing Disorders at Phelps Hospital in Sleepy Hollow, NY.

Zalvan said he thought to study dietary treatment for LPR after seeing that a sizable number of patients don't get much relief with PPIs.

"The standard of care for LPR has always been PPIs, and many of my patients got better with them, but a bunch didn't. At most it helps about 50% of patients," Zalvan said. "I looked at chronic diseases like heart disease, diabetes, and stroke, and their successful treatment with a plant-based diet, so I thought there's got to be a better way to treat LPR with diet [as well] and not have people constantly taking pills."

Zalvan added that the idea to incorporate alkaline water into treatment stemmed from prior research conducted by Jaime Koufman, MD, at the Voice Institute of New York in New York City, which suggests that alkaline water may benefit patients with reflux because it deactivates pepsin and acts as an acid buffer.

Zalvan said that as medication experts and readily accessible members of the health care team, pharmacists can help boost the signal about treatment options for LPR.

"Pharmacists can reinforce that PPIs are meant to be short-term medications for an acute problem, and that in order to get off them, diet will play a major part," Zalvan said. "If patients come to me and I say they should try diet, and then they go to the pharmacy and the pharmacist says they should try diet, patients are more likely to try diet."

For the full article, please visit www.pharmacytoday.org for the November 2017 issue of Pharmacy Today.

Cancers, Vol. 11, Pages 272: Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12

Cancers, Vol. 11, Pages 272: Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12

Cancers doi: 10.3390/cancers11030272

Authors: Frank A. Giordano Barbara Link Martin Glas Ulrich Herrlinger Frederik Wenz Viktor Umansky J. Martin Brown Carsten Herskind

Radiotherapy is a mainstay in glioblastoma therapy as it not only directly targets tumor cells but also depletes the tumor microvasculature. The resulting intra-tumoral hypoxia initiates a chain of events that ultimately leads to re-vascularization, immunosuppression and, ultimately, tumor-regrowth. The key component of this cascade is overexpression of the CXC-motive chemokine ligand 12 (CXCL12), formerly known as stromal-cell derived factor 1 (SDF-1). We here review the role of CXCL12 in recruitment of pro-vasculogenic and immunosuppressive cells and give an overview on future and current drugs that target this axis.

https://ift.tt/2XqIVSD

Issue Information

https://ift.tt/2tD1TrD

Whole‐exome sequencing in 20,197 persons for rare variants in Alzheimer's disease

https://ift.tt/2H3KReq

Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies

Abstract

Objective

We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1).

Methods

We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single‐molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed "qualifying" variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls.

Results

We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients (P = 0.006; exact unconditional test, one‐tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes.

Interpretation

Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.

https://ift.tt/2tBdNT3

Surgical fasciectomy versus collagenase injection in treating recurrent Dupuytren disease: study protocol of a randomised controlled trial

Introduction

There is no definitive cure for Dupuytren disease (DD), and recurrence of finger contractures after treatment is common. Surgical fasciectomy is considered the standard treatment method for recurrence, although associated with a high incidence of complications. Collagenase injection, a non-surgical treatment option, has been shown to be a safe and effective method; however, most studies regarding collagenase have involved first-time treatment. Collagenase efficacy in patients with recurrent DD beyond the immediate effect has not yet been determined. The aim of our study is to compare surgical fasciectomy and collagenase injection in treating recurrent DD.

Methods and analysis

The study is a single-centre randomised controlled trial. Inclusion criteria are recurrence of DD in one or more fingers after previous treatment with fasciectomy or collagenase injection, a passive extension deficit ≥30° in the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joint, and a palpable cord causing the recurrent contracture. A total of 56 patients will be randomised to either surgical fasciectomy or collagenase injection. A hand therapist blinded to patients' group allocation will measure range of motion at baseline, 3 months, 12 months, 24 months and 60 months. The primary outcomes are the total active extension deficit (MCP plus PIP) at 3 months and the proportion of patients with contracture worsening ≥20° in the treated finger joint at 2 years compared with 3 months. The secondary outcomes include changes in total active motion, active and passive extension deficit from baseline up to 5 years, scores on patient-reported outcome measures, adverse events and costs of treatment.

Ethics and dissemination

Ethical approval has been obtained from the Regional Ethical Review Board, Lund University, Sweden(2017/623). The trial will be conducted according to the Helsinki Declaration of 1975, revised in 2000. The results of the trial will be disseminated as published articles in peer-reviewed journals.

Trial registration

NCT03406338; Pre-results.

https://ift.tt/2IMMC1I

Targeted agents or immuno-oncology therapies as first-line therapy for BRAF-mutated metastatic melanoma: a real-world study

Future Oncology, Ahead of Print.


https://ift.tt/2TnqO17

Effectiveness and safety of nicotine patches combined with e-cigarettes (with and without nicotine) for smoking cessation: study protocol for a randomised controlled trial

Introduction

Evidence indicates e-cigarettes can help people quit smoking; however, more confirmatory trials are needed. To date, no trials have evaluated the effectiveness and safety of combining nicotine patches with e-cigarettes (with and without nicotine) for smoking cessation.

Methods and analysis

This study is a pragmatic, three-arm, community-based, single-blind, randomised trial undertaken in New Zealand. Eligible participants are daily/non-daily smokers, aged ≥18 years, naive e-cigarette users and motivated to quit smoking in the next 2 weeks. Participants (n=1809), recruited using multi-media advertising, are randomised to 14 weeks of (1) 21 mg nicotine patches (n=201); (2) 21 mg nicotine patches+18 mg/mL nicotine e-cigarette (n=804); or (3) 21 mg nicotine patches+nicotine free e-cigarette (n=804). Participants receive weekly withdrawal-oriented behavioural support calls for 6 weeks post-randomisation. The primary outcome is self-reported biochemically verified continuous abstinence (CA) at 6 months post quit-date. The primary comparison is nicotine patch + nicotine e-cigarette versus nicotine patch + nicotine free e-cigarette, and the secondary comparison is nicotine patch versus nicotine patch +nicotine e-cigarette (90% power, p=0.05, to detect an absolute difference in 6 month CA rates of 8% and 15% respectively). Secondary outcomes, collected by phone interview at quit date, then 1, 3, 6 and 12 months post-quit date, include self-reported CA, 7 day point prevalence abstinence, cigarettes per day (if smoking, or when smoking for non-daily smokers), time to relapse (if returned to smoking), belief in ability to quit, use of other cessation support, side effects/serious adverse events, treatment compliance, seeking additional support around e-cigarette use, daily use of both e-cigarettes and cigarettes, use of treatment past 14 weeks, views on treatment and recommendation to others, weight and cost-per-quitter.

Ethics and dissemination

The Northern A Health and Disability Ethics Committee approved the trial. Findings will be disseminated through publication, conference/meeting presentations, and media.

Trial registration number

NCT02521662; Pre-results.

https://ift.tt/2Tn5lFy

Atrial fibrillation among adults with heart failure in sub-Saharan Africa -- prevalence, incidence and all-cause mortality: a systematic review and meta-analysis protocol

Introduction

Heart failure (HF) remains a major non-communicable disease in sub-Saharan Africa (SSA) associated with high rates of readmission, mortality and loss of economic productivity as it affects mostly young and economically active adults. Atrial fibrillation (AFib) is a major determinant of mortality among patients with HF in SSA. Meanwhile, the use of anti-arrhythmic medications in the region remains unacceptably low. This review aims to evaluate the prevalence and incidence of AFib in adult patients with HF in SSA, and the all-cause mortality rate among patients with HF and AFib.

Methods and analysis

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols 2015 statement was used to prepare this protocol. All eligible studies from database inception to December, 31 2018 in MEDLINE, Embase, Google Scholar, Web of science and Africa-specific databases (AFROLIB, African Index Medicus and African Journals Online) will be included without language restrictions. The process of study screening, selection, data extraction and assessment of risk of bias will be conducted independently by two reviewers. Disagreements will be arbitrated by a third reviewer. Study-specific estimates will be pooled using random-effect meta-analysis and summary measures obtained will be presented in forest plots. The ² test on Cochrane's Q and the I² statistics will be used to assess and quantify heterogeneity, respectively. The Egger's test and funnel plots will be used to assess publication bias.

Ethics and dissemination

Since our review will be based on already published data, an ethical approval is not required. The findings of this review will be presented in conferences and peer-reviewed journals and shared on social media such as Researchgate, Facebook, WhatsApp and Twitter.

PROSPERO registration number

CRD42018087564.

https://ift.tt/2IQfYwz

Autoimmune Connective Tissue Diseases and the Risk of Rotator Cuff Repair Surgery: A Population-Based Retrospective Cohort Study

Objectives

Autoimmune connective tissue diseases (ACTDs) commonly involve the shoulder joint; however, clinical epidemiological studies investigating their association with tendons are scant. Rotator cuff (RC) tears can cause shoulder disability, and surgical intervention is usually required. The study investigated RC repair surgery risk in ACTD patients. The effect of anti-inflammatory medication on RC repair surgery risk was also investigated.

Methods

We conducted a retrospective cohort study with a 7-year longitudinal follow-up period. Patients with systemic lupus erythematosus, systemic sclerosis, sicca syndrome, dermatomyositis and polymyositis diagnoses between 2004 and 2008 were enrolled. The control cohort comprised age- and sex-matched controls. The HR and adjusted HR (aHR) were estimated for the risk of RC surgery between ACTD and control cohorts after adjustment for confounders. Furthermore, the effects of steroid and non-steroidal anti-inflammatory drug (NSAID) use on the HR and aHR of RC surgery risk were analysed.

Results

We enrolled 5019 ACTD patients and 25 095 controls in the ACTD and control cohorts, respectively. RC surgery incidence was 49 and 24 per 100 000 person-years in the ACTD and control cohorts, respectively. In the ACTD cohort, the crude HR for RC surgery was 2.08 (95% CI , 1.08 to 4.02, p<0.05), and the aHR was 1.97 (95% CI, 1.01 to 3.82, p<0.05). The ACTD patients who used NSAIDs had an aHR of 3.13 (95% CI, 1.21 to 8.07, p<0.05) compared with the controls, but the ACTD patients who used steroids did not have a significantly higher aHR than the controls.

Conclusions

ACTD patients had an increased risk of RC repair surgery. However, no difference was found in RC surgery risk when steroids were used compared with the control cohort. This could indicate that inflammation control may be a strategy for managing subsequent RC lesions.

https://ift.tt/2TnqMq1

A qualitative study exploring how routinely collected Medication Safety Thermometer data have been used for quality improvement purposes using case studies from three UK hospitals

Objectives

The Medication Safety Thermometer (MedsST) is a medication safety data collection tool, which has been used by over 100 UK healthcare organisations to enable measurement of medication safety for improvement purposes. This study aimed to explore whether, and how, data collected by the MedsST have been used in organisations to facilitate medication safety improvements.

Design

Routine MedsST data collected between October 2013 and July 2016 were analysed using Run charts. Identified changes were investigated using interviews with staff from each hospital trust. The interviews were analysed using a framework based on Normalisation Process Theory, focusing on use of the MedsST and its data.

Setting

Three National Health Service hospital trusts in the North West of England, which have used the MedsST for the longest period.

Participants

Eight interview participants, purposely sampled based on their involvement with the MedsST, included pharmacists, pharmacy technicians and nurses.

Results

Improvement was often at ward level and focused on particular areas of medication safety, led by clinical champions. The most sustainable improvements involved changes to systems, such as introducing new guidelines. Although some improvement occurred, internal communication about improvements was poor, and large amounts of data remained unused, often due to a lack of ownership of data review and use.

Conclusions

Simply collecting data is not sufficient; a system of data collection, review and use for improvement is required. Issues with such systems may have been recognised and averted if implementation theory had been used in the early stages of national development and implementation. However, implementation theory could be used within organisations to fix issues locally, particularly to increase ward-level ownership of this system, which could lead to considerable improvements.

https://ift.tt/2IFa554

Reversal of defunctioning stoma following rectal cancer surgery: are we getting better? A population‐based single centre experience

We evaluate timing of stoma reversal and reasons of delayed stoma closure after low anterior resection of rectum for cancer in two different time frames in our institute. We find that in one fourth of the cases the temporary stoma was reversed within the scheduled 120 days after index surgery. In one third of cases delayed stoma reversal was due to low medical priority by healthcare provider.

Background

The aim was to assess factors influencing the timing of defunctioning stoma (DS) reversal following low anterior resection of rectum for cancer (LAR).

Methods

All patients operated with LAR and a primary DS during a 9‐year period were included. Reversal later than 120 days after LAR was considered as delayed. A DS not reversed within 2 years was considered as permanent.

Results

In the present study, median age at LAR was 67 years, 45% were females, median body mass index was 25, 87% had American Society of Anesthesiologists class I or II, 64% had pre‐operative radiotherapy, and 3% had cancer stage IV. A total of 79% (92/116) underwent stoma reversal, whereof 25% (23/92) were reversed within 120 days. The most common health‐related reasons for delayed stoma reversal were adjuvant chemotherapy in 38%, symptomatic anastomotic leakage in 16% and other post‐operative adverse events in 13%. In 35% delayed stoma reversal was because of low priority within the healthcare system. A total of 18% (20/110) never had their DS reversed (n = 11) or had their DS converted to a permanent end colostomy (n = 9). Major risk factors for permanent stoma were stage IV cancer in 55%, and symptomatic anastomotic leakage in 30%.

Conclusion

One fourth of the patients had their defunctioning stoma reversed within 120 days. The most common identifiable medical reasons for delayed stoma reversal were adjuvant chemotherapy and symptomatic anastomotic leakage, while in one out of three patients it was because of low priority by the healthcare provider.

https://ift.tt/2T31k9R

Cancers, Vol. 11, Pages 271: Brain Metastases from Lung Cancer: Is MET an Actionable Target?

Cancers, Vol. 11, Pages 271: Brain Metastases from Lung Cancer: Is MET an Actionable Target?

Cancers doi: 10.3390/cancers11030271

Authors: Giulia M. Stella Alessandra Corino Giulia Berzero Stefan Kolling Andrea R. Filippi Silvia Benvenuti

The process of metastatic dissemination begins when malignant cells start to migrate and leave the primary mass. It is now known that neoplastic progression is associated with a combination of genetic and epigenetic events. Cancer is a genetic disease and this pathogenic concept is the basis for a new classification of tumours, based precisely on the presence of definite genetic lesions to which the clones are addicted. Regarding the scatter factor receptors MET and Recepteur d&rsquo;Origin Nantais (RON), it is recognised that MET is an oncogene necessary for a narrow subset of tumours (MET-addicted) while it works as an adjuvant metastogene for many others. This notion highlights that the anti-MET therapy can be effective as the first line of intervention in only a few MET-addicted cases, while it is certainly more relevant to block MET in cases of advanced neoplasia that exploit the activation of the invasive growth program to promote dissemination in other body parts. Few data are instead related to the role played by RON, a receptor homologous to MET. We have already demonstrated an implication of MET and RON genes in brain metastases from lung cancer. On this basis, the aim of this work is to recapitulate and dissect the molecular basis of metastatic brain dissemination from lung cancer. The latter is among the big killers and frequently gives rise to brain metastases, most often discovered at diagnosis. Molecular mechanisms leading to tumour spread to the brain are mostly unknown and in turn these tragic cases are still lacking effective therapies. Based on previously published data from our group, we aim to summarise and analyse the pathogenic mechanisms leading to activation of the scatter factor receptor in brain metastatic lesions of lung primaries, from the point of view of replacing the currently used empirical treatment with a more targeted approach.

https://ift.tt/2Xpa9ZW

The interleukin-17 G-197A polymorphism is associated with cyclosporine metabolism and transplant rejection in liver transplant recipients

Pharmacogenomics, Ahead of Print.


https://ift.tt/2BNbO2r

Outcomes following restrictive or liberal red blood cell transfusion in patients with lower gastrointestinal bleeding

Summary

Background

Restrictive red blood cell (RBC) transfusion reduces mortality and rebleeding after upper gastrointestinal bleeding (UGIB). However, there is no evidence to guide transfusion strategies in lower gastrointestinal bleeding (LGIB).

Aim

To assess the association between RBC transfusion strategies and outcomes in patients with LGIB

Methods

This was a post hoc analysis of the UK National Comparative Audit of LGIB and the Use of Blood. The relationships between liberal RBC transfusion and clinical outcomes of rebleeding, mortality and a composite outcome for safe discharge were examined. Transfusion strategy was dichotomised and defined as "liberal" when transfusion was administered for haemoglobin (Hb) ≥80 g/L (or ≥90 g/L in patients with acute coronary syndrome) or major haemorrhage, and "restrictive" otherwise. Multivariable logistic regression models were used to assess the independent association between liberal RBC transfusion and outcomes.

Results

Of 2528 consecutive patients enrolled from 143 hospitals in the original study, 666 (26.3%) received RBC transfusion (mean age 73.3 ± 16 years, 49% female, initial mean haemoglobin 90 ± 24 g/L, 2.3% had haemodynamic instability). The rebleeding rate in transfused patients was 42.3%. After adjusting for potential confounders, there was no difference between liberal and restrictive RBC transfusion strategies for the odds of rebleeding (OR 0.89, 95% CI 0.6‐1.22), in‐hospital mortality (OR 0.54, 95% CI 0.3‐1.1) or of achieving the composite outcome (OR 0.72, 95% CI 0.5‐1.1).

Conclusion

Although these results could be due to residual confounding, they provide an important foundation for the design of randomised trials to evaluate transfusion strategies for LGIB.

https://ift.tt/2IClAdE

Mutation profile of pfdhfr and pfdhps in Plasmodium falciparum among returned migrant workers in China from Africa [Epidemiology and Surveillance]

We evaluated markers of sulfadoxine-pyrimethamine (SP) resistance in P. falciparum among 254 returned migrant workers in China from Africa during 2013-2016. High prevalence of pfdhfr (97.2%) and pfdhps (96.5%) mutations were observed. The partially resistant genotype was homogeneously distributed in Africa with a modestly high prevalence (48%), whereas the super resistant genotype was only found in West Africa with a very low frequency (1.2%). The findings provided baseline data of molecular markers of SP resistance.

https://ift.tt/2GIUwrj

Whole-genome sequencing analysis of multidrug-resistant serotype 15A Streptococcus pneumoniae in Japan and the emergence of a highly resistant serotype 15A-ST9084 clone [Mechanisms of Resistance]

Since the introduction of pneumococcal conjugate vaccines, an increase in the incidence of disease attributable to serotype 15A-ST63 pneumococci has been observed in many regions worldwide. We conducted a nationwide pediatric pneumococcal infection surveillance study between 2012 and 2014 in Japan. In the surveillance study, we detected multidrug-resistant serotype 15A-CC63 strains (resistant to macrolides, penicillin, cefotaxime and meropenem); in this study, we analyzed these resistant isolates to determine the dynamics and mechanism of resistance using whole-genome sequencing. In most of the penicillin-, cefotaxime- and meropenem-resistant strains, recombination occurred in the pbp2x region resulting in the acquisition of additional cefotaxime resistance to penicillin and meropenem. In the multidrug-resistant serotype 15A-CC63 strains, we identified a specific clone with ST9084, and all of the isolates were recovered from Yamaguchi prefecture in Japan. All of the serotype 15A-ST9084 isolates had a novel pbp2x-43 that was inserted by recombination events. The conserved amino acid motif profiles of pbp1a, pbp2b and pbp2x of the strains were identical to those in serotype 19A-ST320. A Bayesian analysis-based date estimation suggested that this clone emerged in approximately 2002 before the introduction of PCV in Japan. This clone should be monitored because serotype 15A is not contained in the currently used PCV13 and it was resistance to beta-lactams, which are often use in a clinical setting.

https://ift.tt/2Nv6NQD

Comparison of the Antiviral Activity of Bictegravir Against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants [Antiviral Agents]

We compared the activity of the integrase inhibitor bictegravir against HIV-1 and HIV-2 using a culture-based, single-cycle assay. EC₅₀ values ranged from 1.2 to 2.5 nM for nine HIV-1 isolates and 1.4 to 5.6 nM for 15 HIV-2 isolates. HIV-2 integrase mutants G140S/Q148R and G140S/Q148H were 34- and 110-fold resistant to bictegravir, respectively; other resistance-associated mutations conferred ≤5-fold changes in bictegravir susceptibility. Our findings indicate that bictegravir-based ART should be evaluated in HIV-2–infected individuals.

https://ift.tt/2GLPUjZ

Pharmacokinetics of levofloxacin in children treated for drug-resistant TB exposure [Clinical Therapeutics]

Levofloxacin is used to treat and prevent drug-resistant tuberculosis in children. We assessed levofloxacin serum drug concentrations for 24 children 2–10 years old receiving levofloxacin-based tuberculosis preventive therapy in Karachi, Pakistan. Only 9 (37.5%) children achieved adequate drug exposure. Target serum drug concentration was met in 4 (26.6%) of 15 children dosed consistently with World Health Organization recommendations, and 4 (80.0%) of 5 who received higher-than-recommended doses. Levofloxacin dosing recommendations may require reevaluation.

https://ift.tt/2Nv6K7p

A Nationwide Screen of carbapenem-resistant Klebsiella pneumoniae reveals an isolate with enhanced virulence and clinically undetected colistin-heteroresistance [Epidemiology and Surveillance]

The convergence of hypervirulence and multidrug-resistance in Klebsiella pneumoniae is a significant concern. We report the first screen for hypermucoviscosity, a trait associated with increased virulence, using a US surveillance collection of carbapenem-resistant K. pneumoniae. We identified one hypermucoviscous isolate, encoding the KPC-3 carbapenemase among numerous resistance genes. The strain further exhibited colistin heteroresistance undetected by diagnostics. This convergence of diverse resistance mechanisms and increased virulence underscores the need for enhanced K. pneumoniae surveillance.

https://ift.tt/2GKhUok

Resistance Analysis of Bictegravir/Emtricitabine/Tenofovir Alafenamide in HIV-1 Treatment-Naïve Patients Through 48 Weeks [Antiviral Agents]

In Studies 1489 and 1490, bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), or DTG+F/TAF treatment achieved high rates of virologic suppression in HIV-1 treatment-naïve participants through Week 48. Pre-existing primary drug resistance was present at 1.3% INSTI resistance (-R), 2.7% NRTI-R, 14.1% NNRTI-R, and 3.5% PI-R in the 1274 participants from these studies. These mutations did not affect treatment outcomes. Resistance analyses in 13 virologic failures found no emergent resistance to study drugs.

https://ift.tt/2NxrHyI

Serum Levels of Crushed Posaconazole Delayed Release Tablets [Letters]

Posaconazole (POS) delayed release tablets (DRT) are favored over the suspension formulation due to once-daily dosing and improved absorption....

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Fluoroquinolone efficacy against tuberculosis is driven by penetration into lesions and activity against resident bacterial populations [Pharmacology]

Fluoroquinolones are the pillar of multi-drug resistant tuberculosis (MDR-TB) treatment, with either moxifloxacin, levofloxacin or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of 'universal' drug regimens, aiming to treat drug susceptible and resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacy in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than plasma concentrations and potency measured in standard growth inhibition assays, and to determine whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK-/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. Based on these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (plasma AUC/MIC range is 46-86 for moxifloxacin and 74-258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level, and sterilizing cellular and necrotic lesions. Collectively, these results show that PK-PD at the site of infection is an adequate predictor of drug efficacy against TB, and constitute the baseline required to explore synergies, antagonism and drug-drug interactions in fluoroquinolone-containing regimens.

https://ift.tt/2NxrCLq

Resistance and virulence mechanisms of Escherichia coli selected by enrofloxacin in chicken [Mechanisms of Resistance]

This study aimed to investigate the genetic characteristics, antibiotic resistance patterns and novel mechanisms involved in fluoroquinolone (FQ) resistance in commensal Escherichia coli (E. coli). The E. coli were recovered from a previous clinical study and subjected to antimicrobial susceptibility testing and molecular typing. Known mechanisms of FQ resistance (target sites mutation, plasmid-mediated quinolone resistance (PMQR) genes, relative expression levels of efflux pumps and porins) were detected using DNA sequencing of PCR products and real-time qPCR. Whole genome shotgun sequencing was performed on 11 representative strains to screen for SNPs. The function of a key SNP (A1541G) was investigated by site-directed mutagenesis and allelic exchange. Results showed that long term enrofloxacin treatment selected multidrug resistant (MDR) E. coli in chicken gut and these E. coli isolates had diverse genetic backgrounds. Multiple genetic alterations including double mutations on GyrA (S83L and D87N), single mutation on ParC (S80I) and ParE (S458E), activation of efflux pumps and QnrS1 protein contributed to the high-level FQ resistance (MIC_ENR≥128 μg/mL), while the relative low-level FQ resistance (MIC_ENR=8 or 16 μg/mL) was commonly mediated by decreased expression of the porin OmpF, besides enhancement of the efflux pumps. No significant relationship was observed between resistance mechanisms and virulence genes. Introduction of A1541G mutation on aegA was able to increase the FQ susceptibility by 2-fold. This study contributed to better understanding of the development of MDR and differences underlying mechanisms of high-level and low-level FQ resistance in E. coli.

https://ift.tt/2GLGUeG

Antibiotic treatment duration for bacteremia due to Enterobacteriaceae: A systematic review and meta-analysis [Clinical Therapeutics]

Background: The duration of antibiotic therapy for bacteremia due to Enterobacteriaceae is not well-defined. We sought to evaluate the clinical outcomes with shorter versus longer-course treatment.

Methods: We performed a systematic search of the PubMed and EMBASE databases through May 2018. Studies presenting comparative outcomes between patients receiving antibiotic treatment for ≤10 days ("short-course") and those treated for >10 days ("long-course") were considered eligible.

Results: Four retrospective cohort studies and one randomized controlled trial comprising 2,865 patients met the inclusion criteria. Short and long-course antibiotic treatment did not differ in 30-day all-cause mortality (1,374 patients, RR= 0.99, 95% CI (0.69-1.43)), 90-day all-cause mortality (1,750 patients, RR= 1.16 (95% CI, 0.81-1.66)), clinical cure (1,080 patients, RR= 1.02 (95% CI, 0.96-1.08)), or relapse at 90 days (1,750 patients, RR= 1.08 95% CI (0.69-1.67)).

Conclusions: In patients with bacteremia due to Enterobacteriaceae, short and long-course antibiotic treatment did not differ significantly in terms of clinical outcomes. Further well-designed studies are needed before treatment for 10 days or less is adopted in clinical practice.

https://ift.tt/2NxryeE

Measuring Antimicrobial Efficacy against Biofilms: A Meta-Analysis [Analytical Procedures]

Through a statistical meta-analysis of published data on antimicrobial efficacy against biofilms formed by two common bacterial species it was concluded that the particular experimental method used is the most important factor determining the outcome of the test. An expected dose-response behavior (greater killing with higher dose concentrations or longer treatment times) was observed for data sets derived from a single method, but was not observed when data from multiple studies using diverse methods were pooled. Method specific properties such as the surface area to volume ratio, areal biofilm cell density, and microbial species were shown to influence quantitative measurements of biofilm killing. A better appreciation of the method characteristics that affect anti-biofilm efficacy tests could aid decision-making related to investment in research and development and regulatory approvals for biofilm control strategies. These recommendations are offered to those working in research and development related to biofilm control: 1) report the log reduction, surface area to volume ratio, and biofilm areal cell density; 2) include data for a benchmark agent, making sure that this agent performs competitively at the dose tested; 3) measure a dose response, i.e., make measurements at multiple treatment concentrations or dose durations; and 4) use a standardized method in addition to research methods.

https://ift.tt/2GLO96C

Molecular characterization of multidrug-resistant Pseudomonas aeruginosa isolates in hospitals in Myanmar [Epidemiology and Surveillance]

The emergence of multidrug-resistant (MDR) Pseudomonas aeruginosa has become a serious worldwide medical problem. This study was designed to clarify the genetic and epidemiological properties of MDR P. aeruginosa strains isolated from hospitals in Myanmar. Forty-five MDR P. aeruginosa isolates obtained from different patients in seven hospitals in Myanmar were screened by the broth microdilution method. The whole genomes of the MDR isolates were sequenced by MiSeq (Illumina). Phylogenetic trees were constructed from single nucleotide polymorphism concatemers. Multilocus sequence types were deduced and drug resistance genes were identified. Of the 45 isolates, 38 harbored genes encoding carbapenemases, including DIM-1, IMP-1, NDM-1, VIM-2 and VIM-5; and nine had genes encoding 16S rRNA methylases, including RmtB, RmtD3, RmtE and RmtF2. Most strains of MDR P. aeruginosa isolated in Myanmar belonged to ST1047. This is the first molecular epidemiological analysis of MDR P. aeruginosa clinical isolates in Myanmar. These findings strongly suggest that P. aeruginosa ST1047 harboring carbapenemases, including DIM-, IMP-, NDM- and VIM-type metallo-β-lactamases, have been spreading throughout medical settings in Myanmar.

https://ift.tt/2Nv6sxl

NG-test Carba5 for rapid detection of carbapenemase-producing Enterobacterales from positive blood cultures [Mechanisms of Resistance]

The immunochromatographic assay, NG-test Carba5 (NG-biotech), has been evaluated for detection of carbapenemase-producing Enterobacterales (CPE) from spiked blood cultures (n=205). It detected and discriminated in less than 30 minutes KPC-, IMP-, VIM-, NDM- and OXA-48-like-producers with a sensitivity and specificity of 97.7% and 96.1%. Thus, it might help the rapid optimization of treatment of bloodstream infections due to CPE.

https://ift.tt/2GOFQa6

Chlorotoxin targets ERα/VASP signaling pathway to combat breast cancer

Chlorotoxin can directly interact with estrogen receptor (ER)α to inhibit the expression of ERα, which inhibits the ERα/VASP signaling pathway, leading to suppression of cell growth and migration in breast cancer.

Abstract

Breast cancer is one of the most common malignant tumors among women worldwide. About 70‐75% of primary breast cancers belong to estrogen receptor (ER)‐positive breast cancer. In the development of ER‐positive breast cancer, abnormal activation of the ERα pathway plays an important role and is also a key point leading to the failure of clinical endocrine therapy. In this study, we found that the small molecule peptide chlorotoxin (CTX) can significantly inhibit the proliferation, migration and invasion of breast cancer cells. In in vitro study, CTX inhibits the expression of ERα in breast cancer cells. Further studies showed that CTX can directly bind to ERα and change the protein secondary structure of its LBD domain, thereby inhibiting the ERα signaling pathway. In addition, we also found that vasodilator stimulated phosphoprotein (VASP) is a target gene of ERα signaling pathway, and CTX can inhibit breast cancer cell proliferation, migration, and invasion through ERα/VASP signaling pathway. In in vivo study, CTX significantly inhibits growth of ER overexpressing breast tumor and, more importantly, based on the mechanism of CTX interacting with ERα, we found that CTX can target ER overexpressing breast tumors in vivo. Our study reveals a new mechanism of CTX anti‐ER‐positive breast cancer, which also provides an important reference for the study of CTX anti‐ER‐related tumors.

https://ift.tt/2EwT2Op

Comprehensive clinical profiling of the Gauting locoregional lung adenocarcinoma donors

We designed a study that longitudinally profiled the phenotype of 366 patients with resected lung adenocarcinoma and identified multiple novel aspects of the phenotype of contemporary locoregional lung adenocarcinoma, such as its sex indifference, its striking upper lobe predominance, and the early timing of pleural relapse and we developed a simple clinical tool to predict survival that outperforms the current staging system.

Abstract

A comprehensive characterization of lung adenocarcinoma (LADC) clinical features is currently missing. We prospectively evaluated Caucasian patients with early‐stage LADC. Patients with LADC diagnosed between 2011 and 2015 were prospectively assessed for lung resection with curative intent. Fifty clinical, pathologic, radiologic, and molecular variables were recorded. Patients were followed till death/study conclusion. The main findings were compared to a separate cohort from France. Of 1943 patients evaluated, 366 were enrolled (18.8%; 181 female; 75 never‐smokers; 28% of registered Bavarian cases over the study period). Smoking and obstruction were significantly more prevalent in GLAD compared with adult Bavarians (P < 0.0001). Ever‐smoker tumors were preferentially localized to the upper lobes. We observed 120 relapses and 74 deaths over 704 cumulative follow‐up years. Median overall and disease‐free survival were >7.5 and 3.6 years, respectively. Patients aged <45 or >65 years, resected >60 days postdiagnosis, with abnormal FVC/DL_COV_A, N2/N3 stage, or solid histology had significantly decreased survival estimates. These were fit into a weighted locoregional LADC death risk score that outperformed pTNM7 in predicting survival in the GLAD and in our second cohort. We define the clinical gestalt of locoregional LADC and provide a new clinical tool to predict survival, findings that may aid future management and research design.

https://ift.tt/2VkiNXW

Brain Tumor Micro-environment and Host State - Implications for Immunotherapy

Glioblastoma (GBM) is a highly lethal brain tumor with poor responses to immunotherapies which have been successful in more immunogenic cancers with less immunosuppressive tumor microenvironments (TMEs). GBM's TME is uniquely challenging to treat due to tumor cell extrinsic components that are native to the brain, as well as tumor intrinsic mechanisms which aid in immune evasion. Lowering the barrier of immunosuppression by targeting the genetically stable tumor stroma presents opportunities to treat the tumor in a way that circumvents the complications of targeting a constantly mutating tumor with tumor antigen directed therapies. Tumor associated monocytes, macrophages, and microglia (TAMs) are a stromal element of particular interest. Macrophages and monocytes compose the bulk of infiltrating immune cells and are considered to have pro-tumor and immunosuppressive effects. Targeting these cells or other stromal elements is expected to convert what is considered the "cold" TME of GBM to a more "hot" TME phenotype. This conversion could increase the effectiveness of what have become conventional frontline immunotherapies in GBM - creating opportunities for better treatment through combination therapy.

https://ift.tt/2Xpf0KB

Single-Application FIT Moderately Sensitive, Specific for CRC

MONDAY, Feb. 25, 2019 -- Single-application fecal immunochemical tests (FITs) have moderate-to-high sensitivity and specificity for colorectal cancer (CRC), according to a review published online Feb. 26 in the Annals of Internal Medicine. Thomas F....

https://ift.tt/2UfL4P2

FDA: Thermography No Substitute for Mammograms

MONDAY, Feb. 25, 2019 -- Despite claims to the contrary, thermography should not be used in place of mammography for breast cancer screening, detection, or diagnosis, according to the U.S. Food and Drug Administration. Thermography devices -- also...

https://ift.tt/2BUCKNJ

Knowledge of Transgender Health Care Not Linked to Education

MONDAY, Feb. 25, 2019 -- Transphobia -- not formal or informal education -- predicts provider knowledge of transgender health care, according to a study recently published in Medical Education. Daphna Stroumsa, M.D., M.P.H., from the University of...

https://ift.tt/2BRqOwg

Prognostic Bleeding Risk Models Developed for Aspirin Use

MONDAY, Feb. 25, 2019 -- Prognostic bleeding risk models that can estimate the absolute bleeding harms of aspirin have been developed for individuals in whom aspirin is being considered for primary prevention of cardiovascular disease (CVD),...

https://ift.tt/2U5B62M

Post hoc analyses of surrogate markers of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis in patients with type 2 diabetes in a digitally supported continuous care intervention: an open-label, non-randomised controlled study

Objective

One year of comprehensive continuous care intervention (CCI) through nutritional ketosis improves glycosylated haemoglobin(HbA1c), body weight and liver enzymes among patients with type 2 diabetes (T2D). Here, we report the effect of the CCI on surrogate scores of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis.

Methods

This was a non-randomised longitudinal study, including adults with T2D who were self-enrolled to the CCI (n=262) or to receive usual care (UC, n=87) during 1 year. An NAFLD liver fat score (N-LFS) >–0.640 defined the presence of fatty liver. An NAFLD fibrosis score (NFS) of >0.675 identified subjects with advanced fibrosis. Changes in N-LFS and NFS at 1 year were the main endpoints.

Results

At baseline, NAFLD was present in 95% of patients in the CCI and 90% of patients in the UC. At 1 year, weight loss of ≥5% was achieved in 79% of patients in the CCI versus 19% of patients in UC (p<0.001). N-LFS mean score was reduced in the CCI group (–1.95±0.22, p<0.001), whereas it was not changed in the UC (0.47±0.41, p=0.26) (CCI vs UC, p<0.001). NFS was reduced in the CCI group (–0.65±0.06, p<0.001) compared with UC (0.26±0.11, p=0.02) (p<0.001 between two groups). In the CCI group, the percentage of individuals with a low probability of advanced fibrosis increased from 18% at baseline to 33% at 1 year (p<0.001).

Conclusions

One year of a digitally supported CCI significantly improved surrogates of NAFLD and advanced fibrosis in patients with T2D.

Trial registration number

NCT02519309; Results.

https://ift.tt/2Ssoi4W

Deciphering the Genetics of Major End-Use Quality Traits in Wheat

Improving the end-use quality traits is one of the primary objectives in wheat breeding programs. In the current study, a population of 127 recombinant inbred lines (RILs) derived from a cross between Glenn (PI-639273) and Traverse (PI-642780) was developed and used to identify quantitative trait loci (QTL) for 16 end-use quality traits in wheat. The phenotyping of these 16 traits was performed in nine environments in North Dakota, USA. The genotyping for the RIL population was conducted using the wheat Illumina iSelect 90K SNP assay. A high-density genetic linkage map consisting of 7,963 SNP markers identified a total of 76 additive QTL (A-QTL) and 73 digenic epistatic QTL (DE-QTL) associated with these traits. Overall, 12 stable major A-QTL and three stable DE-QTL were identified for these traits, suggesting that both A-QTL and DE-QTL played an important role in controlling end-use quality traits in wheat. The most significant A-QTL (AQ.MMLPT.ndsu.1B) was detected on chromosome 1B for mixograph middle line peak time. The AQ.MMLPT.ndsu.1B A-QTL was located very close to the position of the Glu-B1 gene encoding for a subunit of high molecular weight glutenin and explained up to 24.43% of phenotypic variation for mixograph MID line peak time. A total of 23 co-localized QTL loci were detected, suggesting the possibility of the simultaneous improvement of the end-use quality traits through selection procedures in wheat breeding programs. Overall, the information provided in this study could be used in marker-assisted selection to increase selection efficiency and to improve the end-use quality in wheat.

https://ift.tt/2NutDrs