Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Πέμπτη 2 Αυγούστου 2018

21st Century Biological Nomenclature—the Enduring Power of Names

Synopsis
Nomenclature and taxonomy are complementary and distinct aspects of the study of biodiversity, but the two are often confused even by biologists. Taxonomy is the part of the science of systematics that deals with identifying, describing, and categorizing organisms from species to higher taxa. Nomenclature is a system of giving names to organisms based on rules established for the process. Adoption of a system of binomial nomenclature by end of the 18th century helped standardize the process of naming the wealth of new organisms collected during the Age of Exploration, but before the middle of the 19th century, the turmoil resulting from differences in procedures and philosophies among practicing taxonomists necessitated the development of codes of nomenclature to regulate naming. By the early 20th century, codified sets of rules for the names of both plants and animals, nowadays usually abbreviated as ICBN (Botanical Code) and ICZN (Zoological Code), were in place internationally. These codes worked reasonably well through most of the 20th century, under the aegis of various international bodies, in part because procedures exist to bypass them when their provisions threaten nomenclatural stability. They also inspired the development of other nomenclatural codes for specific groups of organisms like bacteria, and, alternatively, the proposal of unified codes for all organisms. The rapid development of electronic communications and various means of electronic publication at the end of the 20th century, combined with what may be the advent of a new age of biological extinction, resulted in pressure to revise the codes to allow at least some degree of electronic publication and speedier description of new taxa in the 21st century. Consistent and unambiguous names are the platforms on which biological research and conservation practices are built. As we pursue the goals of documenting and conserving biodiversity, for which a stable nomenclature is essential, we must do so without restricting the freedom of the science of systematics.

https://ift.tt/2Mfa1Go

A review of midwifery in mainland China: Contemporary developments within historical, economic and sociopolitical contexts

Publication date: Available online 2 August 2018

Source: Women and Birth

Author(s): Ling-ling Gao, Hong Lu, Nicky Leap, Caroline Homer

Abstract
Background

With the recent surging economic and social development in China, midwifery has undergone transformation.

Aim

A narrative review of literature relating to midwifery in mainland China was undertaken to examine the characteristics of midwifery's potential development within relevant historical, economic and sociopolitical contexts. The aim was to assist future planning and the setting of strategic directions in policy in China.

Methods

Online bibliographic databases from 2000 to 2015 were searched including MEDLINE, WanFang Data and Chinese National Knowledge Infrastructure. A process of narrative synthesis was used to analyse the selected papers and major issues were identified.

Results

Twenty-one papers were included in the review. Two overarching issues were identified in relation to midwifery in mainland China: the history and status of midwifery education; and the practice and regulation of the midwifery profession. In recent decades, midwifery education, regulation and practice have occurred within systems that view midwifery as a specialisation of nursing. This means that there continues to be little opportunity for midwives to practise according to the international definition and scope of practice of the midwife.

Conclusion

Midwifery in China must continue to develop in parallel with international trends. Investment in midwifery education alone will not suffice; it will have to operate within strong government policy regarding regulation, effective human resources management, visibility of the role of the midwife and development of the service delivery environment in which future midwives will work in China.



https://ift.tt/2O9jRud

Sequencing Detects Lung Cancer in Blood [News in Brief]

Genome sequencing that analyzes cell-free DNA in blood samples may be a useful approach for detecting lung cancer: In preliminary results from the ongoing Circulating Cell-Free Genome Atlas study, three different sequencing approaches detected lung cancer in 38% to 51% of patients with early-stage disease and in 87% to 89% of patients with late-stage disease, with 98% specificity.



https://ift.tt/2LOgCvz

Carcinosarcoma of Tongue with Predominant Osteosarcomatous Component

Abstract

Carcinosarcoma is exceedingly rare in the oral cavity and shows presence of both carcinomatous and sarcomatous components. We report a case of carcinosarcoma of tongue in a 51-year-old male with predominant osteosarcomatous and squamous cell carcinoma components. There was no evidence of regional or systemic metastatic disease. This case represents the first reported example of this unusual neoplasm with a predominant osteosarcomatous component, arising in the tongue.



https://ift.tt/2vwIOYS

Transcription Factor Low-Complexity Domain Hubs Drive Transcription [Transcription]

Low-complexity domains (LCD) in transcription factors can form high-concentration interaction hubs.



https://ift.tt/2vByiQa

Engineered T Cells in Synovial Sarcoma: Persistence Pays Off! [In the Spotlight]

Summary: Synovial sarcoma (SS) is an aggressive malignancy that typically affects adolescents and young adults and is associated with poor prognosis. Although SS has failed to respond to immune checkpoint blockade, other strategies designed to generate an immune response, including adoptive cell therapies targeting the cancer testis antigen NY-ESO-1, have shown encouraging results. In this issue, D'Angelo and colleagues confirm the safety and feasibility of adoptive T-cell therapy with autologous T cells engineered to express NY-ESO-1c259, an affinity-enhanced T-cell receptor recognizing an HLA-A2–restricted NY-ESO-1–derived peptide, and demonstrate encouraging antitumor responses in 50% of treated patients, particularly in the setting of persistence of polyfunctional NY-ESO-1c259–expressing T cells in circulation for at least 6 months. Cancer Discov; 8(8); 914–7. ©2018 AACR.

See related article by D'Angelo et al., p. 944.



https://ift.tt/2vByeQq

Upping Enrollment of Veterans in Trials [News in Brief]

The NCI and Department of Veterans Affairs (VA) are collaborating on the NCI and VA Interagency Group to Accelerate Trials Enrollment, or NAVIGATE, which will launch at 12 VA facilities across the country. The program aims to increase participation of veterans with cancer in NCI-sponsored clinical trials.



https://ift.tt/2n81WZt

IL23 Produced by MDSCs Promotes Castration-Resistant Prostate Cancer [Prostate Cancer]

In patients with CRPC an increase in tumor-infiltrating MDSCs that secrete IL23 upregulates AR.



https://ift.tt/2vx2USK

Immunotherapy Resistance by Inflammation-Induced Dedifferentiation [Research Brief]

A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor-acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T-cell transfer therapy (ACT) to the MART1 antigen, a phenomenon that had been observed only in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART1 T cell receptor–expressing T cells or with TNFα, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.

Significance: We report a patient whose metastatic melanoma underwent inflammation-induced dedifferentiation as a resistance mechanism to ACT to the MART1 antigen. Our results suggest that future melanoma ACT protocols may benefit from the simultaneous targeting of multiple tumor antigens, modulating the inflammatory response, and inhibition of inflammatory dedifferentiation-inducing signals. Cancer Discov; 8(8); 935–43. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 899



https://ift.tt/2n81Hh1

By the Numbers: Cancer Mortality, 2011-2015 [News in Brief]

From 2011 to 2015, patients with lung cancer had the highest cancer mortality rates, followed by patients with breast cancer and prostate cancer.



https://ift.tt/2vx2OKS

Autologous T Cells Targeting Four Neoantigens Induce Tumor Regression [Immunotherapy]

Autologous T-cell transfer achieves a durable regression in a patient with metastatic breast cancer.



https://ift.tt/2n81CKf

Phase Separation Concentrates Transcription Proteins at Superenhancers [Transcription]

Intrinsically disordered regions of MED1 and BRD4 promote formation of phase-separated condensates.



https://ift.tt/2vvICc7

CBF{beta}-SMMHC Activates MYC Enhancers to Promote Leukemogenesis [Leukemia]

CBFβ–SMMHC inhibition induces RUNX1-mediated repression of MYC to induce apoptosis in inv(16) AML cells.



https://ift.tt/2LQekf6

Quizartinib Bests Chemo for FLT3-Mutant AML [News in Brief]

The FLT3 inhibitor quizartinib provided a survival benefit over chemotherapy in a phase III trial of patients with relapsed or refractory FLT3-mutant acute myeloid leukemia. The drug, along with other FLT3 inhibitors, could become a first-line treatment based on results from ongoing studies.



https://ift.tt/2LLXT3v

Paralog Dependency May Be Exploitable in Tumors Lacking Chromosome 1p [Genomics]

Cells with chromosome 1p loss and hemizygous deletion of MAGOH are dependent on its paralog, MAGOHB.



https://ift.tt/2O8d2sV

Enzymes That Catalyze Wobble tRNA Modification Promote Melanomagenesis [Translation]

Enzymes that modify wobble uridine 34 tRNAs (U34 enzymes) maintain HIF1α levels in BRAFV600E melanoma.



https://ift.tt/2vxRgXT

Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins [Research Articles]

Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes influence melanoma are poorly understood. Using in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAFV600E in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. Pharmacologic blockade of FATPs with the small-molecule inhibitor Lipofermata abrogates lipid transport into melanoma cells and reduces melanoma growth and invasion. These data demonstrate that stromal adipocytes can drive melanoma progression through FATP lipid transporters and represent a new target aimed at interrupting adipocyte–melanoma cross-talk.

Significance: We demonstrate that stromal adipocytes are donors of lipids that mediate melanoma progression. Adipocyte-derived lipids are taken up by FATP proteins that are aberrantly expressed in melanoma. Inhibition of FATPs decreases melanoma lipid uptake, invasion, and growth. We provide a mechanism for how stromal adipocytes drive tumor progression and demonstrate a novel microenvironmental therapeutic target. Cancer Discov; 8(8); 1006–25. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 899



https://ift.tt/2vvF8q3

Positive Results for Tazemetostat in Follicular Lymphoma [News in Brief]

A recently reported clinical trial indicates that the EZH2 inhibitor tazemetostat is effective against relapsed or refractory follicular lymphoma. Three of 28 patients with EZH2 mutations had complete responses, and 17 had partial responses.



https://ift.tt/2LKmLc5

CAR T-cell Integration of Multiple Input Signals Allows for Precise Targeting of Cancer [In the Spotlight]

Summary: Chimeric antigen receptor (CAR)–mediated adoptive T-cell therapy has achieved unprecedented success in the treatment of relapsed and refractory hematologic malignancies. However, this success may be more difficult to recapitulate in the treatment of metastatic solid tumors, where the lack of costimulatory signals and cytokine support as well as the strongly inhibitory microenvironment pose a substantial challenge to unleashing the antitumor potential of CAR T cells. Furthermore, nearly all described target antigens are expressed on normal tissue. In this issue of Cancer Discovery, Sukumaran and colleagues address these challenges by engineering T cells to recognize a specific expression pattern unique to the tumor site using independent chimeric molecules that cooperatively deliver a fully functional T-cell response selectively in the tumor microenvironment. Cancer Discov; 8(8); 918–20. ©2018 AACR.

See related article by Sukumaran et al., p. 972.



https://ift.tt/2vuPSFp

Abiraterone-Olaparib Combo Aids Men with mCRPC [News in Brief]

Recent findings from a phase II trial suggest that combining the antiandrogen abiraterone and the PARP inhibitor olaparib significantly improves progression-free survival among patients with metastatic castration-resistant prostate cancer, regardless of their homologous recombination repair–mutation status.



https://ift.tt/2n67JP1

Noted [News in Brief]

A collection of recently published news items.



https://ift.tt/2vz58AX

Trastuzumab Deruxtecan Targets HER2+ Cancers [News in Brief]

The antibody–drug conjugate trastuzumab deruxtecan may be an effective treatment for patients with HER2-positive cancers whose disease has progressed despite the use of other therapies. In a phase I trial, patients treated with the drug had high overall response rates and rates of tumor shrinkage, but many also experienced serious gastrointestinal and hematologic side effects.



https://ift.tt/2n6eY9x

BAI1 Stabilizes p53 to Suppress Medulloblastoma Tumorigenesis [Medulloblastoma]

Epigenetic silencing of BAI1 results in p53 degradation and accelerated medulloblastoma tumorigenesis.



https://ift.tt/2vwG4uy

Erdafitinib Efficacious in Bladder Cancer [News in Brief]

Findings from a phase II study indicate clinical efficacy with erdafitinib in patients with FGFR-altered inoperable or metastatic urothelial carcinoma. Robust responses were seen with this investigational pan-FGFR inhibitor, including in patients who did not respond to prior immunotherapy.



https://ift.tt/2LKmGFj

Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1c259T Cells in Synovial Sarcoma [Research Articles]

We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2–restricted NY-ESO-1/LAGE1a–derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.

Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944–57. ©2018 AACR.

See related commentary by Keung and Tawbi, p. 914.

This article is highlighted in the In This Issue feature, p. 899



https://ift.tt/2vz54RJ

Study Reveals Germline Genetics of Medulloblastoma [News in Brief]

Researchers have identified six germline mutations that explain 6% of medulloblastoma cases; the mutations were associated with four consensus subgroups of the disease. Their results could inform future genetic testing, treatment, and surveillance of patients with medulloblastoma.



https://ift.tt/2nd66iN

Ivosidenib Deemed Safe, Effective in AML [News in Brief]

A phase I study suggests that ivosidenib can induce remission in patients with relapsed or refractory acute myeloid leukemia characterized by IDH1 mutations. The drug spurred complete remission or complete remission with partial hematologic recovery in 30.4% of patients. The most common side effects of at least grade 3 were prolonged QT interval and IDH differentiation syndrome.



https://ift.tt/2vxRgqR

An Immunosuppressive Role for Eya3 in TNBC [News in Brief]

A recent study indicates that the protein Eya3 influences the adaptive immune response to promote tumor growth, not only decreasing the number of tumor-infiltrating CD8+ T cells, but also driving their exhaustion through PD-L1 upregulation. These findings could spur new strategies to treat triple-negative breast cancer, which currently lacks targeted therapies.



https://ift.tt/2nd65eJ

Pembrolizumab Monotherapy for NSCLC Extends Survival [News in Brief]

The PD-1 inhibitor pembrolizumab may be a better first-line treatment than chemotherapy for many patients with advanced non–small cell lung cancer: In a phase III trial, patients with PD-L1 expression of 1% or higher treated with the drug had better overall survival, a longer duration of response, and fewer side effects than patients who received chemotherapy alone.



https://ift.tt/2vuVmjn

The Histone Demethylase LSD1 Inhibits Tumor Cell Immunogenicity [Immunology]

Loss of LSD1 enhances tumor immunogenicity and sensitizes refractory mouse melanoma to anti–PD-1 therapy.



https://ift.tt/2nd62zz

Squamous NSCLC Improves with Atezolizumab Plus Chemo [News in Brief]

A combination of chemotherapy and the PD-L1 inhibitor atezolizumab may be an effective initial therapy for patients with advanced squamous non–small cell lung cancer. In a clinical trial, patients who received the combination had longer progression-free survival, a higher objective response rate, and a longer duration of response than patients who received chemotherapy alone, regardless of PD-L1 expression level.



https://ift.tt/2vdkYSu

Second-Site IDH2 Mutations Confer Resistance to Enasidenib In Trans [Drug Resistance]

Two patients with IDH2R140Q AML acquired resistance to an IDH2 inhibitor via secondary IDH2 mutations.



https://ift.tt/2n6DM1f

Maintenance Chemo Improves Pediatric RMS [News in Brief]

Findings from a 10-year clinical trial show improved survival rates among children with high-risk rhabdomyosarcoma who receive low-dose maintenance chemotherapy following standard treatment. The results have established a new standard of care for this disease in the EU.



https://ift.tt/2vykOEr

Availability and sufficiency of phenobarbital, an essential medication, in Bhutan: a survey of global and neuropsychiatric relevance

We aimed to provide a reliable evidence-based conclusion around manufacturing, import, availability and sufficiency of one essential medication, phenobarbital (PB) through our example location (Bhutan). The re...

https://ift.tt/2vcXRHR

Assessment of genetic diversity in Coho salmon (Oncorhynchus kisutch) populations with no family records using ddRAD-seq

Selective breeding for desirable traits is becoming popular in aquaculture. In Miyagi prefecture, Japan, a selectively bred population of Coho salmon (Oncorhynchus kisutch) has been established with the original,...

https://ift.tt/2ACsk7a

Body iron status of children and adolescents with transfusion dependent β-thalassaemia: trends of serum ferritin and associations of optimal body iron control

This cross sectional study aims to describe the body iron status, trends of serum ferritin and associations of optimal body iron control in patients aged below 16 years with transfusion dependent β-thalassaemi...

https://ift.tt/2vfnYxz

Niraparib: A Review in Ovarian Cancer

Abstract

Niraparib (Zejula®), a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for the maintenance treatment of recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy. Approval was based on the results of the randomized, double-blind, placebo-controlled phase III NOVA trial. In NOVA, niraparib significantly prolonged progression-free survival (primary endpoint), chemotherapy-free interval and time to first subsequent therapy compared with placebo in patients with recurrent, platinum-sensitive, high grade serous ovarian, fallopian tube or primary peritoneal cancer. The beneficial effects of niraparib were consistent regardless of BRCA mutation or homologous recombination deficiency (HRD) status. Niraparib had a manageable tolerability profile, with the majority of grade 3 or 4 adverse events being haematologic abnormalities (e.g. thrombocytopenia, anaemia, neutropenia). Adverse events were generally well managed with dose interruption or modification of niraparib. Current evidence suggests that niraparib is an effective new option with a manageable tolerability profile for the maintenance treatment of recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer in adults, with or without BRCA1/2 mutation or HRD.



https://ift.tt/2n8LrfG

An open-label feasibility study of nintedanib combined with docetaxel in Japanese patients with locally advanced or metastatic lung adenocarcinoma after failure of first-line chemotherapy

Abstract

Purpose

This open-label feasibility study assessed the tolerability of nintedanib 200 mg in combination with docetaxel 75 mg/m2 as a starting dose in Japanese patients with a body surface area (BSA) < 1.5 m2 and locally advanced or metastatic lung adenocarcinoma.

Methods

Eligible patients received docetaxel 75 mg/m2 every 21 days and nintedanib administered at 200 mg twice daily (bid), starting on day 2 of each cycle. Treatment was continued until disease progression or undue toxicity. The primary endpoint was the number of patients experiencing dose-limiting toxicities (DLTs) in cycle 1 (days 1–21).

Results

Of 10 treated patients, 2 patients (20%) experienced DLTs during cycle 1. These DLTs were grade 3 liver enzyme elevations [alanine aminotransferase (2 patients) and aspartate aminotransferase (2 patients)], and grade 2 hyperbilirubinemia (1 patient). Nine patients met the predefined criteria for nintedanib 200 mg bid plus docetaxel 75 mg/m2 to be considered a tolerable starting dose. All patients experienced ≥ 1 adverse event (AE) during the treatment period (all drug-related), but no patients experienced AEs that led to discontinuation of nintedanib. Of the five serious AEs reported during treatment, none were drug-related. There was no apparent effect of nintedanib on the pharmacokinetics of docetaxel. The objective response and disease control rates were 40 and 70%, respectively.

Conclusion

Nintedanib 200 mg bid plus docetaxel 75 mg/m2 is a tolerable starting dose in Japanese patients with a BSA < 1.5 m2 with locally advanced or metastatic lung adenocarcinoma.

ClinicalTrials.gov number

NCT02300298.



https://ift.tt/2vgdSfU

Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma

Abstract

Phase I testing of the hu14.18-IL2 immunocytokine (IC) in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m2/day. Preclinical data in IC-treated tumor-bearing mice with low tumor burden documented striking antitumor effects. Patients with completely resectable recurrent stage III or stage IV melanoma were scheduled to receive 3 courses of IC at 6 mg/m2/day i.v. on days 1, 2 and 3 of each 28-day course. Patients were randomized to complete surgical resection either following neoadjuvant (Group A) or prior to adjuvant (Group B) IC course 1. Primary objectives were to: (1) evaluate histological evidence of anti-tumor activity and (2) evaluate recurrence-free survival (RFS) and OS. Twenty melanoma patients were randomized to Group A (11 patients) or B (9 patients). Two Group B patients did not receive IC due to persistent disease following surgery. Six of 18 IC-treated patients remained free of recurrence, with a median RFS of 5.7 months (95% confidence interval (CI) 1.8-not reached). The 24-month RFS rate was 38.9% (95% CI 17.5–60.0%). The median follow-up of surviving patients was 50.0 months (range: 31.8–70.4). The 24-month OS rate was 65.0% (95% CI 40.3–81.5%). Toxicities were similar to those previously reported. Exploratory tumor-infiltrating lymphocyte (TIL) analyses suggest prognostic value of TILs from Group A patients. Prolonged tumor-free survival was seen in some melanoma patients at high risk for recurrence who were treated with IC.



https://ift.tt/2MfhO7g

Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma

Abstract

Phase I testing of the hu14.18-IL2 immunocytokine (IC) in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m2/day. Preclinical data in IC-treated tumor-bearing mice with low tumor burden documented striking antitumor effects. Patients with completely resectable recurrent stage III or stage IV melanoma were scheduled to receive 3 courses of IC at 6 mg/m2/day i.v. on days 1, 2 and 3 of each 28-day course. Patients were randomized to complete surgical resection either following neoadjuvant (Group A) or prior to adjuvant (Group B) IC course 1. Primary objectives were to: (1) evaluate histological evidence of anti-tumor activity and (2) evaluate recurrence-free survival (RFS) and OS. Twenty melanoma patients were randomized to Group A (11 patients) or B (9 patients). Two Group B patients did not receive IC due to persistent disease following surgery. Six of 18 IC-treated patients remained free of recurrence, with a median RFS of 5.7 months (95% confidence interval (CI) 1.8-not reached). The 24-month RFS rate was 38.9% (95% CI 17.5–60.0%). The median follow-up of surviving patients was 50.0 months (range: 31.8–70.4). The 24-month OS rate was 65.0% (95% CI 40.3–81.5%). Toxicities were similar to those previously reported. Exploratory tumor-infiltrating lymphocyte (TIL) analyses suggest prognostic value of TILs from Group A patients. Prolonged tumor-free survival was seen in some melanoma patients at high risk for recurrence who were treated with IC.



https://ift.tt/2MfhO7g

Stab wounds of the chest caused by penetration of duralumin rods

Abstract

Sharp force injuries are uncommon in routine forensic practice. While the majority of these cases are homicides or suicides, a significant minority of accidental deaths means that a careful investigation of the circumstances of the death is necessary. We present the case of a young man who presented with stab and cut injuries due to a duralumin rod embedded in his chest. Examination of the body revealed that death was due to penetration of the thoracic aorta by a duralumin rod. Careful investigation of the circumstances surrounding the death was able to confim a case of accidental death due to falling from a ladder onto tomato seedlings that were supported by duralumin rods.



https://ift.tt/2n35hsy

A polysome-based microRNA screen identifies miR-24-3p as a novel pro-migratory miRNA in mesothelioma

The expression of miRNAs in cancer has been widely studied and has allowed the definition of oncomirs and oncosuppressors. We note that it is often underestimated that many mRNAs are expressed, but translationally silent. In spite of this, systematic identification of miRNAs in equilibrium with their target mRNAs on polysomes has not been widely exploited. In order to identify biologically active oncomirs, we performed a screen for miRNAs acting on the polysomes of malignant mesothelioma (MPM) cells. Only a small percentage of expressed miRNAs physically associated with polysomes. On polysomes, we identified miRNAs already characterized in MPM, as well as novel ones like miR-24-3p, which acted as a promigratory miRNA in all cancer cells tested. miR-24-3p positively regulated Rho-GTP activity, and inhibition of miR-24-3p reduced growth in MPM cells. Analysis of miR-24-3p common targets, in two mesothelioma cell lines, identified a common subset of down-regulated genes. These same genes were down-regulated during the progression of multiple cancer types. Among the specific targets of miR-24-3p was cingulin, a tight junction protein that inhibits Rho-GTP activity. Overexpression of miR-24-3p only partially abrogated cingulin mRNA, but completely abrogated cingulin protein, confirming its action via translational repression. We suggest that miR-24-3p is an oncomir, and speculate that identification of polysome-associated miRNAs efficiently sorts out biologically active miRNAs from inactive ones.

https://ift.tt/2vxP0j1

Small-Cell Prostate Cancer Variety Surprisingly Common [News in Brief]

Study distinguishes post-treatment type of small-cell prostate cancer.



https://ift.tt/2LMcT1s

Replication Protein A Availability During DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells

Intrinsic and acquired resistance to cisplatin remains a primary hurdle to treatment of high-grade serous ovarian cancer (HGSOC). Cisplatin selectively kills tumor cells by inducing DNA crosslinks that block replicative DNA polymerases. Single-stranded DNA (ssDNA) generated at resulting stalled replication forks (RF) is bound and protected by heterotrimeric replication protein A (RPA), which then serves as a platform for recruitment and activation of replication stress response factors. Cells deficient in this response are characterized by extensive ssDNA formation and excessive RPA recruitment that exhausts the available pool of RPA, which (i) inhibits RPA-dependent processes such as nucleotide excision repair (NER) and (ii) causes catastrophic failure of blocked RF. Here we investigated the influence of RPA availability on chemosensitivity using a panel of human HGSOC cell lines. Our data revealed a striking correlation among these cell lines between cisplatin sensitivity and the inability to efficiently repair DNA via NER, specifically during S phase. Such defects in NER were attributable to RPA exhaustion arising from aberrant activation of DNA replication origins during replication stress. Reduced RPA availability promoted Mre11-dependent degradation of nascent DNA at stalled RF in cell lines exhibiting elevated sensitivity to cisplatin. Strikingly, defective S-phase NER, replication fork instability, and cisplatin sensitivity could all be rescued by ectopic overexpression of RPA. Taken together, our findings indicate that RPA exhaustion represents a major determinant of cisplatin sensitivity in HGSOC cell lines.

https://ift.tt/2vxjl1v

A targeted quantitative proteomic approach assesses the reprogramming of small GTPases during melanoma metastasis

Small GTPases of the Ras superfamily are master regulators of intracellular trafficking and constitute essential signaling components in all eukaryotes. Aberrant small GTPase signaling is associated with a wide spectrum of human diseases including cancer. Here we developed a high-throughput, multiple-reaction monitoring-based workflow coupled with stable isotope labeling by amino acids in cell culture, for targeted quantification of approximately 100 small GTPases in cultured human cells. Using this method, we investigated the differential expression of small GTPases in three pairs of primary and metastatic melanoma cell lines. Bioinformatic analyses of The Cancer Genome Atlas data and other publicly available data as well as cell-based assays revealed previously unrecognized roles of RAB38 in promoting melanoma metastasis. Diminished promoter methylation and the subsequent augmented binding of transcription factor MITF contributed to elevated expression of RAB38 in metastatic versus primary melanoma cells. Moreover, RAB38 promoted invasion of cultured melanoma cells by modulating the expression and activities of matrix metalloproteases-2 and -9. Together, these data establish a novel targeted proteomic method for interrogating the small GTPase proteome in human cells and identify epigenetic reactivation of RAB38 as a contributing factor to metastatic transformation in melanoma.

https://ift.tt/2n3zZls

Glutamate-weighted chemical exchange saturation transfer magnetic resonance imaging (GluCEST MRI) detects glutaminase inhibition in a mouse model of triple-negative breast cancer

Glutamate is an important metabolite of glutaminolysis, a metabolic pathway employed by many aggressive cancers including triple-negative breast cancer. With the exception of the brain, in vivo detection of glutamate using 1H magnetic resonance spectroscopy (MRS) is challenging in tissues. Compared to MRS, glutamate chemical exchange saturation transfer MR imaging (GluCEST MRI) offers a more sensitive detection mechanism that is free of glutamine interference. Here we developed a robust, highly repeatable GluCEST MRI protocol in mice bearing human triple-negative breast cancer xenografts and treated with the potent glutaminase inhibitor CB-839. In paired studies, treatment with CB-839 for 2 days reduced the GluCEST asymmetry value compared to baseline (P < 0.05, n=10). The absolute change of the GluCEST asymmetry value was -2.5 percent points after CB-839 treatment versus +0.3 after vehicle (P < 0.01). Correspondingly, treatment with CB-839 reduced tumor glutamate concentrations by 1.5 mM, consistent with prior calibration between changes of the GluCEST value versus tissue glutamate concentration; CB-839, however, did not change tumor intracellular pH. These results demonstrate in a mouse model of TNBC the clinical utility of GluCEST MRI as a means to detect the early response to glutaminase inhibition.

https://ift.tt/2n4E88u

Amplification of wild type KRAS imparts resistance to crizotinib in MET exon 14 mutant non-small cell lung cancer

Purpose: MET inhibitors can be effective therapies in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC). However, long term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild type (WT) KRAS as a molecular mechanism behind crizotinib resistance in three cases of METex14 mutant NSCLC and propose a combination therapy to target it. Experimental Design: The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant METex14 mutant patient tumor with massive focal amplification of WT KRAS. To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative. Sensitivity of the cell line to ligand stimulation was assessed and KRAS-dependent expression of EGFR ligands was quantified. Drug combinations were screened for efficacy in vivo and in vitro using viability and apoptotic assays. Results: KRAS amplification is a recurrent genetic event in crizotinib-resistant METex14 mutant NSCLC. The key characteristics of this genetic signature include uncoupling MET from downstream effectors, relative insensitivity to dual MET/MEK inhibition due to compensatory induction of PI3K signaling, KRAS-induced expression of EGFR ligands and hypersensitivity to ligand-dependent and independent activation, and reliance on PI3K signaling upon MET inhibition. Conclusions: Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by KRAS amplification in METex14 mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.



https://ift.tt/2LXigdv

Effect of botulinum toxin injection on length and force of the rectus femoris and triceps surae muscles during locomotion in patients with chronic hemiparesis (FOLOTOX)

After stroke, spasticity of the rectus femoris (RF) and triceps surae (TS) muscles frequently alters the gait pattern. Knee flexion and ankle dorsiflexion in swing are often reduced, respectively called Stiff ...

https://ift.tt/2ODpIZG

NIH Releases Large-Scale Dataset of CT Images

THURSDAY, Aug. 2, 2018 -- To help improve detection accuracy of lesions, the National Institutes of Health (NIH)'s Clinical Center has made available a large-scale dataset of 32,000 annotated lesions identified on computed tomography (CT)...

https://ift.tt/2vfLESu

CDC: Salmonella Outbreaks in 44 States Linked to Backyard Poultry

THURSDAY, Aug. 2, 2018 -- At least 212 people in 44 states have been sickened in Salmonella outbreaks linked to contact with live poultry in backyard flocks, according to the U.S. Centers for Disease Control and Prevention. Twenty-six percent of the...

https://ift.tt/2O8eYkZ

Health Affairs Announces Launch of New Three-Year Initiative

THURSDAY, Aug. 2, 2018 -- A council on health care spending and value has been established by the journal Health Affairs. The council will examine health care spending in the United States and provide a focal point for discussion, analysis, and...

https://ift.tt/2vecw5A

Three Financial Metrics Can Improve Practice Performance

THURSDAY, Aug. 2, 2018 -- By understanding three indices and metrics, physicians can change the financial outcome of their medical practice, according to a report published in Medical Economics. A collection rate represents the measure of the...

https://ift.tt/2Mb4BfB

New Ebola Outbreak in Congo

THURSDAY, Aug. 2, 2018 -- Just a week after being declared Ebola-free, the Democratic Republic of Congo said yesterday that a new outbreak of the deadly virus has killed at least 20 people. Authorities in North Kivu Province notified the country's...

https://ift.tt/2M037ba

Importance of Evaluating Cardiovascular Risk and Hepatic Fibrosis in Patients With Newly Diagnosed Nonalcoholic Fatty Liver Disease



https://ift.tt/2AyHpqv

Primary gastrointestinal stromal tumor of the liver



https://ift.tt/2OGAJt4

Unusual Masquerader of an Adenomatous Colorectal Polyp



https://ift.tt/2AyHfiT

Clinical practice of endoscopic submucosal dissection in the United States



https://ift.tt/2vee7s2

Coexistence of Complete Pancreas Divisum and Anomalous Pancreaticobiliary junction in a Patient with Type IA Choledochal Cyst



https://ift.tt/2AyH86X

Serum proteins in healthy and diseased Florida manatees ( Trichechus manatus latirostris )

Abstract

A major goal of this study was to determine whether serum protein fractions of healthy Florida manatees differ with age, sex, or living environments (wild versus housed). A second goal was to determine which serum protein fractions vary in diseased versus healthy manatees. Serum protein fractions were determined using agarose gel electrophoresis. Healthy adults had slightly higher total serum protein and total globulin concentrations than younger animals. This largely resulted from an increase in gamma globulins with age. Total serum protein, albumin, alpha-1 globulin, beta globulin, and total globulin concentrations were slightly higher in housed manatees compared to wild manatees, but there was no significant difference in the albumin/globulin (A/G) ratio, suggesting a difference in hydration between these groups. No significant differences were attributable to sex or pregnancy. Serum albumin concentrations and A/G ratios were significantly lower for manatees with boat trauma, entanglements, emaciation, or cold stress compared to healthy manatees. Variable increases were seen in alpha-1globulins, alpha-2 globulins, beta globulins, and gamma globulins. These globulin fractions contain positive acute-phase proteins and immunoglobulins, and their increases may reflect acute or chronic active inflammation. Changes in serum protein fractions were not consistent enough to justify the use of serum protein electrophoresis as a routine diagnostic test for manatees. However, serum (or plasma) protein electrophoresis is required when accurate values for albumin and globulins are needed in manatees and in determining which protein fractions may account for a hyperproteinemia or hypoproteinemia reported in a clinical chemistry panel.



https://ift.tt/2LXhkpf

Comparative hypolipidaemic effects of crude seed powder, aqueous and methanolic seed extracts of Buchholzia coriacea in carbon tetrachloride-induced toxicity in albino rats ( Rattus norvegicus )

Abstract

Comparative hypolipidaemic effects of aqueous seed extracts, methanolic seed extracts and crude seed powder of Buchholzia coriacea in rats intoxicated with carbon tetrachloride were evaluated for 56 days. A total of male albino rats (150–200 g) comprising of 12 normal and 132 CCl4-induced toxic rats were divided into 4 major groups: control groups (normal, positive and negative controls) and 3 treatment groups (B. coriacea aqueous extract (BCAE) group, B. coriacea methanolic extract (BCME) group and B. coriacea crude powder (BCCP) group) of 36 albino rats. The major group was split into three sub-groups consisting of three replicates of four rats each. The normal, negative and positive control groups were given 1 ml/kg distilled water, 150 mg/kg of CCl4 and 200 mg/kg of silymarin respectively, while each treatment group was administered 200, 400 and 800 mg/kg respectively. Serum samples were collected from selected rats in each replicate of both treatment and control groups after 7 days of intoxication and at 2 weeks interval for various lipid profile parameters using standard methods. A time-independent significant decrease (p < 0.05) was observed in total cholesterol; LDL-cholesterol, triglycerides, VLDL-cholesterol and significant increase (P < 0.05) in HDL-cholesterol were observed in hepatotoxic rats treated with the BCCP, BCAE and BCME in comparison with the control groups. Conclusively, post treatment with aqueous seed extracts, methanolic seed extracts and crude seed powder of B. coriacea significantly attenuated hyperlipidaemic activities. Therefore, it can be suggested that B. coriacea extracts could have a protective effects against cardiovascular diseases.



https://ift.tt/2KncJrz

Glucocorticoids in multiple myeloma: past, present, and future

Abstract

Glucocorticoids are a backbone of treatment for multiple myeloma in both the upfront and relapsed/refractory setting. While glucocorticoids have single agent activity in multiple myeloma, in the modern era, they are paired with novel agents to induce high clinical response rates. On the other hand, toxicities of steroid therapy limit high dose delivery and impact patient quality of life. We provide a history of steroid use in multiple myeloma with the aim to understand how steroids have emerged and persisted in the treatment of multiple myeloma. We review mechanisms of glucocorticoid sensitivity and resistance and highlight potential future directions to evaluate steroid responsiveness. Further research in this area will aid in optimizing steroid utilization and help determine when glucocorticoid therapy may no longer benefit patients.



https://ift.tt/2vcNtj1

Serial mutational tracking in surgically resected locally advanced colorectal cancer with neoadjuvant chemotherapy



https://ift.tt/2OC8QT8

Phase III study of cisplatin with or without S-1 in patients with stage IVB, recurrent, or persistent cervical cancer



https://ift.tt/2AAVJPj

Body balance function of cochlear implant patients with and without sound conditions

A cochlear implant (CI) is a standard treatment for profound sensorineural hearing loss patients where hearing aids are no longer sufficient. A CI is generally comprised of a speech processor, a receiver-stimulator, and an electrode array. The receiver-stimulator is surgically implanted subcutaneously behind the ear, while the electrode array is inserted into the cochlea. The sound is sensed and processed in the speech processor. The processed sound signal is transcutaneously transmitted to the receiver-stimulator which stimulates the intracochlear electrode according to the transmitted sound signal.

https://ift.tt/2MeZTxr

Decreasing subthalamic deep brain stimulation frequency reverses cognitive interference during gait initiation in Parkinson’s disease

Parkinson's disease (PD) is a neurodegenerative disorder due to a loss of nigrostriatal dopaminergic neurons. From a clinical point of view, PD patients present both motor and cognitive deficits. The classical motor triad consists of akinesia, tremor and rigidity. With time, about 50-70% of patients will develop gait and balance disorders and show freezing of gait (FOG) which is characterised by brief episodes of inability to step and lift their feet from the ground or by extremely short steps (Bloem et al., 2004, Nutt et al., 2011).

https://ift.tt/2va4ZV4

A Phase I Study of Nilotinib plus Radiation in High-Risk Chordoma

In this phase I study we treated 23 high-risk chordoma patients with nilotinib plus radiation therapy. We determined the maximum tolerated dose was 200 mg per day when combined with radiation. The median progression free survival was 58.15 months (95% CI: 39.10-inf) and 2-year overall survival rate was 95%. Nilotinib plus radiotherapy is safe in this population. Further study will be required to determine if this is superior than radiation with or without surgery alone.

https://ift.tt/2Mea6dD

Short Hypofractionated Radiotherapy in Palliation of Pediatric Malignancies: Outcomes and Toxicities

This study analyzed outcomes in 62 pediatric patients who were treated with a total of 104 courses of short hypofractionated radiotherapy to the sites of recurrent or metastatic disease. Hypofractionation to a median cumulative biologically effective dose (BED10) of 43 Gy produced robust short-term local control and resulted in favorable treatment response and toxicities. Nevertheless, survival outcomes remained dismal. Large-scale prospective studies are required to identify optimal dose schemes for palliation of incurable childhood tumors.

https://ift.tt/2LWtBdU

Foundation Ambulance welcomes Scott Frazier as production manager

Foundation Ambulance, the industry's newest expert in high-quality emergency vehicle remounting and Type II transits, announced today that EMS veteran Scott Frazier will be joining our team as Production Manager. Frazier brings his 30 years of experience in the field to Foundation, whose goal is to use its cutting-edge remounting facility to build better ambulances at a tremendous value. He...

https://ift.tt/2LZq9Ps

Case report: persistently seronegative neuroborreliosis in an immunocompromised patient

Infection with Borrelia burgdorferi sensu lato complex (B. b. sl) spirochetes can cause Lyme borreliosis, manifesting as localized infection (e.g. erythema migrans) or disseminated disease (e.g. Lyme neuroborreli...

https://ift.tt/2LOV4yP

A randomized, controlled study to investigate the efficacy and safety of a topical gentamicin-collagen sponge in combination with systemic antibiotic therapy in diabetic patients with a moderate or severe foot ulcer infection

An adjunctive topical therapy with gentamicin-sponges to systemic antibiotic therapy might improve the healing of infected diabetic foot ulcers (DFUI).

https://ift.tt/2vuYdZz

Spatial, temporal, and spatiotemporal analysis of mumps in Guangxi Province, China, 2005–2016

The resurgence of mumps around the world occurs frequently in recent years. As the country with the largest number of cases in the world, the status of mumps epidemics in China is not yet clear. This study, ta...

https://ift.tt/2LMqW7a

Fatal Fournier’s gangrene caused by Clostridium ramosum in a patient with central diabetes insipidus and insulin-dependent diabetes mellitus: a case report

Clostridium ramosum is a generally non-pathogenic enteric anaerobe, and Fournier's gangrene is a rare necrotizing soft tissue infection with male predisposition affecting the perineum and the genital area. We rep...

https://ift.tt/2vuPira

Comparison of EEG measurement of upper limb movement in motor imagery training system

One of the most promising applications for electroencephalogram (EEG)-based brain computer interface is for stroke rehabilitation. Implemented as a standalone motor imagery (MI) training system or as part of a...

https://ift.tt/2vu1iZX

The First National Institutes of Health Institutional Training Program in Emergency Care Research: Productivity and Outcomes

We assess the productivity, outcomes, and experiences of participants in the National Institutes of Health/National Heart, Lung, and Blood Institute–funded K12 institutional research training programs in emergency care research.

https://ift.tt/2vsS1Bm

Performance of the CURB-65 Score in Predicting Critical Care Interventions in Patients Admitted With Community-Acquired Pneumonia

Confusion, uremia, elevated respiratory rate, hypotension, and aged 65 years or older (CURB-65) is a clinical prediction rule intended to stratify patients with pneumonia by expected mortality. We assess the predictive performance of CURB-65 for the proximal endpoint of receipt of critical care intervention in emergency department (ED) patients admitted with community-acquired pneumonia.

https://ift.tt/2LQAu1b

Assessing Positive Child Health among Individuals Born Extremely Preterm

To assess the development of a Positive Child Health Index (PCHI) based on 11 adverse outcomes and evaluate the association of PCHI with quality of life (QoL) scores in a preterm cohort.

https://ift.tt/2vdH07I

Phosphopeptide Enrichment Coupled with Label-free Quantitative Mass Spectrometry to Investigate the Phosphoproteome in Prostate Cancer

57996fig1.jpg

This protocol describes a procedure to extract and enrich phosphopeptides from prostate cancer cell lines or tissues for an analysis of the phosphoproteome via mass spectrometry-based proteomics.

https://ift.tt/2n513kj

An Automated T-maze Based Apparatus and Protocol for Analyzing Delay- and Effort-based Decision Making in Free Moving Rodents

57895fig1.jpg

This article introduces an automated T-maze apparatus that we invented, and a protocol based on this apparatus for analyzing delay-based decision making and effort-based decision making in free moving rodents.

https://ift.tt/2O5Mkki

Expression and Purification of Mammalian Bestrophin Ion Channels

The purification of ion channels is often challenging, but once achieved, it can potentially allow in vitro investigations of the functions and structures of the channels. Here, we describe the stepwise procedures for the expression and purification of mammalian bestrophin proteins, a family of Ca2+-activated Cl- channels.

https://ift.tt/2AC4OHm

Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions

Here we describe a co-immunoprecipitation protocol to study protein-protein interactions between endogenous nuclear proteins under hypoxic conditions. This method is suitable for demonstration of the interactions between transcription factors and transcriptional co-regulators at hypoxia.

https://ift.tt/2OF70kz

LC3-II may mediate ATR-induced mitophagy in dopaminergic neurons through SQSTM1/p62 pathway

Abstract
Atrazine (2-chloro-4-ethylamino-6-isopropylamine-1,3,5-triazine; ATR) has been demonstrated to regulate autophagy- and apoptosis-related proteins in doparminergic neuronal damage. In our study, we investigated the role of LC3-II in ATR-induced degeneration of dopaminergic neurons. In vivo dopaminergic neuron degeneration model was set up with ATR treatment and confirmed by the behavioral responses and pathological analysis. Dopaminergic neuron cells were transfected with LC3-II siRNA and treated with ATR to observe cell survival and reactive oxygen species release. The process of mitochondrial autophagy and the neurotoxic effects of mitochondrial autophagy were detected by immunofluorescence assay, immunohistochemical analysis, real-time PCR, and western blot analysis. Results showed that after ATR treatment, the grip strength of Wistar rats was significantly decreased, and behavioral signs of anxiety were clearly observed. The mRNA and protein levels of tyrosine hydroxylase, LC3-II, PINK1, and Parkin were significantly decreased in ATR-induced rat dopaminergic neurons and PC-12 cells, while the mRNA expression and protein levels of SQSTM1/p62 and Parl were increased. Exposure to ATR also led to accumulation of autophagic lysosomes and autophagic bodies along with significantly decreased levels of dopaminergic neurons and alterations in mitochondrial homeostasis, which was reversed by LC3-II siRNA. Our results suggest that ATR affects the mitochondria-mediated dopaminergic neuronal death, which may be mediated by LC3-II and other autophagy markers in vivo and in vitro through SQSTM1/p62 signaling pathway.

https://ift.tt/2Mesmnd

Experimental Study of the Relationship Between Particle Size and Methane Sorption Capacity in Shale

We use an isothermal adsorption apparatus, the gravimetric sorption analyzer, to test the adsorption capacity of different particle sizes of shale, in order to find out the relationship between particle size and the adsorption capacity of shale.

https://ift.tt/2OEWXMn

Adeno-Associated Virus-Mediated Delivery of CRISPR for Cardiac Gene Editing in Mice

Here we provide a detailed protocol to carry out in vivo cardiac gene editing in mice using recombinant Adeno-Associated Virus(rAAV)-mediated delivery of CRISPR. This protocol offers a promising therapeutic strategy to treat dystrophic cardiomyopathy in Duchenne muscular dystrophy and can be used to generate cardiac-specific knockout in postnatal mice.

https://ift.tt/2O5QkRT

New Short-Term Health Plans Have Large Coverage Gaps

THURSDAY, Aug. 2, 2018 -- There are large coverage gaps in short-term health plans that were approved Wednesday by the Trump administration, and are described by critics as "junk insurance." The plans are meant to be a low-cost alternative to...

https://ift.tt/2AASR4L

TGFB1 Mutation Ups Radiation-Induced Breast Fibrosis Risk

THURSDAY, Aug. 2, 2018 -- The C-509T allele in the promoter region of transforming growth factor β (TGFB1) is associated with radiation-induced breast fibrosis risk among patients with early-stage breast cancer, according to study published online...

https://ift.tt/2OCCJTn

PET Imaging Can Measure Synaptic Loss From Alzheimer's

THURSDAY, Aug. 2, 2018 -- Positron emission tomographic (PET) imaging can directly measure synaptic loss with Alzheimer's disease, according to a small study published online July 16 in JAMA Neurology. Ming-Kai Chen, M.D., Ph.D., from the Yale...

https://ift.tt/2Aw3plE

AHA Introduces Heart Failure Certification Program

THURSDAY, Aug. 2, 2018 -- A hospital certification program offered by the American Heart Association (AHA) and The Joint Commission will be made available to hospitals seeking to implement exceptional efforts to foster better quality of care and...

https://ift.tt/2Aw3l5o

How Doctors Receive Feedback Is Key for Antimicrobial Programs

THURSDAY, Aug. 2, 2018 -- Anticipation of how providers will receive feedback is important for antimicrobial stewardship programs to consider in informing educational messaging, according to a study published online June 7 in Infection Control &...

https://ift.tt/2n8HaIR

Single Threshold May Not Be Feasible for Gestational Diabetes

THURSDAY, Aug. 2, 2018 -- Uniform application of gestational diabetes mellitus diagnostic thresholds may not be appropriate in populations across the world, according to a study published in the July issue of Diabetes Care. H. David McIntyre, M.D.,...

https://ift.tt/2AAFKRf

E-Cigarettes Don't Seem to Aid Smoking Cessation Efforts

THURSDAY, Aug. 2, 2018 -- Electronic cigarette (e-cigarette) use is most common among current smokers, according to a study published online July 20 in JAMA Network Open. Linnea Hedman, Ph.D., from Umeå University in Sweden, and colleagues used...

https://ift.tt/2n6dRXJ

AMA Calls for Alleviating Racial Housing Segregation

THURSDAY, Aug. 2, 2018 -- The American Medical Association (AMA) opposes policies that enable racial housing segregation, according to an article published in the association's AMA Wire. As part of its efforts, the AMA will not only oppose policies...

https://ift.tt/2AykhrX

Obesity Worsens Skilled Nursing Facility Outcomes After Hip Fx

THURSDAY, Aug. 2, 2018 -- Obesity is associated with worse outcomes in skilled nursing facility (SNF) residents receiving post-acute care for hip fracture, according to a study published in the June issue of the Journal of the American Geriatrics...

https://ift.tt/2n4mKkj

Respiratory changes of the inferior vena cava diameter predict fluid responsiveness in spontaneously breathing patients with cardiac arrhythmias

Whether the respiratory changes of the inferior vena cava diameter during a deep standardized inspiration can reliably predict fluid responsiveness in spontaneously breathing patients with cardiac arrhythmia i...

https://ift.tt/2vbwY79

What does the 2018 EMS Trend Report tell us about the future of the industry?

Our co-hosts are joined by EMS1 Editor-in-Chief Greg Friese discuss the most EMS trend report and what it means for industry personnel

https://ift.tt/2OCFpAp

Multiplexed assays of variant effects contribute to a growing genotype–phenotype atlas

Abstract

Given the constantly improving cost and speed of genome sequencing, it is reasonable to expect that personal genomes will soon be known for many millions of humans. This stands in stark contrast with our limited ability to interpret the sequence variants which we find. Although it is, perhaps, easiest to interpret variants in coding regions, knowledge of functional impact is unknown for the vast majority of missense variants. While many computational approaches can predict the impact of coding variants, they are given a little weight in the current guidelines for interpreting clinical variants. Laboratory assays produce comparatively more trustworthy results, but until recently did not scale to the space of all possible mutations. The development of deep mutational scanning and other multiplexed assays of variant effect has now brought feasibility of this endeavour within view. Here, we review progress in this field over the last decade, break down the different approaches into their components, and compare methodological differences.



https://ift.tt/2ODhmkU

Confocal Microscopy Reveals Cell Surface Receptor Aggregation Through Image Correlation Spectroscopy

57164eq1v2.jpg

Antibodies that bind to target receptors on the cell surface can confer conformation and clustering alterations. These dynamic changes have implications for characterizing drug development in target cells. This protocol utilizes confocal microscopy and image correlation spectroscopy through ImageJ/FIJI to quantify the extent of receptor clustering on the cell surface.

https://ift.tt/2Mhv6jq

New Immunotherapy Option Approved for Cervical Cancer, Rare Lymphoma

FDA has approved pembrolizumab (Keytruda) for some women with advanced cervical cancer and some patients with primary mediastinal large B-cell lymphoma (PMBCL), a rare type of non-Hodgkin lymphoma.



https://ift.tt/2OEOxV5

Reply: Optimal use of cholinergic drugs in Alzheimer’s disease

Sir,

https://ift.tt/2AvRCUq

Optimal use of cholinergic drugs in Alzheimer’s disease

Sir

https://ift.tt/2n4zKGL

GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia

Abstract
Autosomal recessive cerebellar ataxias are a group of rare disorders that share progressive degeneration of the cerebellum and associated tracts as the main hallmark. Here, we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations in GDAP2, a gene previously not implicated in disease. Both patients had onset of ataxia in the fourth decade. Other features included progressive spasticity and dementia. Neuropathological examination showed degenerative changes in the cerebellum, olive inferior, thalamus, substantia nigra, and pyramidal tracts, as well as tau pathology in the hippocampus and amygdala. To provide further evidence for a causative role of GDAP2 mutations in autosomal recessive cerebellar ataxia pathophysiology, its orthologous gene was investigated in the fruit fly Drosophila melanogaster. Ubiquitous knockdown of Drosophila Gdap2 resulted in shortened lifespan and motor behaviour anomalies such as righting defects, reduced and uncoordinated walking behaviour, and compromised flight. Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation. Thus, Gdap2 knockdown in Drosophila and GDAP2 loss-of-function mutations in humans lead to locomotor phenotypes, which may be mediated by altered responses to cellular stress.

https://ift.tt/2AAoaMZ

The classification of Charcot-Marie-Tooth diseases, a never-ending story: CMT4?



https://ift.tt/2OAsvmi

Reply: The classification of Charcot-Marie-Tooth diseases, a never-ending story: CMT4?



https://ift.tt/2AABGAk

High ligation of the inferior mesenteric artery during sigmoid colon and rectal cancer surgery increases the risk of anastomotic leakage: a meta-analysis

Abstract

Background

The ideal level of ligation of the inferior mesenteric artery (IMA) during curative resection of sigmoid colon and rectal cancer is still controversial. The aim of this meta-analysis was to examine the impact of high ligation and low ligation of the IMA on anastomotic leakage, overall morbidity, postoperative mortality, and oncological outcomes in patients undergoing surgery for sigmoid colon and rectal cancer.

Methods

PubMed, EMBASE, Web of Science, and BioMed Central databases were searched to identify relevant articles published from May 1953 to March 2018. A total of 18 articles (14 non-randomized studies and 4 randomized clinical trials) were identified. Review Manager 5.3 software was used for analysis of data. The pooled odds ratio (OR) and weighted mean difference (WMD), with 95% CI, were calculated using either the fixed effects model or random effects model.

Results

Of the 5917 patients included in this meta-analysis, 3652 patients underwent low ligation of the IMA and 2265 patients underwent high ligation of the IMA. Anastomotic leakage rate was 9.8% in high ligation patients vs. 7.0% in low ligation patients; the risk of anastomotic leakage was significantly higher in high ligation patients (OR = 1.33; 95% CI 1.10–1.62; P = 0.004). What is more, overall morbidity was also significantly higher in high ligation patients (OR = 1.39; 95% CI, 1.05–1.68; P = 0.05). Postoperative mortality, number of harvested lymph nodes, overall recurrence rate, and 5-year survival rate did not differ significantly between the two groups.

Conclusion

Low ligation of the IMA during curative resection of sigmoid colon and rectal cancer appears to be associated with lower risk of anastomotic leakage and overall morbidity. However, there was no significant advantage of low ligation over high ligation of IMA in terms of postoperative mortality, the number of harvested lymph nodes, overall recurrence rate, or 5-year survival rate.



https://ift.tt/2LQ90Zy

Impact of adjuvant chemotherapy on patients with ypT0–2 ypN0 rectal cancer after neoadjuvant chemoradiation: a cohort study from a tertiary referral hospital

Abstract

Background

To investigate the importance of adjuvant chemotherapy in locally advanced rectal cancer (≥ cT3 or N+) staged ypT0–2 ypN0 on final histological work-up after neoadjuvant chemoradiation and radical resection.

Methods

The clinical course of patients with rectal cancer and ypT0–2 ypN0 stages after neoadjuvant chemoradiation and radical resection was analyzed from 1999 to 2012. Patients were divided into two groups depending on whether adjuvant chemotherapy was administered or not. Overall survival, distant metastases, and local recurrence were compared between both groups.

Results

Fifty-four patients with adjuvant (ACT) and 50 patients without adjuvant chemotherapy (NACT) after neoadjuvant chemoradiation followed by radical resection for rectal cancer were included in the analysis. Mean follow-up was 68 ± 33.7 months. One patient without adjuvant chemotherapy and none in the ACT group developed a local recurrence. Five patients in the NACT group and three patients in the ACT group had distant recurrences. Median disease-free survival for all patients was 65.5 ± 34.5 months. Multivariate analysis showed adjuvant chemotherapy to be the most relevant factor for disease-free and overall survival. Patients staged ypT2 ypN0 showed a significantly better disease-free survival after application of adjuvant chemotherapy. Disease-free survival in ypT0–1 ypN0 patients showed no correlation to the administration of adjuvant chemotherapy.

Conclusion

Administration of adjuvant chemotherapy after neoadjuvant chemoradiation and radical resection in rectal cancer improved disease-free and overall survival of patients with ypT0–2 ypN0 tumor stages in our study. In particular, ypT2 ypN0 patients seem to profit from adjuvant treatment.



https://ift.tt/2vwVVt1

FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity

(Cell Stem Cell 18, 104–117; January 7, 2016)

https://ift.tt/2LTVCTg

Time Matters: Gene Editing at the Mouse 2-Cell Embryo Stage Boosts Knockin Efficiency

Although endonuclease-mediated genome editing techniques offer significant improvement over traditional methods, they are still ineffective for introduction of large DNA sequences. Recently in Nature Biotechnology, Gu et al. (2018) developed a CRISPR-Cas strategy termed 2C-HR-CRISPR that generates fluorescent reporter tagging of genes with up to 95% knockin efficiency in mouse embryos.

https://ift.tt/2KlZfMJ

AML: Predicting the Unpredictable

Acute myeloid leukemia (AML) has been considered an unpredictable and unpreventable disease. Recently in Nature, Abelson et al. (2018) presented two models of AML risk prediction, one using the detection of high-risk age-related clonal hematopoiesis and the other using dynamic clinical attributes available from routine blood work.

https://ift.tt/2LUoivq

Off-the-Shelf CAR-NK Cells for Cancer Immunotherapy

CAR-T therapy has shown great success treating blood cancers, but drawbacks include high manufacturing costs and potentially fatal toxicities such as cytokine release syndrome. In this issue of Cell Stem Cell, Li et al. (2018) describe how engineered iPSC-derived NK cells armed with NK-tailored CAR constructs (CAR-iPSC-NK cells) provide better options for anti-cancer immunotherapy.

https://ift.tt/2KlZ4Rz

Mentoring the Next Generation: Connie Eaves

Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Connie Eaves about her views.

https://ift.tt/2n59iN2

Gli1+ Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target

(Cell Stem Cell 20, 785–800; June 1, 2017)

https://ift.tt/2O6MuYR

Pioneering of Enhancer Landscapes during Pluripotent State Transitions

The transitions between different pluripotency states are regulated by large changes in enhancer landscapes. Two publications in this issue of Cell Stem Cell suggest that the pioneering and subsequent activation of silent enhancers by transcription factors (i.e., ESRRB and GRHL2) is a crucial event during these transitions (Adachi et al., 2018; Chen et al., 2018).

https://ift.tt/2n4LV6l

Fat and Bone: PGC-1α Regulates Mesenchymal Cell Fate during Aging and Osteoporosis

PGC-1α is a transcriptional co-activator associated with PPARγ that regulates thermogenic gene expression in brown fat. In this issue, Yu et al. (2018) show that PGC-1α regulates marrow mesenchymal stromal cell lineage allocation in vivo, inhibiting marrow adipogenesis and associated bone loss in the aging skeleton and following ovariectomy-induced osteoporosis.

https://ift.tt/2O1yAXU

GFAP Mutations in Astrocytes Impair Oligodendrocyte Progenitor Proliferation and Myelination in an hiPSC Model of Alexander Disease

Shi and colleagues used Alexander disease (AxD) patient iPSC-derived astrocytes to recapitulate AxD patient phenotypes that could not be achieved in animal models and uncover molecular mechanisms underlying myelination defect in the disease. They found that disease astrocytes secret molecules to inhibit oligodendrocyte progenitor cell function and impair myelination.

https://ift.tt/2LTUEq6

Endothelial Regeneration of Large Vessels Is a Biphasic Process Driven by Local Cells with Distinct Proliferative Capacities

Quiescent endothelial cells are able to mount a robust mitotic response even in the presence of pulsatile and high-velocity blood flow. McDonald et al. showed that regeneration of aortic inner lining involves a subset of cells with hidden proliferative capacity that undergo rapid and significant transcriptional changes.

https://ift.tt/2KlLvlh

Resident Endothelial Progenitors Make Themselves at Home

Vascular endothelial cells adapt to their microenvironment and physiological demands to perform many essential functions. Recent studies (McDonald et al., 2018; Wakabayashi et al., 2018) suggest that quiescent endothelial stem/progenitor cells reside within blood vessels and are activated in response to injury, suggesting they can be harnessed for therapeutic applications.

https://ift.tt/2n6LZmd

Intestinal Crypts Assume the Fetal Position in Response to Injury

Distinct stem/progenitor cells generate intestinal epithelium during fetal and postnatal life. In a recent issue of Nature, Nusse and Savage et al. use helminth infection to show that Lgr5+ intestinal stem cells are replaced by fetal-like progenitors following injury, suggesting that some fetal developmental pathways are repurposed during injury-induced tissue regeneration.

https://ift.tt/2O84GBx

A fragment of SPARC reflecting increased collagen affinity shows pathological relevance in lung cancer – implications of a new collagen chaperone function of SPARC

.


https://ift.tt/2vrZsc0

Great efficacy of bevacizumab plus erlotinib for leptomeningeal metastases from non-small cell lung cancer with initially positive EGFR mutation: a case report

.


https://ift.tt/2vCqBcv

Pancreatic and bile duct cancer circulating tumor cells (CTC) form immune-resistant multi-cell type clusters in the portal venous circulation

.


https://ift.tt/2LIKxFc

Antidiabetic drugs influence molecular mechanisms in prostate cancer

.


https://ift.tt/2vrZzEs

The role of JNK phosphorylation as a molecular target to enhance adenovirus replication, oncolysis and cancer therapeutic efficacy

.


https://ift.tt/2LN6TWk

Mutational landscape and clonal diversity of pulmonary adenoid cystic carcinoma

.


https://ift.tt/2vrZv7G

Clinical and molecular predictors of long-term response in HER2 positive metastatic breast cancer patients

.


https://ift.tt/2LIKrgO

Autophagy as a mechanism of Apo2L/TRAIL resistance

.


https://ift.tt/2LIKo4C

Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer

.


https://ift.tt/2vCqmhB

iTRAQ-based quantitative proteomic analysis of differentially expressed proteins in chemoresistant nasopharyngeal carcinoma

.


https://ift.tt/2LIKl8W

Using Quick Response Codes to Increase Students' Participation in Case-Based Learning Courses

The purpose of this study was to use Quick Response codes to increase engagement in a case-based learning course. A quasi-experiment was conducted, and 103 students enrolled in a pharmacology course participated. The students were divided into high-, medium-, and low-scoring groups, based on their previous semester grades in the pharmacology course. A Chinese-version questionnaire of the Nursing Students' Attitude Toward Quick Response Codes in Case-Based Learning Scale was used. The major findings were as follows: (1) Most participants held positive attitudes toward the use of Quick Response codes in case-based learning courses. It was suggested that participants perceived the use of Quick Response codes to be easy and useful in learning activities. They also demonstrated positive attitudes toward the Quick Response codes and expressed their intention to use this application in the future. (2) After applying Quick Response codes in classroom teaching, students performed better in asking questions and discussions than they did before. The performance of the medium-level students improved significantly. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Corresponding author: Kai-Yin Lin, PhD, 193, Sec 1, Sanmin Rd, Shi, Taichung City, Taiwan, Republic of China (kai.yin.lin2011@gmail.com). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2Kn3rfo

An Electronic Handover System to Improve Information Transfer for Surgical Patients

Proper clinical transfers of patient care (known as handovers) are important to patient safety. The aim of this study was to investigate the efficacy and satisfaction of an electronic system for clinical transfers of patients with complex surgical procedures. The design was a single-center observational study auditing the handover process. The electronic handover system combined with an electronic health record system was developed to help verbal handover. The system has a checklist to guide the structured handover process and provided information from the health record system. With the system, the elapsed time for surgical handover decreased from 10.5 to 5.4 minutes. The questionnaire analysis showed that clinician satisfaction with surgical handover increased from 69.4% to 79.3%, and the perception of communication completeness increased from 67.2% to 81.6%. The electronic handover system improved communication for the transfer of care for surgical patients. This study was exempted from review by the Institutional Research Ethics Committee of MacKay Memorial Hospital. The data archive is held in the Nursing Department of MacKay Memorial Hospital. The design of the questionnaire used in the study is available directly upon request from the corresponding author. The study was supported by MacKay Memorial Hospital Team-Resource-Management project. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Corresponding author: Kuang-Hua Cheng, MD, MSc, Department of Critical Care Medicine, MacKay Memorial Hospital, No. 92, Sec. 2, Zhongshan N Rd, Taipei City 10449, Taiwan (jeff01@mmh.org.tw). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2n3fyoF

Observation of the cytoarchitecture of the human esophageal mucosa with special attention to the lamina muscularis mucosae and the distribution of lymphatic vessels

Abstract

The cytoarchitecture of the esophageal mucosa was examined by using light microscopy, transmission electron microscopy, and scanning electron microscopy. The cytoarchitecture of the muscularis mucosae varied greatly among the cervical, thoracic, and abdominal esophagus, especially in the cervical esophagus, the muscularis mucosae suffered a loss and the distribution of lymphatic vessels also varied according to the site. It was suggested that these morphological differences would have a strong influence on the infiltration of esophageal cancer and the mode of lymph node metastasis.



https://ift.tt/2AAUBuM

Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors

Abstract

Background

Reprogramming of cancers into normal-like tissues is an innovative strategy for cancer treatment. Recent reports demonstrate that defined factors can reprogram cancer cells into pluripotent stem cells. Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor in humans. Despite multimodal therapy, the outcome for patients with GBM is still poor. Therefore, developing novel therapeutic strategy is a critical requirement.

Methods

We have developed a novel reprogramming method that uses a conceptually unique strategy for GBM treatment. We screened a kinase inhibitor library to find which candidate inhibitors under reprogramming condition can reprogram GBM cells into neurons. The induced neurons are identified whether functional and loss of tumorigenicity.

Results

We have found that mTOR and ROCK kinase inhibitors are sufficient to reprogram GBM cells into neural-like cells and "normal" neurons. The induced neurons expressed neuron-specific proteins, generated action potentials and neurotransmitter receptor-mediated currents. Genome-wide transcriptional analysis showed that the induced neurons had a profile different from GBM cells and were similar to that of control neurons induced by established methods. In vitro and in vivo tumorigenesis assays showed that induced neurons lost their proliferation ability and tumorigenicity. Moreover, reprogramming treatment with ROCK-mTOR inhibitors prevented GBM local recurrence in mice.

Conclusion

This study indicates that ROCK and mTOR inhibitors-based reprogramming treatment prevents GBM local recurrence. Currently ROCK-mTOR inhibitors are used as anti-tumor drugs in patients, so this reprogramming strategy has significant potential to move rapidly toward clinical trials.



https://ift.tt/2McADYA

Treatment of Advanced Merkel Cell Carcinoma: Current Therapeutic Options and Novel Immunotherapy Approaches

Abstract

Advanced Merkel cell carcinoma (MCC) is a very aggressive, rare neuroendocrine tumor of the skin with a high frequency of locoregional recurrence and metastasis, and a high mortality rate. Surgical resection, sentinel lymph node biopsy, and radiotherapy represent the gold standard of treatment in patients with localized disease, while chemotherapy has a significant role in the treatment of advanced disease. However, no definitive evidence on the survival impact of radiotherapy in the advanced stages has been provided to date, and response to chemotherapy remains brief in the majority of cases, indicating an urgent need for alternative approaches. Biological and genome sequencing studies have implicated multiple molecular pathways in MCC, thus leading to the development of new agents that target angiogenic factors, anti-apoptosis molecules, poly-ADP ribose polymerase, intracellular signal proteins such as the PI3K/AKT/mTOR pathway, and peptide receptors such as somatostatin receptors. More recently, immunotherapy agents such as avelumab, pembrolizumab, and nivolumab, which act by blocking the programmed cell-death (PD)-1/PD-L1 immune checkpoint, have shown promising results, especially in the advanced setting, and should now be considered standard of care for metastatic MCC. Current research is focusing on developing new immunotherapeutic strategies, identifying predictive biomarker to aid in the selection of patients responsive to immunotherapy, and defining combination approaches to increase efficacy in refractory patients.



https://ift.tt/2KlVNC9

Evidence that cell surface localization of serine protease activity facilitates cleavage of the protease activated receptor CDCP1

Authors: He, Yaowu / Reid, Janet C. / He, Hui / Harrington, Brittney S. / Finlayson, Brittney / Khan, Tashbib / Hooper, John D.


https://ift.tt/2LGR5DA

MAC30 knockdown involved in the activation of the Hippo signaling pathway in breast cancer cells

Authors: Song, Guo-Qing / Zhao, Yi


https://ift.tt/2zXGwaJ

Activation and activity of glycosylated KLKs 3, 4 and 11

Authors: Guo, Shihui / Briza, Peter / Magdolen, Viktor / Brandstetter, Hans / Goettig, Peter


https://ift.tt/2zZZSvN

Total yield of reactive species originating from an atmospheric pressure plasma jet in real time

Authors: Adhikari, Ek R. / Samara, Vladimir / Ptasinska, Sylwia


https://ift.tt/2LC7YvO

Involvement of mitophagy in cisplatin-induced cell death regulation

Authors: Abdrakhmanov, Alibek / Kulikov, Andrey V. / Luchkina, Ekaterina A. / Zhivotovsky, Boris / Gogvadze, Vladimir


https://ift.tt/2uG5h5Z

BNIP3 contributes to the glutamine-driven aggressive behavior of melanoma cells

Authors: Vara-Perez, Monica / Maes, Hannelore / Van Dingenen, Sarah / Agostinis, Patrizia


https://ift.tt/2uMWOwY

Host cell-surface proteins as substrates of gingipains, the main proteases of Porphyromonas gingivalis

Authors: Hočevar, Katarina / Potempa, Jan / Turk, Boris


https://ift.tt/2LmAc0V

Frontmatter



https://ift.tt/2NYWaFx

Selective BH3-mimetics targeting BCL-2, BCL-XL or MCL-1 induce severe mitochondrial perturbations

Authors: Henz, Kristina / Al-Zebeeby, Aoula / Basoglu, Marion / Fulda, Simone / Cohen, Gerald M. / Varadarajan, Shankar / Vogler, Meike


https://ift.tt/2KIyFm6

Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer

Authors: Zhang, Ling-li / Zhang, Lian-feng / Shi, Yun-bo


https://ift.tt/2N51B4y

Sphingolipids in early viral replication and innate immune activation

Authors: Bezgovsek, Judith / Gulbins, Erich / Friedrich, Sarah-Kim / Lang, Karl S. / Duhan, Vikas


https://ift.tt/2M2CVwV

The Latitudinal Distribution of Morphological Diversity among Holocene Angiosperm Pollen Grains from eastern North America and the Neotropics

Abstract
Current knowledge about the biogeographic patterns of biodiversity is based mostly on taxonomic diversity, which is typically measured as the number of species or higher taxa. In this paper I analyse 26 previously published Holocene lake core pollen records in order to assess how the morphological diversity of angiosperm pollen grains varies with latitude on a transect that includes eastern North America and the Neotropics. This represents a step towards understanding the evolution of plant morphology in a biogeographical context. I employ a system of eight discrete characters to describe first-order features of angiosperm pollen morphology and use algorithms written in the Python programming language to assess their morphological diversity. There is no statistically significant relationship between taxonomic diversity and morphological diversity in the samples of Holocene angiosperm pollen investigated here. The number of pollen morphotypes in the sediment samples investigated here increases from high latitudes to the tropics, but the highest morphological diversity occurs at high latitudes, and the lowest morphological diversity occurs at mid-latitudes around 40–50°N. At the biome level, there are peaks in morphological diversity at low and high latitudes with a trough in mid latitudes. There is evidence of high levels of pollen morphotype endemism in the tropical biome, and further work on how the volume of morphological space varies with latitude is needed in order to understand whether taxa in species-rich tropical ecosystems are more densely packed into morphological space.

https://ift.tt/2OCAbEQ

A phase II trial to determine the cosmetic outcomes and toxicity of 27 Gy in five-fraction accelerated partial breast irradiation: the ACCEL trial

Abstract

Background

Accelerated partial breast irradiation (APBI) has been investigated in randomized controlled trials with the goals of reducing side effects and treatment burden. There is accumulating evidence that local control for multi-fraction APBI is not inferior to whole breast irradiation (WBI) but an external beam prescription that can be safely delivered in five consecutive days has not been reported. The aim of this study is to investigate an APBI prescription delivered once per day in 1 week.

Methods

This is a single-arm, phase II, prospective cohort study. Two hundred seventy-four eligible women with newly diagnosed, early-stage, invasive, or in situ ductal carcinoma treated with breast-conserving surgery and sentinel lymph node biopsy or axillary dissection who are candidates for whole breast radiation without a boost will be recruited. Twenty-seven Gray (Gy) in five fractions will be delivered once daily over five consecutive working days to the target volume. The primary outcome is the rate of global cosmetic deterioration from an excellent or good score at baseline (prior to radiation therapy) to a fair or poor score at 2 years after treatment. The study is powered to demonstrate non-inferiority compared to the use of WBI arm in the RAPID trial.

Discussion

The ACCEL trial aims to demonstrate the safe and effective delivery of a five-fraction APBI treatment using IMRT or 3D-conformal radiation. The study is designed to account for an updated α/β ratio for breast tissue and compares cosmesis to the WBI arm of the RAPID trial. The ACCEL trial was registered in February 2016 and began accrual in the subsequent May.

Conclusions

This trial will assess the cosmetic and normal tissue outcomes of external beam APBI delivered in 1 week for early-stage breast cancer.

Trial registration

Registration number: NCT02681107 (clinicaltrials.gov), registered February 2, 2016.



https://ift.tt/2KlNPsJ

Cerebrospinal fluid free kappa light chains and kappa index perform equal to oligoclonal bands in the diagnosis of multiple sclerosis

Authors: Christiansen, Mikael / Gjelstrup, Mikkel Carstensen / Stilund, Morten / Christensen, Tove / Petersen, Thor / Jon Møller, Holger


https://ift.tt/2AjibfH

The utility of saliva testing in the estimation of uremic toxin levels in serum

Authors: Korytowska, Natalia / Sankowski, Bartłomiej / Wyczałkowska-Tomasik, Aleksandra / Pączek, Leszek / Wroczyński, Piotr / Giebułtowicz, Joanna


https://ift.tt/2vbCXYF

A particular case of AML patient with the polymorphism G105G (rs11554137) and the missense mutation R132C in IDH1 gene

Authors: Accetta, Raffaella / Campiotti, Leonardo / Elli, Lorenzo / Casalone, Rosario / Pallotti, Francesco


https://ift.tt/2Oq8nmL

New biomarkers and traditional cardiovascular risk scores: any crystal ball for current effective advice and future exact prediction?

Authors: Vassalle, Cristina


https://ift.tt/2uF9ohN

Clinical Chemistry and Laboratory Medicine continues to shine brightly in the constellation of laboratory medicine

Authors: Plebani, Mario / Lippi, Giuseppe


https://ift.tt/2L98t04

Harmonization in laboratory medicine: Blowin’ in the wind

Authors: Plebani, Mario / Graziani, Maria Stella / Tate, Jillian R.


https://ift.tt/2MXdsl2

Frontmatter



https://ift.tt/2LVOQw5

Role of industry funders in oncology RCTs published in high-impact journals and its association with trial conclusions and time to publication

Abstract
Background
Previous studies have shown that industry funded trials are associated with pro-industry conclusions and publication bias. Less is known about the role of industry funders and their influence on trial conclusions and time to publication.
METHODS
We identified all industry funded RCTs published in six high-impact clinical journals between 2014 and 2016 to estimate the prevalence of the role of industry funders in trial design, data collection, data analyses, data interpretation and manuscript writing. Ordinal logistic regression was used to assess the association between the role of industry funders and trial conclusions, which was classified on a 5-point scale. Cox proportional-hazards were used to examine the effect of role of funder on time to publication.
Results
Of the 255 eligible RCTs, industry funders had a role in trial design in 179 (70.2%) trials, data collection in 160 (62.7%) trials, data analyses in 173 (67.8%) trials, data interpretation in 135 (52.9%) trials and manuscript writing in 168 (65.9%) trials. Trials with any role of industry funders had 3.6 times (95% CI, 2.0-6.6) higher odds of having positive conclusions compared with those without role of industry funders. In trials with any role of industry funders, positive trials were published more rapidly than negative trials (hazard ratio=4.3; 95% CI: 2.7-6.7, P<0.001), while for trials without role of industry funders, there was no association (hazard ratio=1.07; 95% CI: 0.57-1.99, P=0.84)
Conclusion
The involvement of industry funders is common in all stages of clinical trials, and was associated with more positive conclusions and more rapid publication of RCTs with positive results.

https://ift.tt/2M2nHbe

Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase 3, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma

Abstract
Background
Treatment options for soft tissue sarcoma patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase 3 trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma (LPS/LMS) after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we performed a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial.
Patients and Methods
Patients were randomized 2:1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every-3-weeks. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup.
Results
Among 131 (trabectedin=94; dacarbazine=37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median 4 versus 2 cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the trabectedin arm (43% versus 23%, respectively; p=0.04). Elderly patients treated with trabectedin showed significantly improved PFS (4.9 versus 1.5 months, respectively; hazard ratio [HR]=0.40; p=0.0002) but no statistically significant improvement in OS (15.1 versus 8.0 months, respectively; HR = 0.72; p=0.18) or ORR (9% versus 3%, respectively; p=0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population.
Conclusions
This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with soft tissue sarcoma and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients.
Trial registration
www.clinicaltrials.gov, NCT01343277

https://ift.tt/2KldNMW

Linear accelerator-based stereotactic fractionated photon radiotherapy as an eye-conserving treatment for uveal melanoma

Abstract

Background

The purpose of this retrospective analysis is to analyze clinical outcome, visual acuity and enucleation rates after linear accelerator-based stereotactic fractionated photon radiotherapy for primary uveal melanoma.

Methods

Twenty-four patients with primary uveal melanoma treated at the Department of Radiation and Oncology of the University Hospital Heidelberg between 1991 and 2015 were analyzed regarding survival and treatment-related toxicity including eye- and sight-preservation.

Results

Photon radiotherapy (RT) offered good overall local control rates with a local progression-free survival (LPFS) of 82% after 5 years and a median LPFS of 5.5 years at a median follow-up time of 5.2 years. Gender had a significant impact on LPFS yielding a mean LPFS of 8.1 years for women and 8.7 years for men (p = 0.04). Of all local progressions, 80% occurred within the first 5 years after RT. In one case, enucleation as final therapy option was necessary. Enucleation-free survival (EFS) was related to the radiotherapy dose (p < 0.0001). Thus, higher prescribed doses led to a significantly higher enucleation rate. T-stage had no significant impact on EFS, but affected the enucleation rate (p = 0.01). The overall survival (OS) rate was 100% after 2 years and 70% after 5 years with a median OS of 5.75 years. Age (p = 0.046), T stage (p = 0.019), local control rate (p = 0.041) and the time between diagnosis and the first radiation session (p = 0.01) had a significant effect on OS. Applied biologically effective dose (BED) did not significantly influence OS or PFS. A 2-year sight preservation rate of 75% could be achieved. In all patients, irradiation could be applied safely without any interruptions due to side effects. Six significant late toxicities with consequential blindness could be observed, making a secondary enucleation necessary in four patients. An impairment of visual acuity due to chronic optic nerve atrophy was identified in five patients within 2 years after treatment.

Conclusions

Linear accelerator-based stereotactic fractionated photon radiotherapy is an effective method in the treatment of uveal melanoma with excellent local control rates and a 2-year vision retention rate comparable to brachytherapy (BRT) or proton beam radiotherapy, even available in small centers and easy to implement. Interdisciplinary decision making is necessary to guarantee best treatment for every patient.



https://ift.tt/2KgqGYx

Cancers, Vol. 10, Pages 258: Circular RNAs: Characteristics, Function and Clinical Significance in Hepatocellular Carcinoma

Cancers, Vol. 10, Pages 258: Circular RNAs: Characteristics, Function and Clinical Significance in Hepatocellular Carcinoma

Cancers doi: 10.3390/cancers10080258

Authors: Man Wang Fei Yu Peifeng Li

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. HCC patients are commonly diagnosed at an advanced stage, for which highly effective therapies are limited. Moreover, the five-year survival rate of HCC patients remains poor due to high frequency of tumor metastasis and recurrence. These challenges give rise to the emergent need to discover promising biomarkers for HCC diagnosis and identify novel targets for HCC therapy. Circular RNAs (circRNAs), a class of long-overlook non-coding RNA, have been revealed as multi-functional RNAs in recent years. Growing evidence indicates that circRNA expression alterations have a broad impact in biological characteristics of HCC. Most of these circRNAs regulate HCC progression by acting as miRNA sponges, suggesting that circRNAs may function as promising diagnostic biomarkers and ideal therapeutic targets for HCC. In this review, we summarize the current progress in studying the functional role of circRNAs in HCC pathogenesis and present their potential values as diagnostic biomarkers and therapeutic targets. In-depth investigations on the function and mechanism of circRNAs in HCC will enrich our knowledge of HCC pathogenesis and contribute to the development of effective diagnostic biomarkers and therapeutic targets for HCC.



https://ift.tt/2Kk4I6I

The hedgehog pathway and ocular developmental anomalies

Abstract

Mutations in effectors of the hedgehog signaling pathway are responsible for a wide variety of ocular developmental anomalies. These range from massive malformations of the brain and ocular primordia, not always compatible with postnatal life, to subtle but damaging functional effects on specific eye components. This review will concentrate on the effects and effectors of the major vertebrate hedgehog ligand for eye and brain formation, Sonic hedgehog (SHH), in tissues that constitute the eye directly and also in those tissues that exert indirect influence on eye formation. After a brief overview of human eye development, the many roles of the SHH signaling pathway during both early and later morphogenetic processes in the brain and then eye and periocular primordia will be evoked. Some of the unique molecular biology of this pathway in vertebrates, particularly ciliary signal transduction, will also be broached within this developmental cellular context.



https://ift.tt/2AAr7x6

Tear meniscus evaluation after microkeratome laser in situ keratomileusis, femtosecond laser and femtosmile laser techniques using anterior segment optical coherence tomography

88x31.png



https://ift.tt/2vcAs9b

Economic Evaluation of Letrozole for Early Breast Cancer in a Health Resource-Limited Setting

Objective. Long-term aromatase inhibitor (AI) therapy is expected to improve the health outcomes with high health resource consumption in early breast cancer. The aim of the study was to assess the cost-effectiveness of letrozole for postmenopausal women with estrogen receptor positive early breast cancer in a health resource-limited setting. Methods. A Markov model was developed to project the lifetime outcomes based on the clinical course of early breast cancer. The clinical and utility data were derived from reported results. Costs were estimated from the perspective of Chinese health care. The quality-adjusted life-year (QALY) and incremental cost-effective ratio (ICER) were measured. Probabilistic sensitivity and one-way analyses were conducted. Results. Compared to 5 years of tamoxifen therapy, 5 years of AI treatment with letrozole improved the QALYs (10.44 versus 10.84) and increased the lifetime costs (CNY ¥13,613 versus CNY ¥28,797), resulting in an ICER of CNY ¥38,092 /QALY. The ICER of 5 years of letrozole versus 2–3 years of tamoxifen and then letrozole was CNY ¥68,233 /QALY. Sensitivity analyses showed that the age of initiating adjuvant endocrine therapy was the most influential parameter. Conclusions. In health resource-limited settings, adjuvant endocrine therapy with letrozole is a cost-effective strategy compared to tamoxifen in women with early breast cancer.

https://ift.tt/2LSXbAJ

Aging and Thermoregulatory Control: The Clinical Implications of Exercising under Heat Stress in Older Individuals

Climate change is predicted to bring about a greater variability in weather patterns with an increase in extreme weather events such as sustained heat waves. This change may have a direct impact on population health since heat waves can exceed the physiological limit of compensability of vulnerable individuals. Indeed, many clinical reports suggest that individuals over the age of 60 years are consistently the most vulnerable, experiencing significantly greater adverse heat-related health outcomes than any other age cohort during environmental heat exposure. There is now evidence that aging is associated with an attenuated physiological ability to dissipate heat and that the risk of heat-related illness in these individuals is elevated, particularly when performing physical activity in the heat. The purpose of this review is to discuss mechanisms of thermoregulatory control and the factors that may increase the risk of heat-related illness in older individuals. An understanding of the mechanisms responsible for impaired thermoregulation in this population is of particular importance, given the current and projected increase in frequency and intensity of heat waves, as well as the promotion of regular exercise as a means of improving health-related quality of life and morbidity and mortality. As such, the clinical implications of this work in this population will be discussed.

https://ift.tt/2vx9Y1w

Why Asplenic Patients Should Not Take Care of the Neighbour’s Dog? A Fatal Course of Capnocytophaga canimorsus Sepsis

Capnocytophaga canimorsus (CC) belongs to the family Flavobacteriaceae which physiologically occurs in the natural flora of the oral mucosa of dogs and cats. In patients with a compromised immune system, CC can induce a systemic infection with a fulminant course of disease. Infections with CC are rare, and the diagnosis is often complicated and prolonged. We describe a patient with a medical history of prior splenectomy who presented with an acute sepsis and disseminated intravascular coagulation (DIC) and was initially treated on Waterhouse–Friderichsen syndrome (WFS). After the patient had died despite forced treatment in the intermediate care unit, the differential diagnosis of CC was confirmed by culture of blood smears. Later on, a retrospective third-party anamnesis revealed that the patient had contact to his neighbour's dog a few days before disease onset. In conclusion, patients with CC infection can mimic WFS and therefore must be included in the differential diagnosis, especially in patients with a corresponding medical history of dog or cat bites, scratches, licks, or simple exposure.

https://ift.tt/2vsrHaE

Chemical Differentiation of Genetically Identified Atractylodes japonica, A. macrocephala, and A. chinensis Rhizomes Using High-Performance Liquid Chromatography with Chemometric Analysis

The rhizome of Atractylodes japonica, which is a herbal medicine used for gastrointestinal therapeutics, has been categorized with A. macrocephala rhizome or A. chinensis rhizome based on different therapeutic criteria in Korea, China, and Japan. In the present study, 61 A. japonica, A. macrocephala, and A. chinensis rhizomes were collected from Korea and China and were genetically identified by internal transcribed spacer sequencing analysis. Chromatographic profiles were obtained from high-performance liquid chromatography analysis of the methanol and hot-water extracts of Atractylodes rhizomes and chemical differentiation of the rhizomes was carried out using chemometric statistical analyses such as principal component analysis, hierarchical clustering analysis, and Pearson's correlation coefficient analysis. The results from chromatographic profiles and chemometric analyses demonstrate that A. japonica rhizomes showed apparent chemical differences from A. macrocephala and A. chinensis rhizomes in the methanol extracts. In contrast, no clear distinction was apparent for the hot-water extracts of Atractylodes rhizomes, especially A. chinensis rhizomes. These results indicate that there is a clear chemical difference between A. japonica and A. macrocephala rhizomes; however, the chemical diversity of A. chinensis rhizome shows different chemical relationships with A. japonica or A. macrocephala rhizome, dependent on the chemical features.

https://ift.tt/2LJtIde

Cancers, Vol. 10, Pages 257: Stereotactic Body Radiation Therapy for Patients with Pulmonary Interstitial Change: High Incidence of Fatal Radiation Pneumonitis in a Retrospective Multi-Institutional Study

Cancers, Vol. 10, Pages 257: Stereotactic Body Radiation Therapy for Patients with Pulmonary Interstitial Change: High Incidence of Fatal Radiation Pneumonitis in a Retrospective Multi-Institutional Study

Cancers doi: 10.3390/cancers10080257

Authors: Hiroshi Onishi Hideomi Yamashita Yoshiyuki Shioyama Yasuo Matsumoto Kenji Takayama Yukinori Matsuo Akifumi Miyakawa Haruo Matsushita Masahiko Aoki Keiji Nihei Tomoki Kimura Hiromichi Ishiyama Naoya Murakami Kensei Nakata Atsuya Takeda Takashi Uno Takuma Nomiya Tuyoshi Takanaka Yuji Seo Takafumi Komiyama Kan Marino Shinichi Aoki Ryo Saito Masayuki Araya Yoshiyasu Maehata Licht Tominaga Kengo Kuriyama

Pretreatment pulmonary interstitial change (PIC) has been indicated as a risk factor of severe radiation pneumonitis (RP) following stereotactic body radiation therapy (SBRT) for early-stage lung cancer, but details of its true effect remain unclear. This study aims to evaluate treatment outcomes of SBRT for stage I non-small cell lung cancer in patients with PIC. A total of 242 patients are included in this study (88% male). The median age is 77 years (range, 55&ndash;92 years). A total dose of 40&ndash;70 Gy is administered in 4 to 10 fractions during a 4-to-25 day period. One, two, and three-year overall survival (OS) rates are 82.1%, 57.1%, and 42.6%, respectively. Fatal RP is identified in 6.9% of all patients. The percent vital capacity &lt;70%, mean percentage normal lung volume receiving more than 20 Gy (&gt;10%), performance status of 2&ndash;4, presence of squamous cell carcinoma, clinical T2 stage, regular use of steroid before SBRT, and percentage predicting forced expiratory volume in one second (&lt;70%) are associated with worse prognoses for OS. Our results indicate that fatal RP frequently occurs after SBRT for stage I lung cancer in patients with PIC.



https://ift.tt/2LHxUdH

Changes in feeding habits promoted the differentiation of the composition and function of gut microbiotas between domestic dogs (Canis lupus familiaris) and gray wolves (Canis lupus)

Wolves (Canis lupus) and their domesticated and close relatives, dogs (Canis lupus familiaris), have great differences in their diets and living environments. To the best of our knowledge, the fundamental questio...

https://ift.tt/2Mblreu

PAK2–c-Myc–PKM2 axis plays an essential role in head and neck oncogenesis via regulating Warburg effect

PAK2–c-Myc–PKM2 axis plays an essential role in head and neck oncogenesis via regulating Warburg effect

PAK2–c-Myc–PKM2 axis plays an essential role in head and neck oncogenesis via regulating Warburg effect, Published online: 01 August 2018; doi:10.1038/s41419-018-0887-0

PAK2–c-Myc–PKM2 axis plays an essential role in head and neck oncogenesis via regulating Warburg effect

https://ift.tt/2LTYdwn

Screening for long noncoding RNAs associated with oral squamous cell carcinoma reveals the potentially oncogenic actions of DLEU1

Screening for long noncoding RNAs associated with oral squamous cell carcinoma reveals the potentially oncogenic actions of DLEU1

Screening for long noncoding RNAs associated with oral squamous cell carcinoma reveals the potentially oncogenic actions of DLEU1, Published online: 01 August 2018; doi:10.1038/s41419-018-0893-2

Screening for long noncoding RNAs associated with oral squamous cell carcinoma reveals the potentially oncogenic actions of DLEU1

https://ift.tt/2MblFCm

Double-edged sword of gonadotropin-releasing hormone (GnRH): A novel role of GnRH in the multiple beneficial functions of endometrial stem cells

Double-edged sword of gonadotropin-releasing hormone (GnRH): A novel role of GnRH in the multiple beneficial functions of endometrial stem cells

Double-edged sword of gonadotropin-releasing hormone (GnRH): A novel role of GnRH in the multiple beneficial functions of endometrial stem cells, Published online: 01 August 2018; doi:10.1038/s41419-018-0892-3

Double-edged sword of gonadotropin-releasing hormone (GnRH): A novel role of GnRH in the multiple beneficial functions of endometrial stem cells

https://ift.tt/2LXEoEk

Selective killing of human T-ALL cells: an integrated approach targeting redox homeostasis and the OMA1/OPA1 axis

Selective killing of human T-ALL cells: an integrated approach targeting redox homeostasis and the OMA1/OPA1 axis

Selective killing of human T-ALL cells: an integrated approach targeting redox homeostasis and the OMA1/OPA1 axis, Published online: 01 August 2018; doi:10.1038/s41419-018-0870-9

Selective killing of human T-ALL cells: an integrated approach targeting redox homeostasis and the OMA1/OPA1 axis

https://ift.tt/2KiHkH2