Anomalous origin of left main coronary artery from non-coronary sinus (LCANCS) is an extremely rare anomaly. Aortic coarctation in association with LCANCS has not been previously described in literature.
https://ift.tt/2AfiMgm
Τρίτη 16 Οκτωβρίου 2018
Complex regional pain syndrome type II arising from a gunshot wound (GSW) associated with infective endocarditis and aortic valve replacement
A 34-year-old man with a history of gunshot wound (GSW) to the right upper chest developed secondary aortic valve endocarditis (AVE) and was treated with an artificial valve placement (AVP). Three months after, he presented to an outpatient pain management clinic right arm pain and was diagnosed with complex regional pain syndrome type II (CRPS II). The patient underwent a diagnostic sympathetic ganglion block, before undergoing endoscopic thoracic sympathectomy surgery. Successful outcomes revealed decreased pain, opioid utilisation and improved tolerance to therapy and activities of daily living. To our knowledge, this is the first case reporting CRPS II arising from a GSW complicated by AVE followed by AVP, which emphasises how unforeseen syndromes can arise from the management of seemingly unrelated pathology. This case demonstrates the importance of timely and proper diagnosis of uncharacterised residual pain status post-trauma and differential diagnosis and management of chronic pain syndromes.
https://ift.tt/2AdXaAI
Metropolitan W135 meningococcal compressive pericarditis treated with intrapericardial fibrinolysis
Meningococcal pericarditis is a rare but severe form of acute purulent pericarditis. It is a classic complication of Neisseria meningitidis of serotype W135, usually occurring in pilgrims to Mecca and their household contacts. This severe form of meningococcaemia is difficult to diagnose and evolves frequently and gradually towards a tamponade, requiring emergency drainage. We report a case of meningococcal pericarditis caused by N. meningitidis W135 in an immunocompetent patient, without any other organ involvement especially meningeal, requiring pericardium drainage in emergency and then intrapericardial fibrinolysis.
https://ift.tt/2QU39jO
Fits, feet and HIV: lessons from a case of coexisting epilepsy and neuropathy in a patient with perinatally acquired HIV-1 infection
An 18-year-old black African man with well-controlled perinatally acquired HIV-1 was diagnosed in late adolescence with the unrelated diagnoses of Charcot-Marie-Tooth type 1A (CMT1A), epilepsy due to polymicrogyria and subsequently developed severe depression. The CMT1A diagnosis occurred after transfer of care from a local paediatric HIV service to a tertiary paediatric referral centre and was precipitated by recognition of a history and neurological signs not typically associated with perinatal HIV. The case resulted in the establishment of a quarterly combined paediatric HIV and paediatric neurology multidisciplinary team clinic to assess children and adolescents living with HIV with neurological symptoms.
https://ift.tt/2QUJQ9Z
A Rare case of recurrent Guillain-Barre syndrome without albuminocytological dissociation
Guillain-Barré syndrome (GBS) is an immune-mediated polyneuropathy, often preceded by an illness. It is a self-limiting illness in most of the cases, but recurrence is rare and can be seen in about 1%–6% of patients. GBS is characterised by progressive, symmetrical, proximal and distal weakness. Areflexia and sensory disturbances are also common. Patients with GBS usually have albuminocytological dissociation on cerebrospinal fluid (CSF) analysis. This is a case of a 69-year-old woman with recurrent GBS and normal CSF findings.
https://ift.tt/2Aet3sS
Sinus arrest with prolonged asystole due to the trigeminocardiac reflex during application of local anaesthetic in the nasal mucosa
The trigeminocardiac reflex (TCR) is defined as a sudden onset of parasympathetic dysrhythmias during stimulation of the trigeminal nerve. We describe a peripheral variation of TCR during manipulation of the nasal mucosa. A 42-year-old patient suffering from severe obstructive sleep apnoea was scheduled for surgical treatment. After inducted anaesthesia, the surgeon infiltrated the nasal mucosa with a local anaesthetic. The patient immediately showed an asystole and was treated with ephedrine and five chest compressions, despite spontaneous sinus rhythm return after ceasing of manipulation. Treatment with atropine established this TCR episode and ensured an event-free surgery.
The authors present here, for the first time, a prolonged asystole caused by the TCR, triggered by minimal manipulation of the nasal mucosa. This severe manifestation of peripheral TCR demonstrates its importance in daily clinical business. This case was treated according to a modified treatment algorithm for all subtypes of TCR which is presented here.
https://ift.tt/2QXlf4w
Friedreichs sign
Description
An 82-year-old man with chronic atrial fibrillation treated with anticoagulation was admitted to the hospital for subacute progressive exertional dyspnoea. On examination, the jugular venous waveform was elevated to the mandibular angle with the patient sitting upright. Heart sounds were muffled. Transthoracic echocardiography (TTE) revealed a large circumferential pericardial effusion with early tamponade physiology. Pericardiocentesis yielded a large volume of sanguineous fluid. Following the procedure, there was improvement in jugular venous pressure to 14 cm H2O. The height of the waveform increased with inspiration (Kussmaul's sign) and there was a prominent y descent, known as Friedreich's sign (see video 1). Repeat TTE revealed thickened pericardium, early diastolic septal bounce and respirophasic changes in early diastolic filling consistent with constrictive pericardial physiology. Friedreich's sign is a physical finding of constrictive pericarditis. The normal jugular venous waveform contains two descents, x and y. The x descent, which corresponds...
https://ift.tt/2Aero6G
Fungal thyroiditis in a lung transplant recipient
Description
A 59-year-old man was admitted with 3 weeks of worsening shortness of breath 18 months after receiving a bilateral lung transplant for idiopathic pulmonary fibrosis. His immunosuppression included tacrolimus, everolimus and low-dose prednisone with no antifungal prophylaxis at the time of admission. CT chest revealed multiple, bilateral pulmonary nodules (figure 1—red arrows). CT-guided biopsy revealed fungal hyphae (figure 2). The initial CT and ultrasound of the neck at the onset of sore throat was negative; however, repeat CT neck for evolving neck pain and dysphasia during hospital course showed a mass-like lesion in the right thyroid lobe with extensive surrounding inflammatory changes (figure 3—green arrow). The lesion was also visualised on ultrasound, where it appeared as a hypoechoic solitary nodule (figure 4). Laboratory evaluation revealed hyperthyroidism, with a Thyroid Stimulating Hormone (TSH) of <0.01 µIU/mL (normal: 0.35–4.94 µIU/mL) and a...
https://ift.tt/2CPWJ2b
Cancers, Vol. 10, Pages 386: Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
Cancers, Vol. 10, Pages 386: Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
Cancers doi: 10.3390/cancers10100386
Authors: Hiroshi Sugano Yoshihiro Shirai Takashi Horiuchi Nobuhiro Saito Yohta Shimada Ken Eto Tadashi Uwagawa Toya Ohashi Katsuhiko Yanaga
Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC.
https://ift.tt/2QV6AXk
The colors of biotechnology: general overview and developments of white, green and blue areas
Abstract
Biotechnology is responsible for the manipulation of living organisms or their components for the production of products that are of benefit to human kind. Due to the wide range of applications, colors have been used to differentiate the main areas of research, such as white (industrial), green (agricultural) and blue (marine and fresh-water), among others. Thus, this review outlines the impacts of these areas of biotechnology, emphasizing their impact and potential to replace carbon-based technologies with more sustainable technologies.https://ift.tt/2PDLPPE
The Smallest Intestine (TSI)—a low volume in vitro model of the small intestine with increased throughput
Abstract
There is a growing interest in understanding the fate and behaviour of probiotic microorganisms and bioactive compounds during passage of the human gastrointestinal tract (GIT). Here, we report the development of a small volume in vitro model called The smallest Intestine (TSI) with increased throughput focusing on simulating passage through the stomach and small intestine (SI). The basic TSI module consists of five reactors, with a working volume of 12 ml each. During the simulated passage through the SI, bile is absorbed and pH is adjusted to physiologically relevant values for duodenum, jejunum and ileum. A consortium of seven representative bacterial members of the ileum microbiota is included in the ileal stage of the model. The behaviour of three putative probiotic Lactobacillus strains during in vitro simulated upper GIT passage was tested in the model and results were compared to previous studies describing probiotic survival. It was found, that probiotic persistence is strongly related to whether food was ingested, but also to presence of the ileal microbiota, which significantly impacted probiotic survival. In conclusion, TSI allows testing a substantial number of samples, at low cost and short time, and is thus suitable as an in vitro screening platform.https://ift.tt/2P2jQfD
Correction to: Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis
In the original publication of this article, the author Magarida Rodrigues was written incorrectly.
https://ift.tt/2pXJofF
Fulvestrant for Untreated Hormone-Receptor Positive Locally Advanced or Metastatic Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
Abstract
Clinical and cost-effectiveness evidence on fulvestrant for untreated hormone-receptor positive locally advanced or metastatic breast cancer was submitted to the single technology appraisal process of the National Institute for Health and Care Excellence by the manufacturer of fulvestrant. The Southampton Health Technology Assessments Centre was commissioned by the National Institute for Health and Care Excellence as an independent Evidence Review Group to critique the company's submitted evidence. Fulvestrant was compared directly with anastrozole in two randomised controlled trials and was compared indirectly by means of a network meta-analysis with anastrozole, letrozole and tamoxifen. This article summarises the Evidence Review Group's review of the company's submission and summarises the guidance the National Institute for Health and Care Excellence Appraisal Committee issued in January 2018. The Evidence Review Group had several concerns, the most important of which related to the degree to which fulvestrant might confer a benefit in overall survival. This was because mature data were not available from the key phase III trial FALCON. The economic model was sensitive to changes in overall survival and the Evidence Review Group considered the incremental cost-effectiveness ratio was uncertain and likely to increase once mature results from FALCON become available. The National Institute for Health and Care Excellence Appraisal Committee concluded that fulvestrant could not be recommended for treating locally advanced or metastatic estrogen-receptor-positive breast cancer in postmenopausal women who have not received previous endocrine therapy.
https://ift.tt/2J0BaMt
Oseltamivir in pregnancy and birth outcomes
Prenatal exposure to influenza or fever is associated with risk of congenital malformations. Oseltamivir is used to treat influenza and to provide post-exposure prophylaxis. We examined the association between...
https://ift.tt/2CP8whg
Evaluation of cardiac function by global longitudinal strain before and after treatment with sofosbuvir-based regimens in HCV infected patients
Possible cardiotoxicity of sofosbuvir in humans has not been demonstrated yet. Also, since HCV can exert deleterious effects on hearth function, it is of interest to know whether HCV eradication provides any b...
https://ift.tt/2ClAakR
Ischemic stroke as a complication of cryptococcal meningitis and immune reconstitution inflammatory syndrome: a case report
Cryptococcal meningitis remains the leading cause of adult meningitis in Sub-Saharan Africa. Immune Reconstitution Inflammatory Syndrome (IRIS) following anti-retroviral therapy (ART) initiation is an importan...
https://ift.tt/2CNSeoD
Protective effect of royal jelly on the DNA integrity of sperms and early in vitro embryonic development in ofloxacin treated rats
Abstract
Protective effects of royal jelly on ofloxacin in male rat reproductive system are not well-known. This study was designed to determine the protective effects of royal jelly on the DNA integrity of sperms and early in vitro embryonic development in ofloxacin treated rats. In this study, 32 adult male rats were used and randomly allocated into 4 groups, each consisted of eight rats and dosed daily for 28 days by oral gavage: control—distilled water (216 mg/kg BW); ofloxacin group—ofloxacin (216 mg/kg BW); royal jelly group—royal jelly (100 mg/kg BW); royal jelly with ofloxacin group—216 mg/kg BW ofloxacin and 100 mg/kg BW royal jelly. The results showed that sperm viability, sperm population, sperm maturation, DNA maturity, hatching, IVF, GSH, and blastocyst significantly decreased (P < 0.05) in the ofloxacin group compared to the control. However, ofloxacin only caused significant increases (P < 0.05) in testis weight, immature sperm, and DNA damage of sperm compared to control group. In the ofloxacin with royal jelly group, there were not any important alterations detected and all sperm parameter returned to normal range. Royal jelly has protective effects on the DNA maturity of sperms and early in vitro embryonic development in ofloxacin treated rats.
https://ift.tt/2pSwtvE
Genetic Contributions to Ectopic Sperm Cell Migration in Caenorhabditis Nematodes
Reproductive barriers involving gametic incompatibilities can act to enhance population divergence and promote the persistence of species boundaries. Observing gametic interactions in internal fertilizing organisms, however, presents a considerable practical challenge to characterizing mechanisms of such gametic isolation. Here we exploit the transparency of Caenorhabditis nematodes to investigate gametic isolation mediated by sperm that can migrate to ectopic locations, with this sperm invasion capable of inducing female sterility and premature death. As a step toward identifying genetic factors and mechanisms associated with female susceptibility to sperm invasion, we characterized a panel of 25 C. elegans genetic mutants to test for effects on the incidence and severity of sperm invasion in both conspecific and inter-species matings. We found genetic perturbations to contribute to distinct patterns of susceptibility that identify ovulation dynamics and sperm guidance cues as modulators of ectopic sperm migration incidence and severity. Genotypes confer distinctive phenotypic sensitivities to the sperm from conspecific C. elegans males versus heterospecific C. nigoni males, implicating evolution of functional divergence in the history of these species for components of sperm-reproductive tract interactions. Sexually-antagonistic co-evolution within species that drives divergent trait and molecular evolution between species provides a working model to explain mismatched species-specific gametic interactions that promote or mitigate ectopic sperm migration.
https://ift.tt/2EpG9Yt
ClonoSEQ Cleared for Residual Cancer Testing [News in Brief]
First deep-sequencing assay can detect low levels of blood cancer down one in a million cells.
https://ift.tt/2pYs9uQ
Durvalumab Extends OS in NSCLC [News in Brief]
Additional data from PACIFIC trial show further benefit of PD-L1 inhibitor.
https://ift.tt/2NIDU1P
CDC Warns of Polio-Like Virus Striking More U.S. Children
TUESDAY, Oct. 16, 2018 -- A rare but devastating polio-like virus appears to have made itself at home in the United States, partially paralyzing hundreds of children. There have been 127 cases reported in 22 states so far this year, with 62...
https://ift.tt/2J6Mjf3
Bariatric Sx Cuts Macrovascular Complications in Obesity, T2DM
TUESDAY, Oct. 15, 2018 -- For patients with severe obesity and type 2 diabetes, bariatric surgery is associated with a lower risk for macrovascular outcomes compared with not undergoing surgery, according to a study published in the Oct. 16 issue of...
https://ift.tt/2J3rot5
Harvard: Heart Researcher's Papers Contain Fraudulent Data
TUESDAY, Oct. 16, 2018 -- Dozens of scientific papers from the laboratory of well-known heart researcher Piero Anversa contain fraudulent data, according to a Harvard Medical School internal investigation. Anversa and other members of his laboratory...
https://ift.tt/2IZCjUw
American College of Chest Physicians, Oct. 6-10
The 84th Annual Meeting of the American College of Chest Physicians The annual meeting of the American College of Chest Physicians was held from Oct. 6 to 10 in San Antonio and attracted approximately 6,000 participants from around the world,...
https://ift.tt/2OvP7bc
Positive HPV Status Tied to Better Cervical Cancer Prognosis
TUESDAY, Oct. 16, 2018 -- Women with high-risk human papillomavirus (hrHPV)-positive cervical tumors have a substantially better prognosis than women with hrHPV-negative tumors, according to a study published online Oct. 1 in PLOS Medicine. Jiayao...
https://ift.tt/2OvP5jA
Zebrafish: Speeding Up the Cancer Drug Discovery Process
Zebrafish (Danio rerio) is an ideal in vivo model to study a wide variety of human cancer types. In this review, we provide a comprehensive overview of zebrafish in the cancer drug discovery process, from (i) approaches to induce malignant tumors, (ii) techniques to monitor cancer progression, and (iii) strategies for compound administration to (iv) a compilation of the 355 existing case studies showing the impact of zebrafish models on cancer drug discovery, which cover a broad scope of scenarios. Finally, based on the current state-of-the-art analysis, this review presents some highlights about future directions using zebrafish in cancer drug discovery and the potential of this model as a prognostic tool in prospective clinical studies. Cancer Res; 78(21); 1–11. ©2018 AACR.
https://ift.tt/2J59INW
Reactive Oxygen and Nitrogen Species-Induced Protein Modifications: Implication in Carcinogenesis and Anticancer Therapy
Cancer is a complex disorder extremely dependent on its microenvironment and highly regulated by multiple intracellular and extracellular stimuli. Studies show that reactive oxygen and nitrogen species (RONS) play key roles in cancer initiation and progression. Accumulation of RONS caused by imbalance between RONS generation and activity of antioxidant system (AOS) has been observed in many cancer types. This leads to alterations in gene expression levels, signal transduction pathways, and protein quality control machinery, that is, processes that regulate cancer cell proliferation, migration, invasion, and apoptosis. This review focuses on the latest advancements evidencing that RONS-induced modifications of key redox-sensitive residues in regulatory proteins, that is, cysteine oxidation/S-sulfenylation/S-glutathionylation/S-nitrosylation and tyrosine nitration, represent important molecular mechanisms underlying carcinogenesis. The oxidative/nitrosative modifications cause alterations in activities of intracellular effectors of MAPK- and PI3K/Akt-mediated signaling pathways, transcription factors (Nrf2, AP-1, NFκB, STAT3, and p53), components of ubiquitin/proteasomal and autophagy/lysosomal protein degradation systems, molecular chaperones, and cytoskeletal proteins. Redox-sensitive proteins, RONS-generating enzymes, and AOS components can serve as targets for relevant anticancer drugs. Chemotherapeutic agents exert their action via RONS generation and induction of cancer cell apoptosis, while drug resistance associates with RONS-induced cancer cell survival; this is exploited in selective anticancer therapy strategies. Cancer Res; 78(21); 1–8. ©2018 AACR.
https://ift.tt/2OuoCmN
A prediction model for underestimation of invasive breast cancer after a biopsy diagnosis of ductal carcinoma in situ: based on 2892 biopsies and 589 invasive cancers
A prediction model for underestimation of invasive breast cancer after a biopsy diagnosis of ductal carcinoma in situ: based on 2892 biopsies and 589 invasive cancers
A prediction model for underestimation of invasive breast cancer after a biopsy diagnosis of ductal carcinoma in situ: based on 2892 biopsies and 589 invasive cancers, Published online: 17 October 2018; doi:10.1038/s41416-018-0276-6
A prediction model for underestimation of invasive breast cancer after a biopsy diagnosis of ductal carcinoma in situ: based on 2892 biopsies and 589 invasive cancershttps://ift.tt/2PCn1I1
Breast osteoblast-like cells: a new biomarker for the management of breast cancer
Breast osteoblast-like cells: a new biomarker for the management of breast cancer
Breast osteoblast-like cells: a new biomarker for the management of breast cancer, Published online: 17 October 2018; doi:10.1038/s41416-018-0255-y
Breast osteoblast-like cells: a new biomarker for the management of breast cancerhttps://ift.tt/2P5Ct2m
Waist circumference and risk of 23 site-specific cancers: a population-based cohort study of Korean adults
Waist circumference and risk of 23 site-specific cancers: a population-based cohort study of Korean adults
Waist circumference and risk of 23 site-specific cancers: a population-based cohort study of Korean adults, Published online: 17 October 2018; doi:10.1038/s41416-018-0214-7
Waist circumference and risk of 23 site-specific cancers: a population-based cohort study of Korean adultshttps://ift.tt/2PDTEFl
Time to progression ratio in cancer patients enrolled in early phase clinical trials: time for new guidelines?
Time to progression ratio in cancer patients enrolled in early phase clinical trials: time for new guidelines?
Time to progression ratio in cancer patients enrolled in early phase clinical trials: time for new guidelines?, Published online: 17 October 2018; doi:10.1038/s41416-018-0245-0
Time to progression ratio in cancer patients enrolled in early phase clinical trials: time for new guidelines?https://ift.tt/2P4PNnB
Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancer
Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancer
Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancer, Published online: 17 October 2018; doi:10.1038/s41416-018-0296-2
Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancerhttps://ift.tt/2PDZeHB
Combination VEGFR/immune checkpoint inhibitor therapy: a promising new treatment for renal cell carcinoma
Combination VEGFR/immune checkpoint inhibitor therapy: a promising new treatment for renal cell carcinoma
Combination VEGFR/immune checkpoint inhibitor therapy: a promising new treatment for renal cell carcinoma, Published online: 17 October 2018; doi:10.1038/s41416-018-0175-x
Combination VEGFR/immune checkpoint inhibitor therapy: a promising new treatment for renal cell carcinomahttps://ift.tt/2P5dsnP
CD24 regulates cancer stem cell (CSC)-like traits and a panel of CSC-related molecules serves as a non-invasive urinary biomarker for the detection of bladder cancer
CD24 regulates cancer stem cell (CSC)-like traits and a panel of CSC-related molecules serves as a non-invasive urinary biomarker for the detection of bladder cancer
CD24 regulates cancer stem cell (CSC)-like traits and a panel of CSC-related molecules serves as a non-invasive urinary biomarker for the detection of bladder cancer, Published online: 17 October 2018; doi:10.1038/s41416-018-0291-7
CD24 regulates cancer stem cell (CSC)-like traits and a panel of CSC-related molecules serves as a non-invasive urinary biomarker for the detection of bladder cancerhttps://ift.tt/2PEEQpO
Response to ‘Comment on ‘Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study”
Response to 'Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study"
Response to 'Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study", Published online: 17 October 2018; doi:10.1038/s41416-018-0177-8
Response to 'Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study"https://ift.tt/2P1N5z3
Parallel MapReduce: Maximizing Cloud Resource Utilization and Performance Improvement Using Parallel Execution Strategies
MapReduce is the preferred cloud computing framework used in large data analysis and application processing. MapReduce frameworks currently in place suffer performance degradation due to the adoption of sequential processing approaches with little modification and thus exhibit underutilization of cloud resources. To overcome this drawback and reduce costs, we introduce a Parallel MapReduce () framework in this paper. We design a novel parallel execution strategy of Map and Reduce worker nodes. Our strategy enables further performance improvement and efficient utilization of cloud resources execution of Map and Reduce functions to utilize multicore environments available with computing nodes. We explain in detail makespan modeling and working principle of the framework in the paper. Performance of is compared with Hadoop through experiments considering three biomedical applications. Experiments conducted for BLAST, CAP3, and DeepBind biomedical applications report makespan time reduction of 38.92%, 18.00%, and 34.62% considering the framework against Hadoop framework. Experiments' results prove that the cloud computing platform proposed is robust, cost-effective, and scalable, which sufficiently supports diverse applications on public and private cloud platforms. Consequently, overall presentation and results indicate that there is good matching between theoretical makespan modeling presented and experimental values investigated.
https://ift.tt/2PCBljD
Manifestations and Outcomes of Patients with Parkinson’s Disease and Serious Infection in the Emergency Department
Background. Several comorbidities contribute to an increased risk of infections in Parkinson's disease (PD) as the disease progresses. However, few studies have examined the correlation between sepsis and PD. Aim. The aim of this study is to disclose the presentation and outcome of serious infection in patients with PD in the emergency department. Methods. This retrospective cohort study enrolled patients with PD who had serious infection and were admitted to the emergency department between January 2007 and December 2013. For clinical comparison, we compared the clinical features, laboratory data, and outcomes with those of age- and sex-matched patients who had serious infection but not PD. Results. There were a total of 1,200 episodes of infected PD patients and 2,400 age- and sex-matched infected patients without PD as disease controls. PD patients had fewer comorbidities and lower severity of infectious disease but longer hospital stays than control group patients. The incidences of respiratory tract and urinary tract infections were higher in PD patients. The levels of inflammatory and organ dysfunction biomarkers in PD were lower and compatible with the severity of infectious disease. A total of 86 (7.2%) infected PD patients died during the 28-day admission compared to 339 (14.1%) in non-PD patients. Serum C-reactive protein, bandemia, and lactate could be used to predict mortality in infected PD patients. Conclusions. In infected patients with PD, respiratory and urinary tract infections were the two most common infectious sources. Empiric therapy based on experience could treat both respiratory and urinary tract infections. Early diagnosis and treatment are essential for survival.
https://ift.tt/2P5yXFc
Understanding Deep Brain Stimulation: In Vivo Metabolic Consequences of the Electrode Insertional Effect
Deep brain stimulation (DBS) is a neurosurgery technique widely used in movement disorders, although its mechanism of action remains unclear. In fact, apart from the stimulation itself, the mechanical insertion of the electrode may play a crucial role. Here we aimed to distinguish between the insertional and the DBS effects on brain glucose metabolism. To this end, electrodes were implanted targeting the medial prefrontal cortex in five adult male Wistar rats. Positron Emission Tomography (PET) studies were performed before surgery (D0) and seven (D7) and nine days (D9) after that. DBS was applied during the 18FDG uptake of the D9 study. PET data were analysed with statistical parametric mapping. We found an electrode insertional effect in cortical areas, while DBS resulted in a more widespread metabolic pattern. The consequences of simultaneous electrode and DBS factors revealed a combination of both effects. Therefore, the insertion metabolic effects differed from the stimulation ones, which should be considered when assessing DBS protocols.
https://ift.tt/2PCmXrP
Corporal punishment bans and physical fighting in adolescents: an ecological study of 88 countries
Objective
To examine the association between corporal punishment bans and youth violence at an international level.
DesignEcological study of low-income to high-income 88 countries.
SettingSchool-based health surveys of students.
Participants403 604 adolescents.
InterventionsNational corporal punishment bans.
Primary outcome measureAge-standardised prevalence of frequent physical fighting (ie, 4+ episodes in the previous year) for male and female adolescents in each country.
ResultsFrequent fighting was more common in males (9.9%, 95% CI 9.1% to 10.7%) than females (2.8%, 95% CI 2.5% to 3.1%) and varied widely between countries, from 0.9% (95% CI 0.8% to 0.9%) in Costa Rican females to 34.8% (95% CI 34.7 to 35.0) in Samoan males. Compared with 20 countries with no ban, the group of 30 countries with full bans (in schools and in the home) experienced 69% the rate of fighting in males and 42% in females. Thirty-eight countries with partial bans (in schools but not in the home) experienced less fighting in females only (56% the rate found in countries without bans).
ConclusionsCountry prohibition of corporal punishment is associated with less youth violence. Whether bans precipitated changes in child discipline or reflected a social milieu that inhibits youth violence remains unclear due to the study design and data limitations. However, these results support the hypothesis that societies that prohibit the use of corporal punishment are less violent for youth to grow up in than societies that have not.
https://ift.tt/2EziG7w
Delivery of Glucosylceramidase Beta Gene Using AAV9 Vector Therapy as a Treatment Strategy in Mouse Models of Gaucher Disease
Human Gene Therapy, Ahead of Print.
https://ift.tt/2EtqcR5
Gene Therapy Rescues Retinal Degeneration in Receptor Expression-Enhancing Protein 6 Mutant Mice
Human Gene Therapy, Ahead of Print.
https://ift.tt/2RSmaUZ
Changing the Face of Modern Medicine: Stem Cell and Gene Therapy Abstract Author Index
Human Gene Therapy, Ahead of Print.
https://ift.tt/2Etq7gf
Changing the Face of Modern Medicine: Stem Cell and Gene Therapy; Organized Jointly by the; European Society of Gene & Cell Therapy (ESGCT),; International Society for Stem Cell Research (ISSCR); and the French Society of Gene and Cell Therapy (SFTCG); Lausanne, Switzerland; October 16–19, 2018; Abstracts
Human Gene Therapy, Ahead of Print.
https://ift.tt/2RSytkh
Cradlepoint LTE network solutions certified FirstNet Ready™ — delivering secure and resilient branch, mobile, and IoT connectivity to first responder organizations
Cradlepoint's new FirstNet Ready™ MC400 Modem Module for compatible IBR and AER Series 4G LTE Router solutions receives FirstNet certification and approval LAS VEGAS — Cradlepoint, the global leader in cloud-delivered 4G and 5G wireless network edge solutions, today announced, at the annual Association of Public-Safety Communications Officials International (APCO) show in Las...
https://ift.tt/2PIcj2Q
Recombinant neuraminidase pseudotyped baculovirus: a dual vector for delivery of Angiotensin II peptides and DNA vaccine
Baculovirus is a promising vaccine deliver vector due to its biosafety profiles, gene transfer efficiency, ability to display small foreign antigens on its surface, strong adjuvant activities, etc. A dual vect...
https://ift.tt/2CRZfF8
PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age
To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given.
https://ift.tt/2J35Z3g
Maternal Education Is Inversely Related to Vaccination Delay among Infants and Toddlers
To determine the association between parents' level of education and delay in vaccination among infants and toddlers.
https://ift.tt/2J3NtaM
Risk Factors for Delayed Antimicrobial Treatment in Febrile Children with Urinary Tract Infections
To identify factors associated with delayed antimicrobial treatment in febrile children with urinary tract infection (UTI).
https://ift.tt/2OwnuPx
Growth and Intellectual Abilities of Six-Year-Old Children with Congenital Heart Disease
To determine growth and its relationship to IQ in children with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery within the first year of life.
https://ift.tt/2OrZugh
Sustained Neonatal Inflammation Is Associated with Poor Growth in Infants Born Very Preterm during the First Year of Life
To determine whether a sustained neonatal systemic inflammatory response was associated with poor postnatal growth among infants born very preterm during the first year of life.
https://ift.tt/2OtAEwz
Rate of Breast-Conserving Surgery vs Mastectomy in Breast Cancer: a Tertiary Care Centre Experience from South India
Abstract
Worldwide, breast conservation has become increasingly accepted as the surgical management of breast cancer in clinical practice. Cancer care in India is also evolving tremendously with many cancer treatment centres following evidence-based practice hence the rates of breast conservation are expected to increase. Here, we are reporting the rate of breast-conserving surgery (BCS) at our centre. A retrospective study of 401 patients who underwent breast cancer surgery at a tertiary care centre in South India from January 2015 to August 2017 were analysed to study the rate of BCS. All early breast cancers (EBC) were offered BCS. For large operable breast cancer (LOBC) and locally advanced breast cancer (LABC), neoadjuvant chemotherapy (NACT) followed by BCS was offered to these patients who wish to conserve their breast. The mean age was 45 years. A total of 163 patients underwent BCS. Yearly, BCS rates were 38.8% in 2015, 36.7% in 2016 and 46.5% in 2017. Majority had EBC 310 (77.3%) of which 62.7% of T1 lesions (n = 51) had BCS, and 45.7% of T2 lesions (n = 258) had BCS of which 5 patients had to undergo NACT to preserve their breast whereas 100% Tis patient (n = 1) had mastectomy. Fifty patients had LOBC and only 2 (4%) patients had upfront BCS whereas 9 of them had to undergo NACT (18%). cT4 lesions had NACT followed by BCS in 2 patients. The rates of BCS have been increasing in India over the past few years. The majority of the women presented with EBC which makes them suitable for BCS.
https://ift.tt/2QWwKcs
Clear liquid diet before bowel preparation predicts successful chromoendoscopy in patients with inflammatory bowel disease
Chromoendoscopy (CE) has been shown to generate both a superior diagnostic yield and dysplasia detection rate than conventional white-light endoscopy and requires a high-quality bowel preparation. The aim of this study was to identify predictors of the ability to perform CE in patients with inflammatory bowel disease (IBD).
https://ift.tt/2AdYVOE
Outcome of endoscopic mucosal resection in Barrett’s esophagus determined by systematic quantification of epithelial glands using volumetric laser endomicroscopy
Dysplastic Barrett's esophagus (BE) lesions ≤2 cm in size can be targeted for en-bloc endoscopic mucosal resection (EMR). White-light endoscopy can underestimate the size of a lesion, limiting complete resection. Volumetric laser endomicroscopy (VLE) provides high-resolution cross-sectional imaging of BE. Epithelial glands are a VLE feature associated with BE dysplasia. We study the association between VLE gland quantification and outcome of resection.
https://ift.tt/2QWtpKy
UVA Health System deploys always-connected telemedicine toolkits in ambulances for faster stroke care
Sponsored by Cradlepoint University of Virginia Health System deploys iTREAT (Improving Treatment with Rapid Evaluation of Acute Stroke via Mobile Telemedicine) telemedicine toolkits in ambulances for stroke victims. With constant connectivity being an essential part of this innovative tool, UVA Health System chose Cradlepoint's ruggedized in-vehicle routing solutions with integrated 4G LTE...
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GEN-1 immunotherapy for the treatment of ovarian cancer
Future Oncology, Ahead of Print.
https://ift.tt/2QSCt32
A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells
https://ift.tt/2PxfuKh
Use of Principal Components for Scaling Up Topographic Models to Map Soil Redistribution and Soil Organic Carbon
https://ift.tt/2Px9b9z
Pleuroparenchymal fibroelastosis as a histological background of autoimmune diseases
Abstract
Patients with autoimmune disease–related interstitial lung disease (AID-ILD) occasionally develop radiologic pleuroparenchymal fibroelastosis (PPFE)–like lesions. However, the significance of AID as an etiology of PPFE has not been fully elucidated. The aim of this study is to verify the increase of elastic fibers in AID-ILD patients and evaluate the prevalence of histological PPFE in patients with AID-ILD. We selected cases of clinically diagnosed AID-ILD and idiopathic pulmonary fibrosis (IPF), in which an autopsy had been performed or in which the patient had undergone pneumonectomy for lung transplantation. We quantified the collagen fibers and elastic fibers in each lobe as the percentage of the non-aerated lung area (collagen fiber score and elastic fiber score, respectively) in histological specimens from a total of 73 patients (AID-ILD, n = 24; IPF, n = 49). There were no significant differences in the collagen fiber scores of the AID-ILD and IPF groups. Meanwhile, the elastic fiber scores of the AID-ILD group were significantly greater than those of the IPF group in the whole lung (17.3 ± 7.70 vs 11.6 ± 4.55), and the upper (16.6 ± 8.11 vs 11.2 ± 5.18), and lower (18.0 ± 9.68 vs 12.0 ± 5.55) lobes (all p < 0.01). Histological PPFE pattern was found in 12 of 24 AID-ILD patients (50%), and histological PPFE pattern as a dominant pattern of fibrosis was found in 2 of the 24 patients (8%). Thus, PPFE can be a manifestation of AID-ILD.
https://ift.tt/2yGMqcc
PTEN Expression, Not Mutation Status for TSC1, TSC2 or mTOR, Correlates With Outcome on Everolimus in Patients With Renal Cell Carcinoma Treated on RECORD-3
Purpose: Genomic alterations in key components of PI3K/mTOR pathway have been proposed as candidate predictive markers for rapalog therapy in renal cell carcinoma (RCC). We tested this hypothesis in patients from a randomized phase 2 trial of everolimus vs sunitinib. Experimental Design: Archival specimens collected at baseline were analyzed with targeted next-generation sequencing (NGS). Focus of interest were alterations in key PI3K pathway components. PTEN expression was assessed by immunohistochemistry (IHC). Association between molecular findings and treatment outcomes was investigated; same associations were tested for 2 everolimus-treated trial cohorts in gastric and hepatocellular carcinoma (HCC). Results: Among 184 everolimus-treated RCC patients with NGS data, mutation rates in genes of interest were 6% (TSC1), 4.4% (TSC2), and 8.2% (mTOR); 44% harbored alterations in ≥1 PI3K pathway component. For subjects with presence vs. absence of mutations in TSC1, TSC2, or mTOR progression-free survival (PFS) neither differed on univariate analysis (HR, 1.0; P=.895) nor on multivariate testing stratified by MSKCC risk group and other established prognostic factors (HR, 1.1; P=.806). Everolimus-treated patients with retained (n=50) vs lost (n=50) PTEN IHC expression had median PFS of 5.3 vs 10.5 months (HR, 2.5; P<0.001). Such differences were not seen with sunitinib (10.9 vs 10.3 months; HR, 0.8; P=.475). Molecular findings did not correlate with outcomes in gastric and HCC cohorts. Conclusions: Association between mutation status for TSC1/TSC2/mTOR and therapeutic outcome on everolimus was not confirmed. Clinically meaningful differences in PFS were seen based on PTEN expression by IHC, lost in >50% of patients.
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Targeting PIM Kinase with PD1 inhibition Improves Immunotherapeutic Anti-Tumor T Cell Response
Purpose: Adoptive T cell therapy (ACT) of cancer, which involves the infusion of ex vivo engineered tumor epitope reactive autologous T cells into the tumor-bearing host, is a potential treatment modality for cancer. However, the durable anti-tumor response following ACT is hampered either by loss of effector function or survival of the anti-tumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the anti-tumor T cells are of immense importance. Given the role of metabolism in determining the therapeutic efficacy of T cells, we hypothesize that inhibition of PIM kinases, a family of serine/threonine kinase that promote cell cycle transition, cell growth, and regulate mTORC1 activity, can improve the potency of T cells in controlling tumor. Experimental design: The role of PIM kinases in T cells was studies either by genetic ablation (PIM1-/-PIM2-/-PIM3-/-) or its pharmacological inhibition (pan-PIM kinase inhibitor, PimKi). Subcutaneous murine melanoma B16 was established subcutaneously and treated by transferring tumor epitope gp100 reactive T cells along with treatment regimen that involved inhibiting PIM kinases, anti-PD1 or both. Results: With inhibition of PIM kinases, T cells had significant reduction in their uptake of glucose, and upregulated expression of memory-associated genes that inversely correlate with glycolysis. Additionally, the expression of CD38, which negatively regulates the metabolic fitness of the T cells, was also reduced in PimKi-treated cells. Importantly, the efficacy of anti-tumor T cell therapy was markedly improved by inhibiting PIM kinases in tumor-bearing mice receiving ACT, and further enhanced by adding anti-PD1 antibody to this combination. Conclusion: The present study highlights the potential therapeutic significance of combinatorial strategies where ACT and inhhibition of signaling kinase with check-point inhibition could improve tumor control.
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Thyroid Nodule DNA Methylation Signatures: An Important Diagnostic Annotation
Molecular profiling in thyroid cancer has made significant progress in part due to advances in somatic mutation profiling. Yet, differentiating benign from malignant thyroid nodules remains elusive. A unique set of DNA methylation signatures has the potential of improving thyroid cancer molecular diagnostics based on the DNA methylome.
https://ift.tt/2pUPnlt
A Phase 1 Dose-Escalation Study of Veliparib Combined with Carboplatin and Etoposide in Patients with Extensive-Stage Small Cell Lung Cancer and Other Solid Tumors
Purpose: This study examined safety, pharmacokinetics and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors. Experimental Design: 3+3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on Day 1) and etoposide (100 mg/m2 on Days 1-3) in 21-day cycles. Veliparib dose was explored from 80-240mg twice daily (BID) on 7-day, 14-day or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400mg BID) until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled to determine the recommended phase 2 dose (RP2D) of 240 mg veliparib for 14-days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in one patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg BID 7-days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg BID with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17/39 (44%) and 16/25 (64%) of all enrolled and ED SCLC patients, respectively. At the recommended phase 2 dose, confirmed responses occurred in 6/13 (46%) and 5/6 (83%) of all enrolled and ED SCLC patients, respectively. Conclusions: Veliparib (240mg BID 14-days) plus carboplatin/etoposide can be safely combined. Phase 2 of this study is ongoing in first-line patients with ED SCLC.
https://ift.tt/2NMfpkB
Antibody-based delivery of TNF to the tumor neo-vasculature potentiates the therapeutic activity of a peptide anti-cancer vaccine
Purpose: There is a growing interest in the use of tumor antigens for therapeutic vaccination strategies. Unfortunately, in most cases, the use of peptide vaccines in patients does not mediate shrinkage of solid tumor masses. Experimental Design: Here, we studied the opportunity to boost peptide vaccination with F8-TNF, an antibody fusion protein that selectively delivers TNF to the tumor extracellular matrix. AH1, a model antigen to investigate CD8+T cell immunity in BALB/c mice, was used as vaccine. Results: Peptide antigens alone exhibited only a modest tumor growth inhibition. However, anti-cancer activity could be substantially increased by combination with F8-TNF. Analysis of T cells in tumors and in draining lymph nodes revealed a dramatic expansion of AH1-specific CD8+T cells, which were strongly positive for PD-1, LAG-3 and TIM-3. The synergistic anti-cancer activity, observed in the combined use of peptide vaccination and F8-TNF, was largely due to the ability of the fusion protein to induce a rapid hemorrhagic necrosis in the tumor mass, thus leaving few residual tumor cells. While the cell surface phenotype of tumor-infiltrating CD8+T cells did not substantially change upon treatment, the proportion of AH1-specific T cells was strongly increased in the combination therapy group, reaching more than 50% of the CD8+T cells within the tumor mass. Conclusions: Since both peptide vaccination strategies and tumor-homing TNF fusion proteins are currently being studied in clinical trials, our study provides a rationale for the combination of these two regimens for the treatment of patients with cancer.
https://ift.tt/2pVF6p7
Biomarkers and Bone Imaging Dynamics associated with Clinical outcomes of Oral Cabozantinib Therapy in Metastatic Castrate Resistant Prostate Cancer
Background: Cabozantinib is a multitargeted tyrosine kinase inhibitor demonstrating remarkable responses in prostate cancer bone metastases . We studied the dynamics of biomarker changes with imaging, and biopsies pre- and post-therapy to explore factors that are likely to be predictive of efficacy with cabozantinib. Methods: Eligibility included metastatic castrate resistant prostate cancer patients with normal organ function and performance status 0-2. Cabozantinib 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans (BS), positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) thymine (FMAU-PET) scans were conducted. Pre and post therapy tumor biopsies were conducted, and serum and urine bone markers were measured. Results: 20 evaluable pts were treated. 8 patients had a PSA decline, of which 2 had a decline ≥50%. Median progression free survival (PFS) and overall survival (OS) were 4.1 and 11.2 months, respectively and 3 patients were on therapy for 8, 10 and 13 months. The NaF-PET demonstrated a median decline in SUVmax of -56% (range -85 to -5%, n = 11) and -41% (range -60 to -25%, n = 9) for patients on therapy for ≥ 4 or < 4 cycles, respectively. The FMAU-PET demonstrated a median decline in SUVmax of -44% (-60 to -14%) and -42% (-63% to -23%) for these groups. The changes in bone markers and mesenchymal epithelial transition/MET testing did not correlate with clinical benefit. Conclusions: Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.
https://ift.tt/2NJHrwJ
KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition.
Purpose: KRAS mutant lung cancers have been recalcitrant to treatments including those targeting the MAPK pathway. Covalent inhibitors of KRAS p.G12C allele allow for direct and specific inhibition of mutant KRAS in cancer cells. However, as for other targeted therapies, the therapeutic potential of these inhibitors can be impaired by intrinsic resistance mechanisms. Therefore, combination strategies are likely needed to improve efficacy. Experimental Design: To identify strategies to maximally leverage direct KRAS inhibition we defined the response of a panel of NSCLC models bearing the KRAS G12C activating mutation in vitro and in vivo. We used a second-generation KRAS G12C inhibitor, ARS1620 with improved bioavailability over the first generation. We analyzed KRAS downstream effectors signaling to identify mechanisms underlying differential response. To identify candidate combination strategies, we performed a high-throughput drug screening across 112 drugs in combination with ARS1620. We validated the top hits in vitro and in vivo including patient derived xenograft models. Results: Response to direct KRAS G12C inhibition was heterogeneous across models. Adaptive resistance mechanisms involving reactivation of MAPK pathway and failure to induce PI3K-AKT pathway inactivation were identified as likely resistance events. We identified several model-specific effective combinations as well as a broad sensitizing effect of PI3K-AKT-mTOR pathway inhibitors. The G12Ci+PI3Ki combination was effective in vitro and in vivo on models resistant to single agent ARS1620 including patient derived xenografts models. Conclusions: Our findings suggest that signaling adaptation can in some instances limit the efficacy of ARS1620 but combination with PI3K inhibitors can overcome this resistance.
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Patritumab with Cetuximab Plus Platinum-Containing Therapy in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: An Open-Label, Phase-Ib Study
Background: Patritumab plus cetuximab with platinum as first-line therapy for patients with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) was evaluated for safety and to determine the recommended phase-II combination dose. Methods: Patients aged ≥18 years with confirmed R/M SCCHN received intravenous patritumab (18-mg/kg loading dose [LD]); 9-mg/kg maintenance dose [MD] every 3 weeks [q3w]) + cetuximab (400-mg/m2 LD; 250-mg/m2 MD weekly) + cisplatin (100 mg/m2 q3w) or carboplatin (area under the curve [AUC] of 5) for 6 cycles or until toxicity, disease progression, or withdrawal. Primary endpoints were dose-limiting toxicities (DLTs; grade ≥3 [21-day observation period]) and treatment-emergent adverse events (TEAEs). Pharmacokinetics, human antihuman antibodies (HAHA), tumor response, progression free survival (PFS), and overall survival (OS) were assessed. Results: Fifteen patients completed a median (range) of 8.7 (2.0-20.7) patritumab cycles. No DLTs were reported. Serious AEs were reported in 9 patients (patritumab-related n=4). TEAEs (N=15 patients) led to patritumab interruption in 7 patients. Patritumab-related dose reductions were reported in 1 patient. Patritumab (18 mg/kg) pharmacokinetics (N=15) showed mean (standard deviation) AUC0-21d of 2,619 (560) µg•day/mL and maximum concentration of 499.9 (90.4) µg/mL. All patients were HAHA-negative at study end (single, transient low titer in 1 patient). Tumor response rate (complete plus partial response; N=15) was 47%. Median (95% confidence interval) PFS and OS (N=15) were 7.9 (3.7-9.7) and 13.5 (6.6-17.5) months, respectively. Conclusion: Patritumab (18-mg/kg LD, 9-mg/kg MD) plus cetuximab/platinum was tolerable, active in SCCHN, and was selected as the phase II dose-regimen.
https://ift.tt/2NETsUp
Transcriptomic and protein analysis of small cell bladder cancer (SCBC) identifies prognostic biomarkers and DLL3 as a relevant therapeutic target
Purpose: Transcriptomic profiling can shed light on the biology of SCBC, nominating biomarkers and novel therapeutic targets. Experimental Design: Sixty-three SCBC patients had small cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody-drug conjugate (ADC). Results: Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most "normal-like" pattern of gene expression had longer OS compared to the other 3 clusters while patients with the most "metastasis-like" pattern had the shortest OS (p=0.047). Expression of DLL3, PDL1, ASCL1 and CD56 was confirmed by IHC in 68%, 30%, 52% and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (p=0.03 each). A DLL3-targeting ADC showed durable anti-tumor efficacy in a SCBC PDX model. Conclusions: Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.
https://ift.tt/2pX1Hl2
The Effectiveness of Checkpoint Inhibitor Combinations and Administration Timing Can Be Measured by Granzyme B PET Imaging
Purpose: The lack of a timely and reliable measure of response to cancer immunotherapy has confounded understanding of mechanisms of resistance and subsequent therapeutic advancement. We hypothesized that PET imaging of granzyme B using a targeted peptide, GZP, could be utilized for early response assessment across many checkpoint inhibitor combinations, and that GZP uptake could be compared between therapeutic regimens and dosing schedules as an early biomarker of relative efficacy. Experimental Design: Two models, MC38 and CT26, were treated with a series of checkpoint inhibitors. GZP PET imaging was performed to assess tumoral GZP uptake, and tumor volume changes were subsequently monitored to determine response. The average GZP PET uptake and response of each treatment group were correlated to evaluate the utility of GZP PET for comparing therapeutic efficacy. Results: In both tumor models, GZP PET imaging was highly accurate for predicting response, with 93% sensitivity and 94% negative predictive value. Mean tumoral GZP signal intensity of treatment groups linearly correlated with percent response across all therapies and schedules. Moreover, GZP PET correctly predicted that sequential dose scheduling of PD-1 and CTLA-4 targeted therapies demonstrates comparative efficacy to concurrent administration. Conclusion: Granzyme B quantification is a highly sensitive and specific early measure of therapeutic efficacy for checkpoint inhibitor regimens. This work provides evidence that GZP PET imaging may be useful for rapid assessment of therapeutic efficacy in the context of clinical trials for both novel drugs as well as dosing regimens.
https://ift.tt/2NL0V46
Association of CD4+ radiation-induced lymphocyte apoptosis with fibrosis and telangiectasia after radiotherapy in 272 breast cancer patients with >10-year follow-up
Purpose: Radiation-induced lymphocyte apoptosis (RILA) has been suggested as a predictive assay for adverse late reactions after radiotherapy. Thus low RILA values of T-lymphocyte subpopulations have been associated with increased risk for various endpoints at 2-3 years follow-up. The purpose was to test if such associations persist for specific endpoints (subcutaneous fibrosis, telangiectasia) in breast cancer patients with at least 10 years follow-up. Experimental design: 272 female patients who had received breast-conserving therapy within the German ISE study were included (median follow-up: 11.6 years). Radiotherapy-induced side effects were scored according to LENT-SOMA. RILA in the CD4+, CD8+ and NK subpopulations from peripheral blood was analyzed by flow cytometry. Multivariate predictive modeling was performed including relevant clinical risk factors. Results: Low CD4+ RILA was associated with increased risk for both fibrosis (p=0.011) and telangiectasia (p<0.001). For fibrosis, the association was stronger outside the surgical area (Fibout; p=0.004) than within (Fibin; p=0.17). Predictive multivariate modeling including clinical risk factors yielded OR=3.48 (95% CI 1.84-6.58) for any fibrosis and 8.60 (2.71-27.3) for telangiectasia. Addition of CD4+ RILA to the clinical variables improved discrimination (c statistics) from 0.62 to 0.68 for any fibrosis, 0.62 to 0.66 for Fibin, 0.61 to 0.69 for Fibout and from 0.65 to 0.76 for telangiectasia. CD8+ and NK RILA were not significantly associated with radiotherapy-related late reactions. Conclusions: The results provide first evidence that low CD4+ RILA is associated with increased subcutaneous fibrosis and telangiectasia even after 10 years. This supports the potential usefulness for predicting individual clinical risk.
https://ift.tt/2pXwo9Y
The impact of early phase trial design in the drug development process
Purpose: Many of the therapeutic agents that are being used currently were developed using the 3+3 decision rule for dose-finding. Over the past 30 years, several dose-finding designs have been proposed and evaluated, including the 'continual reassessment method' (CRM) and the 'Bayesian optimal interval design' (BOIN). This research investigates the role of the choice of an early phase design on the likelihood that drugs entering the drug development pipeline will have two successful phase III trials. Experimental Design: Using simulation, each agent in a population of hypothetical agents was tracked through the drug development process, from initial dose-finding to two confirmatory phase III trials. Varying the designs of the phase I, II, and III trials allows for an assessment of the effect of the choice of designs on the proportion of agents with successful phase III trials. Results: The results indicate that using the CRM or BOIN, rather than the 3+3 substantially enhances the proportion of effective agents that have successful phase III trials, with the CRM having a greater effect than BOIN. A larger phase II trial magnifies the effect of the phase I design. Conclusions:The results underscore the importance of the choice of the early phase designs. Use of the 3+3 results in fewer agents with successful phase III trials compared to the CRM or BOIN. The difference is more pronounced among highly effective agents. In addition, the results show the importance of a sufficiently powered phase II trial.
https://ift.tt/2NKJ6lK
Job Market for Nephrologists Continuing to Improve
TUESDAY, Oct. 16, 2018 -- The job market for new nephrologists is continuing to improve, and most fellows would recommend nephrology to medical students or residents, according to a report published online Oct. 15 by the American Society of...
https://ift.tt/2Ow1sMP
CHF in Pregnancy Up for Cancer Survivors With Cardiac Toxicity
TUESDAY, Oct. 16, 2018 -- The incidence of congestive heart failure (CHF) during pregnancy is 31 percent among women with a history of cardiotoxicity associated with cancer treatment, according to a study published in the Oct. 23 issue of the...
https://ift.tt/2J1EyXB
Change in Shelter Eligibility Policy Tied to More ED Visits
TUESDAY, Oct. 16, 2018 -- A policy change to Massachusetts' shelter eligibility was tied to increased pediatric emergency department visits for homelessness and substantial health care costs, according to a study published online Oct. 15 in...
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2006 to 2015 Saw Decrease in Medicare Beneficiary ICU Use
TUESDAY, Oct. 16, 2018 -- From 2006 to 2015, there was a significant decrease in intensive care unit (ICU) admissions among Medicare fee-for-service beneficiaries, according to a research letter published online Oct. 15 in the Annals of Internal...
https://ift.tt/2J1f50j
Few Seniors Who Self-Harm Referred for Mental Health Care
TUESDAY, Oct. 16, 2018 -- Most older adults who self-harm are not referred to mental health services, according to a study published online Oct. 15 in The Lancet Psychiatry. Catharine Morgan, Ph.D., from Manchester University in the United Kingdom,...
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Gastric Banding, Metformin Similar for Improving Glycemia
TUESDAY, Oct. 16, 2018 -- In adults with moderate obesity and either impaired glucose tolerance (IGT) or recently diagnosed mild type 2 diabetes (T2D), gastric banding and metformin are similarly effective for slowing disease progression over a...
https://ift.tt/2OvmKdi
ASA: Patients Assume Post-Op Opioids Are Best for Pain Relief
TUESDAY, Oct. 16, 2018 -- Patients undergoing surgery assume opioids will be most effective for postoperative pain relief, even if they don't expect to be prescribed opioids, according to a study presented at the annual meeting of the American...
https://ift.tt/2J1eXhl
Clinical Trials Support Efficacy of Tretinoin Lotion for Tx of Acne
TUESDAY, Oct. 15, 2018 -- Tretinoin 0.05 percent lotion (ALTRENO Lotion) provides statistically significant improvement in patients with moderate-to-severe acne, compared to placebo, according to two phase 3 studies published in the October issue of...
https://ift.tt/2Ot4PUt
High Risk for Readmission for Takotsubo Syndrome
TUESDAY, Oct. 16, 2018 -- Patients with Takotsubo syndrome (TTS), which is characterized by transient left ventricular dysfunction with symptoms and electrocardiogram changes mimicking acute myocardial infarction (AMI), have lower mortality during...
https://ift.tt/2OqswNk
Web-Based Lifestyle Program Works for Liver Disease Patients
TUESDAY, Oct. 16, 2018 -- Web-based programs may be effective in helping patients make lifestyle changes to control non-alcoholic fatty liver disease (NAFLD), according to a study published in the November issue of the Journal of Hepatology. Arianna...
https://ift.tt/2IZKa4J
Effect of Changes in Skeletal Muscle Mass on Oncological Outcomes During First-Line Sunitinib Therapy for Metastatic Renal Cell Carcinoma
Abstract
Background
Sarcopenia is a state of degenerative skeletal muscle wasting induced by cancer cachexia.
Objective
To evaluate the prognostic impact of changes in skeletal muscle mass (SMM) during first-line sunitinib therapy on oncological outcomes in metastatic renal cell carcinoma (mRCC).
Patients and Methods
Sixty-nine patients were evaluated retrospectively. The skeletal muscle index (SMI) was calculated based on computed tomography images obtained before the initiation (pre-treatment SMI) and after two cycles of sunitinib treatment (post-treatment SMI). The change in SMM was evaluated based on the value of ΔSMI, which was calculated as [(posttreatment SMI – pretreatment SMI)/ pretreatment SMI] × 100. Oncological outcomes were compared between patients with ΔSMI <0 (SMM decrease) and ΔSMI ≥0 (SMM maintenance).
Results
A decrease in SMM was observed in 38 patients (55.1%). Progression-free survival (PFS) and overall survival (OS) after sunitinib therapy initiation were significantly shorter in patients with ΔSMI <0 than in those with ΔSMI ≥0 (median PFS: 9.53 vs. 28.4 months, p < 0.0001; OS: 19.8 vs. 52.6 months, p = 0.0001). ΔSMI was an independent predictive factor for PFS (HR 3.25, 95% CI 1.74–6.29, p = 0.0002) and OS (HR 4.53, 95% CI 2.15–10.5, p < 0.0001). The objective response rate was significantly lower in patients with ΔSMI <0 than in those with ΔSMI ≥0 (23.7% vs. 51.6%, p = 0.0164).
Conclusion
Decreased SMM during first-line sunitinib therapy can be an effective marker of outcome prediction for mRCC.
https://ift.tt/2CkM1Qa
Amplification of Near Full-length HIV-1 Proviruses for Next-Generation Sequencing
https://ift.tt/2QSob2o
Assays for Studying the Role of Vitronectin in Bacterial Adhesion and Serum Resistance
This report describes protocols for characterizing interactions between bacterial outer membrane proteins and the human complement regulator vitronectin. The protocols can be used to study the binding reactions and biological function of vitronectin in any bacterial species.
https://ift.tt/2Aebl9f
Comparative diagnosis of Mycobacterium avium subspecies paratuberculosis in the tissues of clinical and subclinical sheep of paratuberculosis endemic farm
Abstract
Paratuberculosis (Johne's disease) is the chronic infectious granulomatous enteritis of ruminants caused by Mycobacterium avium subspecies paratuberculosis. Due to the lack of definite diagnostic tests, the early detection of the disease is difficult. The present study was undertaken to assess comparative efficacy of diagnostic methods routinely used in the identification and confirmation of Mycobacterium avium subspecies paratuberculosis (MAP) in the tissue samples of naturally infected clinical and subclinical sheep. The ileum and mesenteric lymph node (MLN) tissues were collected from 20 paratuberculous sheep from organized farm of Rajasthan. These animals were further classified as paucibacillary (PB) (n = 8) or multibacillary (MB) (n = 12) on the basis of histopathological findings and mycobacterial loads. The ileum and MLN sections from PB and MB and uninfected control groups were tested by indirect immunoperoxidase technique (IPT), Ziehl Neelsen's (ZN) method, bacterial culture, IS900 PCR and 251 gene PCR. In PB sheep, IPT and ZN were positive in 87.5 and 50% of intestinal sections and 75 and 37.5% of MLN sections, respectively. In MB sheep, IPT and ZN had equal sensitivity. The overall sensitivity of IPT was found to be superior (95%) than ZN method (80%) in demonstration of acid-fast bacteria in intestinal tissues. On the bacterial cultural examination of the intestinal and MLN tissues using Herrold's egg yolk medium, MAP was isolated in eight (66.6%) MB and in four (50%) PB sheep. Among 20 sheep, IS900 PCR detected 13 (65.0%) and 251 gene PCR detected 16 (80%) sheep as positive for MAP. In the PB sheep, the culture, ZN test and PCR sensitivity was found low in comparison to MB sheep. The sensitivity of IPT in PB sheep was better than other tests in detecting the MAP infection, which underlines its utility in confirmation of subclinical and clinical cases of paratuberculosis in sheep. The sensitivity of 251 gene PCR assay was found better than IS900 gene PCR and has potential to be used as screening test for clinical and subclinical paratuberculosis in sheep flocks.
https://ift.tt/2PyTRtf
Co-culture of dendritic cells and cytokine-induced killer cells effectively suppresses liver cancer stem cell growth by inhibiting pathways in the immune system
Abstract
Background
Application of dendritic cells (DC) for cancer immunotherapy involves tumor-associated immunogenic antigens for effective therapeutic strategies. The present study investigated whether DC co-cultured with autologous cytokine-induced killer cells (CIK) could induce a more specific immune response against liver cancer stem cells (LCSC) generated from human hepatocellular carcinoma (HCC) cells in vitro and in vivo.
Methods
Human DC and CIK were generated from peripheral blood mononuclear cells (PBMCs) taken from consenting liver cancer patients. Flow cytometry was used to determine the phenotypes of DC and CIK, and cell proliferation. The tumor growth and anti-tumor activity of these cells were further evaluated using a nude mouse tumor model.
Results
We demonstrated that DC and CIK significantly enhanced the apoptosis ratio, depending on DC-CIK cell numbers, by increasing caspase-3 protein expression and reducing proliferating cell nuclear antigen (PCNA) protein expression against LCSC. The in vivo data indicated that DC-CIK exhibited significant LCSC cell-induced tumor growth inhibition in nude mice, which was most significant with LCSC antigen loaded DCs.
Conclusions
The results showed, that DC-CIK cells could inhibit HCC and LCSC growths in vitro and in vivo and the most successful DC triggering of cell cytotoxic activity could be achieved by their LCSC antigen loading.
https://ift.tt/2yGjK2X
Impact of tumor size on survival of patients with resected pancreatic ductal adenocarcinoma: a systematic review and meta-analysis
Abstract
Background
The impact of tumor size on prognosis for surgically treated patients with pancreatic ductal adenocarcinoma (PDAC) remains controversial. A systematic review and meta-analysis was performed to evaluate this issue.
Methods
Relevant studies published from January 2000 to June 2017 were identified through EMBASE and PUBMED. Data were pooled for meta-analysis using Review Manager 5.3.
Results
Twenty eight observational studies involving a total of 23,945 patients were included. Tumors > 2 cm was associated with poor prognosis: the pooled hazard ratio (HR) estimate for overall survival was 1.52 (95% confidence interval [CI]: 1.41–1.64; P < 0.0001) by univariate analysis and 1.61 (95% CI: 1.35–1.91; P < 0.0001) by multivariate analysis; the pooled HR estimate for disease-free survival was 1.74 (95% CI: 1.46–2.07; P < 0.0001) by univariate analysis and 1.38 (95% CI: 1.12–1.68; P = 0.002) by multivariate analysis. When compared with patients with tumors ≤2 cm, those with the tumors > 2 cm had higher incidences of lymph node metastasis, poor tumor differentiation, lymph vessel invasion, vascular invasion, perineural invasion, and positive intraoperative peritoneal cytology.
Conclusion
These data demonstrate that PDAC size > 2 cm is an independent predictive factor for poor prognosis after surgical resection and associated with more aggressive tumor biology.
https://ift.tt/2ylxPDQ
A prospective clinical and biological database for pancreatic adenocarcinoma: the BACAP cohort
Abstract
Background
The prognosis for pancreatic cancer remains poor despite diagnostic advances and treatments with new chemotherapeutic regimens. The five year survival rate remains below 3%. Consequently, there is an urgent need for new treatments to significantly improve the prognosis. In addition, there is a big gap in terms of the screening, early diagnosis and prevention of pancreatic cancer the incidence of which is increasing dramatically.
Methods
Design: the BACAP cohort is a prospective multicenter pancreatic cancer cohort (pancreatic ductal carcinoma) with clinical and multiple biological samples; Participating centers: 15 French academic and private hospitals; Study Population: any cytologically and/or histologically proven pancreatic carcinoma regardless of the stage (resectable, borderline, locally advanced or metastatic) or treatment (surgery, palliative chemotherapy, best supportive care). At least 1500 patients will be included. Clinical data collected include: disease presentation, epidemiological and social factors, baseline biology, radiology, endoscopic ultrasound, staging, pathology, treatments, follow-up (including biological and radiological), and survival. All these data are collected and stored through an e-observation system at a centralized data center. Biological samples and derived products (i.e. before any treatment): blood, saliva, endoscopic ultrasound-guided fine needle aspiration materials from the primary tumor, fine needle biopsy of metastases and surgically resected tissue. DNA and RNA are extracted from fine needle aspiration materials and are quantified and characterized for quality. Whole blood, plasma and serum are isolated from blood samples. Frozen tissues were specifically allocated to the cohort. All derived products and saliva are stored at − 80 °C. Main end-points: i) to centralize clinical data together with multiple biological samples that are harmonized in terms of sampling, the post sampling process and storage; ii) to identify new molecular markers for the diagnosis, prognosis and possibly the predictive response to pancreatic cancer surgery and or chemotherapy.
Discussion
The BACAP cohort is a unique prospective biological clinical database that provides the opportunity to identify correlations between the presence/expression of a broad panel of biomarkers (DNA, RNA, miRNA, proteins, etc.), epidemiological and social data, various clinical situations, various stages and the differentiation of the tumor, treatments and survival.
Trial registration
ClinicalTrials.gov Identifier: NCT02818829. Registration date: June 30, 2016.
https://ift.tt/2yLYE3c
Risk factors for erlotinib-induced hepatotoxicity: a retrospective follow-up study
Abstract
Background
Erlotinib is a drug used for the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer. Severe hepatotoxicity was observed in 4% to 31% of patients receiving erlotinib treatment prompting delay or termination of treatment. Only a few factors related to hepatotoxicity of erlotinib have been reported. No study has investigated the role of concomitant medications and erlotinib-induced hepatotoxicity. The aim of this study was to investigate the association between erlotinib-induced hepatotoxicity and various factors including concomitant medications in patients with NSCLC and pancreatic cancer.
Methods
From January 2014 to June 2017, a retrospective study was conducted in patients with NSCLC and pancreatic cancer, who were treated with erlotinib. Various data were reviewed, including sex, age, body weight, height, body surface area (BSA), underlying disease, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), smoking history, erlotinib dose, EGFR mutation, and concomitant drugs.
Results
The incidence of grade 2 or higher hepatotoxicity in the study group of patients was 17.2%. Multivariate analysis showed a 2.7-fold increase in hepatotoxicity with the concomitant use of CYP3A4 inducers. In NSCLC patients, co-administration of H2-antagonist/PPI increased hepatotoxicity 3.5-fold. Among the demographic factors, liver metastasis and age ≥ 65 years were significant risk factors in all study patients and NSCLC patients, respectively; the attributable risks for liver metastasis and age were 46.3% and 71.8%, respectively. Subgroup analysis using pancreatic cancer patients yielded marginally significant results with CYP3A4 inducers and erlotinib-induced hepatotoxicity. Liver metastasis and CYP3A4 inducers also shortened time to hepatotoxicity 2.1 and 2.3-fold, respectively.
Conclusions
Our study showed that concomitant use of CYP3A4 inducers and H2-antagonist/PPI, liver metastasis, and age ≥ 65 were associated with erlotinib-induced hepatotoxicity. Thus, close monitoring of liver function is recommended, especially in patients using CYP3A4 inducers and anti-acid secreting agents.
https://ift.tt/2ylxLUC
Combination of gemcitabine and docetaxel: a regimen overestimated in refractory metastatic osteosarcoma?
Abstract
Background
The combination of gemcitabine and docetaxel (GT) has been demonstrated to be effective against various types of solid tumors, including sarcoma. However, the regimen has not been confirmed in large, well-designed clinical trials in refractory metastatic osteosarcoma.
Methods
We retrospectively reviewed the records of patients with refractory metastatic osteosarcoma at Peking University People's Hospital who were treated with gemcitabine (1000 mg/m2) intravenously (IV) on Day 1 and Day 8, and docetaxel (75 mg/m2) IV on Day 8, repeated every 21 days.
Results
A total of 52 patients with a median age of 18.4 years were treated with GT at the Peking University People's Hospital from August 2012 to August 2017. A total of 174 courses were administered. Only five patients with pulmonary metastasis achieved a best response of stable disease (SD), while all other patients had progressive disease. The result was disappointing with an ORR of 0%, a DCR of 9.6%, and a median DOR of 3.5 months. Grade 3 or 4 toxicities were observed in 69 (39.7%) courses and in 28 (53.8%) patients, most of which were myelosuppression, especially thrombocytopenia. No fatal adverse effect (AE) was found.
Conclusion
The combination of gemcitabine and docetaxel (GT) as a salvage regimen is well-tolerated but not as effective as expected in refractory metastatic osteosarcoma. This report highlights the need for the development of new approaches with higher activity in these patients.
https://ift.tt/2yIUtFD
Barrett’s esophagus is negatively associated with eosinophilic esophagitis in Japanese subjects
Abstract
Background
Although both eosinophilic esophagitis (EoE) and Barrett's esophagus (BE) are considered to be associated with T helper (Th) 2-mediated immune responses, the association between EoE and BE is unclear. We investigated the clinical relationship between EoE and BE.
Methods
We conducted a single-center retrospective observational study. The study included 95 patients with EoE and randomly selected age- and sex-matched controls who underwent esophagogastroduodenoscopy during a medical health check-up at Osaka City University in a ratio of 1:2 for comparison. We compared the clinical characteristics and the prevalence rate of BE, reflux esophagitis (RE), hiatal hernia, and atrophic gastritis between EoE patients and controls by univariate analysis. Furthermore, we performed multivariate logistic regression analysis to investigate the association of these factors with EoE.
Results
On univariate analysis, the prevalence rate of BE was significantly lower in patients with EoE than in controls (2.1% vs. 13.2%; p = 0.00528). In contrast, the prevalence rate of RE was higher in EoE patients than in controls, but it was not statistically significant (absence and Grades A, B, and C: 74.7%, 18.9%, 5.3%, and 1.1% vs. 83.7%, 12.6%, 3.7%, and 0%; p = 0.193, respectively). Multivariate analysis showed that BE was negatively associated with EoE (odds ratio: 0.132; 95% confidence interval: 0.0302–0.573; p = 0.00686).
Conclusions
BE is negatively associated with EoE in Japanese subjects. The mechanism behind the inverse relationship between EoE and BE should be examined.
https://ift.tt/2J21aY7
My 'why': How the first responder community helped me heal
After losing her sister six years ago, EMS1, FireRescue1 Associate Editor Sarah Calams explains how she was able to heal by working closely with the first responder community
https://ift.tt/2AdtFiM
Long noncoding RNA AFAP1-AS1 acts as a competing endogenous RNA of miR-423-5p to facilitate nasopharyngeal carcinoma metastasis through regulating the Rho/Rac pathway
Abstract
Background
Actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1), a long noncoding RNA, is significantly highly expressed and associated with metastasis and poor prognosis in many cancers, including nasopharyngeal carcinoma (NPC). In this study, we aim to identify the role of AFAP1-AS1 acting as an oncogenic lncRNA to promote NPC metastasis.
Methods
The role of AFAP1-AS1, miR-423-5p, and FOSL2 in NPC metastasis was investigated in vitro and in vivo. Bioinformatics analysis and luciferase activity assays were used to identify the interaction between AFAP1-AS1, miR-423-5p, and FOSL2. Additionally, real-time PCR and western blotting were used to assess the function of AFAP1-AS1 acting as an oncogenic lncRNA to promote NPC progression by regulating miR-423-5p and the downstream Rho/Rac pathway.
Results
In this study, we determined that AFAP1-AS1 functions as a competing endogenous RNA in NPC to regulate the Rho/Rac pathway through miR-423-5p. These interactions can mediate the expression of RAB11B, LASP1, and FOSL2 and accelerate cell migration and invasion via the Rho/Rac signaling pathway or FOSL2. AFAP1-AS1 and FOSL2 could competitively bind with miR-423-5p to regulate several molecules, including RAB11B and LASP1 of the Rho/Rac signaling pathway. AFAP1-AS1 can also regulate the expression of LASP1, which was transcriptionally regulated by FOSL2, resulting in increased migration and invasion of NPC cells via the Rho/Rac signaling pathway.
Conclusions
The observations in this study identify an important role for AFAP1-AS1 as a competing endogenous RNA (ceRNA) in NPC pathogenesis and indicate that it may serve as a potential target for cancer diagnosis and treatment.
https://ift.tt/2QUbe86
MicroRNA-302a/d inhibits the self-renewal capability and cell cycle entry of liver cancer stem cells by targeting the E2F7/AKT axis
Abstract
Background
There is increasing evidence that liver cancer stem cells (LCSCs) contribute to hepatocellular carcinoma (HCC) initiation and progression. MicroRNA (miRNA) plays a significant functional role by directly regulating respective targets in LCSCs-triggered HCC, however, little is known about the function of the miRNA-302 family in LCSCs.
Methods
MiRNAs microarray was used to detect the miRNAs involved in LCSCs maintenance and differentiation. Biological roles and the molecular mechanism of miRNA-302a/d and its target gene E2F7 were detected in HCC in vitro. The expression and correlation of miRNA-302a/d and E2F7 in HCC patients was evaluated by quantitative PCR and Kaplan–Meier survival analysis.
Results
We found that the miRNA-302 family was downregulated during the spheroid formation of HCC cells and patients with lower miRNA-302a/d expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, E2F7 was confirmed to be directly targeted and inhibited by miRNA-302a/d. Furthermore, concomitant low expression of miRNA-302a/d and high expression of E2F7 correlated with a shorter median OS and PFS in HCC patients. Cellular functional analysis demonstrated that miRNA-302a/d negatively regulates self-renewal capability and cell cycle entry of liver cancer stem cells via suppression of its target gene E2F7 and its downstream AKT/β-catenin/CCND1 signaling pathway.
Conclusions
Our data provide the first evidence that E2F7 is a direct target of miRNA-302a/d and miRNA-302a/d inhibits the stemness of LCSCs and proliferation of HCC cells by targeting the E2F7/AKT/β-catenin/CCND1 signaling pathway.
https://ift.tt/2Afr3Rr
Temozolomide-Perillyl alcohol conjugate impairs Mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation
Abstract
Background
Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed strong anticancer potency in multiple cancer types. In this study, we aimed to clarify the relationship between TMZ-POH and autophagy, and explore the underlying mechanisms involved in.
Methods
The proteins involved in autophagy, mitochondrial fission, lysosomal function and membrane traffic were detected by western blots; Autophagosome, mitochondria and lysosome were visualized by transmission electron microscope (TEM) and immunostaining; Apoptosis analysis and fluorescence probe detection were applied by flow cytometry.
Results
TMZ-POH blocked mitophagy flux although the number of autophagosomes which colocalized with mitochondria in the cells was increased via inducing lysosomal dysfunction as evidence from impaired lysosomal acidification, maturation and hampered autophagosome- lysosome fusion, which largely depended on its downregulation on the small GTPase RAB7A via mevalonate pathway. More importantly, our data demonstrated TMZ-POH sensitized cancer cell to irradiation induced apoptosis.
Conclusions
Temozolomide-perillyl alcohol conjugate impairs mitophagy flux by inducing lysosomal dysfunction in Non-Small Cell Lung Cancer (NSCLC) cells and sensitizes them to irradiation, thereby proposing TMZ-POH as a potential radiosensitizer.
https://ift.tt/2QQRz95
Synergistic inhibitory effects of capsaicin combined with cisplatin on human osteosarcoma in culture and in xenografts
Abstract
Background
The combination of phytochemicals with chemotherapy drugs is an emerging new strategy for cancer therapy to increase antitumor responses.
Methods
The present study investigates the effect of the combination of capsaicin (CAP) with cisplatin (DDP) and the potential underlying anticancer mechanisms in osteosarcoma (OS) cells in vitro and in vivo.
Results
Cell viability assays and isobolographic analyses demonstrated that the combination of CAP and DDP showed synergistic cytotoxic effects on OS cells. We chose relatively low concentrations of CAP (100 μM) and DDP (16.7 μM) for subsequent experiments. Generally, the combination of CAP and DDP had significant effects on apoptosis induction, cell cycle arrest and cell invasion inhibition in OS cells compared with the individual-treatment groups and the control group. Moreover, cotreatment with CAP and DDP triggered prosurvival autophagy through reactive oxygen species (ROS)/JNK and p-AKT/mTOR signaling in OS cells. The combination regimen of CAP and DDP also inhibited tumor growth in an OS xenograft model.
Conclusion
These results suggest that the combination of CAP and DDP has strong inhibitory effects on OS cells and identify CAP as a promising agent for supplementing standard chemotherapy and possible future targeted therapy in OS.
https://ift.tt/2AdTM95
AFF3 upregulation mediates tamoxifen resistance in breast cancers
Abstract
Background
Although tamoxifen is a highly effective drug for treating estrogen receptor–positive (ER+) breast cancer, nearly all patients with metastasis with initially responsive tumors eventually relapse, and die from acquired drug resistance. Unfortunately, few molecular mediators of tamoxifen resistance have been described. Here, we describe AFF3 (AF4/FMR2 family member 3), which encodes a nuclear protein with transactivation potential that confers tamoxifen resistance and enables estrogen-independent growth.
Methods
We investigated AFF3 expression in breast cancer cells and in clinical breast cancer specimens with western blot and Real-time PCR. We also examined the effects of AFF3 knockdown and overexpression on breast cancer cells using luciferase, tetrazolium, colony formation, and anchorage-independent growth assays in vitro and with nude mouse xenografting in vivo.
Results
AFF3 was overexpressed in tamoxifen-resistant tumors. AFF3 overexpression in breast cancer cells resulted in tamoxifen resistance, whereas RNA interference–mediated gene knockdown reversed this phenotype. Furthermore, AFF3 upregulation led to estrogen-independent growth in the xenograft assays. Mechanistic investigations revealed that AFF3 overexpression activated the ER signaling pathway and transcriptionally upregulated a subset of ER-regulated genes. Clinical analysis showed that increased AFF3 expression in ER+ breast tumors was associated with worse overall survival.
Conclusions
These studies establish AFF3 as a key mediator of estrogen-independent growth and tamoxifen resistance and as a potential novel diagnostic and therapeutic target.
https://ift.tt/2QVTvNM
Mass. island residents raising money for AEDs
Plum Island residents are aiming to make their isolated island safer by raising money to install two AEDs and train community members on how to use them
https://ift.tt/2NKwwmw
Status of hydration assessed by bioelectrical impedance analysis: a valuable predictive factor for radiation-induced oral mucositis in head and neck cancer patients
Abstract
Background
Apart from surgery, the methods of treatment of HNC are radiotherapy (RTH) and/or chemotherapy (CRTH/CHT). One of the most frequent and serious complications of RTH is oral mucositis (OM). There is a strict correlation between the inflammation and the status of hydration. The aim of the study was to evaluate the changes in hydration, occurring in the course of RTH, measured by means of bioelectrical impedance analysis (BIA) and to analyze them in correlation with the intensification of OM in HNC patients.
Patients and methods
Data from 49 HNC patients (stages I–IV) were analyzed. All of them were irradiated using IMRT technique with the doses of 50–70 Gy. Oral mucositis (OM) was evaluated according to RTOG/EORTC guidelines. BIA was performed using ImpediMed bioimpedance analysis SFB7 BioImp v1.55.
Results
In the fourth week of RTH, 4–5 days before the occurrence of severe OM, it was found that patients with OM grade 3 or higher compared to OM grade 2 or lower had significantly: lower ICW% values (respectively, 53.02% vs 50.72%; p = 0.0047), higher: ECW%: (47.95% vs 46.92%; p = 0.0020), TBW% (respectively, 56.34% vs 51.06%; p = 0.0455), ECW/ICW (respectively, 0.96 vs 0.86; p = 0.0007) and ECW/TBW (respectively, 0.49 vs 0.46, p = 0.0033).
Conclusion
Our study indicates that HNC patients undergo changes in hydration in the course of RTH. We have also confirmed that the intensification of OM leads to ICW decrease and the increase of ECW, TBW as well as ECW/ICW and ECW/TBW values.
https://ift.tt/2P27dBc
Analysis of definitive chemo-radiotherapy for esophageal cancer with supra-clavicular node metastasis based on CT in a single institutional retrospective study: a propensity score matching analysis
Abstract
Background
The prognostic value of supra-clavicular lymph node (SCLN) metastases in esophageal cancer (EC) is still not clear.
Method
From January 2009 to December 2015, a survival analysis was performed to retrospectively identify the prognostic value of SCLN metastasis on survival on 751 patients with EC treated with definitive chemo-radiotherapy (dCRT).
Results
The median follow-up duration for living patients was 56.6 months. The median overall survival (OS) for all patients was 16.6 months. Patients with SCLN metastasis had a much poorer prognosis for OS (χ2 = 17.342, P < 0.001), distant metastasis-free survival (DMFS) (χ2 = 24.793, P < 0.001) and progression-free survival (PFS) (χ2 = 25.802, P < 0.001) than those without SCLN metastasis. The same results were found after propensity score matching. Nonetheless, the prognosis of patients with cervical or upper thoracic EC metastasis in SCLN was better than those of patients with middle or lower thoracic EC metastasis in SCLN for OS (χ2 = 4.516, P = 0.038), DMFS (χ2 = 8.326, P = 0.004) and PFS (χ2 = 6.255, P = 0.012). Univariate analysis showed that gender, middle or lower thoracic EC with SCLN metastasis, tumor length, tumor diameter, concurrent chemo-radiotherapy (CCR) and number of lymph nodes were prognostic factors for PFS. Gender, age, middle or lower thoracic EC with SCLN metastasis, tumor diameter, tumor length, and number of lymph nodes were prognostic factors for DMFS. According to the multivariate analysis, only middle or lower thoracic EC with SCLN metastasis and number of lymph nodes were independent prognostic factors for DMFS and PFS.
Conclusion
For patients with cervical or upper thoracic EC, metastasis in SCLN should be considered to be regional lymph nodes and treated with curative intent if the total number of lymph nodes is limited. However, for patients with middle or lower thoracic EC, metastasis should be considered to be a higher level N stage or M1 stage, and it is thus necessary to provide consolidation chemotherapy after dCRT.
https://ift.tt/2Ov6edi
Ability of the ALBI grade to predict posthepatectomy liver failure and long-term survival after liver resection for different BCLC stages of HCC
Abstract
Background
Underlying liver function is a major concern when applying surgical resection for hepatocellular carcinoma (HCC). We aimed to explore the capability of the albumin-bilirubin (ALBI) grade to predict post-hepatectomy liver failure (PHLF) and long-term survival after hepatectomy for HCC patients with different Barcelona Clinic Liver Cancer (BCLC) stages.
Methods
Between January 2010 and December 2014, 338 HCC patients who were treated with liver resection were enrolled. The predictive accuracy of ALBI grade system for PHLF and long-term survival across different BCLC stages was examined.
Results
A total of 26 (7.7%) patients developed PHLF. Patients were divided into BCLC 0/A and BCLC B/C categories. ALBI score was found to be a strong independent predictor of PHLF across different BCLC stages by multivariate analysis. In terms of overall survival (OS), it exhibited high discriminative power in the total cohort and in BCLC 0/A subgroup. However, differences in OS between ALBI grade 1 and 2 patients in BCLC B/C subgroup were not significant (P = 0.222).
Conclusion
The ALBI grade showed good predictive ability for PHLF in HCC patients across different BCLC stages. However, the ALBI grade was only a significant predictor of OS in BCLC stage 0/A patients and failed to predict OS in BCLC stage B/C patients.
https://ift.tt/2CjpgMw
Immune landscape and in vivo immunogenicity of NY-ESO-1 tumor antigen in advanced neuroblastoma patients
Abstract
Background
Indirect evidence suggesting the immunosensitivity/immunogenicity of neuroblastoma is accumulating. The aims of this study were to investigate the immune landscape of neuroblastoma and to evaluate the in vivo immunogenicity of the NY-ESO-1 tumor antigen in advanced neuroblastoma patients.
Methods
The immune infiltrating cells of the NY-ESO-1+ tumors from three HLA*A201 patients with metastatic neuroblastoma who relapsed after conventional treatments were evaluated by immunohistochemistry. The patients were vaccinated with the HLA-A*0201-restricted peptide NY-ESO-1157-165(V). The peptide was emulsified in Montanide ISA51 and given subcutaneously in a phase I pilot study. The immunogenicity of NY-ESO-1 antigen was evaluated by monitoring mononuclear cells in patient peripheral blood, pre- and post-vaccine, by short-term in vitro sensitization, HLA-multimer staining and IFN-γ ELISpot analysis.
Results
Both CD3 T cells and CD163 myeloid cells were present in pre-vaccine tumors and PD-1 and PD-L1 expression was mainly found in the immune infiltrate. Despite the advanced stage of the disease, the vaccination induced systemic NY-ESO-1 specific CD8 T cells releasing IFN-γ in response to activation with the NY-ESO-1 peptide and an HLA-A2 positive neuroblastoma cell line.
Conclusions
Our results indicate that vaccination with a tumor-associated peptide is able to boost NY-ESO-1-specific, functionally active T cells in advanced neuroblastoma patients with lymphocyte infiltration in their pre-vaccine tumors.
Trial registration
EudraCT #2006–002859-33.
https://ift.tt/2CkVfvI
A rare case of primary breast angiosarcoma in a male: a case report
Abstract
Background
Sarcomas account for less than 1% of primary breast cancers, and breast angiosarcomas are responsible for only 0.05% of all breast malignancies. The male breast has the same potential for malignant transformation as the female breast. However, due to anatomical differences in the breast and the low incidence of angiosarcoma, it is difficult to determine how male breasts can be affected by this type of tumor.
Case presentation
A 36-year-old male patient was admitted to the hospital with a palpable lump in his right breast. Lymphadenopathy was negative. Ultrasonography showed a hypoechoic mass with partially defined contours, measuring 4.0 × 3.0 cm, with muscle infiltration. Histological examination revealed a malignant tumor. Radical mastectomy was then performed with clear surgical margins. The patient began chemotherapy with paclitaxel. Following the second cycle of chemotherapy, he presented with headache and seizures due to a frontal lobe metastasis. Twenty days after the onset of neurological symptoms, the patient died.
Conclusions
Primary angiosarcomas of the male breast are extremely rare. This is the sixth case published in the literature. It is in agreement with other studies in the literature concerning clinical presentation and poor prognosis. Treatment consists in surgical removal of the tumor with clear margins and without axillary lymphadenectomy.
https://ift.tt/2CNY8pW
Estrogen receptor β is associated with expression of cancer associated genes and survival in ovarian cancer
Abstract
Background
In ovarian cancer, the role of estrogen receptors (ERs), particularly of ERβ, being suggested as tumor suppressor in breast and prostate cancer, remains unclear. We examined the expression of nuclear and cytoplasmic ERβ in ovarian cancer and correlated it with expression of ovarian cancer markers CA125, CEA and CA72–4, steroid hormone receptors ERα and PR, cancer-associated genes EGFR, p53, HER2 and proliferation marker Ki-67. Additionally we examined to what extent expression of ERβ and the other proteins affects survival of ovarian cancer patients.
Methods
We established a tissue microarray from 171 ovarian cancer patients and performed immunohistochemical analyses of the mentioned proteins.
Results
Nuclear ERβ was detected in 47.31% of the ovarian cancer tissues and cytoplasmic expression of this receptor was observed in 23.08%. Nuclear expression of ERβ was significantly decreased in the G3 subgroup compared to better differentiated cancers (p < 0.01) and correlated with ovarian cancer markers CEA (95% CI 0.1598–0.4465; p < 0.0001) and CA72–4 (95% CI 0.05953–0.3616; p < 0.01). Cytoplasmic ERβ expression correlated with EGFR levels (95% CI 0.1059–0.4049; p < 0.001). ERα expression was associated with expression of CA125 and PR. Overall survival of patients with tumors expressing cytoplasmic ERβ was significant longer compared to those with ERβ-negative ovarian cancer (chi-square statistic of the log-rank, p < 0.05). Progression-free survival was dependent on expression of PR (chi-square statistic of the log-rank, p < 0.05) and Ki-67 (p = 0.05).
Conclusions
Our data suggest an important, but distinct role of nuclear and cytoplasmic ERβ expression in ovarian cancer and encourage further studies on its role in this cancer entity.
https://ift.tt/2CmfxFm
Impact of CDX2 expression status on the survival of patients after curative resection for colorectal cancer liver metastasis
Abstract
Background
The prognostic biomarker for patients undergoing curative liver metastasectomy for colorectal cancer (CRC) is lacking. The purpose was to investigate the prognostic role of a lack of CDX2 expression, which has been proposed as a potential biomarker for high-risk relapse in early-stage CRC, in patients undergoing curative liver metastasectomy.
Methods
A total of 396 consecutive patients with CRC liver metastasis who underwent potentially curative liver metastasectomy at a single center in Japan between 2005 and 2015 were included. For the immunohistochemical analysis of nuclear CDX2 expression, we adopted the tissue microarray approach using the resected metastatic liver CRCs. Patient subgroups were compared with respect to disease-free survival (DFS) and overall survival (OS) by applying the Kaplan-Meier curve, log-rank tests, and multivariate analyses based on the Cox proportional hazards method. OS is defined as the period from the date of curative liver resection for metastatic CRC until death. DFS is defined as the length of time from curative liver resection to either the first recurrence or death. In patients without recurrence, the latest imaging inspection date was used as the censored date.
Results
Thirty-six of the 396 CRCs (9.1%) reduced CDX2 expression. The reduced expression of CDX2 was associated with poor differentiation (P = 0.02). DFS in days was lower in the patients with CDX2-low CRC than in the patients with CDX2-high CRC (median DFS: 245 days versus 420 days; hazard ratio for disease recurrence: 1.64; 95% confidence interval: 1.08–2.38; P = 0.02). OS in days was lower in the patients with CDX2-low CRC than in the patients with CDX2-high CRC (median OS: 1024 days versus 3145 days; hazard ratio: 2.41; 95% confidence interval: 1.52–3.85; P < 0.001). In patients with CDX2-low CRC, both DFS and OS were similar between the with and without pre- or post-operative chemotherapy groups (median DFS: 243 versus 247 days; P = 0.73, median OS: 1016 versus 1363 days; P = 0.69).
Conclusions
Reduced expression of CDX2 indicates poor DFS and OS, however, it might not represent chemosensitivity in patients undergoing curative liver metastasectomy. (339/350).
https://ift.tt/2CLTpFb
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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...
