Erythrocyte-Membrane-Enveloped Perfluorocarbon as Nanoscale Artificial Red Blood Cells to Relieve Tumor Hypoxia and Enhance Cancer Radiotherapy

Hypoxia, a common feature within many types of solid tumors, is known to be closely associated with limited efficacy for cancer therapies, including radiotherapy (RT) in which oxygen is essential to promote radiation-induced cell damage. Here, an artificial nanoscale red-blood-cell system is designed by encapsulating perfluorocarbon (PFC), a commonly used artificial blood substitute, within biocompatible poly(d,l-lactide-co-glycolide) (PLGA), obtaining PFC@PLGA nanoparticles, which are further coated with a red-blood-cell membrane (RBCM). The developed PFC@PLGA-RBCM nanoparticles with the PFC core show rather efficient loading of oxygen, as well as greatly prolonged blood circulation time owing to the coating of RBCM. With significantly improved extravascular diffusion within the tumor mass, owing to their much smaller nanoscale sizes compared to native RBCs with micrometer sizes, PFC@PLGA-RBCM nanoparticles are able to effectively deliver oxygen into tumors after intravenous injection, leading to greatly relieved tumor hypoxia and thus remarkably enhanced treatment efficacy during RT. This work thus presents a unique type of nanoscale RBC mimic for efficient oxygen delivery into solid tumors, favorable for cancer treatment by RT, and potentially other types of therapy as well.

Artificial nanoscale red blood cells (RBCs) are fabricated by coating perfluorocarbon-loaded nanoparticles with an RBC membrane. Upon intravenous injection, such nanoparticles, with efficient oxygen-loading function, prolonged blood-circulation time, and great extravascular diffusion ability, are able to effectively deliver oxygen into tumors, leading to greatly relieved tumor hypoxia and thus remarkably enhanced treatment efficacy during radiotherapy.

http://ift.tt/2uB64Gc

Direct Synthesis of Large-Area 2D Mo2C on In Situ Grown Graphene

As a new member of the MXene group, 2D Mo₂C has attracted considerable interest due to its potential application as electrodes for energy storage and catalysis. The large-area synthesis of Mo₂C film is needed for such applications. Here, the one-step direct synthesis of 2D Mo₂C-on-graphene film by molten copper-catalyzed chemical vapor deposition (CVD) is reported. High-quality and uniform Mo₂C film in the centimeter range can be grown on graphene using a Mo–Cu alloy catalyst. Within the vertical heterostructure, graphene acts as a diffusion barrier to the phase-segregated Mo and allows nanometer-thin Mo₂C to be grown. Graphene-templated growth of Mo₂C produces well-faceted, large-sized single crystals with low defect density, as confirmed by scanning transmission electron microscopy (STEM) measurements. Due to its more efficient graphene-mediated charge-transfer kinetics, the as-grown Mo₂C-on-graphene heterostructure shows a much lower onset voltage for hydrogen evolution reactions as compared to Mo₂C-only electrodes.

The one-step direct synthesis of a 2D Mo₂C-on-graphene heterostructure by molten Cu-catalyzed chemical vapor deposition is reported. Graphene acts as a diffusion barrier to phase-segregated Mo, thus allowing the thickness of Mo₂C to be kinetically controlled. The heterostructure functions as a highly stable electrode in hydrogen evolution reactions.

http://ift.tt/2vAFHNQ

3D Anisotropic Thermal Conductivity of Exfoliated Rhenium Disulfide

ReS₂ represents a different class of 2D materials, which is characterized by low symmetry having 1D metallic chains within the planes and extremely weak interlayer bonding. Here, the thermal conductivity of single-crystalline ReS₂ in a distorted 1T phase is determined at room temperature for the in-plane directions parallel and perpendicular to the Re-chains, and the through-plane direction using time-domain thermoreflectance. ReS₂ is prepared in the form of flakes having thicknesses of 60–450 nm by micromechanical exfoliation, and their crystalline orientations are identified by polarized Raman spectroscopy. The in-plane thermal conductivity is higher along the Re-chains, (70 ± 18) W m⁻¹ K⁻¹, as compared to transverse to the chains, (50 ± 13) W m⁻¹ K⁻¹. As expected from the weak interlayer bonding, the through-plane thermal conductivity is the lowest observed to date for 2D materials, (0.55 ± 0.07) W m⁻¹ K⁻¹, resulting in a remarkably high anisotropy of (130 ± 40) and (90 ± 30) for the two in-plane directions. The thermal conductivity and interface thermal conductance of ReS₂ are discussed relative to the other 2D materials.

The 3D thermal-conductivity tensor of ReS₂, a transition-metal dichalcogenide with Re-chains on the plane, is determined using time-domain thermoreflectance. The thermal conductivity is higher along the Re-chains, 70 W m⁻¹ K⁻¹, compared to transverse to the chains, 50 W m⁻¹ K⁻¹. The through-plane thermal conductivity is the lowest observed for 2D materials, 0.55 W m⁻¹ K⁻¹.

http://ift.tt/2u6IizK

Precise and Arbitrary Deposition of Biomolecules onto Biomimetic Fibrous Matrices for Spatially Controlled Cell Distribution and Functions

Advances in nano-/microfabrication allow the fabrication of biomimetic substrates for various biomedical applications. In particular, it would be beneficial to control the distribution of cells and relevant biomolecules on an extracellular matrix (ECM)-like substrate with arbitrary micropatterns. In this regard, the possibilities of patterning biomolecules and cells on nanofibrous matrices are explored here by combining inkjet printing and electrospinning. Upon investigation of key parameters for patterning accuracy and reproducibility, three independent studies are performed to demonstrate the potential of this platform for: i) transforming growth factor (TGF)-β1-induced spatial differentiation of fibroblasts, ii) spatiotemporal interactions between breast cancer cells and stromal cells, and iii) cancer-regulated angiogenesis. The results show that TGF-β1 induces local fibroblast-to-myofibroblast differentiation in a dose-dependent fashion, and breast cancer clusters recruit activated stromal cells and guide the sprouting of endothelial cells in a spatially resolved manner. The established platform not only provides strategies to fabricate ECM-like interfaces for medical devices, but also offers the capability of spatially controlling cell organization for fundamental studies, and for high-throughput screening of various biomolecules for stem cell differentiation and cancer therapeutics.

With the demonstration of biomolecule deposition (single or multiple types) onto biomimetic extracellular matrix–like nanofibrous matrices with arbitrary shape, pattern, and dosage using an inkjet-printing-based technology, a cost-effective and high-throughput platform is presented for controllably organizing various cells for cell–cell and cell–matrix interactions or potentially screening various biomolecules for stem cell differentiation and therapeutics for cancer therapy.

http://ift.tt/2toB4K5

Engineering Single Nanopores on Gold Nanoplates by Tuning Crystal Screw Dislocation

Compared with the large variety of solid gold nanostructures, synthetic approaches for their hollow counterparts are limited, largely confined to chemical and irradiation-based etching of preformed nanostructures. In particular, the preparation of through nanopore structures is extremely challenging. Here, a unique strategy for direct synthesis of gold nanopores in solution without the need for sacrificial templates or postsynthesis processing is reported. By controlling the degree of crystal screw dislocation, a single through pore with diameter ranging from sub-nanometer to tens of nanometers, in the center of large gold nanoplates, can be engineered with precision. Ionic current rectification behaviors are observed using the gold nanopore, potentially enabling new capabilities in biosensing, sequencing, and imaging.

High-throughput production of solid-state nanopores is a major challenge. A novel methodology is reported for solution-phase synthesis of Au nanoplates with a single through pore with diameters ranging from sub-nanometers to tens of nanometers in the center, based on crystal screw dislocation.

http://ift.tt/2u6M8Zx

Nutrition at the End of Life: It’s Not What You Say, It’s How You Say It

Abstract

Purpose of Review

The purpose of this review is to describe and appraise the available scientific evidence to guide the use of artificial nutrition and hydration at the end of life, with a focus on communicating with patients and families who are facing these decisions.

Recent Findings

Research suggests artificial nutrition and hydration (ANH) may be burdensome at the end of life, yet disparities for its use in clinical practice persist. While no clear evidence supports the use of ANH for the majority of terminally ill patients, emerging data suggests that a subset of patients may derive some benefit.

Summary

No clear criteria exist to ascertain the beginning of the dying phase, which can present challenges surrounding ANH. A better understanding of symptom burden and thoughtful communication between the clinician and patient can facilitate development of a medical plan of care, with or without ANH, that best meets the patient's goals of care.

http://ift.tt/2uH6o7j

Editorial: Infections, reproductive health, non - communicable diseases and health systems dominate articles in this June issue of African Health Sciences

No Abstract

http://ift.tt/2toQXQN

Letter to editor: Emerging epidemic of drug resistant tuberculosis in vulnerable populations of developing countries

No Abstract

http://ift.tt/2u75mOz

Letter to editor: Humidity is an ambient parameter to development of Zika virus: an Indonesian case

No Abstract

http://ift.tt/2toZnI4

Recovery from severe dysphagia in systemic sclerosis - myositis overlap: a case report

Background: Dysphagia is common in inflammatory myopathies and usually responds to corticosteroids. Severe dysphagia requiring feeding by percutaneous endoscopic gastrostomy is associated with significant morbidity and high mortality.

Clinical case: A 56-year old African Black woman initially presented with systemic sclerosis (SSC) - myositis overlap and interstitial lung disease. She responded to high dose corticosteroids and cyclophosphamide followed by azathioprine, with improvement in her lung function and regression of the skin changes. Six years later she had a myositis flare with severe dysphagia. Her myositis improved after high doses of corticosteroids, azathioprine and two doses of intravenous immunoglobulin (IVIG). As her dysphagia persisted, she was fed via a percutaneous endoscopic gastrostomy (PEG) tube and given a course of rituximab. Her dysphagia gradually resolved and the PEG tube was removed within two months. She received another dose of rituximab six months later and continued low dose prednisone and azathioprine. Her muscle power improved, weight returned to normal and she remained well 20 months after hospital discharge.

Conclusion: Our patient with SSC-myositis overlap and severe dysphagia requiring PEG feeding, improved with high dose corticosteroids, azathioprine, two courses of IVIG and rituximab, and remained in remission 20 months after hospital discharge.

Keywords: Severe dysphagia, systemic sclerosis, myositis overlap

http://ift.tt/2u7d8b6

Effect of economic and security challenges on the Nigerian health sector

No Abstract

http://ift.tt/2toZof6

Responsible conduct of research: enhancing local opportunities

Introduction: Research integrity is the foundation of credible research and a pre-requisite for a successful academic research environment. Lately, a lot of revelations of fraud and other unacceptable behaviour in research have been highly publicized in scientific journals and mass media. Whereas institutions in developed countries have developed guidelines and regulations to ensure responsible conduct of research and appropriately deal with cases of research misconduct, low- and middle-income countries seem to be lagging behind. In Uganda, there seems to be lack of coordinated efforts to address the problem of research misconduct both at the national and institutional level.

Objective: To propose a framework for fostering scientific integrity and deterring misconduct in research in Ugandan research and academic institutions.

Methods: A review of literature on scientific integrity, scientific misconduct, responsible conduct of research, and international ethical guidelines was done.

Results: Basing on the 2012 Inter-Academy Council policy report, initiatives to promote responsible conduct of research in Ugandan research and academic institutions are proposed.

Conclusion: With the proposed framework, an honest and trustworthy research enterprise in Uganda based on principles of scientific integrity is envisioned.

Keywords: Research misconduct, scientific integrity, responsible conduct of research

http://ift.tt/2u6I0J1

Psychosocial health challenges of the elderly in Nigeria: a narrative review

Background: Globally, national health systems are challenged to build successful aging models to prepare for biomedical, psychological and social changes. The integral component of psychosocial health in overall quality of life and well-being, however, is underscored and requires greater focus. Changing demographics in Nigeria, in addition to cultural considerations and absence of a social security system, present unique challenges to elderly.

Objective: We aimed to review the literature that describes the current situation and challenges in psychosocial health status in the elderly in Nigeria and provide recommendations that promote health and well-being during the aging process.

Results: Four primary factors affect psychosocial health status of elderly Nigerians, namely: changes in family dynamics, increased demand for healthcare services, increased economic stress, and decreased functional independence.

Conclusion: Like other developing countries, the Nigerian national system faces similar challenges in preparing a national framework that can maximize coverage to citizens in the midst of demographic changes in aging. By focusing on five target areas such as the educational system, health services, community-based initiatives, local or regional policies and national strategies, current framework in Nigeria can be modified to prepare for changing demographics in aging.

Keywords: Aging, family support, Nigeria, psychosocial

http://ift.tt/2toZfbl

Characterization and antitumor activity of camptothecin from endophytic fungus Fusarium solani isolated from Camptotheca acuminate

Background: Camptothecin (CPT) is a potent drug against cancers, originally from plants. The endophytic fungi could produce the secondary metabolite same as the host and is used as medicine.

Objectives: The aim of this paper was to investigate an endophytic fungal CPT with anti-neoplastic activity.

Methods: Endophytic fungi were isolated from Camptotheca acuminata in China. CPT from strain S-019 was characterized by TLC, HPLC and EI-MS analysis. Anti-tumor activity of fungal CPT was detected by MTT and fluorescent dye methods using Vero and PC-3 cells.

Results: A total of 94 endophytic fungi strains were isolated from tissues of C. acuminata and 16 fungi strains displayed cytotoxic activity on Vero or PC3 cells. Of which, the fungal strain S-019, classified as Fusarium solani, displayed impressive cytotoxic activity on cancer cells and was found to produce CPT by analysis of TLC, HPLC and EI-MS methods. Bioassay studies confirmed that the fungi CPT had potent cytotoxicity on Vero cells and induced apoptosis of Vero cells.

Conclusion: The endophytic fungi from camptotheca trees are a reliable source for natural anticancer compounds. The endophytic fungi could produce CPT same as plant. The fungal CPT exhibited effective activity at inhibiting cell growth and inducing apoptosis on Vero cells.

Keywords: Endophytic fungi, camptothecin, anti-tumor, Camptotheca acuminate

http://ift.tt/2u7c5Z2

Vitamin B6 and homocysteine levels in carbamazepine treated epilepsy of Khyber Pakhtunkhwa

Objectives: The study focused on the plasma levels of vitamin B₆ and homocysteine in different genotypes of MTHFR (C677T, A1298C) and GABRG2 (C588T, C315T) genes in carbamazepine resistant epilepsy in the population of Khyber Pakhtunkhwa.

Methodology: Patients who were possible candidates for carbamazepine therapy were followed for six months for their seizure control. Plasma levels of vitamin B₆ and homocysteine were determined using immunoassay based techniques at baseline and after six months. MTHFR (C677T, A1298C) and GABRG2 (C588T, C315T) genes were genotyped using restriction fragment length polymorphisms. Seizure control during therapy was recorded on a standardized proforma.

Results: Low vitamin B₆ levels and hyperhomocysteinemia were found in 61.7% of resistant patients (n=34). Resistant patients had the following frequencies of variant genotypes (677CT=38.1% and 677TT=24.4%; 1298AC=42.2% and 1298CC=26.1%; 588CT= 47.6% and 315TT= 33.3%) of MTHFR (C677T and A1298C) and GABRG2 (C588T and C315T) genes. A significant decline in vitamin B₆ (P<0.0001) and hyperhomocysteinemia were found in variant genotypes of MTHFR (C677T, A1298C) and GABRG2 (C588T, C315T) genes.

Conclusion: Following six months of carbamazepine of therapy in heterozygous variant genotypes of MTHFR (677CT and 1298AC) and GABRG2 (588CT and 315CT) genes, we observed a significant fall in vitamin B₆ levels and hyperhomocysteinemia.

Keywords: Carbamazepine, epileptics, homocysteine, seizure control, RFLP, vitamin B₆

http://ift.tt/2tolH4y

Why should modified Atkins diet be encouraged for treating epilepsy in emerging countries?

No Abstract

http://ift.tt/2u6HYkn

Near vision spectacle coverage and barriers to near vision correction among adults in the Cape Coast Metropolis of Ghana

Purpose: To determine the near vision spectacle coverage and barriers to obtaining near vision correction among adults aged 35 years and older in the Cape Coast Metropolis of Ghana.

Methods: A population-based cross-sectional study design was adopted and 500 out of 576 participants aged 35 years and older were examined from 12 randomly selected clusters in Cape Coast, Ghana. All participants underwent a comprehensive eye examination which included: distance and near visual acuities measurements and external and internal ocular health assessments. Distance and near refractions were performed using subjective refraction technique. Information on participants' demographics, near vision correction status, near visual needs and barriers to acquiring near vision correction were obtained through a questionnaire administered as part of the study.

Results: The mean age of participants was 52.3±10.3 years of whom 280 (56%) were females and 220 (44%) were males. The near vision spectacle coverage was 25%, 33% "met need" for near vision correction in the presbyopic population, and 64% unmet need in the entire study population. After controlling for other variables, age (5^th and 6^th decades) and educational level were associated with "met need" for near vision correction (OR=2.7 (1.55-4.68), p =0.00, and OR=2.36 (1.18-4.72), p=0.02 respectively). Among those who needed but did not have near vision correction, 64 (26%) did not feel the need for correction, 55 (22%) stated that they were unaware of available interventions, and 53 (21%) found the cost of near vision correction prohibitive.

Conclusion: There was a low near vision spectacle coverage in this population which suggests the need for strategies on health education and promotion to address the lack of awareness of spectacle need and cost of services.

Keywords: Presbyopia, near vision, spectacle coverage, unmet needs, Ghana

http://ift.tt/2toPiuB

Family type, domestic violence and under-five mortality in Nigeria

Background: Nigeria still showcases unacceptably high under-five mortality despite all efforts to reduce the menace. Investigating the significant predictors of this occurrence is paramount.

Objective: To examine the interplay between family setting, domestic violence and under-five death in Nigeria.

Methods: Cross-sectional secondary data, the 2013 Nigeria Demographic and Health Survey, (NDHS) women dataset was utilized. Subset of 26,997 ever married and ever had childbirth experience respondents were extracted from the nationally representative women dataset. Dependent and Independent variables were recoded to suit the statistical analysis for the study.

Results: The study revealed that 33.7% of the respondents were in polygyny family setting; one-quarter of the ever married women reported ever experiencing one form of domestic violence or the other. The results of the logistic regressions indicate that family type and domestic violence were significant predictors of under-five children mortality in Nigeria.

Conclusion: The study concludes that women who belong to polygyny family setting and who ever experienced sexual domestic violence are highly susceptible to experience under-five children mortality than their counterparts. The study recommends that strategies and policies aimed at improving child survival should strengthen women empowerment initiatives, discourage multiple wives and campaign against domestic violence in Nigeria.

Keywords: Polygyny, monogamous, domestic violence, Nigerians

http://ift.tt/2u6Hfzr

Secular trend of the leading causes of death in China from 2003 to 2013

Background: To analyze the epidemiological characteristics and secular trends of the leading causes of death in China.

Methods: Data on the leading causes of death was collected from the Statistical Yearbook of China. Data for 11 years, from 2003 to 2013, was analyzed by regression analysis and chi-square test.

Results: The top 3 causes of death from 2009 to 2013 were cancer, cerebrovascular disease, and cardiopathy, with the role of cardiopathy increasing over time (P<0.01). The proportion of deaths related to cardio-cerebrovascular diseases in urban and rural areas increased to 41.9% and 44.8%, respectively, in 2013, and was significantly higher than that for cancer, 25.5% and 22.4% (both P<0.01). Injury and poisoning in urban or rural areas represented the fifth leading cause of death. In 2006, endocrine, nutritional, and metabolic diseases were the sixth main cause of death, with 3.3% in urban areas. The role of genito-urinary,
respiratory, and digestive system diseases in urban areas and genito-urinary system diseases in rural areas decreased during this period (all P<0.05).

Conclusion: Cancer, cerebrovascular disease, and cardiopathy accounted for more than 67% of all deaths from 2007 to 2013 in China, and significantly increased in proportion from 2003 to 2013.

Keywords: Causes of death; China; cancer; cardiovascular disease

http://ift.tt/2tovqrB

Lifestyle factors influencing bone health in young adult women in Saudi Arabia

Aim: To analyze risk factors leading to osteopenia and osteoporosis among young female students.

Methods: Quantitative Ultrasonography measurements were performed in the calcaneal region of 101 young Saudi females. Dietary habits, exercising and sun exposure were assessed using questionnaires. The association between the different studied factors was assessed by Pearson test and multiple linear regression model.

Results: Participants diagnosed with either osteopenia or osteoporosis (>33%.) showed significant higher soft drinks consumption, reduced exercise, limited intake of milk and dairy products, calcium and vitamin D supplementation compared to the healthy group. Multiple regression analysis showed that T-score and Z-score were negatively associated with soft drink intake and positively associated with exercising, milk and dairy products consumption, and calcium and vitamin D supplementation use (p <0.05)

Conclusion: High soft drink intake, lack of exercising and limited calcium and vitamin D supplementation are the combined lifestyle factors leading to osteopenia and osteoporosis among young Saudi females. These findings might serve as a basis of nutrition education intervention to promote healthy bones among this population.

Keywords: Lifestyle factors, osteoporosis, osteopenia, young women, Saudi Arabi

http://ift.tt/2u6LzyK

Disordered eating attitudes: demographic and clinico-anthropometric correlates among a sample of Nigerian students

Objectives: We set out in this study to determine the demographic and clinico-anthropometric correlates of disordered eating attitudes among undergraduate students of two higher institutions in Lagos, Nigeria.

Methods: This cross-sectional descriptive study was conducted among 1,054 participants after written informed consent. A socio-demographic questionnaire, the Eating Attitude Test (EAT-26) and 12-item General Health Questionnaire (GHQ-12) were administered to the participants. In addition, their blood pressure, height and weight were measured, and body mass index (BMI) was calculated.

Results: The study participants comprised of 561(55.6%) males with median age of 21.4 years. The mean (±SD) score on EAT-26 was 11.52(±8.54), and 16% of all the respondents were categorized as having disordered eating attitude. A significant relationship was found between disordered eating attitude and age (p= 0.027), gender (p= <0.001), institution of study (p= 0.005), systolic blood pressure (p=0.019), BMI (p= 0.027) and psychological distress (p=0.005).

Conclusion: Our study observed disordered eating attitude to be prevalent among young adults, and demographic along with clinico-anthropometric factors constituted associated factors. Our findings strengthen the basis to incorporate health awareness programs aimed at improving nutrition and eating behavior among the young adult population. Future research is needed.

Keywords: Anthropometric, correlates, disordered eating attitudes, Nigeria, students

http://ift.tt/2toKzsD

Major limb amputations in a tertiary hospital in North Western Nigeria

Background: Amputation is the removal of whole or part of a limb, often as a life saving measure. It is a mutilating surgical procedure altering the body image and producing severe functional deficit. It is a common orthopedic surgical procedure performed worldwide.

Aims and objectives: The aim of this study was to determine the pattern and indications for amputation in Federal Medical Centre, Birnin Kebbi, Kebbi State, Nigeria; between January 2008 and December 2014, in a bid to proffer preventive measures.

Patients and methods: This was a retrospective study of consecutive patients who had major limb amputations at the Federal Medical Centre, Birnin Kebbi, Kebbi State, Nigeria; between January 2008 and December 2014. Case notes of patients were retrieved with relevant information extracted and analyzed.

Results: A total of 112 amputations were studied. The age range of patients was between 3-89 years. Amputation in 23.5% of patients was due to trauma, followed by diabetic foot gangrene in 21% of cases. About 42.9% of the amputations were above knee, followed by below knee amputations in 37% of cases. The lower limbs were involved in 84.8% of cases and upper limbs in 15.2% of cases.

Conclusion: Trauma was the most predominant indication for amputation in this study. This was followed by diabetic foot gangrene. This is usually due to the high rate of road traffic accidents and consequent mismanagement by traditional bone setters.

Keywords: Limb amputations, tertiary hospital, North Western Nigeria

http://ift.tt/2u79dLP

Effect of low-dose ketamine on post-operative serum IL-6 production among elective surgical patients: a randomized clinical trial

Background: Surgery and Anesthesia cause an excessive pro-inflammatory response. Mulago Hospital is faced with staff shortage making post-operative pain management difficult.Interleukin-6 (IL-6) drives inflammatory pain, endothelial cell dysfunction and fibrogenesis. Ketamine is cheap and, readily available. We hypothesized that its attenuation of serum IL-6 was a surrogate for clinical benefit.

Materials and methods: Institutional Review Board's approval was sought and RCT was registered at clinical trials.gov (identifier number: NCT01339065). Consenting patients were randomized to receive pre-incision intravenous ketamine - 0.5mg/kg or 0.9% saline placebo in weighted dosing. Blood samples were collected and laboratory analyzed at baseline, post-operatively in PACU, 24 and 48 hours respectively.

Results: We recruited 39 patients of whom 18 were randomized to the ketamine arm and 21 in the placebo arm with follow up at 24 and 48 hours. Serum IL-6 and IL-1β levels were analyzed using ELIZA assay of pre-coated micro wells. Ketamine suppressed serum IL-6 at PACU with reduced increase at 24 hours. There was no reaction in 98% of IL-1β assayed.

Conclusion: Low-dose ketamine attenuated early serum IL-6 levels due to surgical response with reduced 24 hour increase, but the difference was not statistically significant and we recommend more studies.

Keywords: Ketamine, post-operative inflammation, interleukin 6, interleukin 1- β

http://ift.tt/2toPeLn

Distraction-related road traffic collisions

Objectives: We aimed to prospectively study distraction-related road traffic collision injuries, their contributory factors, severity, and outcome.

Methods: Data were prospectively collected on all hospitalized road traffic collision trauma patients in Al-Ain City who were drivers at the collision time over one and half years. Driver's inattentive behaviors preceding the collision were collected by interviewing the admitted drivers.

Results: There were 444 drivers, 330 of them were fully oriented patients, out of them only 44 (13%) were distracted. Nineteen (5.8%) drivers were distracted by using mobile phones, 12 (3.6%) were pre-occupied with deep thinking, six (1.8%) were talking with other passengers, four (1.2%) were picking things in the vehicle, and three (0.9%) were using entertainment systems. The maximum distraction occurred during the time of 6 am - 12 noon when the traffic was crowded. There were no significant differences between distracted and non-distracted drivers in demographical and physiological factors, injured regions, and outcomes.

Conclusion: Distraction of alert drivers causes 13% of road traffic collisions in Al-Ain city. About 40 percent of the distracted drivers involved in road traffic collisions (RTC) were using mobile phones. Our study supports the ban of use of cell phones while driving.

Keywords: Distraction, prevention, road traffic collision, mobile phone

http://ift.tt/2u6HdYl

Expression of miR-126 and its potential function in coronary artery disease

Objective: This study aimed to explore the role of miR-126 in coronary artery disease (CAD) patients and the potential gene targets of miR-126 in atherosclerosis.

Methodology: A total of 60 CAD patients and 25 healthy control subjects were recruited in this study. Among the 60 CAD patients, 18 cases were diagnosed of stable angina pectoris (SAP), 20 were diagnosed of unstable angina pectoris (UAP) and 22 were diagnosed of acute myocardial infarction (AMI). Plasma miR-126 levels from both groups of participants were analyzed by real-time quantitative PCR. ELISA was used to measure plasma level of placenta growth factor (PLGF).

Results: The results showed that the miR-126 expression was significantly down-regulated in the circulation of CAD patients compared with control subjects (P<0.01). Plasma PLGF level was significantly upregulated in patients with unstable angina pectoris and acute myocardial infarction (AMI) compared with controls (both P<0.01) the miR-126 expression in AMI was significantly associated with PLGF.

Conclusion: miR-126 may serve as a novel biomarker for CAD.

Keywords: miR-126; PLGF; PCR; coronary artery disease; atherosclerosis

http://ift.tt/2toXcnJ

Assessment of hospital-based adult triage at emergency receiving areas in hospitals in Northern Uganda

Background: Limited health service resources must be used in a manner which does "the most for the most". This is partly achieved through the use of a triage system. Whereas efforts have been made to introduce paediatric triage in Uganda such as Emergency Triage Assessment and Treatment Plus (ETAT+), it is not clear if hospitals have local protocols for adult triage being used in each setting.

Objectives: To determine the presence of existing hospital triage systems, the cadre of staff undertaking triage and barriers to development/improvement of formal triage systems.

Methodology: This was a descriptive cross-sectional study. Acholi sub-region was randomly selected for the study among the three sub-regions in Northern Uganda. The study was conducted in 6 of the 7 hospitals in the region. It was a written self-administered questionnaire.

Results: Thirty-three participants from 6 hospitals consented and participated in the study. Only one hospital (16.7%) of the 6 hospitals surveyed had a formal hospital-based adult triage protocol in place. Only 2 (33.3%) hospitals had an allocated emergency department, the rest receive emergency patients/perform triage from OPD and wards. Lack of training, variation of triage protocols from hospital to another, shortage of staff on duty, absence of national guidelines on triage and poor administrative support were the major barriers to improvement /development of formal triage in all these hospitals.

Conclusion: Formal adult hospital-based triage is widely lacking in Northern Uganda and staff do perform subjective "eyeball" judgments to make triage decisions.

Keywords: Triage, "eyeball" triage, emergency receiving areas, and emergency health conditions

http://ift.tt/2u6VV1C

Use of antibiotics during pregnancy and the risk of major congenital malformations: A population based cohort study

Abstract

Introduction

Few studies have investigated the link between individual antibiotics and major congenital malformations (MCMs) including specific malformations owing to small sample size. We aimed to quantify the association between exposure to gestational antibiotic and the risk of MCMs.

Methods

Using the Quebec pregnancy cohort (1998 -2008), we included a total of 139,938 liveborn singleton alive whose mothers were covered by the «Régie de l'assurance maladie du Québec" drug plan for at least 12 months before and during pregnancy. Antibiotics exposure was assessed in the first trimester and MCMs were identified within the first year of life.

Results

After adjusting for potential confounders, clindamycin exposure was associated with an increased risk of MCMs (aOR 1.34, 95%CI, 1.02-1.77, 60 exposed cases), musculoskeletal system malformations (aOR 1.67, 95%CI, 1.12-2.48, 29 exposed cases) and ventricular/atrial septal defect (aOR 1.81, 95%CI, 1.04-3.16, 13 exposed cases).

Doxycycline exposure increased the risk of circulatory system malformation, cardiac malformations and ventricular/atrial septal defect (aOR 2.38, 95%CI ,1.21-4.67, 9 exposed cases; aOR 2.46, 95%CI, 1.21-4.99, 8 exposed cases; aOR 3.19, 95%CI, 1.57-6.48, 8 exposed cases, respectively). Additional associations were seen with quinolone (1 defect), moxifloxacin (1 defect), ofloxacin (1 defect), macrolide (1 defect), erythromycin (1 defect) and phenoxymethylpenicillin (1 defect). No link was observed with amoxicillin, cephalosporins and nitrofurantoin. Similar results were found when penicillins were used as the comparator group.

Conclusions

Clindamycin, doxycycline, quinolones, macrolides and phenoxymethylpenicillin in utero exposure were linked to organ specific malformations. Amoxicillin, cephalosporins and nitrofurantoin were not associated with MCMs.

http://ift.tt/2tEOooS

Appropriateness of antiplatelet therapy for primary and secondary cardio- and cerebrovascular prevention in acutely hospitalized older people

Abstract

Background

Antiplatelet therapy is recommended for the secondary prevention of cardio- and cerebrovascular disease, but for primary prevention it is advised only in patients at very high risk. With this background, this study aims to assess the appropriateness of antiplatelet therapy in acutely hospitalized older people according to their risk profile.

Methods

Data were obtained from the REPOSI register held in Italian and Spanish internal medicine and geriatric wards in 2012 and 2014. Hospitalized patients aged 65 or more assessable at discharge were selected. Appropriateness of the antiplatelet therapy was evaluated according to their primary or secondary cardiovascular prevention profiles.

Results

Of 2535 enrolled patients, 2199 were assessable at discharge. Overall 959 (43.6%, 95%CI 41.5-45.7) were prescribed an antiplatelet drug, aspirin being the most frequently chosen. Among patients prescribed for primary prevention, half of them were inappropriately prescribed (52.1%), being mainly overprescribed (155/209 patients, 74.2%). On the other hand, also a high rate of inappropriate underprescription was seen in the context of secondary prevention (222/726 patiensts, 30.6%, 95%CI 27.3-34.0%).

Conclusions

This study carried out in acutely hospitalized older people shows a high degree of inappropriate prescription among patients prescribed with antiplatelets for primary prevention, mainly due to overprescription. Further, a large proportion of patients who had had overt cardio- or cerebrovascular disease were underprescribed, in spite of the established benefits of antiplatelet drugs in the context of secondary prevention.

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Pharmacokinetics and safety of the anti-human cytomegalovirus drug letermovir in subjects with hepatic impairment

Aim

Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/preemptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on letermovir pharmacokinetics.

Methods

Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n=8) and their matched healthy controls (n=9) received 60 mg letermovir/day and those with severe hepatic impairment (n=8) and their matched healthy controls (n=8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples.

Results

For subjects with moderate hepatic impairment, C_ss,max and AUC_τ,ss for total letermovir were 1.37- (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, C_ss,max and AUC_τ,ss values of total letermovir were 2.34- (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated.

Conclusions

Moderate hepatic impairment increased exposure to letermovir less than twofold, while severe hepatic impairment increased letermovir exposure approximately fourfold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.

http://ift.tt/2tEP6SY

Targeting sphingosine kinase 1 in acute myeloid leukemia: translation to clinic

International Journal of Hematologic Oncology, Ahead of Print.


http://ift.tt/2uxKy5x

Unsettling moods in rural midwifery practice

Publication date: Available online 18 July 2017
Source:Women and Birth
Author(s): Susan Crowther, Liz Smythe, Deb Spence
BackgroundRural midwifery and maternity care is vulnerable due to geographical isolation, staffing recruitment and retention. Highlighting the concerns within rural midwifery is important for safe sustainable service delivery.MethodHermeneutic phenomenological study undertaken in New Zealand (NZ). 13 participants were recruited in rural regions through snowball technique and interviewed. Transcribed interview data was interpretively analysed. Findings are discussed through the use of philosophical notions and related published literature.FindingsUnsettling mood of anxiety was revealed in two themes (a) 'Moments of rural practice' as panicky moments; an emergency moment; the unexpected moment and (b) 'Feelings of being judged' as fearing criticism; fear of the unexpected happening to 'me' fear of losing my reputation; fear of feeling blamed; fear of being identified.ConclusionsAlthough the reality of rural maternity can be more challenging due to geographic location than urban areas this need not be a reason to further isolate these communities through negative judgement and decontextualized policy. Fear of what was happening now and something possibly happening in the future were part of the midwives' reality. The joy and delight of working rurally can become overshadowed by a tide of unsettling and disempowering fears.ImplicationsPositive images of rural midwifery need dissemination. It is essential that rural midwives and their communities are heard at all levels if their vulnerability is to be lessened and sustainable safe rural communities strengthened.



http://ift.tt/2u8oiOA

Midwifery student reactions to workplace violence

Publication date: Available online 18 July 2017
Source:Women and Birth
Author(s): Jesse Shapiro, Malcolm J. Boyle, Lisa McKenna
ProblemWorkplace violence, incidents against people in their workplaces, is a growing problem in Australia causing untold personal suffering as well as costing Australian businesses in productivity.Midwives have been highlighted as a group particularly at risk, yet in Australia there is little research into workplace violence against midwives and even less into midwifery students.AimThis study aimed to explore Australian midwifery students' responses to workplace violence as well as to gauge the impact of workplace violence on them.MethodsCross-sectional survey design was employed. Second and third year students were invited to participate at the end of a scheduled lecture. Fifty-two female midwifery students who had completed their work placement completed a survey indicating their immediate responses to workplace violence as well as the Impact of Event Scale. Data were analysed using descriptive statistics.FindingsMost students notified a co-worker immediately after a workplace violence incident, yet few completed an incident form or received official debriefing.DiscussionThere is a need for the reporting of workplace violence against midwifery students to be made easier to access thereby ensuring they can receive the assistance they require. Midwifery students need to understand the processes and supports in place for managing instances of workplace violence.ConclusionClinical placements can impact on midwifery students' future careers. Universities need to prepare students for the possibility of workplace violence and arm them with appropriate strategies for safely dealing with it.



http://ift.tt/2tEGgVq

Maternal Caffeine Consumption during Pregnancy and Behavioral Disorders in 11-Year-Old Offspring: A Danish National Birth Cohort Study

To examine the association between maternal caffeine consumption from coffee and tea during pregnancy and offspring behavioral disorders.

http://ift.tt/2uH3PSm

Gene Expression Networks in the Murine Pulmonary Myocardium Provide Insight into the Pathobiology of Atrial Fibrillation

The pulmonary myocardium is a muscular coat surrounding the pulmonary and caval veins. Although its definitive physiological function is unknown, it may have a pathological role as the source of ectopic beats initiating atrial fibrillation. How the pulmonary myocardium gains pacemaker function is not clearly defined, although recent evidence indicates that changed transcriptional gene expression networks are at fault. The gene expression profile of this distinct cell type in situ was examined to investigate underlying molecular events that might contribute to atrial fibrillation. Via systems genetics a whole lung transcriptome dataset from the BXD recombinant inbred mouse resource was analysed, uncovering a pulmonary cardiomyocyte gene network of 24 transcripts, coordinately regulated by chromosome 1 and 2 loci. Promoter enrichment analysis and interrogation of publicly available ChIP-seq data suggested that transcription of this gene network may be regulated by the concerted activity of NKX2-5, serum response factor and myocyte enhancer factor 2, and also, at a post-transcriptional level by RNA binding protein motif 20. Gene ontology terms indicate that this gene network overlaps with molecular markers of the stressed heart. Therefore, we propose that perturbed regulation of this gene network might lead to altered calcium handling, myocyte growth and contractile force contributing to aberrant electrophysiological properties observed in atrial fibrillation. We reveal novel molecular interactions and pathways representing possible therapeutic targets for atrial fibrillation. In addition, we highlight the utility of recombinant inbred mouse resources in detecting and characterizing gene expression networks of relatively small populations of cells that have a pathological significance.

http://ift.tt/2uxDWUE

Application of Response Surface Methods To Determine Conditions for Optimal Genomic Prediction

An epistatic genetic architecture can have a significant impact on prediction accuracies of genomic prediction (GP) methods. Machine learning methods predict traits composed of epistatic genetic architectures more accurately than statistical methods based on additive mixed linear models. The differences between these types of GP methods suggest a diagnostic for revealing genetic architectures underlying traits of interest. In addition to genetic architecture, the performance of GP methods may be influenced by the sample size of the training population, the number of QTL, and the proportion of phenotypic variability due to genotypic variability (heritability). Possible values for these factors and the number of combinations of the factor levels that influence the performance of GP methods can be large. Thus, efficient methods for identifying combinations of factor levels that produce most accurate GPs is needed. Herein, we employ Response Surface Methods (RSMs) to find the experimental conditions that produce the most accurate GPs. We illustrate RSM with an example of simulated doubled haploid (DH) populations and identify the combination of factors that maximize the difference between prediction accuracies of best linear unbiased prediction (BLUP) and support vector machine (SVM) GP methods. The greatest impact on the response is due to the genetic architecture of the population, heritability of the trait, and the sample size. When epistasis is responsible for all of the genotypic variance and heritability is equal to one, and the sample size of the training population is large the advantage of using the SVM method versus the BLUP method is greatest. However, except for values close to the maximum, most of the response surface shows little difference between the methods. We also determined that the conditions resulting in the greatest prediction accuracy for BLUP occurred when genetic architecture consists solely of additive effects, and heritability is equal to one.

http://ift.tt/2tdClQb

State of the Science of Spirituality and Palliative Care Research Part I: Definitions and Taxonomy, Measurement, and Outcomes

From its inception, spirituality has been at the core of the definition of whole person palliative care."Where a desolate sense of meaninglessness is encountered by the person at the end of life, one finds the essence of 'spiritual pain'."1 - Dame Cicely Saunders

http://ift.tt/2uGy1x2

State of the Science of Spirituality and Palliative Care Research: Research Landscape and Future Directions

Research conducted over the past few decades has made significant strides towards illuminating the role of spirituality for patients and families living with serious illness. This evidence base demonstrates that spirituality frequently plays a central and complex role in patients' and families' experiences of incurable illness, including influencing quality of life (QOL), and medical decision-making. Advances in this field of research that expand the understanding of the relationships between spirituality and health outcomes and lead to the rigorous development of interventions to address patient and family spiritual needs hold tremendous potential for improving a comprehensive approach to care in serious illness.

http://ift.tt/2vh1BGA

Iranian Brief Pain Inventory: Validation and application in elderly people with cancer pain

Cancer is a major health problem in the elderly, and pain is one of the most common symptoms among older patients with cancer. Sufficient pain treatments depend on the accuracy of the pain assessment tool.

http://ift.tt/2uGO91v

Deubiquitinating Enzyme USP9X Suppresses Tumor Growth via LATS kinase and Core Components of the Hippo pathway

The core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis. Knockdown of USP9X significantly downregulated and destabilized LATS and resulted in enhanced nuclear translocation of YAP and TAZ, accompanied with activation of their target genes. In the absence of USP9X, cells exhibited an epithelial-to-mesenchymal transition phenotype, acquired anchorage-independent growth in soft agar, and led to enlarged, disorganized, three-dimensional acini. YAP/TAZ target gene activation in response to USP9X knockdown was suppressed by knockdown of YAP, TAZ, and TEAD2. Deletion of USP9X in mouse embryonic fibroblasts resulted in significant downregulation of LATS. Furthermore, USP9X protein expression correlated positively with LATS but negatively with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. Overall, these results strongly indicate that USP9X potentiates LATS kinase to suppress tumor growth.

http://ift.tt/2uxxe0Y

Lysyl oxidase-like protein LOXL2 promotes lung metastasis of breast cancer

The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling. In support of this likelihood, cellular and molecular analyses revealed an association of LOXL2 action with elevated levels of the EMT regulatory transcription factor Snail1 and expression of several cytokines that promote pre-metastatic niche formation. Taken together, our findings established a pathophysiological role and new function for LOXL2 in breast cancer metastasis.

http://ift.tt/2te6D5a

Hsp72 and Nek6 cooperate to cluster amplified centrosomes in cancer cells

Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering. Nek6, as well as its upstream activators polo-like kinase 1 (Plk1) and Aurora-A, targeted Hsp72 to the poles of cells with amplified centrosomes. Unlike some centrosome de-clustering agents, blocking Hsp72 or Nek6 function did not induce formation of acentrosomal poles, meaning that multipolar spindles were observable only in cells with amplified centrosomes. Inhibition of Hsp72 in acute lymphoblastic leukaemia cells resulted in increased multipolar spindle frequency that correlated with centrosome amplification, while loss of Hsp72 or Nek6 function in non-cancer derived cells disturb neither spindle formation nor mitotic progression. Hence, the Nek6-Hsp72 module represents a novel actionable pathway for selective targeting of cancer cells with amplified centrosomes.

http://ift.tt/2uxDeHd

Fructose-1,6-bisphosphatase inhibits ERK activation and bypasses gemcitabine resistance in pancreatic cancer by blocking IQGAP1-MAPK interaction

Dysregulation of the mitogen-activated protein kinase (MAPK) pathway correlates with progression of pancreatic ductal adenocarcinoma (PDAC) progression. IQ motif containing GTPase activating protein 1 (IQGAP1) is a MAPK scaffold that directly regulates the activation of RAF, MEK, and extracellular signaling-regulated kinases (ERK). Fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis, is transcriptionally downregulated in various cancers, including PDAC. Here we demonstrate that FBP1 acts as a negative modulator of the IQGAP1-MAPK signaling axis in PDAC cells. FBP1 binding to the WW domain of IQGAP1 impeded IQGAP1-dependent ERK1/2 phosphorylation (pERK1/2) in a manner independent of FBP1 enzymatic activity. Conversely, decreased FBP1 expression induced pERK1/2 levels in PDAC cell lines and correlated with increased pERK1/2 levels in patient specimens. Treatment with gemcitabine caused undesirable activation of ERK1/2 in PDAC cells, but co-treatment with the FBP1-derived small peptide inhibitor FBP1 E4 overcame gemcitabine-induced ERK activation, thereby increasing the anti-cancer efficacy of gemcitabine in PDAC. These findings identify a primary mechanism of resistance of PDAC to standard therapy and suggest that the FBP1-IQGAP1-ERK1/2 signaling axis can be targeted for effective treatment of PDAC.

http://ift.tt/2tdBiQf

Ictal Cardiac Activity: Towards a Wider, Dynamical Vista

The instructive observations of Chouchou et al. in this issue of Clinical Neurophysiology motivate a probing view into cardiac rhtyhmogenicity during ictal and circum-ictal periods through the lens of dynamical cardiology.

http://ift.tt/2tEhRiX

Language and motor function thresholds during pediatric extra-operative electrical cortical stimulation brain mapping

Safe neurosurgical resection of the seizure-onset zone requires localization of language and motor cortices in each individual patient. Electrical cortical stimulation (ECS) is the standard technique for brain mapping with intracranial electrodes. However, it has been shown that in pediatric patients, particularly younger than 10 years of age, ECS may often fail to identify language cortex (Schevon et al., 2007). ECS supposedly creates a transient reversible functional interference to localize critical cortical sites, and has been shown to predict post-operative outcomes (Hermann et al., 1988; Hermann et al., 1999).

http://ift.tt/2u81COo

After-discharges and seizures during pediatric extra-operative electrical cortical stimulation functional brain mapping: incidence, thresholds, and determinants

Electrical cortical stimulation (ECS) is the standard method for pre-surgical mapping of cortical function, particularly language and motor cortices, to optimize safety and efficacy of epilepsy surgery. However, ECS is known to be associated with the risks of after-discharges (ADs) and seizures, with several neurophysiological implications (Jayakar et al., 2008). ADs can potentially evolve into electrographic or electro-clinical seizures, even when the stimulated brain region is not known to generate spontaneous seizures (Blume et al., 2004).

http://ift.tt/2tEyYB5

Risk of depression enhances auditory pitch discrimination in the brain as indexed by the Mismatch Negativity

Depression is a state of aversion to activity and low mood that affects behaviour, thoughts, feelings and individual sense of well-being (Schnaas, 2003). A depressed mood is characterized by anxiety, sadness, anger and empty, hopeless, guilty, restless feelings (Rottenberg, 2005). If depressed mood occurs frequently, becoming a stable pathological state, it can lead to major depressive disorder (MDD). Moreover, differently from a non pathological sad state, depressed mood is characterized by the intensity and pervasiveness of the pain during patients activities, causing social and emotional limitations in their lives (Gotlib and Hammen, 2009).

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Will the liquid biopsy replace traditional hematopathology?

http://ift.tt/2uAR2Ad

Efficient mitochondrial glutamine targeting prevails over glioblastoma metabolic plasticity.

Purpose Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer, however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof-of concept for personalized metabolic targeting of GBM. <p>Experimental Design We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays and mitochondrial respirometry.</p> <p>Results We found that metabolic phenotyping clearly identifies 2 clusters, GLN^High and GLN^Low, mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN^High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN^High cultures are CD133^neg and display a mesenchymal signature in contrast to CD133^pos GLN^Low GBM cells.</p> <p>Conclusions Our results show that metabolic phenotyping identified an essential metabolic pathway ina GBM cell subtype, and provide a proof-of-concept for theranostic metabolic targeting.

http://ift.tt/2vgjGV9

MAPK pathway and TERT promoter gene mutation pattern and its prognostic value in melanoma patients： a retrospective study of 2793 cases

Purpose: Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathological characteristics and disease prognosis in Asian population.<br /><br />Experimental Design: 2793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and TERT promoter region by Sanger sequencing. Mutations were correlated to clinicopathological features and overall survival.<br /><br />Results: The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4% 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of MAPK pathway were all independent negative prognostic factors (P=0.007, other P<0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse OS (all P<0.001); while in mucosal melanoma only C-KIT was (P=0.006). Although correlated with BRAF mutations (P=0.001 and P<0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with OS (P=0.406 and 0.256, respectively).<br /><br />Conclusions: MAPK pathway and TERT promoter gene mutations are differentially represented in Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be directly at these poor prognosis subpopulations for maximum potential impact.

http://ift.tt/2uGSodN

Inactivation of receptor tyrosine kinases reverts aberrant DNA methylation in acute myeloid leukemia

Purpose: Receptor tyrosine kinases (RTKs) are frequently deregulated in leukemia, yet the biological consequences of this deregulation remain elusive. The mechanisms underlying aberrant methylation, a hallmark of leukemia, are not fully understood. Here we investigated the role of RTKs in methylation abnormalities and characterized the hypomethylating activities of RTK inhibitors.<br />Experimental Design: Whether and how RTKs regulate expression of DNA methyltransferases (DNMTs), tumor suppressor genes (TSGs) as well as global and gene specific DNA methylation were examined. The pharmacologic activities and mechanisms of actions of RTK inhibitors in vitro, ex vivo, in mice and in nilotinib-treated leukemia patients were determined. <br />Results: Upregulation of RTKs paralleled DNMT overexpression in leukemia cell lines and patient blasts. Knockdown of RTKs disrupted, whereas enforced expression increased, DNMT expression and DNA methylation. Treatment with the RTK inhibitor, nilotinib, resulted in a reduction of Sp1-dependent DNMT1 expression, the diminution of global DNA methylation and the upregulation of the p15^INK4B gene through promoter hypomethylation in AML cell lines and patient blasts. This led to disruption of AML cell clonogenicity and promotion of cellular apoptosis without obvious changes in cell cycle. Importantly, nilotinib administration in mice and human patients with AML impaired expression of DNMTs followed by DNA hypomethylation, TSG re-expression, and leukemia regression. <br />Conclusions: Our findings demonstrate RTKs as novel regulators of DNMT-dependent DNA methylation and define DNA methylation status in AML cells as a pharmacodynamic marker for their response to RTK-based therapy, providing new therapeutic avenues for RTK inhibitors in overcoming epigenetic abnormalities in leukemia.

http://ift.tt/2vgD1Ws

Targeted exome sequencing of Krebs cycle genes reveals candidate cancer predisposing mutations in pheochromocytomas and paragangliomas

Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but no alterations in the known predisposing genes, could harbor mutations in other Krebs cycle genes. <p>Experimental Design: We used downregulation and methylation of RBP1, as a marker of a hypermethylation phenotype, to select eleven pheochromocytomas and paragangliomas for targeted exome sequencing of a panel of Krebs cycle-related genes. Methylation profiling, metabolite assessment and additional analyses were also performed in selected cases.</p> <p>Results: One of the eleven tumors was found to carry a known cancer-predisposing somatic mutation in IDH1. A variant in GOT2, c.357A>T, found in a patient with multiple tumors, was associated with higher tumor mRNA and protein expression levels, increased GOT2 enzymatic activity in lymphoblastic cells, and altered metabolite ratios both in tumors and in GOT2 knock-down HeLa cells transfected with the variant. Array methylation-based analysis uncovered a somatic epigenetic mutation in SDHC in a patient with multiple pheochromocytomas and a gastrointestinal stromal tumor. Finally, a truncating germline IDH3B mutation was found in a patient with a single paraganglioma showing an altered α-ketoglutarate/isocitrate ratio.</p> Conclusions: This study further attests to the relevance of the Krebs cycle in the development of PCC and PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol.

http://ift.tt/2uGJtbZ

MUC1-mediated metabolic alterations regulate response to radiotherapy in pancreatic cancer

Purpose: MUC1, an oncogene overexpressed in multiple solid tumors including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated metabolism in radiation resistance of pancreatic cancer by utilizing cell lines and in vivo models. <p>Experimental design: We used MUC1 knockdown and overexpressed cell line models for evaluating the role of MUC1-mediated metabolism in radiation resistance through in vitro cytotoxicity, clonogenicity, DNA damage response and metabolomic evaluations. We also investigated if inhibition of glycolysis could revert MUC1-mediated metabolic alterations and radiation resistance using in vitro and in vivo models.</p> <p> </p> <p>Results: MUC1 expression diminished radiation-induced cytotoxicity and DNA damage in pancreatic cancer cells by enhancing glycolysis, pentose phosphate pathway, and nucleotide biosynthesis. Such metabolic reprogramming resulted in high nucleotide pools and radiation resistance in in vitro models. Pre-treatment with the glycolysis inhibitor, 3-bromopyruvate (BrPA) abrogated MUC1-mediated radiation resistance both in vitro and in vivo, by reducing glucose flux into nucleotide biosynthetic pathways and enhancing DNA damage, which could again be reversed by pre-treatment with nucleoside pools.</p> Conclusions: MUC1-mediated nucleotide metabolism plays a key role in facilitating radiation-resistance in pancreatic cancer and targeted effectively through glycolytic inhibition.

http://ift.tt/2vgN0uz

Effects of antithrombotic therapy on bleeding after endoscopic submucosal dissection: A systematic review and meta-analysis

Bleeding is the most common adverse event after ESD. Although several studies have been reported about the use of antithrombotic agents and post-ESD bleeding, many issues remain controversial. We conducted a meta-analysis and systematic review to evaluate the effects of antithrombotic therapy for post-ESD bleeding.

http://ift.tt/2uAtcog

Predictors of complications and readmission following spinal stereotactic radiosurgery

CNS Oncology, Ahead of Print.


http://ift.tt/2tdvO7V

Modern approaches to the management of metastatic epidural spinal cord compression

CNS Oncology, Ahead of Print.


http://ift.tt/2uxknMi

Outcome evaluation of patients with newly diagnosed anaplastic gliomas treated in a single institution

CNS Oncology, Ahead of Print.


http://ift.tt/2tdzoiC

GBM skin metastasis: a case report and review of the literature

CNS Oncology, Ahead of Print.


http://ift.tt/2uxMFGA

Late post-treatment radiographic changes 3 years following chemoradiation for glioma: the importance of histopathology

CNS Oncology, Ahead of Print.


http://ift.tt/2tdv9Ub

A Tribute to Dr. Rammohan Tiwari

http://ift.tt/2tEhAfH

Addressing physician burnout among practicing physicians

http://ift.tt/2toeJMC

Cost-effectiveness of High-performance Biomarker Tests vs Fecal Immunochemical Test for Non-Invasive Colorectal Cancer Screening

Biomarker assays could increase the accuracy of non-invasive detection of colorectal cancer (CRC); fecal immunochemical tests (FITs) are estimated to miss 27%–47% of CRCs and 70%–80% of advanced adenomas per round of screening. We investigated the conditions under which biomarker screens would be cost-effective compared to FIT screens of average risk individuals.

http://ift.tt/2u6nCYw

Sessile serrated adenoma of the appendix in an asymptomatic patient

http://ift.tt/2to0KX7

Significant Hepatic Fibrosis Among Treatment Naïve Chronic HBV with Elevated HBV DNA and Normal Alanine Aminotransferase

http://ift.tt/2u6wCg7

Immunoprophylaxis failure of infants born to Hepatitis B carrier mothers following routine vaccination

http://ift.tt/2tnJPEe

Analysis of FNB vs FNA in Diagnosis of Pancreatic and Abdominal Masses: A Prospective, Multicenter, Randomized Controlled Trial

Endoscopic ultrasound (EUS)-guided fine needles with side fenestrations are used to collected aspirates for cytology analysis and biopsy samples for histologic analysis. We conducted a large, multicenter study to compare the accuracy of diagnosis via specimens collected with fine-needle biopsy (FNB) vs fine-needle aspiration (FNA) for patients with pancreatic and non-pancreatic masses.

http://ift.tt/2u6lxM5

Angiogenesis Dysregulation in Psoriatic Arthritis: Molecular Mechanisms

There is evidence that psoriatic arthritis is closely linked to angiogenesis. Morphological changes described in blood vessels of psoriatic arthritis joints suggest the presence of a dysregulated angiogenesis resulting in the formation of immature vessels. Even if the reason of this inefficient angiogenesis is still unclear, an imbalance between angiogenic and antiangiogenic factors is probably responsible for inducing a dysregulated angiogenesis in psoriatic arthritis, which seems to be involved in its pathogenesis and clinical features. Nevertheless, among chronic arthritides, while angiogenesis in rheumatoid arthritis has been largely studied with a great amount of literature data, limited data on angiogenesis role in psoriatic arthritis are available. This review article is focused on current knowledge on the mechanisms responsible for dysregulated angiogenesis in psoriatic arthritis.

http://ift.tt/2vgryWy

MicroRNA Regulation of Glycolytic Metabolism in Glioblastoma

Glioblastoma (GBM) is the most aggressive and common malignant brain tumour in adults. A well-known hallmark of GMB and many other tumours is aerobic glycolysis. MicroRNAs (miRNAs) are a class of short nonprotein coding sequences that exert posttranscriptional controls on gene expression and represent critical regulators of aerobic glycolysis in GBM. In GBM, miRNAs regulate the expression of glycolytic genes directly and via the regulation of metabolism-associated tumour suppressors and oncogenic signalling pathways. This review aims to establish links between miRNAs expression levels, the expression of GBM glycolytic regulatory genes, and the malignant progression and prognosis of GBM. In this review, the involvement of 25 miRNAs in the regulation of glycolytic metabolism of GBM is discussed. Seven of these miRNAs have been shown to regulate glycolytic metabolism in other tumour types. Further eight miRNAs, which are differentially expressed in GBM, have also been reported to regulate glycolytic metabolism in other cancer types. Thus, these miRNAs could serve as potential glycolytic regulators in GBM but will require functional validation. As such, the characterisation of these molecular and metabolic signatures in GBM can facilitate a better understanding of the molecular pathogenesis of this disease.

http://ift.tt/2vg9tbe

Histologically proved cytomegalovirus as a terrible and neglect disease: a 13-year report of gastrointestinal and hepatobiliary manifestations from single referral center

Abstract

The aim of the present study was to evaluate the gastrointestinal and hepatobiliary manifestation of cytomegalovirus. In a retrospective study, demographic and clinical information of patients with gastrointestinal or hepatobiliary manifestations and histologically confirmed cytomegalovirus infection was investigated among pathological records. The association between serum cytomegalovirus pp65 and blood positivity of cytomegalovirus polymerase chain reaction with histological findings was also evaluated. Of the 74 included patients, 27 cases (36.5%) were female. The most common symptoms were diarrhea (24.3%). Unusual presentations of cytomegalovirus diseases were gastrointestinal obstruction, refractory peptic ulcer, and corticosteroid-refractory inflammatory bowel disease. In total, 54 cases (75.0%) were transplanted, with the most frequency of kidney transplantation in 32 patients (59.2%). These patients had also more mortality rate. The most prescribed medicine in transplanted patients was CellCept and cyclosporine (40.6%). Mortality rate was more in blood polymerase chain reaction-negative patients. Cytomegalovirus diseases in transplanted patients were more primary infection compared with reactivation infection. No significant difference in mortality rate was seen between ganciclovir and non-ganciclovir recipients. The majority of the patients were negative for antigen or polymerase chain reaction. Early detection of cytomegalovirus could be lifesaving, and negative results of antigen and polymerase chain reaction cannot rule out cytomegalovirus diseases. Early endoscopic evaluation for unusual presentations of cytomegalovirus disease and also liver donor evaluation should be done more carefully. Ganciclovir has no significant effect on mortality of the patients, and then, it should be started at appropriate time.

http://ift.tt/2td4maz

Quiz: Capnography for kids: unique considerations

Test your knowledge on the challenges of assessing and treating children with capnography

http://ift.tt/2uAklmq

FOXA1 and CK14 as markers of luminal and basal subtypes in histologic variants of bladder cancer and their associated conventional urothelial carcinoma

Abstract

Invasive bladder cancer is diverse, and includes several named histomorphologies that differ from conventional urothelial carcinoma, termed "histologic variants." By transcriptional analysis, bladder cancers can be divided into luminal and basal subtypes. In this paper, we study associations between markers of transcriptional subtypes and variant histology in a retrospective cohort of 309 cystectomy specimens. Histology slides were methodically reviewed for all cases, and variant histology was documented. Immunohistochemistry for FOXA1 (luminal marker) and CK14 (basal maker) was performed on histologic variants and their associated conventional urothelial carcinomas. Invasive carcinoma was present in 270 of the cystectomy specimens, 35% of which contained a histologic variant. Squamous carcinomas expressed higher CK14 levels than micropapillary, nested, and plasmacytoid carcinomas (p < 0.001, Kruskal-Wallis), keeping with the basal character of squamous carcinoma. Likewise, squamous carcinomas expressed lower FOXA1 levels than micropapillary, nested, and plasmacytoid carcinomas (p < 0.001, Kruskal-Wallis), keeping with the luminal character of micropapillary carcinoma, and suggesting that nested and plasmacytoid cancers have luminal character. FOXA1 was expressed at lower levels in conventional urothelial carcinoma associated with squamous carcinoma than conventional urothelial carcinoma associated with micropapillary carcinoma (p = 0.0072, Wilcoxon rank sum). CK14 expression did not differ between conventional urothelial carcinomas associated with squamous versus micropapillary carcinoma (p = 0.89, Wilcoxon rank sum). Instead, CK14 expression was higher in squamous carcinoma than conventional urothelial carcinoma present in the same bladder (p = 0.014, Wilcoxon rank sum, paired). Overall, the findings show that squamous and micropapillary cancers have different expression patterns of CK14 and FOXA1 and suggest that they arise from distinct precursors.

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A survey of renal impairment pharmacokinetic studies for new oncology drug approvals in the USA from 2010 to early 2015: a focus on development strategies and future directions

The US Food and Drug Administration (FDA) issued a guidance document in 2010 on pharmacokinetic (PK) studies in renal impairment (RI) on the basis of observations that substances such as uremic toxins might result in altered drug metabolism and excretion. No specific recommendations for oncology drugs were included. We surveyed the publicly available FDA review documents of 29 small molecule oncology drugs approved between 2010 and the first quarter of 2015. The objectives were as follows: (i) summarize the impact of RI on PK at the time of the initial new drug application; (ii) identify limitations of the guidance; and (iii) outline an integrated approach to study the impact of RI on these drugs. Our survey indicates that the current FDA guidance does not appear to provide clear strategic or decision pathways for RI studies in terms of small molecule oncology drugs. The FDA review documents indicate an individualized approach to the review because of the complex pharmacologic nature of these drugs and patient populations. Overall, the strategy for carrying out a RI study during clinical development or as a postmarketing study requires integration with the totality of data, including mass balance, absolute bioavailability, drug–drug interaction, hepatic dysfunction, population PK, exposure–response analysis, the therapeutic window for best guidance, and determination of the optimal doses for special oncology populations.

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Clusterin inhibition mediates sensitivity to chemotherapy and radiotherapy in human cancer

Since its discovery in 1983, the protein clusterin (CLU) has been isolated from almost all human tissues and fluids and linked to the development of different physiopathological processes, including carcinogenesis and tumor progression. During the last few years, several studies have shown the cytoprotective role of secretory CLU in tumor cells, inhibiting their apoptosis and enhancing their resistance to conventional treatments including hormone depletion, chemotherapy, and radiotherapy. In an effort to determine the therapeutic potential that the inhibition of this protein could have on the development of new strategies for cancer treatment, numerous studies have been carried out in this field, with results, in most cases, satisfactory but sometimes contradictory. In this document, we summarize for the first time the current knowledge of the effects that CLU inhibition has on sensitizing tumor cells to conventional cancer treatments and discuss its importance in the development of new strategies against cancer.

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Report of two cases of acute cardiac adverse events in patients with colorectal carcinoma receiving oral capecitabine

Capecitabine is an oral fluoropyrimidine chemotherapeutic agent, which, after oral administration, is metabolized to its active cytotoxic compound: 5-fluorouracil (5-FU). Cardiotoxicity is a recognized side effect of 5-FU, a closely related fluorinated pyrimidine antagonist. In the present report, we report on two patients who were admitted to our department after being treated with oral capecitabine for colorectal carcinoma and developed symptoms and signs of acute myocardial infarction that resolved after appropriate treatment and monitoring. The above two cases are discussed in the context of fluoropyrimidine, 5-FU, and capecitabine-induced cardiotoxicity; in addition, a detailed literature review of relevant cases and patient series reports is presented.

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Prevalence and influence on outcome of HER2/neu, HER3 and NRG1 expression in patients with metastatic colorectal cancer

Our aim was to explore the impact of the HER2/neu, HER3 receptor as well as their ligands' neuregulin (NRG1) expression on the outcome of patients with metastatic colorectal cancer (mCRC). NRG1, HER2/neu and HER3 expression was evaluated in 208 patients with mCRC receiving 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as the first-line treatment. Biomarker expression was correlated with the outcome of patients. NRG1 (low: 192 vs. high: 16), HER2/neu (low: 201 vs. high: 7) and HER3 (low: 69 vs. high: 139) expressions were assessed in 208 patients. High versus low NRG1 expression significantly affected progression-free survival (PFS) [4.7 vs. 8.2 months, hazard ratio (HR): 2.45; 95% confidence interval (CI): 1.45–4.13; P=0.001], but not overall survival (OS) (15.5 vs. 20.7 months, HR: 1.33; 95% CI: 0.76–2.35; P=0.32). High versus low HER3 expression (PFS: 7.1 vs. 8.8 months, HR: 1.11; 95% CI: 0.82–1.50; P=0.50; OS: 19.8 vs. 21.1 months, HR: 0.95; 95% CI: 0.70–1.30; P=0.75) and high compared with low HER2/neu expression (PFS: 7.7 vs. 8.0 months, HR: 1.07; 95% CI: 0.71–1.60; P=0.75; OS: 16.6 vs. 21.1 months, HR: 1.13; 95% CI: 0.75–1.71; P=0.57) did not influence outcome. High NRG1 expression was associated with inferior PFS in the FIRE-1 trial. We did not detect a prognostic impact of HER2/neu and HER3 overexpression in mCRC. The frequency of overexpression was comparable with other studies.

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Dexrazoxane added to doxorubicin-based adjuvant chemotherapy of breast cancer: a retrospective cohort study with a comparative analysis of toxicity and survival

Dexrazoxane is indicated as a cardioprotective agent for patients receiving doxorubicin who are at increased risk for cardiotoxicity. Concerns have been raised on the use of dexrazoxane, particularly in adjuvant therapy, because of the risk of interference with the antitumor effect of doxorubicin. Two meta-analyses in metastatic breast cancer have rejected this hypothesis, but have shown an apparent increase in the severity of myelosuppression when dexrazoxane is used. Here, we analyzed retrospectively a cohort of our institute database to assess whether the addition of dexrazoxane causes more bone marrow suppression in breast cancer patients receiving doxorubicin-based adjuvant therapy. The secondary objectives were assessment of the incidence of febrile neutropenia, dose-schedule modifications, recorded cardiac events or cardiac test abnormalities, and overall survival. Eight hundred and twenty-two female patients who received adjuvant (or neoadjuvant) doxorubicin and cyclophosphamide for breast cancer between 2001 and 2013 were included. One hundred and four of these patients also received dexrazoxane concurrently with the adjuvant treatment. Hospital records and, when accessible, community clinic records were reviewed. The median follow-up duration was 7 years for patients receiving dexrazoxane and 7.5 years for patients not receiving dexrazoxane. 85.6% of patients were alive at data lock. Compared with the nondexrazoxane group, patients who received dexrazoxane were older (median age at diagnosis 59 vs. 52 years) and more likely to receive dose-dense AC therapy (73 vs. 59%) and adjuvant trastuzumab treatment (29 vs. 15%). Compared with the nondexrazoxane group, dexrazoxane treatment was associated with a higher rate of hematological side effects: leukopenia (48 vs. 39%), neutropenia (45 vs. 31%, P=0.003), anemia (86 vs. 73%, P=0.005), and thrombocytopenia (37 vs. 22%, P=0.001). There were more febrile neutropenia hospitalizations (20 vs. 10%, P=0.001) and dose reductions (22 vs. 8%, P

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Deguelin induced differentiation of mutated NPM1 acute myeloid leukemia in vivo and in vitro

Nucleophosmin (NPM1), a restricted nucleolar localization protein, shuttles between the nucleus and the cytoplasm. Mutated (Mt)-NPM1 protein, which has aberrant cytoplasmic dislocation of nucleophosmin, occurs in approximately one-third of acute myeloid leukemia cases. Deguelin, a rotenoid isolated from several plant species, is a strong antitumor agent. NOD/SCID mice xenografted with human Mt-NPM1 OCI/AML3 cell lines served as in-vivo models. Wright–Giemsa staining and flow cytometry analysis were used for differentiation assays. Associated molecular events were assessed by western blot and histological analyses. Kaplan–Meier estimates were used to calculate survival. Deguelin toxicity in mice was assessed by immunohistochemistry staining and serum markers. Clinical samples were differentiated by flow cytometry analysis. Deguelin induced differentiation by downregulating the Mt-NPM1 protein levels, which was accompanied by a decrease in SIRT1, p21, and HDAC1 and an increase in CEBPβ and granulocyte colony-stimulating factor receptor protein expression levels. A low-deguelin dose prolonged survival compared with the control group, and there were no apparent lesions to the brain, liver, heart, and kidney in vivo. In clinical samples, deguelin induced the differentiation of fresh blasts with Mt-NPM1 protein, but not with the wild-type NPM1 protein. Taken together, these findings further provide new evidence that the Mt-NPM1 protein plays an important role in inducing differentiation in vivo and in vitro. Mutated NPM1 protein may be a therapeutic target of deguelin in acute myeloid leukemia with the NPM1 mutation.

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Severe complicated neutropenia in two patients with metastatic non-small-cell lung cancer treated with nivolumab

Checkpoint inhibitors effectively enhance the natural immune response against cancer, but they are also known to induce a unique spectrum of immune-related adverse events. Here, we report the first case of isolated neutropenia subsequent to nivolumab therapy. Prominent activated T-cells were found in the patient's serum and bone marrow alongside evidence of maturational defects in neutrophil precursors. Antineutrophil antibodies were not detected despite reliable testing techniques. A T-cell-mediated response is probable, consistent with the established mechanism for the development of other immune-related toxicities. Awareness of this rare and severe side effect reinforces the importance of early diagnosis and prompt initiation of proper treatment.

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3-Bromopyruvate enhances TRAIL-induced apoptosis in human nasopharyngeal carcinoma cells through CHOP-dependent upregulation of TRAIL-R2

Past reports have shown that the sensitivity of cancer cells to TRAIL-induced apoptosis is related to their expression of TRAIL-death receptors on the cell surface. However, the level of TRAIL-death receptors expression on cancer cells is always low. Our previous research showed that nasopharyngeal carcinoma (NPC) cells have a poor sensitivity to low doses of TRAIL. Here, we evaluated combined treatment with the energy inhibitor 3-bromopyruvate (3BP) and TRAIL as a method to produce an increased apoptotic response in NPC cells. The results showed that 3BP and TRAIL together produced higher cytotoxicity and increased TRAIL-R2 expression in NPC cells compared with the effects of either 3BP or TRAIL alone. These findings led us to hypothesize that 3BP may sensitize NPC cells to TRAIL. 3BP is a metabolic blocker that inhibits hexokinase II activity, suppresses ATP production, and induces endoplasmic reticulum (ER) stress. Our results showed that 3BP also activated AMP-activated protein kinase, which we found to play an important role in the induction of ER stress by 3BP. Furthermore, the induction of TRAIL-R2 expression and the sensitization of the NPC cells to TRAIL by 3BP were reduced when we inhibited the expression of CHOP. Taken together, our results showed that a low dose of 3BP sensitized NPC cells to TRAIL-induced apoptosis by the upregulation of CHOP, which was mediated by the activation of AMP-activated protein kinase and ER stress. The results showed that 3BP is a promising candidate agent for enhancing the therapeutic response to TRAIL in NPC.

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Role of the uridine/cytidine kinase 2 mutation in cellular sensitiveness toward 3′-ethynylcytidine treatment of human cancer cells

A nucleosidic medicine, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine [3′-ethynylcytidine (ECyd)], is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors in vitro and in vivo. ECyd is phosphorylated to 3′-ethyntlcytidine 5′-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3′-ethyntlcytidine 5′-diphosphate, 3′-ethyntlcytidine 5′-triphosphate). 3′-Ethyntlcytidine 5′-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively, causing cancer cell death. Here, to identify the UCK2 mutation for detecting responder or nonresponder to ECyd, we investigated the relationship between point mutation of the UCK2 gene and response to ECyd in various human solid tumors. We identified several functional point mutations including the splice-site mutation of the UCK2 gene IVS5+5 G>A. In addition, we found that the IVS5+5 G>A variant generates an aberrant mRNA transcript, namely, truncated mRNA was produced and normal mRNA levels were markedly decreased in the ECyd-resistant cancer cell line HT1080. We concluded that these findings strongly suggest that the IVS5+5 G>A variant would affect the expression level of the UCK2 transcript, resulting in decreased sensitivity to ECyd.

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Feasibility study of adjuvant chemotherapy with modified weekly nab-paclitaxel and carboplatin for completely resected non-small-cell lung cancer: FAST-nab

The aim of this study was to determine the feasibility of adjuvant administration of nab-paclitaxel (nab-P) plus carboplatin and for completely resected patients with stage IB, II, and IIIA non-small-cell lung cancer (NSCLC) (FAST-nab study, UMIN000011225). Twenty-nine eligible NSCLC patients received surgical resection for pathological stage IB, II, or IIIA, followed by postoperative adjuvant chemotherapy with modified 3-week cycles of either nab-P (100 mg/m2) on days 1 and 8, followed by carboplatin area (area under the curve=6) on day 1. Twenty-two (75.9%) of the 29 patients enrolled completed four cycles of this regimen. The most common grade 3 or 4 adverse event experienced during the nab-P plus carboplatin was neutropenia (34.5%), followed by anemia (13.8%). No grade 3 or 4 nonhematologic adverse event was observed during this chemotherapy. The median time to disease recurrence survival was 21 (95% confidence interval: 16–26) months. The administration of modified nab-P plus carboplatin was considered an attractive alternative regimen that was safe and well tolerated as a postoperative adjuvant chemotherapy for completed resected NSCLC.

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Antitumor activities of the synthetic retinoid ST1926 in two-dimensional and three-dimensional human breast cancer models

Despite recent advances in chemotherapy, aggressive and metastatic breast cancers remain refractory to targeted therapy and the development of novel drugs is urgently needed. Retinoids are crucial regulators of cellular proliferation, differentiation, and cell death, and have shown potent chemotherapeutic and chemopreventive properties. The major drawback of the use of all-trans retinoic acid (ATRA) in cancer therapy is disease relapse. Therefore, synthetic retinoids, specifically ST1926, have emerged as potent anticancer agents. Given the importance of the microenvironment in modulating the response of cancer cells to chemotherapeutic drugs, we investigated the antitumor activities of ST1926 in two-dimensional (2D) and different three-dimensional (3D) human breast cancer models and compared them with ATRA. We have shown that in 2D cell culture models, ATRA-resistant MCF-7 and MDA-MB-231 cells were sensitive to ST1926 at submicromolar concentrations that spared the 'normal-like' breast epithelial cells. ST1926 induced apoptosis and S-phase arrest, caused DNA damage, and downregulated the Wnt/β-catenin pathway in breast cancer cells in 2D and 3D cell culture models. ST1926-mediated growth inhibition was independent of the retinoid receptor-signaling pathway. Long-term treatments with low submicromolar ST1926 concentrations reduced the anchorage-independent growth and decreased the sphere-forming ability of breast cancer progenitor cells in the sphere formation assay. Furthermore, ST1926 potently induced cell death of breast cancer cells under 3D conditions and spared the lumen-forming ability of normal-like breast epithelial cells. In tested 3D models, ATRA had minimal effects on the growth of breast cancer cells compared with ST1926. In summary, our results highlight the therapeutic potential of ST1926 in breast cancer and warrant its further clinical development.

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Complete response to anti-PD-1 nivolumab in massive skin metastasis from melanoma: efficacy and tolerability in an elderly patient

The advent of immune checkpoint inhibitors anti-PD-1/PD-L1 has delivered new and effective treatment options with proven clinical benefits for patients affected by metastatic melanoma. The 30–40% of treated patients experience an objective tumour regression, with a significantly prolonged survival and an improved quality of life. Here, we report a case of a 75-year-old Caucasian woman affected by a massive cutaneous metastasis from a BRAF wild-type melanoma who experienced multiple relapses after surgery and repeated electrochemotherapy treatments. A poor response was observed after systemic therapy with ipilimumab, whereas a marked reduction in the lesion size was obtained during the treatment with nivolumab, with an objectively complete response after 6 months. Therapy was well tolerated, without immune-related side effects. During treatment, LDH levels decreased up to the standard values. Our experience confirms the good efficacy and the safety of anti-PD-1 nivolumab for the treatment of relapsed or refractory massive skin lesions, also in elderly patients.

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Hypoxia as a target for drug combination therapy of liver cancer

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths worldwide. The standard of care for intermediate HCC is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxia-adapted cancer cells. The transcription factor that orchestrates responses to hypoxia is hypoxia-inducible factor 1 (HIF-1). The aim of this work is to show that targeting HIF-1 with combined drug therapy presents an opportunity for improving outcomes for HCC treatment. HepG2 cells were cultured under normoxic and hypoxic conditions exposed to doxorubicin, rapamycin and combinations thereof, and analyzed for viability and the expression of hypoxia-induced HIF-1α in response to these treatments. A pilot study was carried out to evaluate the antitumour effects of these drug combinations delivered from drug-eluting beads in vivo using an ectopic xenograft murine model of HCC. A therapeutic doxorubicin concentration that inhibits the viability of normoxic and hypoxic HepG2 cells and above which hypoxic cells are chemoresistant was identified, together with the lowest effective dose of rapamycin against normoxic and hypoxic HepG2 cells. It was shown that combinations of rapamycin and doxorubicin are more effective than doxorubicin alone. Western Blotting indicated that both doxorubicin and rapamycin inhibit hypoxia-induced accumulation of HIF-1α. Combination treatments were more effective in vivo than either treatment alone. mTOR inhibition can improve outcomes of doxorubicin treatment in HCC.

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Long-term use of pegylated liposomal doxorubicin to a cumulative dose of 4600 mg/m2 in recurrent ovarian cancer

Pegylated liposomal doxorubicin (PLD) is used widely in gynecologic oncology and other oncology disciplines. Native doxorubicin use is associated with the potential for significant toxicity. Cardiac toxicity in particular limits lifetime dose. PLD has not been shown to be associated with clinical cardiac toxicity. We report on the long-term use of PLD in a patient with recurrent high-grade serous ovarian cancer to a lifetime dose of 4600 mg/m2. This therapy was associated with long-term stable disease, good performance status, and minimal adverse effects.

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Mesenchymal Stem Cells to Treat Crohn's Disease with Fistula

Human Gene Therapy Jul 2017, Vol. 28, No. 7: 534-540.


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Sleeping Beauty Awakens New Interest

Human Gene Therapy Jul 2017, Vol. 28, No. 7: 533-533.


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Blunt Traumatic Injury to the Aortic Root and Aortic Valve.

No abstract available

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Opioid Reduction Following Interventional Procedures for Chronic Pain: A Synthesis of the Evidence.

The past decade has witnessed the tremendous growth of procedures to treat chronic pain, which has resulted in increased third-party scrutiny. Although most of these procedures appear to be associated with significant pain relief, at least in the short and intermediate term, their ability to improve secondary outcome measures, including function and work status is less clear-cut. One of these secondary outcome measures that has garnered substantial interest in the pain and general medical communities is whether interventions can reduce opioid intake, which is associated with significant risks that in most cases outweigh the benefits in the long term. In the article, we examine whether procedural interventions for chronic pain can reduce opioid intake. Most studies that have examined analgesic reduction as a secondary outcome measure have not separated opioid and nonopioid analgesics, and, among those studies that have, few have demonstrated between-group differences. Reasons for failure to demonstrate opioid reduction can be broadly classified into procedural, design-related, clinical, psychosocial, biological, and pharmacological categories, all of which are discussed. In the future, clinical trials in which this outcome is examined should be designed to evaluate this, at least on a preliminary basis. (C) 2017 International Anesthesia Research Society

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Blood Product Utilization Among Trauma and Nontrauma Massive Transfusion Protocols at an Urban Academic Medical Center.

BACKGROUND: Hospital-wide massive transfusion protocols (MTPs) primarily designed for trauma patients may lead to excess blood products being prepared for nontrauma patients. This study characterized blood product utilization among distinct trauma and nontrauma MTPs at a large, urban academic medical center. METHODS: A retrospective study of blood product utilization was conducted in patients who required an MTP activation between January 2011 and December 2015 at an urban academic medical center. Trauma MTP containers included 6 red blood cell (RBC) units, 5 plasma units, and 1 unit of apheresis platelets. Nontrauma MTP containers included 6 RBC and 3 plasma units. RESULTS: There were 334 trauma MTP activations, 233 nontrauma MTP activations, and 77 nontrauma MTP activations that subsequently switched to a trauma MTP ("switched activations"). All nontrauma MTP activations were among bleeding patients who did not have a traumatic injury (100% [233/233]). Few patients with a nontrauma activation required ad hoc transfusion of RBC units (1.3% [95% confidence interval (CI), 0.3%-3.7%]) or plasma (3.4% [95% CI, 1.5%-6.7%]), and only 45.5% (95% CI, 39.0%-52.1%) required ad hoc transfusion of apheresis platelets. Compared to trauma and switched activations, nontrauma activations transfused a lower median number of RBC, plasma, and apheresis platelet units (P

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Maternal Salvage With Extracorporeal Life Support: Lessons Learned in a Single Center.

The American Heart Association scientific statement on cardiac arrest in pregnancy did not endorse extracorporeal life support for lack of cohort data. We studied all pregnancy and peripartum cases of extracorporeal life support in 1 medical center (n = 11), including collapse due to infection (n = 6, 55%), thromboembolism (n = 3, 27%), and cardiac disease (n = 2, 18%). Half of the cases (n = 5, 45%) involved extracorporeal cardiopulmonary resuscitation. Most mothers survived (n = 7, 64% [95% confidence interval, 32%-88%]). Deaths were attributable to oxygenator blockage (n = 1) and late sepsis (n = 3). The 2 unique clinical challenges were maintenance of high peripartum cardiac outputs and balancing anticoagulation with hemostasis. (C) 2017 International Anesthesia Research Society

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