Publication date: Available online 12 August 2017
Source:Seminars in Spine Surgery
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Σάββατο 12 Αυγούστου 2017
Introduction
Effects of Chinese medicinal herbs on expression of brain-derived Neurotrophic factor (BDNF) and its interaction with human breast cancer MDA-MB-231 cells and endothelial HUVECs
Our previous study demonstrated that an up-regulation of the Brain-Derived Neurotrophic Factor (BDNF) signaling pathway is involved the mechanism causing the recurrence of triple negative breast cancer. The ai...
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The Role of Adenosine A2A Receptor, CYP450s, and PPARs in the Regulation of Vascular Tone
Adenosine is an endogenous mediator involved in a myriad of physiologic functions, including vascular tone regulation. It is also implicated in some pathologic conditions. Four distinct receptor subtypes mediate the effects of adenosine, such as its role in the regulation of the vascular tone. Vascular tone regulation is a complex and continuous process which involves many mechanisms and mediators that are not fully disclosed. The vascular endothelium plays a pivotal role in regulating blood flow to and from all body organs. Also, the vascular endothelium is not merely a physical barrier; it is a complex tissue with numerous functions. Among adenosine receptors, receptor subtype (AR) stands out as the primary receptor responsible for the vasodilatory effects of adenosine. This review focuses on important effectors of the vascular endothelium, including adenosine, adenosine receptors, EETs (epoxyeicosatrienoic acids), HETEs (hydroxyeicosatetraenoic acids), PPARs (peroxisome proliferator-activated receptors), and channels. Given the impact of vascular tone regulation in cardiovascular physiology and pathophysiology, better understanding of the mechanisms affecting it could have a significant potential for developing therapeutic agents for cardiovascular diseases.
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Advanced Oxidation Protein Products and Carbonylated Proteins as Biomarkers of Oxidative Stress in Selected Atherosclerosis-Mediated Diseases
Objectives. The main question of this study was to evaluate the intensity of oxidative protein modification shown as advanced oxidation protein products (AOPP) and carbonylated proteins, expressed as protein carbonyl content (C=O) in abdominal aortic aneurysms (AAA), aortoiliac occlusive disease (AIOD), and chronic kidney disease (CKD). Design and Methods. The study was carried out in a group of 35 AAA patients and 13 AIOD patients. However, CKD patients were divided into two groups: predialysis (PRE) included 50 patients or hemodialysis (HD) consisted of 34 patients. AOPP and C=O were measured using colorimetric assay kit, while C-reactive protein concentration was measured by high-sensitivity assay (hsCRP). Results. The concentration of AOPP in both AAA and AIOD groups was higher than in PRE and HD groups according to descending order: AAA~AIOD > HD > PRE. The content of C=O was higher in the PRE group in comparison to AIOD and AAA according to the descending order: PRE~HD > AAA~AIOD. Conclusions. AAA, AIOD, and CKD-related atherosclerosis (PRE and HD) contribute to the changes in the formation of AOPP and C=O. They may promote modification of proteins in a different way, probably due to the various factors that influence oxidative stress here.
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Automated Classification of Lung Cancer Types from Cytological Images Using Deep Convolutional Neural Networks
Lung cancer is a leading cause of death worldwide. Currently, in differential diagnosis of lung cancer, accurate classification of cancer types (adenocarcinoma, squamous cell carcinoma, and small cell carcinoma) is required. However, improving the accuracy and stability of diagnosis is challenging. In this study, we developed an automated classification scheme for lung cancers presented in microscopic images using a deep convolutional neural network (DCNN), which is a major deep learning technique. The DCNN used for classification consists of three convolutional layers, three pooling layers, and two fully connected layers. In evaluation experiments conducted, the DCNN was trained using our original database with a graphics processing unit. Microscopic images were first cropped and resampled to obtain images with resolution of 256 × 256 pixels and, to prevent overfitting, collected images were augmented via rotation, flipping, and filtering. The probabilities of three types of cancers were estimated using the developed scheme and its classification accuracy was evaluated using threefold cross validation. In the results obtained, approximately 71% of the images were classified correctly, which is on par with the accuracy of cytotechnologists and pathologists. Thus, the developed scheme is useful for classification of lung cancers from microscopic images.
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Green Tea Extracts Epigallocatechin-3-gallate for Different Treatments
Epigallocatechin-3-gallate (EGCG), a component extracted from green tea, has been proved to have multiple effects on human pathological and physiological processes, and its mechanisms are discrepant in cancer, vascularity, bone regeneration, and nervous system. Although there are multiple benefits associated with EGCG, more and more challenges are still needed to get through. For example, EGCG shows low bioactivity via oral administration. This review focuses on effects of EGCG, including anti-cancer, antioxidant, anti-inflammatory, anticollagenase, and antifibrosis effects, to express the potential of EGCG and necessity of further studies in this field.
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Ginsenoside Rg1 Attenuates Cigarette Smoke-Induced Pulmonary Epithelial-Mesenchymal Transition via Inhibition of the TGF-β1/Smad Pathway
Epithelial-mesenchymal transition (EMT) is a process associated with airway remodeling in chronic obstructive pulmonary disease (COPD), which leads to progressive pulmonary destruction. Panax ginseng is a traditional herbal medicine that has been shown to improve pulmonary function and exercise capacity in patients with COPD. Ginsenoside Rg1 is one of the main active components and was shown to inhibit oxidative stress and inflammation. The present study investigated the hypothesis that ginsenoside Rg1 attenuates EMT in COPD rats induced by cigarette smoke (CS) and human bronchial epithelial (HBE) cells exposed to cigarette smoke extract (CSE). Our data showed that CS or CSE exposure increased expression of the mesenchymal marker α-smooth muscle actin (α-SMA) and decreased expression of the epithelial marker epithelial cadherin (E-cad) in both lung tissues and HBE cells, which was markedly suppressed by ginsenoside Rg1. Importantly, CS-induced upregulation of TGF-β1/Smad pathway components, including TGF-β1, TGF-βR1, phospho-Smad2, and phospho-Smad3, was also inhibited by ginsenoside Rg1. Additionally, ginsenoside Rg1 mimicked the effect of SB525334, a TGF-βR1-Smad2/3 inhibitor, on suppression of EMT in CSE-induced HBE cells. Collectively, we concluded that ginsenoside Rg1 alleviates CS-induced pulmonary EMT, in both COPD rats and HBE cells, via inhibition of the TGF-β1/Smad pathway.
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Bone Marrow Metastasis Is an Early Stage of Bone Metastasis in Breast Cancer Detected Clinically by F18-FDG-PET/CT Imaging
Objective. To determine the value of 18F-FDG PET/CT in detection of bone marrow (BM) metastasis in breast cancer which is considered an early stage of bone metastasis. Patients and Methods. Retrospectively, breast cancer patients with bone metastasis were included. BM metastasis was considered if the lesion was PET positive/CT occult while bone metastasis was considered if the lesion was PET positive/ CT positive. BM metastases were observed sequentially on F18-FDG PET/CT. Results. We included 35 patients. Eighteen patients (51%) had BM metastases in addition to other bone metastases. BM metastases comprised 24% of all lesions. Posttreatment scan was performed on 26/35 patients. Twenty-three percent of BM metastases had resolved completely without causing bone destruction after treatment. Sixty-five percent of BM metastases had converted into bone metastases after treatment. Twelve percent of BM metastases had persisted after treatment. Conclusion. This retrospective study showed clinically by 18F-FDG PET/CT imaging that BM metastasis is an early stage of bone metastasis in breast cancer. Interestingly, 18F-FDG-PET/CT showed that early eradication of individual BM metastasis by systemic treatment precluded development of bone metastasis. However, more research is needed to study the impact of an early diagnosis of BM metastases on treatment outcome.
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Cholinergic activity and levodopa-induced dyskinesia: a multitracer molecular imaging study
Abstract
Objective
To investigate the association between levodopa-induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease.
Methods
This study included 13 Parkinson's disease patients with peak-of-dose levodopa-induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine single-photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computed tomography, to measure dopamine reuptake transporter density and 2-[18F]fluoro-2-deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed.
Results
Density of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side.
Interpretation
Our findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic-depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression.
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Advantages in Prognosis of Adult Patients with Ewing Sarcoma: 11-years Experiences and Current Treatment Management
Abstract
Ewing sarcoma (ES) is an exceptionally rare tumor in adults. Data regarding outcomes of adult patients with ES and experiences with age-adapted therapeutic strategies are very limited. The aim of this study was to evaluate prognostic factors and clinical outcome in a cohort of adult patients treated according to pediatric protocols in the Czech Republic. The records of 58 adult ES patients diagnosed between 2002 and 2013 were reviewed and factors relevant to prognosis and survival were analyzed. The median age of study cohort was 29 years (range, 18–59). The most frequent location was axial (36.2%), followed by involvement of extraskeletal tissues (34.5%) and bones of the extremities (29.3%). Twenty-eight (48.3%) patients had metastatic disease. In cases with localized ES, the 5-year overall survival (OS) was 76.5%. Using the log-rank test, the presence of metastasis at diagnosis, local treatment without surgery and a failure to achieve complete remission were associated with significantly shorter survival. In a multivariate Cox proportional hazard analysis, the achievement of complete remission was an independent predictor of patients's survival time. Outcomes of adults with localized ES treated according to multimodal pediatric protocols are similar to children. The achievement of complete remission is an independent predictor of survival time in ES patients. Severe hematological toxicity is foreseeable and manageable. Prognosis of patients with metastases or progression remains dismal.
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Practice of Comparative Effectiveness Research to Identify Treatment Characteristics of Similar Chinese Patent Medicine for Angina Pectoris
Objective. Individualized application of TCM is not easy and may lead to undesirable results, such as poor effect or even adverse reactions. This trial aims to compare two common Chinese patent medicines with similar effects. Background of the Research. Four hospitals carried out the test at the same time in Tianjin city of China. Participants. 144 patients were involved in this study; all patients must meet the diagnostic criteria. Interventions. Qishen Yiqi pills, compound danshen pills, and their placebos; an efficacy analysis was conducted after the first medication and after crossover medication. Primary Outcome Measures. The primary index of end point includes Seattle Angina Questionnaire score-7 and score of 7-point Likert Scale; the curative effect was compared with minimal clinically important differences value. Result. Two drugs have their respective advantages in treating SAP. In practical application, the two drugs shall be discriminated in use based on patients' specific symptoms. Trial Registration. Chinese clinical trials register is ChiCTR-TTRCC-14004406 (registered 23 March 2014).
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CRS and HIPEC for PMP—Use of the LC-CUSUM to Determine the Number of Procedures Required to Attain a Minimal Level of Proficiency in Delivering the Combined Modality Treatment
Abstract
The learning curve for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for pseudomyxoma peritonei (PMP) which peaks at 90 procedures for the surgeon may take several years to reach. The cumulative summation (CUSUM) test of the learning curve (LC-CUSUM) was used to assess the safety of the procedure (minimal level of proficiency for the surgeon) in terms of morbidity, mortality, and completeness of cytoreduction and early oncological failure before the peak of the learning curve had been reached. The limits for h0 and h1 were set based on the results of large series of such cases published before. From 2011 to 2016, 77 patients with PMP underwent CRS and HIPEC. The mean peritoneal cancer index (PCI) was 28 and 75% of the patients had a CC-0/1 resection. The grade 3–4 morbidity was 42.6% and the mortality was 5.2%. The 5-year overall survival (OS) was 62.3% and the 3-year disease-free survival (DFS) was 71%. The LC-CUSUM analysis showed that for in-hospital mortality, acceptable limits are reached after the 57th case, after the 38th case for the grade 3–4 morbidity and CC-2/3 resections both and after the 70th case for early oncological failure. The number of cases required to attain a minimal level of proficiency for each prognostic variable is different. Using the CUSUM test, surgeons can analyze their performance and determine the areas in which they need to improve before the peak of the learning curve is reached. These outcomes reflect the performance of the multidisciplinary team and not the surgeon alone.
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MicroRNAs, promising biomarkers in the diagnosis of Xp11 translocation RCC
Renal cell carcinomas (RCCs) with Xp11 translocation/TFE3 gene fusions (Xp11 RCC) are a characteristic subtype of RCC, distinguished by chromosomal translocations with breakpoints of the TFE3 transcription factor gene, which point to the Xp11.2 locus [1]. Xp11 translocation RCCs are the majority of pediatric RCC with a high degree of malignancy, but only 1%–4% of adult RCC [2]. At present, no standard treatment protocol for a sick person with Xp11 translocation RCC has been found. Research shows that clinical symptoms, image characteristics and pathologic characteristics of Xp11 translocation RCC are similar to other RCC subtypes [3,4].
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MicroRNAs, promising biomarkers in the diagnosis of Xp11 translocation RCC—reply
We read with great interest the Letter to the Editor entitled "MicroRNAs, promising biomarkers in diagnosis of Xp11 translocation RCC" by Li et al, in which the authors provide a synopsis of the microRNA expression profiles associated with distinct renal cell carcinoma (RCC) subtypes in response to our recent paper on Xp11 RCC [1]. This letter further underscores the importance of recognizing the molecular underpinnings of RCC subtypes to advance our knowledge of this disease, provide the rationale for improved RCC molecular classification, and possibly foster the development of targeted therapeutic interventions.
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Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma
Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4.
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Deletion in HSP110 T17: Correlation with wild-type HSP110 expression and prognostic significance in microsatellite-unstable advanced gastric cancers
Deletion of the HSP110 T17 mononucleotide repeat has recently been identified as a prognostic marker that is correlated with wild-type HSP110 (HSP110wt) expression in microsatellite instability-high (MSI-H) colorectal cancers. The aim of this study was to assess the correlation between deletion of the HSP110 T17 repeat and expression of HSP110wt, using DNA testing and immunohistochemistry and to determine the prognostic implications of HSP110 T17 deletion in MSI-H advanced gastric cancers (GCs).
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Quality Improvement Pearls for the Palliative Care and Hospice Professional
Rapid changes in how palliative care clinicians are evaluated and paid present an imperative for clinicians to adeptly and routinely perform quality improvement in usual practice. Like empathic communication and facilitating goals of care discussions, quality improvement skills must be learned, honed, and practiced so identifying problems and brainstorming solutions becomes a natural component of delivering serious illness care. Using our experience in both failures and successes in performing quality improvement, herein we provide a prioritized list of ten pearls specifically aimed to palliative care and hospice professionals.
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“Cross-Cultural Adaptation and Psychometric Evaluation of the Turkish Version of the Cancer Behavior Inventory-Brief Version”
Cancer Behavior Inventory-Brief Version is a simple and non-burdensome tool used to evaluate the self-efficacy of the cancer patients.
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Is early palliative care feasible in patients with Multiple Myeloma?
Evidence for the benefits of early palliative care (EPC) in patients with solid tumors is strong, but EPC has received scant attention in hematological malignancies.
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Factors Associated with Use of U.S. Community-Based Palliative Care for Children with Life-Limiting or Life-Threatening Illnesses and Their Families: An Integrative Review
As children with life-limiting and life-threatening illnesses live longer, challenges to meeting their complex health care needs arise in homes and communities, as well as in hospitals. Integrated knowledge regarding community-based pediatric palliative care (CBPPC) is needed to strategically plan for a seamless continuum of care for children and their families.
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Psychometric Properties of the Fatigue Questionnaire EORTC QLQ-FA12 in a sample of female cancer patients
. Cancer patients frequently suffer from fatigue. Recently, the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life group developed a new 12-item fatigue assessment instrument.
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Late-life suicide in terminal cancer: a rational act or under-diagnosed depression?
Previous studies have reported significantly elevated standardised mortality rates in older people with cancer. Terminally ill people represent a unique group where suicide may be considered as rational.
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The Relationship between Psychological Symptoms and Ventricular Assist Device Implantation
Ventricular assist devices (VADs) improve quality of life in advanced heart failure (HF) patients, but there are little data exploring psychological symptoms in this population.
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Unfinished Business in Families of Terminally Ill with Cancer Patients
Unfinished business often causes psychological issues after bereavement. Providing care for families of terminally ill patients with cancer to prevent unfinished business is important.
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MicroRNA-137 and -195* inhibit vasculogenesis in brain arteriovenous malformations
Abstract
Objectives: Brain arteriovenous malformations (AVMs) are the most common cause of non-traumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs.
Methods: We used a large-scale miRNA analysis on 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8-induced proliferation assays were used to test the miRNAs effect on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics.
Results: A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* which were key signaling proteins involved in vessel development.
Interpretation: Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis. This article is protected by copyright. All rights reserved.
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Receipt of Nephrology Care and Clinical Outcomes Among Veterans With Advanced CKD
Clinical practice guidelines recommend referral to nephrology when estimated glomerular filtration rate (eGFR) decreases to <30mL/min/1.73m2; however, evidence for benefits of nephrology care are mixed.
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Marijuana and Cannabinoids in ESRD and Earlier Stages of CKD
Marijuana is the most commonly used recreational drug in the United States, and legal recreational and medicinal use has gained public acceptance during the last decade. Twenty-nine US states have established medical marijuana programs, 8 of which have also legalized recreational marijuana, and Canada is expected to legalize recreational marijuana in 2018. Advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) are chronic conditions with significant associated morbidity and mortality.
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Acute Kidney Injury After Computed Tomography: A Meta-analysis
Computed tomography (CT) is an important imaging modality used in the diagnosis of a variety of disorders. Imaging quality may be improved if intravenous contrast is added, but there is a concern for potential renal injury. Our goal is to perform a meta-analysis to compare the risk of acute kidney injury, need for renal replacement, and total mortality after contrast-enhanced CT versus noncontrast CT.
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Emergency Department Involvement in Accountable Care Organizations in Massachusetts: A Survey Study
We assess Massachusetts emergency department (ED) involvement and internal ED constructs within accountable care organization contracts.
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Emergency Department Use in the Perinatal Period: An Opportunity for Early Intervention
We characterize emergency department (ED) utilization among perinatal women and identify differences in risk factors and outcomes between women who use versus do not use the ED during the perinatal period.
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Complex Reproductive Traits and Whole-Organism Performance
Synopsis
Arnold's 1983 path-analytic paradigm, considering "morphology, performance, and fitness," has been elaborated in several ways. For example, current versions recognize the level of "behavior" (including aspects of motivation) as a filter between performance abilities (only measurable if motivation is maximal) and fitness components. Performance abilities constrain behavior, but behavioral choices may shield performance from selection. Conceptual and empirical issues remain, such as the extent to which individual variation in lower-level subordinate traits (e.g., circulating hormone concentrations) might directly affect behavior, growth rates, sexual maturation, etc., rather than having effects only through paths involving some aspect of performance. Moreover, empirical studies have yet to encompass more than a few possible paths in a given system, in part because life-history researchers rarely communicate with those focused on performance. Most life-history studies ponder trade-offs associated with reproductive effort, but studies of locomotor performance (e.g., maximal sprint speed) have rarely considered trade-offs with reproduction. This lack of connection is surprising because both life history (e.g., clutch size) and locomotor performance (e.g., locomotor stamina) traits require allocation of energy and other resources, so trade-offs between these trait types may be expected. These perspectives and cultures could be bridged by a focus on the ability of organisms to perform components of reproductive biology (e.g., lactation performance could be studied in animals maximally "motivated" by manipulation of litter size or endocrine function). Alternatively, one could study impacts of reproduction on performance, as when bats and live-bearing fishes lose maneuverability during gestation. We also consider sperm performance in the context of the paradigm and illustrate that the paradigm can easily be utilized as a frame-work within which to consider key aspects of sperm biology.http://ift.tt/2uQ5eC0
Physiological Trade-Offs in Lizards: Costs for Individuals and Populations
Synopsis
The immune system is a critical component of health and fitness, whereby organisms must maintain sufficient health to survive to reproduce. Because of the key role of immunity in an organism's fitness, the use of immunological indices is widespread. However, there is a paucity of empirical support for the best way to interpret immunological data, and the internal energetic state of the organism, as well as the external environmental pressures it faces, are often not considered concurrently. A stronger immune response is not always beneficial to the organism; a more attenuated response may ultimately lead to improved fitness if the animal incurs fewer performance costs on competing systems, especially reproduction. Additionally, the external pressures animals encounter (such as anthropogenic disturbance) must be considered along with the animal's internal state. A synthesis of results addressing resource allocation between the immune and reproductive systems is presented using a well-studied organism, the side-blotched lizard, from a combination of field and laboratory studies under varying environmental conditions. Specifically, experiments involving specific immune, reproductive, metabolic, and performance costs in a laboratory setting are discussed, as well as associated demographic trade-offs between survival and reproductive success, demonstrating essential links between immunity and the population.http://ift.tt/2uyxePc
Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers
Abstract
Diminished ANK3 contributes to cell survival by inhibiting detachment-induced apoptosis. TP53BP1 that interacts with p53 and MFN1 that encodes a mitochondrial membrane protein are considered to have tumor suppressor gene (TSG) functions. HACD4 involving fatty acid synthesis and TCPL10 with transcription regulation functions are considered TSGs. Many genes involved in DNA methylations such as LCMT2, RNMT, TRMT6, METTL8 and METTL16 are often perturbed in cancer. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbored 11 (13.9%), 3 (3.8%), 0 (0%), 5 (6.3%), 1 (1.3%), 2 (2.5%), 4 (5.1%), 3 (3.8%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI-H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. There were ITH of the frameshift mutations of ANK3, MFN1 and TP53BP1 in 1 (6.3%), 1 (6.3%) and 1 (6.3%) cases, respectively. Our data exhibit that cancer-related genes ANK3, HACD4, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC.
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In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients
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Development of a Refined Protocol for Trans-scleral Subretinal Transplantation of Human Retinal Pigment Epithelial Cells into Rat Eyes
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Alpha-synuclein oligomers: a new hope
Abstract
Alpha-synuclein is a protein implicated in Parkinson's disease and thought to be one of the main pathological drivers in the disease, although it remains unclear how this protein elicits its neurotoxic effects. Recent findings indicate that the assembly of toxic oligomeric species of alpha-synuclein may be one of the key processes for the pathology and spread of the disease. The absence of a sensitive in situ detection method has hindered the study of these oligomeric species and the role they play in the human brain until recently. In this review, we assess the evidence for the toxicity and prion-like activity of oligomeric forms of alpha-synuclein and discuss the advances in our understanding of the role of alpha-synuclein in Parkinson's disease that may be brought about by the specific and sensitive detection of distinct oligomeric species in post-mortem patient brain. Finally, we discuss current approaches being taken to therapeutically target alpha-synuclein oligomers and their implications.
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Taurine upregulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma
Abstract
Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of Taurine upregulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion and glycolysis via suppression of miR-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3′-untranslated region (UTR) of AMP-activated protein kinase subunit beta 2 (AMPKβ2). The TUG1/miR-455-3p/AMPKβ2 axis regulates cell growth, metastasis and glycolysis through regulation of Hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. Conclusion: Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKβ2 and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. This article is protected by copyright. All rights reserved.
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Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance
Abstract
Plasma concentrations of amino acids (AA), in particular branched chain (BCAA), are often found increased in non-alcoholic fatty liver disease (NAFLD). However, if this is due to increased muscular protein catabolism, obesity and/or increased insulin resistance (IR) or impaired tissue metabolism is not known. Thus, we evaluated a) if subjects with NAFLD non-obese (NAFLD-NO), compared to obese (NAFLD-Ob) display altered plasma AA compared to controls (CT); b) if AA concentrations are associated to IR and liver histology. Also glutamic acid, serine and glycine concentrations were previously found altered in NAFLD. Since these AA are involved in glutathione synthesis we hypothesized they might be related to the severity of NAFLD.
In 44 non-diabetic NAFLD subjects with liver biopsy, (29 NAFLD-NO and 15 NAFLD-Ob) and 20 non-obese CT we measured AA profile by GCMS, HOMA-IR, hepatic IR [Hep-IR=Endogenous Glucose Production x Insulin] and the new GSG-index [glutamate/(serine+glycine)] and tested if they were associated with liver histology.
Most AA were increased only in NAFLD-Ob. Only alanine, glutamate, isoleucine and valine, but not leucine, were increased in NAFLD-NO compared to CT. Glutamate, tyrosine and GSG-index were correlated with Hep-IR. GSG-index correlated with liver enzymes, in particular GGT (R = 0.70), independently of BMI. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAA and Aromatic-AA, and mildly with GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 vs. F0-2 in this cohort.
Conclusions: Increased plasma AA concentrations were observed mainly in obese NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible new marker of severity of liver disease independently of BMI. This article is protected by copyright. All rights reserved.
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Targeting senescent cholangiocytes and activated fibroblasts with Bcl-xL inhibitors ameliorates fibrosis in Mdr2-/- mice
ABSTRACT
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASF), which are drivers of fibrosis. The activated phenotype of ASF is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASF and explored a combined targeting strategy to deplete senescent cholangiocytes and ASF from fibrotic tissue to ameliorate liver fibrosis. Using a co-culture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a PDGF-dependent manner. We also identified Bcl-xL as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also upregulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule BH3 mimetic A-1331852 or Bcl-xL-specific siRNA induced apoptosis in PDGF-activated fibroblasts but not in quiescent fibroblasts. Likewise, inhibition of Bcl-xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to non-senescent cells. Treatment of Mdr2-/- mice with A-1331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis-inducing growth factors and cytokines, decrease of αSMA-positive ASF and finally in a significant reduction of liver fibrosis. Conclusions: Bcl-xL is a key survival factor in ASF as well as in senescent cholangiocytes. Treatment with the Bcl-xL-specific inhibitor A-1331852 reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This novel mechanism represents an attractive therapeutic strategy in biliary fibrosis. This article is protected by copyright. All rights reserved.
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Hepatitis B virus pregenomic RNA in hepatocellular carcinoma: A nosological and prognostic determinant
Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). However, very little is known about the replication of HBV in HCC tissues.
Patients and Methods. We analysed viral and cellular parameters in HCC (T) and non-tumor liver (NT) samples from 99 HBsAg-positive, virologically suppressed patients treated by tumour resection or liver transplantation. We examined total HBV DNA and RNA as well as covalently closed circular DNA (cccDNA) and pregenomic RNA (pgRNA), which are considered as markers of active HBV replication. Results. Total HBV DNA and RNA were detected in both T and NT samples in a majority of cases, but only a subset of tumors harboured detectable levels of HBV cccDNA and pgRNA (39% and 67%) compared to NT livers (66% and 90%) (p<0.01). Further evidence for HBV replication in tumor tissues was provided by sequencing of the X gene derived from episomal forms, showing that HBV genotypes differed between T and matched NT samples in 11 cases. The detection of pgRNA and cccDNA in tumours was correlated to the absence of tumorous microvascular invasion and to better patient survival. Analysis of gene expression profiles by Agilent microarrays revealed that pgRNA-positive HCCs were characterized by low levels of cell cycle and DNA repair markers, and expression of the HBV receptor: sodium taurocholate cotransporting polypeptide (NTCP), indicating well-differentiated tumors.
Conclusion. HCC replicating HBV represents a subtype of weakly invasive HCC with a transcriptomic signature. PgRNA originating from non-integrated, complete HBV genomes is a sensitive marker for viral replication and prognosis. This article is protected by copyright. All rights reserved.
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Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are highly prevalent in the US, where they are a growing cause of cirrhosis and hepatocellular carcinoma (HCC), and increasingly, an indicator for liver transplantation.
Methods: A Markov model was used to forecast NAFLD disease progression. Incidence of NAFLD was based on historical and projected changes in adult prevalence of obesity and type 2 diabetes mellitus (DM). Assumptions were derived from published literature where available, and validated using national surveillance data for incidence of NAFLD-related HCC. Projected changes in NAFLD-related cirrhosis, advanced liver disease, and liver-related mortality were quantified through 2030.
Results: Prevalent NAFLD cases are forecasted to increase 21%, from 83.1 (2015) to 100.9 million (2030), while prevalent NASH cases will increase 63% from 16.52 to 27.00 million cases. Overall NAFLD prevalence among the adult population (aged ≥15 years) is projected at 33.5% in 2030, and the median age of the NAFLD population will increase from 50 to 55 years during 2015-2030. In 2015, approximately 20% of NAFLD cases were classified as NASH, increasing to 27% by 2030, a reflection of both disease progression and an aging population. Incidence of decompensated cirrhosis will increase 168% to 105,430 cases by 2030, while incidence of HCC will increase by 137% to 12,240 cases. Liver deaths will increase 178% to an estimated 78,300 deaths in 2030. During 2015-2030, there are nearly 800,000 excess liver deaths.
Conclusions: With continued high rates of adult obesity and DM, and an aging population, NAFLD-related liver disease and mortality will increase in the US. Strategies to slow the growth of NAFLD cases and therapeutic options are necessary to mitigate disease burden. This article is protected by copyright. All rights reserved.
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Gene-panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication
ABSTRACT
Gene-panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high-risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene-panel sequencing including also CNV analysis for genomic changes. We identified 12 different pathogenic BRCA1, BRCA2, TP53, PTEN, CHEK2, or RAD51C mutations in 18/95 patients (19%). BRCA1/2 mutations were observed in 8 patients (8.4%) and CHEK2 protein-truncating mutations in 7 patients (7.4%). In addition, we identified a novel duplication encompassing most of the RAD51C gene. We further genotyped the duplication in breast or ovarian cancer families (n = 1149), in unselected breast (n = 1729) and ovarian cancer cohorts (n = 553), and in population controls (n = 1273). Seven additional duplication carries were observed among cases but none among controls. The duplication associated with ovarian cancer risk (3/590 of all ovarian cancer patients, 0.5%, p=0.032 compared to controls) and was found to represent a large fraction of all identified RAD51C mutations in the Finnish population. Our data emphasizes the importance of comprehensive mutation analysis including CNV detection in all the relevant genes.
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Blockade of transforming growth factor-β signaling enhances oncolytic herpes simplex virus efficacy in patient-derived recurrent glioblastoma models
Abstract
Despite the current standard of multimodal management, glioblastoma (GBM) inevitably recurs and effective therapy is not available for recurrent disease. A subset of tumor cells with stem-like properties, termed GBM stem-like cells (GSCs), are considered to play a role in tumor relapse. Although oncolytic herpes simplex virus (oHSV) is a promising therapeutic for GBM, its efficacy against recurrent GBM is incompletely characterized. Transforming growth factor beta (TGF-β) plays vital roles in maintaining GSC stemness and GBM pathogenesis. We hypothesized that oHSV and TGF-β inhibitors would synergistically exert anti-tumor effects for recurrent GBM. Here we established a panel of patient-derived recurrent tumor models from GBMs that relapsed after post-surgical radiation and chemotherapy, based on GSC-enriched tumor sphere cultures. These GSCs are resistant to the standard-of-care temozolomide but susceptible to oHSVs G47Δ and MG18L. Inhibition of TGF-β receptor kinase with selective targeted small molecules reduced clonogenic sphere formation in all tested recurrent GSCs. The combination of oHSV and TGF-βR inhibitor was synergistic in killing recurrent GSCs through, in part, an inhibitor-induced JNK-MAPK blockade and increase in oHSV replication. In vivo, systemic treatment with TGF-βR inhibitor greatly enhanced the anti-tumor effects of single intratumoral oHSV injections, resulting in cures in 60% of mice bearing orthotopic recurrent GBM. These results reveal a novel synergistic interaction of oHSV therapy and TGF-β signaling blockade, and warrant further investigations aimed at clinical translation of this combination strategy for GBM patients. This article is protected by copyright. All rights reserved.
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How will transitioning from cytology to HPV testing change the balance between the benefits and harms of cervical cancer screening? Estimates of the impact on cervical cancer, treatment rates and adverse obstetric outcomes in Australia, a high vaccination coverage country
Abstract
Primary HPV screening enables earlier diagnosis of cervical lesions compared to cytology, however, its effect on the risk of treatment has not been investigated. We estimated the cumulative lifetime risk (CLR) of cervical cancer and excisional treatment; and change in adverse obstetric outcomes in HPV unvaccinated women and cohorts offered vaccination (>70% coverage in 12-13 years) for the Australian cervical screening program. 2-yearly cytology screening (ages 18-69 years) was compared to 5-yearly primary HPV screening with partial genotyping for HPV16/18 (ages 25-74 years). A dynamic model of HPV transmission, vaccination, cervical screening and treatment for precancerous lesions was coupled with an individual-based simulation of obstetric complications. For cytology screening, the CLR of cervical cancer diagnosis, death and treatment would be 0.65%, 0.20% and 13% without vaccination and 0.18%, 0.06% and 7%, in vaccinated cohorts, respectively. For HPV screening, relative reductions of 33% and 22% in cancer risk for unvaccinated and vaccinated cohorts are predicted, respectively, compared to cytology. Without vaccination, a 4% increase in treatment risk for HPV versus cytology screening is predicted, implying a possible increase in pre-term delivery (PTD) and low birthweight (LBW) events of 19-35 and 14-37, respectively, per 100,000 unvaccinated women. However, in vaccinated cohorts treatment risk will decrease by 13%, potentially leading to 4-41 fewer PTD events and from 2 more to 52 fewer LBW events per 100,000 vaccinated women. HPV screening starting at age 25 in populations with high vaccination coverage, is therefore expected to decrease the risks of cervical cancer and excisional treatment. This article is protected by copyright. All rights reserved.
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Cancer risk in different generations of Middle Eastern Immigrants to California, 1988-2013
Abstract
The objective of this study is to compare cancer risk among different generations of Middle Eastern (ME) immigrants and Non-Hispanic Whites (NHW) in California between 1988 and 2013. We used data from the California Cancer Registry to identify invasive primary incident cancer cases in three population groups: a) first generation ME immigrants, b) second or subsequent generations ME immigrants, and c) NHW. Proportional Incidence Ratio (PIR) was used to compare cancer risk of the 15 selected most common cancers in the 3 population groups taking into consideration time since immigration for first generation ME immigrants. First generation ME immigrants were more likely to be at increased risk of stomach (PIR= 3.13) and hepatobiliary (PIR=2.27) cancers in females and thyroid (PIR=2.19) and stomach (PIR=2.13) cancers in males in comparison with NHW. Second or subsequent generations ME immigrants were at increased risk of thyroid cancer (PIR=1.43 in females and 2.00 in males) in comparison with NHW, and malignant melanoma cancer (PIR=4.53 in females and 4.61 in males) in comparison with first generation ME immigrants. The risk levels of breast, thyroid, and bladder cancers in ME first generation were significantly higher compared to NHW regardless of time spent in the United States suggesting the role of genetic predisposition, and/or cultural characteristics associated with these cancers. The results suggest that differences in cancer risk between ME first generation immigrants and NHW change in second or subsequent generations, approaching the risk level of NHW and indicating the impact of acculturation in this immigrant population. This article is protected by copyright. All rights reserved.
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Familial associations of female breast cancer with other cancers
Abstract
Familial risks of breast cancer (BC) are well established but whether BC clusters with other, i.e. discordant, cancers is less certain but of interest for the identification of common genetic and possible environmental factors contributing to a general cancer susceptibility. We apply a novel approach to search for familial associations of BC with other (discordant) cancers based on the Swedish Family-Cancer Database. Relative risks (RRs) were calculated for BC in families with increasing numbers of patients with discordant cancer X, and conversely, familial RRs for cancer X in families with increasing numbers of BC patients. Joint p-values were calculated from independent analyses.
The total number of familial BCs was 12,266, 14.9% with one first-degree relative with BC and 1.2% with at least 2 affected relatives. Ovarian and prostate cancers showed the strongest associations with BC (p-value <10−11). The p-value for melanoma was <10−6, for stomach and male colorectal cancer <2.5x10−6, for cancer of unknown primary <2.5x10−5, and for lung cancer <5x10−5. Significance level <5x10−4 was reached with pancreatic cancer. The remaining associations (p<0.0025) included thyroid, endometrial, testicular, eye cancers (uveal melanoma), nervous system and endocrine tumors and non-Hodgkin lymphoma. The RR for BC increased by increasing numbers of patients with any cancer in family members and it reached 1.62 when three or more family members were affected. The results suggest that BC shares susceptibility with a number of other cancers. This might alert genetic counselors and challenge approaches for gene and gene-environment identification. This article is protected by copyright. All rights reserved.
http://ift.tt/2vYS3Ui
Deep eutectic solvents enable the enhanced production of n-3 PUFA-enriched triacylglycerols
Abstract
Efficient synthesis of n-3 PUFA-enriched triacylglycerol (TAG) by the esterification of glycerol with n-3 PUFA in deep eutectic solvents (DES) is reported. There was a 1.2-fold increase of TAG yield in DES compared with that in the solvent-free system. Adsorption of the produced water by DES during esterification contributed to enhance the conversion efficiency by changing the reaction equilibrium. DES also served as an effective solvent for enriching the n-3 PUFA of TAG in the upper layer of reaction media. A TAG yield of 55% was achieved under the optimal condition.
Practical applications Enzymatic synthesis of n-3 PUFA-enriched triacylglycerol (TAG) is challenged by low yields. Here deep eutectic solvents show great potential for enhancing the production of n-3 PUFA-enriched TAG.
http://ift.tt/2vwnUsh
Alkyl-branched Fatty Compounds: Hydro-alkylation of Non-activated Alkenes with Haloalkanes Mediated by Ethylaluminum Sesquichloride
Abstract
The general method for the cationic hydro-alkyl addition to the nonactivated C=C double bond of alkenes mediated by ethylaluminum sesquichloride (Et3Al2Cl3) has been importantly improved and simplified by using haloalkanes (primary, secondary, tertiary) instead of alkyl chloroformates as alkylating agent and performing the reaction without any additional solvent. The protocol is especially suited to perform the hydro-alkylation of internal double bonds. Reaction of the haloalkane with Et3Al2Cl3 gives an alkyl cation which is added to the alkene; hydride transfer from Et3Al2Cl3 to the adduct carbenium ion gives the saturated addition product. Primary halo alkanes give the same addition product as the respective secondary halo alkane because of 1,2-H shift yielding the secondary carbenium ions. In the case of 1-alkenes triethylsilane has to be used as additional hydride donor to avoid di- and oligomerization. Special interest has been focused on alkylation of unsaturated fatty compounds, which are important renewable feedstocks, mostly (Z)-configured such as methyl oleate, high oleic sunflower oil, neopentyl glycol dioleate, but also (E)-configured i. e. dimethyl (E)-icos-10-enedioate, and with terminal double bond such as methyl 10-undecenoate. The respective alkyl branched fatty compounds were obtained after simple work-up with excellent to good yields. The protocol was scaled up without problems to > 0.5 mol.
Practical Applications The synthesis of alkyl-branched fatty compounds is of high importance since they have interesting properties that make them attractive for use in the cosmetics and lubricant area. We developed an industrially feasible method for the synthesis of well-defined alkyl branched oleochemicals.
http://ift.tt/2vPmCvc
Oncocytic variant of medullary thyroid carcinoma; a rare tumor with numerous diagnostic mimics by fine needle aspiration
Oncocytic variant of medullary thyroid carcinoma is rare form of thyroid carcinoma that is easily misdiagnosed on fine needle aspiration specimens due to it is low incidence and cytomorphologic overlap with other more common Hurtle cell lesions. A correct initial diagnosis by fine needle aspiration is imperative as the clinical treatment for medullary carcinoma differs significantly from the mimickers. We present a case of this rare variant tumor that on initial fine needle aspiration was described as a Hurthle cell lesion and was subsequently correctly classified on the resection specimen. In this brief review, we describe the cytomorphologic features of medullary carcinoma, oncocytic variant of medullary carcinoma and it is most common mimickers, and we discuss the ancillary studies required to confirm the diagnosis. This case highlights the importance of a complete clinical history and radiologic correlation, which in conjunction with a careful attention to the cytologic features of the fine needle aspiration sample, should in most cases ensure a correct initial diagnosis.
http://ift.tt/2vZ4dwv
The diagnostic utility of Merkel cell polyomavirus immunohistochemistry in a fine needle aspirate of metastatic Merkel cell carcinoma of unknown primary to the pancreas
Abstract
Merkel cell carcinoma (MCC) is an aggressive skin tumor with a high tendency for metastases. We report a case of MCC initially presenting as axillary and pancreatic metastases. A 33-year-old HIV-positive Hispanic male presented with a history of a rapidly growing axillary mass. A needle core biopsy demonstrated an epithelioid neoplasm composed of small to medium-sized cells with high nuclear-cytoplasmic ratio, nuclear molding, and frequent mitotic figures. A subsequent PET scan revealed a 1.5 cm FDG avid mass in the pancreas. Endoscopic ultrasound-guided FNA of the pancreatic mass showed neoplastic cells with similar morphology to those of the axillary mass. The tumor cells were positive with pancytokeratin AE1/AE3, CK20, CD56, synatophysin, chromogranin, and Merkel cell polyomavirus (MCPyV). This case of MCC most likely originated from a resolved primary skin lesion drained by the involved axillary lymph node with subsequent metastases to the pancreas and distant lymph nodes.
http://ift.tt/2wSvugo
Ketamine or Ketofol: Do we have enough evidence to know which one to use?
Abstract
Ketamine and propofol are both commonly used emergency department (ED) procedural sedation agents. Their concurrent administration, often referred to as "ketofol", is widely used for procedural sedation. A simple google search can lead to a lot of opinions on why we should use propofol, ketamine, or ketofol in a given situation for moderate or deep procedural sedation in the ED, but finding evidence that supports differences these opinions assume is much harder to come by.
This article is protected by copyright. All rights reserved.
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Persistent detection of alternatively spliced BCR-ABL variant results in a failure to achieve deep molecular response
Abstract
Treatment with tyrosine kinase inhibitors (TKIs) may sequentially induce TKI-resistant BCR-ABL mutants in chronic myeloid leukemia (CML). Conventional polymerase chain reaction (PCR) monitoring of BCR-ABL is an important indicator to determine therapeutic intervention for preventing disease progression. However, PCR cannot quantify separately amounts of BCR-ABL and its mutants, including alternatively spliced BCR-ABL with an insertion of 35 intronic nucleotides (BCR-ABLIns35bp) between ABL exons 8 and 9 which introduces the premature termination and loss of kinase activity. To assess the clinical impact of BCR-ABL mutants, we performed deep sequencing analysis of BCR-ABL transcripts of 409 samples from 37 patients with suboptimal response to frontline imatinib who were switched into nilotinib. At baseline, TKI-resistant mutations were documented in 3 patients, whereas BCR-ABLIns35bp was detected in all patients. After switching to nilotinib, both BCR-ABL and BCR-ABLIns35bp became undetectable in 3 patients who attained complete molecular response (CMR), whereas in remaining all 34 patients, BCR-ABLIns35bp was persistently detected, and minimal residual disease (MRD) fluctuated at low but detectable levels. PCR monitoring underestimated MR in 5 patients whose BCR-ABLIns35bp was persisted, although BCR-ABLIns35bp does not inevitably mark TKI-resistance. Therefore, quantification of BCR-ABLIns35bp is useful for evaluating "functional" MRD and determining effectiveness of TKIs with accuracy.
This article is protected by copyright. All rights reserved.
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Changes in pulmonary vascular responsiveness to hypoxia
Abstract
We read with interest the recent article by Luks et al. (2017), which reports the relationship between arterial oxygen saturation and an echocardiographic index of pulmonary artery pressure (tricuspid transvalvular pressure gradient, TVPG) in healthy volunteers at sea level and after undertaking a two-week trek to Everest base camp.
This article is protected by copyright. All rights reserved
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Cancers, Vol. 9, Pages 107: ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice
Cancers, Vol. 9, Pages 107: ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice
Cancers doi: 10.3390/cancers9080107
Authors: Paul Hofman
Patients with advanced-stage non-small cell lung carcinoma (NSCLC) harboring an ALK rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. Several increasingly effective ALK inhibitors are now available for treatment of patients. However, despite an initial favorable response to treatment, in most cases relapse or progression occurs due to resistance mechanisms mainly caused by mutations in the tyrosine kinase domain of ALK. The detection of an ALK rearrangement is pivotal and can be done using different methods, which have variable sensitivity and specificity depending, in particular, on the quality and quantity of the patient's sample. This review will first highlight briefly some information regarding the pathobiology of an ALK rearrangement and the epidemiology of patients harboring this genomic alteration. The different methods used to detect an ALK rearrangement as well as their advantages and disadvantages will then be examined and algorithms proposed for detection in daily routine practice.
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Cancers, Vol. 9, Pages 106: ALK Status Assessment with Liquid Biopsies of Lung Cancer Patients
Cancers, Vol. 9, Pages 106: ALK Status Assessment with Liquid Biopsies of Lung Cancer Patients
Cancers doi: 10.3390/cancers9080106
Authors: Paul Hofman
Patients with advanced stage non-small cell lung carcinoma (NSCLC) harboring an anaplastic lymphoma kinase ALK gene rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. However, while treatment is initially effective in most cases, relapse or progression occurs due to different resistance mechanisms including mutations in the tyrosine kinase domain of echinoderm microtubule-associated protein-like 4 (EML44)-ALK. The liquid biopsy concept has recently radically changed the clinical care of NSCLC patients, in particular for those harboring an epidermal growth factor receptor (EGFR) gene mutation. Therefore, liquid biopsy is an alternative or complementary method to tissue biopsy for the detection of some resistance mutations in EGFR arising during tyrosine kinase inhibitor treatment. Moreover, in some frail patients, or if the tumor lesion is not accessible to a tissue biopsy, a liquid biopsy can also detect some activating mutations in EGFR on initial assessment. Recent studies have evaluated the possibility of also using a liquid biopsy approach to detect an ALK rearrangement and/or the emergence during inhibitor treatment of some resistance mutations in ALK. These assessments can be performed by studying circulating tumor cells by fluorescent in situ hybridization and by immunocytochemistry and/or after the isolation of RNA from plasma samples, free or associated with platelets. Thus, the liquid biopsy may be a complementary or sometimes alternative method for the assessment of the ALK status in certain NSCLC patients, as well as a non-invasive approach for early detection of ALK mutations. In this review, we highlight the current data concerning the role of the liquid biopsy for the ALK status assessment for NSCLC patients, and we compare the different approaches for this evaluation from blood samples.
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Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses
Abstract
Background
The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study.
Objective
The objective of this study was to quantitatively characterize the benefit–risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule.
Methods
We report early-phase study data and exposure–response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule.
Results
Single-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure–response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity.
Conclusions
These analyses support a favorable benefit–risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program.
Trial Registration Numbers
ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537
http://ift.tt/2wDWuRE
Rapid detection of bacterial meningitis using a point-of-care glucometer.
Background: In case of acute bacterial meningitis, a decision on the need for intensive care admission should be made within the first hour. The aim of this study was to assess the ability of a point-of-care glucometer to determine abnormal cerebrospinal fluid (CSF) glucose concentration at the bedside that contributes toward bacterial meningitis diagnosis. Methods: We carried out a prospective study and simultaneously measured the glucose concentrations in CSF and blood using a central laboratory and a point-of-care glucometer. We compared CSF/blood glucose ratios obtained at the bedside with a glucometer versus those obtained by the central laboratory. We determined the performance characteristics of the CSF/blood glucose ratio provided by a glucometer to detect bacterial infection in the CSF immediately after CSF sampling. Results: We screened 201 CSF collection procedures during the study period and included 172 samples for analysis. Acute bacterial meningitis was diagnosed in 17/172 (9.9%) of CSF samples. The median turnaround time for a point-of-care glucometer analysis was 5 (interquartile range 2-10) min versus 112 (interquartile range 86-154) min for the central laboratory (P
http://ift.tt/2fAsjX8
http://ift.tt/2fAsjX8
Lidocaine spray as a local analgesic for intravenous cannulation: a randomized clinical trial.
Objectives: Lidocaine spray is an effective analgesic of mucous membranes. Lidocaine spray is also used during intravenous (i.v.) cannulation, especially in children. However, the analgesic effect of lidocaine spray during i.v. cannulation has not been studied. We aimed to assess the analgesic effectiveness of lidocaine spray during i.v. cannulation. Methods: We conducted a randomized, double-blinded, placebo-controlled trial in seventeen healthy adults who received an i.v. cannulation in the right and left elbow, respectively, where the order of application of 60 mg lidocaine spray (Xylocaine 10% pump spray) or placebo spray (chlorhexidine gluconate 0.5% in 70% alcohol base) before i.v. cannulation was randomized. Thus, each participant had an i.v. cannulation in both arms: one with lidocaine spray and the other with placebo spray. The primary outcome was pain intensity assessed by a 100 mm Visual Analogue Scale. The secondary outcomes were adverse events, success rate of i.v. cannulation and the degree of difficulty of i.v. cannulation as estimated by the nurse performing the i.v cannulation. Results: The pain score (Visual Analogue Scale) during i.v. cannulation was 18.0 mm (interquartile range: 5.0-34.5 mm) after lidocaine application and 21.0 mm (interquartile range: 11.0-30.5) after placebo application. These scores were not significantly different (95% confidence interval: -9.0-11.0, P=0.698). No adverse events occurred and all i.v. cannulations were successful at first attempt. Conclusion: Local administration of lidocaine is not effective in reducing pain during i.v. cannulation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
http://ift.tt/2hT0NF3
http://ift.tt/2hT0NF3
Liver transplantation for NASH cirrhosis is not performed at the expense of major post-operative morbidity
Non-alcoholic steatohepatitis (NASH) is an emerging indication for liver transplantation (LT) and coexists with multiple comorbidities. Obese and cirrhotic patients experience more perioperative complications. Limited data exist about short-term complications after LT for NASH cirrhosis.
http://ift.tt/2hSYIZL
Fibroblast Growth Factor 15 Deficiency Increases Susceptibility but does not Improves Repair to Acetaminophen-induced Liver Injury in Mice
The leading cause of acute liver failure (ALF) is hepatotoxicity from acetaminophen (APAP) overdose. However, limited options are available to treat this ALF so stimulating liver regeneration maybe a potential treatment. Our previous study has shown that fibroblast growth factor 15 (FGF15) plays a crucial role in liver regeneration, but the roles of FGF15 in liver injury and repair following APAP-overdose are unknown. In this study, treatment of FGF15 knockout (KO) male mice with APAP at 200, 250, or 300mg/kg significantly increased the degree of liver injury compared to wild type (WT) mice.
http://ift.tt/2fAcO1u
Quantitative Evaluation of Head and Neck Cancer Treatment-Related Dysphagia in the Development of a Personalized Treatment De-Intensification Paradigm
We hypothesize that quantifying swallow function with multiple patient-reported outcome (PRO) instruments is an important strategy to yield insights in the development of personalized de-intensified therapies seeking to reduce the risk of head and neck cancer treatment-related dysphagia (HNCTD).
http://ift.tt/2vZhJz7
Geometric image biomarker changes of the parotid gland are associated with late xerostomia
The aim of this study was to identify a surrogate marker for late xerostomia 12 months after radiotherapy based on information obtained shortly after treatment. Differences in parotid gland (PG) were quantified in image biomarkers (ΔIBMs) before and 6 weeks after radiotherapy of 107 patients. The early post-treatment model with parotid gland surface reduction and acute xerostomia scores is a good candidate surrogate marker for late xerostomia.
http://ift.tt/2uzdcjm
Long-term clinical outcomes of Pencil Beam Scanning Proton Therapy for benign and non-benign intracranial meningiomas
Since 1996, 96 patients with complex intracranial meningiomas have been treated with pencil beam scanning proton therapy (PBSPT) at XXXX. The long-term results of the present study demonstrate PBSPT as an effective and safe treatment modality for the definitive, adjuvant, postoperative, and salvage treatment of highly complex intracranial meningiomas. In addition, multiple risk factors influencing local control and overall survival were identified.
http://ift.tt/2uz2gCE
Cancer Clonal Theory, Immune Escape, and Their Evolving Roles in Cancer Multi-Agent Therapeutics
Abstract
Purpose of Review
The knowledge base of malignant cell growth and resulting targets is rapidly increasing every day. Clonal theory is essential to understand the changes required for a cell to become malignant. These changes are then clues to therapeutic intervention strategies. Immune system optimization is a critical piece to find, recognize, and eliminate all cancer cells from the host. Only by administering (1) multiple therapies that counteract the cancer cell's mutational and externally induced survival traits and (2) by augmenting the immune system to combat immune suppression processes and by enhancing specific tumor trait recognition can cancer begin to be treated with a truly targeted focus.
Recent findings
Since the sequencing of the human genome during the 1990s, steady progress in understanding genetic alterations and gene product functions are being unraveled. In cancer, this is proceeding very fast and demonstrates that genetic mutations occur very rapidly to allow for selection of survival traits within various cancer clones. Hundreds of mutations have been identified in single individual cancers, but spread across many clones in the patient's body. Precision oncology will require accurate measurement of these cancer survival-benefiting mutations to develop strategies for effective therapy. Inhibiting these cellular mechanisms is a first step, but these malignant cells need to be eliminated by the host's mechanisms, which we are learning to direct more specifically.
Summary
Cancer is one of the most complicated cellular aberrations humans have encountered. Rapidly developing significant survival traits require prompt, repeated, and total body measurements of these attributes to effectively develop multi-agent treatment of the individual's malignancy. Focused drug development to inhibit these beneficial mutations is critical to slowing cancer cell growth and, perhaps, triggering apoptosis. In many cases, activation and targeting of the immune system to kill the remaining malignant cells is essential to a cure.
http://ift.tt/2uzcSkQ
Palliative care – Albania
Sixty-percent of cancer patients are diagnosed with advanced stages of disease and those diagnosed in early stages face challenges to receive adequate treatment. Palliative care has had significant developments in recent years in Albania, due to a close partnership with the Ministry of Health, local non-profit organizations, and the Open Society Foundation Albania. In 2011, a five-year action plan for palliative care as one of four parts of the National Cancer Control Plan was approved. At the end of 2014, the first palliative care law was approved by Parliament.
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Communication Challenges of Oncologists and Intensivists Caring for Pediatric Oncology Patients: A Qualitative Study
The families of oncology patients requiring intensive care often face increasing complexity in communication with their providers, particularly when patients are cared for by providers from different disciplines.
http://ift.tt/2uPiYg3
Case of Nonspinal Osteomyelitis Due to Bartonella and Review of the Literature.
Spine osteomyelitis resulting from Bartonella infection is well described in the literature; however, little is known about nonspinal manifestations of Bartonella osteomyelitis. Here, we describe a case of femur osteomyelitis in a 5-year-old child and review the literature related to nonspinal manifestations of Bartonella. In the 33 cases reviewed, infection of the pelvic girdle was most commonly observed (42%), followed by femur (21%) and humerus infections (21%). Fever was the most common symptom, and interestingly, 18% of patients did not have any history of cat exposure. Osteomyelitis was most commonly identified by magnetic resonance imaging; however, Bartonella serology and tissue polymerase chain reaction testing were also positive when used. Recovery for most patients occurred after combination antibiotic therapy and did not require surgical debridement. In our patient, full recovery was achieved through surgical debridement and stabilization of the bone, followed by antibiotics. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2vOik7b
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
