Medicine by Alexandros G.Sfakianakis: 10/08/18

Δευτέρα 8 Οκτωβρίου 2018

A gaze-independent audiovisual brain-computer Interface for detecting awareness of patients with disorders of consciousness

Currently, it is challenging to detect the awareness of patients who suffer disorders of consciousness (DOC). Brain-computer interfaces (BCIs), which do not depend on the behavioral response of patients, may s...

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FOXC2 promotes epithelial–mesenchymal transition and cisplatin resistance of non-small cell lung cancer cells

Abstract

Purpose

Platinum-based drugs, particularly cisplatin (DDP), are used in the treatment of non-small cell lung cancer (NSCLC). However, development of drug resistance remains the major therapeutic barrier in NSCLC.

Methods

The potential cisplatin resistance-related genes were identified from the global transcriptomes of cisplatin-resistant A549/DDP cells using microarray analysis. Gain- and loss-of-function assays were performed to analyze the effects of Forkhead Box Protein C2 (FOXC2) on the in vitro and in vivo sensitivity of NSCLC cells to cisplatin and its possible molecular mechanisms.

Results

Using global transcriptome analysis, we found that FOXC2 was one of the most upregulated molecules in A549/DDP cells compared with A549 cells. We further confirmed that the expression of FOXC2 was significantly increased in cisplatin-resistant NSCLC tissues. FOXC2 knockdown significantly increased the in vitro and in vivo sensitivity of A549/DDP cells to cisplatin, whereas overexpression of FOXC2 increased cisplatin resistance in cisplatin-sensitive NSCLC cells. Moreover, we found that FOXC2 promoted cisplatin resistance by induction of epithelial–mesenchymal transition (EMT) in NSCLC cells. Furthermore, FOXC2 activated the AKT/GSK3β signaling pathway, and then increased the protein expression of EMT-related transcription factor Snail. Inhibition of AKT or knockdown of Snail reversed FOXC2-induced EMT and cisplatin resistance of NSCLC cells.

Conclusion

FOXC2 enhanced cisplatin resistance of NSCLC cells through activating AKT/GSK3β/Snail/EMT signaling pathway, which may be a potential novel therapeutic target for overcoming drug resistance in human NSCLCs.

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Prevalence of methicillin resistant Staphylococcus aureus, multidrug resistant and extended spectrum β-lactamase producing gram negative bacilli causing wound infections at a tertiary care hospital of Nepal

Treatment and prevention of wound infection continues to be a challenging issue in clinical settings of Nepal especially in the context of globally growing problem of antimicrobial resistance. Study on opportu...

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Urachal carcinoma: from gross specimen to morphologic, immunohistochemical, and molecular analysis

Abstract

Urachal carcinoma (UrC) is an exceedingly rare neoplasm that develops from the urachus, an embryologic remnant of the urogenital sinus and allantois. The most commonly encountered histologic subtype is adenocarcinoma. The aim of this study is to characterize a series of UrC by morphology, immunohistochemistry, and molecular analysis. We retrospectively investigated seven cases of UrCs and assessed patient symptoms, imaging, histologic features, immunohistochemical profile, molecular characteristics, pathologic stages, and type of treatment. Immunostaining for CK7, CK20, Muc-2, CDX2, GATA3, β-catenin, and CK34βE12 was carried out on each neoplasm and on seven non-neoplastic urachal remnants as the control group. Additionally, a mutational analysis was performed using the QIAact Actionable Insights Tumor Panel Kit, which analyzes KRAS, NRAS, KIT, BRAF, PDGFRA, ALK, EGFR, ERBB2, PIK3CA, ERBB3, ESR1, and RAF1. Our cohort comprised five females and two males with a mean age of 64 years. UrCs consisted of two mucinous cystadenocarcinomas and five invasive, non-cystic adenocarcinomas. Carcinoma antigen expression profile was positive for CK20 and negative for CK34βE12 and GATA3 in all cases. Five of seven cases stained positively for Muc-2 and CDX2. On the contrary, non-neoplastic urachal remnants were immunoreactive for CK34βE12, CK7, and GATA3. Mutational analysis gave a positive result in four out of seven (57.1%) cases. All four positive tumors showed RAS mutation and one an additional mutation in PIK3CA. Urachal tumors exhibit peculiar morphologic, immunohistochemical, and molecular features. Due to the advanced stage at presentation, individualized treatment should be undertaken.

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Unintended consequences of focusing on accommodations and supports as barriers for medical trainees with disabilities [Letters]

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Use of the emergency department as a first point of contact for mental health care by immigrant youth in Canada: a population-based study [Research]

BACKGROUND:

Emergency department visits as a first point of contact for people with mental illness may reflect poor access to timely outpatient mental health care. We sought to determine the extent to which immigrants use the emergency department as an entryway into mental health services.

METHODS:

We used linked health and demographic administrative data sets to design a population-based cohort study. We included youth (aged 10–24 yr) with an incident mental health emergency department visit from 2010 to 2014 in Ontario, Canada (n = 118 851). The main outcome measure was an emergency department visit for mental health reasons without prior mental health care from a physician on an outpatient basis. The main predictor of interest was immigrant status (refugee, non-refugee immigrant and non-immigrant). Immigrant-specific predictors included time since migration, and region and country of origin. We used Poisson models to estimate adjusted rate ratios (aRRs) and 95% confidence intervals (CIs).

RESULTS:

The cohort included 2194 (1.8%) refugee, 6680 (5.6%) non-refugee immigrant and 109 977 (92.5%) nonimmigrant youth. Rates of first mental health contact in the emergency department were higher among refugee (61.3%) and non-refugee immigrant youth (57.6%) than non-immigrant youth (51.3%) (refugee aRR 1.17, 95% CI 1.13–1.21; non-refugee immigrant aRR 1.10, 95% CI 1.08–1.13). Compared with non-refugee immigrants, refugees had a higher rate of first mental health contact in the emergency department (aRR 1.06, 95% CI 1.02–1.11). We also observed higher rates among recent versus longer-term immigrants (aRR 1.10, 95% CI 1.05–1.16) and immigrants from Central America (aRR 1.17, 95% CI 1.08–1.26) and Africa (aRR 1.15, 95% CI 1.06–1.24) versus from North America and Western Europe.

INTERPRETATION:

Immigrant youth are more likely to present with a first mental health crisis to the emergency department than non-immigrants, with variability by region of origin and time since migration. Immigrants may face barriers to access and use of outpatient mental health services from a physician. Efforts are needed to reduce stigma and identify mental health problems early, before crisis, among immigrant populations.

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Improving youth mental health supports in Canada [Commentary]

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Canadian Cardiovascular Harmonized National Guidelines Endeavour (C-CHANGE) guideline for the prevention and management of cardiovascular disease in primary care: 2018 update [Guideline]

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Growing concern over medical students excessive drinking [News]

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Malnutrition in Canadian hospitals [Practice]

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Addressing bias and lack of objectivity in the Canadian resident matching process [Letters]

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Are physicians too busy to ask about patients concerns? [News]

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The ethics of new technologies to track drug adherence [Humanities]

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Do doctors experiencing burnout make more errors? [News]

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Stem Cell Therapy in Cerebrovascular Disease

Abstract

Purpose of review

The purpose of this article is to provide a review of state-of-the-art cellular therapy in cerebrovascular diseases by discussing published and ongoing clinical trials.

Recent findings

In spite of the challenge in translating the success of cellular therapy in acute strokes from preclinical models to clinical trials, early phase clinical trial have recently shown promise in overcoming these challenges. Various stem cell types and doses are being studied, different routes of administration are under investigation, as well as defining the optimal time window to intervene. In addition, experimental methods to enhance cellular therapy, such as ischemic preconditioning, are evolving.

Summary

After the failure of neuroprotectants in cerebrovascular diseases, researchers have been keen to provide a way of replacement of damaged brain tissue and to promote recovery in order to achieve better outcomes. The field has progressed from intravenous delivery in the 24- to 36-h time window to later intracerebral administration in chronic stroke in clinical trials. New optimism in acute stroke care fostered by the success of mechanical thrombectomy will hopefully extend into cell therapy to promote recovery.

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EMS From a Distance: Forget me not

What skills and practices should be routine for EMS providers in the field?

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The Monetary Value of Informal Care: Obtaining Pure Time Valuations Using a Discrete Choice Experiment

Abstract

Background

Interventions in health care often not only have an effect on patients, but also on their informal caregivers. Caregiving can have a profound impact on the health and wellbeing of carers. Ignoring these spillovers in economic evaluations risks labelling interventions mistakenly as cost-effective, at the expense of informal caregivers.

Objective

This paper investigates willingness-to-accept (WTA) values for an hour of informal care, corrected for positive and negative impacts of informal care, to facilitate the inclusion of informal care hours on the cost side of economic evaluations without double-counting spillover effects.

Methods

A discrete choice experiment (DCE) was conducted among a representative sample of the adult population in the Netherlands (n = 552) in September 2011. An experimental design minimizing the D-error was used to construct choice sets with two unlabelled alternatives with the attributes 'hours caregiving', 'monetary compensation for caregiving' and seven impacts of caregiving. To operationalize the random utility model, we used a panel mixed multinomial logit (MMNL) parameter model. For calculation of WTA, we used both population-level parameters and individual-level parameters.

Results

The mean WTA for an additional hour of informal care, corrected for positive and negative impacts of informal care, was €14.57. The signs of the coefficients were all in the expected directions.

Conclusions

This study reports a preference-based monetary value for informal care, corrected for other impacts. This valuation facilitates the inclusion of informal care hours on the cost side in economic evaluations without double-counting any spillover effects included on the effects side.

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The Caenorhabditis elegans Oxidative Stress Response Requires the NHR-49 Transcription Factor

The overproduction of reactive oxygen species (ROS) in cells can lead to the development of diseases associated with aging. We have previously shown that C. elegans BRAP-2 (Brca-1 associated binding protein 2) regulates phase II detoxification genes such as gst-4, by increasing SKN-1 activity. Previously, a transcription factor (TF) RNAi screen was conducted to identify potential activators that are required to induce gst-4 expression in brap-2(ok1492) mutants. The lipid metabolism regulator NHR-49/HNF4 was among 18 TFs identified. Here, we show that knockdown of nhr-49 suppresses the activation of gst-4 caused by brap-2 inactivation and that gain-of-function alleles of nhr-49 promote gst-4 expression. We also demonstrate that nhr-49 and its cofactor mdt-15 are required to express phase II detoxification enzymes upon exposure to chemicals that induce oxidative stress. Furthermore, we show that NHR-49 and MDT-15 enhance expression of skn-1a/c. These findings identify a novel role for NHR-49 in ROS detoxification by regulating expression of SKN-1C and phase II detoxification genes.

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A European Whitefish Linkage Map and Its Implications for Understanding Genome-Wide Synteny Between Salmonids Following Whole Genome Duplication

Genomic datasets continue to increase in number due to the ease of production for a wider selection of species including non-model organisms. For many of these species, especially those with large or polyploid genomes, highly contiguous and well-annotated genomes are still rare due to the complexity and cost involved in their assembly. As a result, a common starting point for genomic work in non-model species is the production of a linkage map. Dense linkage maps facilitate the analysis of genomic data in a variety of ways, from broad scale observations regarding genome structure e.g. chromosome number and type or sex-related structural differences, to fine scale patterns e.g. recombination rate variation and co-localization of differentiated regions. Here we present both sex-averaged and sex-specific linkage maps for Coregonus sp. "Albock", a member of the European whitefish lineage (C. lavaretus spp. complex), containing 5395 single nucleotide polymorphism (SNP) loci across 40 linkage groups to facilitate future investigation into the genomic basis of whitefish adaptation and speciation. The map was produced using restriction-site associated digestion (RAD) sequencing data from two wild-caught parents and 156 F1 offspring. We discuss the differences between our sex-averaged and sex-specific maps and identify genome-wide synteny between C. sp. "Albock" and Atlantic Salmon (Salmo salar), which have diverged following the salmonid-specific whole genome duplication. Our analysis confirms that many patterns of synteny observed between Atlantic Salmon and Oncorhynchus and Salvelinus species are also shared by members of the Coregoninae subfamily. We also show that regions known for their species-specific rediploidization history can pose challenges for synteny identification since these regions have diverged independently in each salmonid species following the salmonid-specific whole genome duplication. The European whitefish map provided here will enable future studies to understand the distribution of loci of interest, e.g. F_ST outliers, along the whitefish genome as well as assisting with the de novo assembly of a whitefish reference genome.

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Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer [Research Briefs]

KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL) mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS mutant lung cancers, remains obscure. Here we report that LKB1 loss results in marked silencing of STING expression and insensitivity to cytoplasmic double strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine (SAM) levels, and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape.

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Pathological Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC). Germline inactivating alterations in fumarate hydratase (FH) cause HLRCC and result in elevated levels of reactive oxygen species (ROS). Recent work indicates that FH-/- PRCC cells have increased activation of ABL1, which promotes tumor growth, but how ABL1 is activated remains unclear. Given that oxidation can regulate protein-tyrosine phosphatase (PTP) catalytic activity, inactivation of an ABL-directed PTP by ROS might account for ABL1 activation in this malignancy. Our group previously developed "q-oxPTPome", a method that globally monitors the oxidation of classical PTPs. In this study, we present a refined q-oxPTPome, increasing its sensitivity by >10X. Applying q-oxPTPome to FH-deficient cell models showed that multiple PTPs were either highly oxidized (including PTPN12) or overexpressed. Highly oxidized PTP were those with relatively high sensitivity to exogenous H2O2. Most PTP oxidation in FH-deficient cells was reversible, although nearly 40% of PTPN13 was irreversibly oxidized to the sulfonic acid state. Using substrate-trapping mutants, we mapped PTPs to their putative substrates and found that only PTPN12 could target ABL1. Furthermore, knockdown experiments identified PTPN12 as the major ABL1 phosphatase, and overexpression of PTPN12 inhibited ABL1 phosphorylation and HLRCC cell growth. These results show that ROS-induced oxidation of PTPN12 accounts for ABL1 phosphorylation in HLRCC-associated PRCC, revealing a novel mechanism for inactivating a tumor suppressor gene product and establishing a direct link between pathological PTP oxidation and neoplastic disease.

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Pharmacological inhibition of PARP6 triggers multipolar spindle formation and elicits therapeutic effects in breast cancer

PARP (poly ADP-ribose polymerase) proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been limited to targeting poly(ADP-ribose) (PAR) generating PARP including PARP1/2/3 and tankyrases. The cancer-related functions of mono(ADP-ribose) (MAR) generating PARP, including PARP6, remain largely uncharacterized. Here, we report a novel therapeutic strategy targeting PARP6 using the first reported PARP6 inhibitors. By screening a collection of PARP compounds for their ability to induce mitotic defects, we uncovered a robust correlation between PARP6 inhibition and induction of multipolar spindle (MPS) formation, which was phenocopied by PARP6 knockdown. Treatment with AZ0108, a PARP6 inhibitor with a favorable pharmacokinetic profile, potently induced the MPS phenotype, leading to apoptosis in a subset of breast cancer cells in vitro and antitumor effects in vivo. In addition, Chk1 was identified as a specific substrate of PARP6 and was further confirmed by enzymatic assays and by mass spectrometry. Furthermore, when modification of Chk1 was inhibited with AZ0108 in breast cancer cells, we observed marked upregulation of p-S345 Chk1 accompanied by defects in mitotic signaling. Together these results establish proof-of-concept antitumor efficacy through PARP6 inhibition and highlight a novel function of PARP6 in maintaining centrosome integrity via direct ADP-ribosylation of Chk1 and modulation of its activity.

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Targeting PARP1 in XRCC1 deficient sporadic invasive breast cancer or pre-invasive ductal carcinoma in situ induces synthetic lethality and chemoprevention

Targeting PARP1 for synthetic lethality is a new strategy for breast cancers harboring germline mutations in BRCA. However, these mutations are rare, and reactivation of BRCA-mediated pathways may result in eventual resistance to PARP1 inhibitor therapy. Alternative synthetic lethality approaches targeting more common sporadic breast cancers and pre-invasive ductal carcinoma in situ (DCIS) are desirable. Here we show that downregulation of XRCC1, which interacts with PARP1 and coordinates base excision repair, is an early event in human breast cancer pathogenesis. XRCC1-deficient DCIS were aggressive and associated with increased risk of local recurrence. Human invasive breast cancers deficient in XRCC1 and expressing high PARP1 levels also manifested aggressive features and poor outcome. The PARP1 inhibitor Olaparib was synthetically lethal in XRCC1-deficient DCIS and invasive breast cancer cells. We conclude that targeting PARP1 is an attractive strategy for synthetic lethality and chemoprevention in XRCC1-deficient breast cancers, including pre-invasive DCIS.

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Intratumoral immunotherapy with XCL1 and sFlt3L encoded in recombinant Semliki Forest Virus-derived vectors fosters dendritic cell-mediated T cell cross-priming

Multiple lines of evidence indicate a critical role for antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L and XCL1 respectively constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to tumor cells in culture and when engrafted as subcutaneous mouse tumor models. In syngeneic mice, intratumoral injection of SFV-XCL1-sFlt3L (SFV-XF) delayed progression of MC38- and B16-derived tumors. Therapeutic activity was observed and exerted additive effects in combination with anti-PD-1, anti-CD137, or CTLA-4 immunostimulatory monoclonal antibodies. Therapeutic effects were abolished by CD8β T cell depletion and were enhanced by CD4 T cell depletion, but not by Treg pre-depletion with anti-CD25 mAb. Antitumor effects were also abolished in BATF3- and IFNAR-deficient mice. In B16-OVA tumors, SFV-XF increased the number of infiltrating CD8 T cells, including those recognizing OVA. Consistently, following intratumoral SFV-XF treatment courses, we observed increased BATF3-dependent cDC1 among B16-OVA tumor-infiltrating leukocytes. Such an intratumoral increase was not seen in MC38-derived tumors, but both resident and migratory cDC1 were boosted in SFV-XF-treated MC38 tumor-draining lymph nodes. In conclusion, viral gene transfer of sFlt3L and XCL1 is feasible, safe, and biologically active in mice, exerting antitumor effects that can be potentiated by CD4 T cell depletion.

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The dawn of a new era: performance measurement for the pathologic diagnosis of Barrett’s esophagus–associated dysplasia

Esophageal columnar metaplastic epithelium (ie, Barrett's esophagus [BE]) carries the risk of progressive transformation into low-grade dysplasia (LGD) and high-grade dysplasia (HGD) and eventually adenocarcinoma.1,2 Endoscopic inspection with biopsy remains the cornerstone of surveillance of BE patients for identifying dysplasia and early malignancy. As a result, the histopathologic diagnosis plays a pivotal role in clinical decision making and treatment of patients. However, the diagnosis of dysplasia, particularly LGD, in BE can be challenging and highly variable.

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MSCs inhibit tumor progression and enhance radiosensitivity of breast cancer cells by down-regulating Stat3 signaling pathway

MSCs inhibit tumor progression and enhance radiosensitivity of breast cancer cells by down-regulating Stat3 signaling pathway

MSCs inhibit tumor progression and enhance radiosensitivity of breast cancer cells by down-regulating Stat3 signaling pathway, Published online: 08 October 2018; doi:10.1038/s41419-018-0949-3

MSCs inhibit tumor progression and enhance radiosensitivity of breast cancer cells by down-regulating Stat3 signaling pathway

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Information for readers

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In upcoming issues...

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Is 35 the new 50? Challenges in determining colonoscopy surveillance recommendations for young patients with incidentally detected adenomas

There has been significant publicity recently regarding increasing rates of colorectal carcinoma (CRC) in young patients aged 20 to 45 years. Last year in the Journal of the National Cancer Institute, a publication by Siegel et al1 entitled "Colorectal cancer incidence patterns in the United States, 1974-2013" demonstrated that young adults now have double the risk for the development of colon cancer and quadruple the risk for the development of rectal cancer, compared with their age-matched counterparts born in 1950.

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EUS versus transpapillary drainage of malignant biliary obstruction: still a long way to go

We read with great interest the article by Park et al,1 "Efficacy of EUS-guided and ERCP-guided biliary drainage for malignant biliary obstruction: prospective randomized controlled study." The authors concluded that the safety of EUS-guided biliary drainage (EUS-BD) is similar to that of ERCP-guided biliary drainage (ERCP-BD).

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Barrett’s ablation: blowing hot, blowing cold

The cryoballoon focal ablation system (CbFAS) is the most recent tool added to the therapeutic repertoire for early Barrett's neoplasia. On the basis of current robust evidence, radiofrequency ablation (RFA) is the treatment of choice for ablating Barrett's epithelium, whereas the role of cryoablation is undetermined. In this issue of Gastrointestinal Endoscopy, van Munster et al1 present the first study comparing the efficacy of the CbFAS device with that of RFA in treating early Barrett's neoplasia.

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Focus on...

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Continuing Medical Education Exam: November 2018

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The FUSE enigma: Wide-angle or wide-minded?

Although the event is rare, it remains an undeniable fact that approximately 1 in every 1500 colonoscopies is later followed by a postcolonoscopy cancer.1 The most immediate reaction is to assume it is a de novo cancer. This is the most persuasive and convenient—and defendable—argument for both ourselves as endoscopists and our patients. It is also indirectly supported by epidemiologic data, which show a surge of proximal cancer in the elderly with lower, if any, protection by screening colonoscopy.

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ASGE update

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Risk of diabetes after para-aortic radiation for testicular cancer

Risk of diabetes after para-aortic radiation for testicular cancer

Risk of diabetes after para-aortic radiation for testicular cancer, Published online: 09 October 2018; doi:10.1038/s41416-018-0248-x

Risk of diabetes after para-aortic radiation for testicular cancer

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Reply to comment of “ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer”

Reply to comment of "ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer"

Reply to comment of "ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer", Published online: 09 October 2018; doi:10.1038/s41416-018-0275-7

Reply to comment of "ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer"

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Serially measured pre-diagnostic levels of serum cytokines and risk of brain cancer in active component military personnel

Serially measured pre-diagnostic levels of serum cytokines and risk of brain cancer in active component military personnel

Serially measured pre-diagnostic levels of serum cytokines and risk of brain cancer in active component military personnel, Published online: 09 October 2018; doi:10.1038/s41416-018-0272-x

Serially measured pre-diagnostic levels of serum cytokines and risk of brain cancer in active component military personnel

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Lipase precursor like protein promotes miltefosine tolerance in Leishmania donovani by enhancing parasite infectivity and eliciting anti-inflammatory responses in host macrophages [Mechanisms of Resistance]

Oral drug miltefosine (MIL) was introduced in the Indian subcontinent in the year 2002 for the treatment of visceral leishmaniasis (VL). However, recent reports on its declining efficacy and increasing relapse rates pose a serious concern. An understanding of the factors contributing to MIL tolerance in Leishmania parasites is critical. In the present study, we assessed the role of lipase precursor like protein (Lip) in conferring tolerance towards miltefosine by episomally overexpressing Lip into L. donovani (LdLip⁺⁺). We observed significant increase (~3 fold) in MIL IC₅₀ both at promastigote (3.90 ± 0.68 µM, P<0.05) and at intracellular amastigote (9.10 ± 0.60 µM, P<0.05) stages compared to the wild type counterpart (LdNeo; MIL IC₅₀ promastigote 1.49 ± 0.20 µM; MIL IC₅₀ amastigote 3.95 ± 0.45 µM). LdLip⁺⁺ parasites exhibited significantly (P<0.05) increased infectivity to host macrophages, increased metacyclogenesis and tolerance to MIL induced oxidative stress. The susceptibility of LdLip⁺⁺ towards other antileishmanial drugs (sodium antimony gluconate and amphotericin B) remained unchanged. In comparison to LdNeo, the LdLip⁺⁺ parasites elicited higher host IL-10 cytokine expression (1.6 fold, P<0.05) with reduced expression of TNF-α cytokine (1.5 fold, P<0.05), leading to significantly (P<0.01) increased ratio of IL-10/TNF- α. The above findings suggest a role of lipase precursor like protein in conferring tolerance towards oral antileishmanial drug MIL in L. donovani parasites.

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Role of capsule in resistance to disinfectants, host antimicrobials and desiccation in Acinetobacter baumannii [Mechanisms of Resistance]

Acinetobacter baumannii strain AB5075 forms two cell types distinguished by their opaque (VIR-O) or translucent (AV-T) colonies. VIR-O cells possess a thicker capsule and are more resistant to a variety of stressors. However, the direct role of capsule in these stressors was unknown. This study demonstrates that capsule is required for resistance to disinfectants, lysozyme and desiccation in Acinetobacter baumannii. In addition, capsule is required for survival in a mouse lung model of infection.

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Drug repurposing for Leishmania. Molecular basis of the leishmanicidal activity of the antidepressant sertraline. [Mechanisms of Action]

Drug repurposing affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the clinical drugs against Leishmania share this origin. The antidepressant sertraline has been successfully assayed in a murine model of visceral leishmaniasis. Nevertheless, sertraline targets in Leishmania were poorly defined. In order to get a detailed insight into the leishmanicidal mechanism of sertraline on Leishmania infantum, unbiased multiplatform metabolomics and transmission electron microscopy were combined with a focused insight into the sertraline effects on bioenergetics metabolism of the parasite. Sertraline induced respiration uncoupling, a significant decrease of intracellular ATP level, and oxidative stress in L. infantum promastigotes. Metabolomics evidenced an extended metabolic disarray caused by sertraline. This encompasses a remarkable variation of the levels of thiol-redox and polyamine biosynthetic intermediates, as well as shortage of intracellular amino acids used as metabolic fuel by Leishmania. Sertraline killed Leishmania through a multitarget mechanism of action, tackling essential metabolic pathways of the parasite. As such, sertraline is a valuable candidate for visceral leishmaniasis treatment under a drug repurposing strategy.

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Effects of Food and Omeprazole on Novel Formulation SUBA-Itraconazole in Healthy Subjects [Pharmacology]

To address the limited bioavailability and intolerance of the conventional itraconazole formulations, a new formulation labelled SUBA-itraconazole (for SUper BioAvailability) has been developed, however the specific effect of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA-itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. The effect of food was assessed in an open-label, randomized, cross-over bioavailability study of SUBA-itraconazole capsules 65 mg (2 x 65 mg BID) in healthy adults (n = 20) under fasting and fed conditions to steady-state levels. Secondly, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults (n=28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA-itraconazole capsules (2 x 65 mg/day) with and without co-administration of daily omeprazole delayed-release capsules (1 x 40 mg/day) under steady-state conditions. In the fed and fasted state SUBA-itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak itraconazole (ITZ) exposure when administered under fed conditions compared to the fasted state; fed/fasted ratios of 78.09% (90%CI 74.49-81.86%) for AUC_tau [14183.2 vs. 18479.8 hr·ng/mL], 73.05% (90%CI 69.01-77.33%) for C_max,ss [1519.1 vs. 2085.2 ng/mL] and 91.53% (90%CI 86.41-96.96%) for C_trough [1071.5 vs. 1218.5 ng/mL]. When dosed concomitantly with omeprazole there was a 22% increase in total plasma exposure of ITZ, as measured by AUC_0- (p = 0.0069), and a 31% increase in peak plasma exposure of ITZ, as measured by C_max (p = 0.0083).

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Amixicile reduces severity of cryptosporidiosis, but does not have in vitro activity against Cryptosporidium [Mechanisms of Action]

Cryptosporidium causes significant morbidity in malnourished children. Nitazoxanide (NTZ) is the only approved treatment for cryptosporidiosis, but NTZ has diminished effectiveness during malnutrition. Here we show that amixicile, a highly selective water soluble derivative of NTZ diminishes Cryptosporidium severity in a malnourished mouse model despite a lack of direct anti-cryptosporidial activity. We suggest that amixicile; by tamping down anaerobes associated with intestinal inflammation, reverses weight loss and indirectly mitigates infection-associated pathology.

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Polymorphism of polymeric amino acid regions in fungal proteins: correlation with altered echinocandin and azole susceptibility [Mechanisms of Resistance]

Polymorphism of polymeric amino acid (polyX) regions within fungal proteins represents a potential mechanism for rapid genotypic adaptation to environmental pressures including antifungal exposure. PolyQ was the most abundant repeat in the proteomes of 8 diverse fungal species, and was preferentially found in regulatory proteins. In Candida glabrata, polyX polymorphisms were characterized in 36 proteins implicated in azole or echinocandin susceptibility. General transcriptional repressor Tup1A exhibited Q44/Q45 polymorphism, and Hog1 signalling component Ssk2 exhibited N44/N45, in phylogenetically matched echinocandin and azole, respectively, susceptible/resistant strains.

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Competitive fitness of essential gene knockdowns reveals a broad-spectrum antibacterial inhibitor of the cell division protein FtsZ [Mechanisms of Action]

To streamline elucidation of antibacterial compounds' mechanism of action, comprehensive high-throughput assays interrogating multiple putative targets are necessary. However, current chemogenomic approaches for antibiotic target identification have not fully utilized the multiplexing potential of next-generation sequencing. Here, we used Illumina sequencing of transposon insertions to track the competitive fitness of a Burkholderia cenocepacia library containing essential gene knockdowns. Using this method, we characterized a novel benzothiadiazole derivative, 10126109 (C109) with antibacterial activity against B. cenocepacia, for which whole-genome sequencing of low-frequency, spontaneous drug-resistant mutants had failed to identify the drug target. By combining identification of hypersusceptible mutants and morphology screening, we show that C109 targets cell division. Furthermore, fluorescence microscopy of bacteria harboring GFP-cell division protein fusions revealed that C109 prevents divisome formation by altering the localization of the essential cell division protein FtsZ. In agreement with this, C109 inhibited both the GTPase and polymerization activities of purified B. cenocepacia FtsZ. C109 displayed antibacterial activity against Gram-positive and Gram-negative cystic fibrosis pathogens, including Mycobacterium abscessus. C109 effectively cleared B. cenocepacia infection in the Caenorhabditis elegans model and exhibited additive interactions with clinically relevant antibiotics. Hence, C109 is an enticing candidate for further drug development.

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Weaning from Mechanical Ventilation in ARDS: Aspects to Think about for Better Understanding, Evaluation, and Management

Acute respiratory distress syndrome (ARDS) is characterized by severe inflammatory response and hypoxemia. The use of mechanical ventilation (MV) for correction of gas exchange can cause worsening of this inflammatory response, called "ventilator-induced lung injury" (VILI). The process of withdrawing mechanical ventilation, referred to as weaning from MV, may cause worsening of lung injury by spontaneous ventilation. Currently, there are few specific studies in patients with ARDS. Herein, we reviewed the main aspects of spontaneous ventilation and also discussed potential methods to predict the failure of weaning in this patient category. We also reviewed new treatments (modes of mechanical ventilation, neuromuscular blocker use, and extracorporeal membrane oxygenation) that could be considered in weaning ARDS patients from MV.

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Reply to comment of “ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer”

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Comment on “ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer”

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Risk of diabetes after para-aortic radiation for testicular cancer

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Serially measured pre-diagnostic levels of serum cytokines and risk of brain cancer in active component military personnel

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ASO Author Reflections: Neoadjuvant Treatment of Resectable and Borderline-Resectable Pancreatic Head Adenocarcinoma: Is FOLFIRINOX Better than Gem/Nab-Paclitaxel?

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ASO Author Reflections: A Population-Based Study on Lymph Node Retrieval in Patients with Esophageal Cancer

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ASO Author Reflections: Hepatic Artery Infusion (HAI) Chemotherapy is Associated with Improved Survival Compared with Radioembolization (Y90) in Patients with Isolated Unresectable Colorectal Liver Metastases

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ASO Author Reflections: Immunoinflammatory Prognostics in Cancer

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Association Between Very Small Tumor Size and Decreased Overall Survival in Node-Positive Pancreatic Cancer

Abstract

Background

In pancreatic adenocarcinoma (PDAC), increasing tumor size usually correlates with a worse prognosis. However, patients with a very small primary tumor who experience lymph node involvement may have a different disease biology. This study sought to determine the interaction between tumor size and lymph node involvement in terms of overall survival (OS).

Methods

The study identified 17,073 patients with a diagnosis of M0 resected PDAC between 1983 and 2013 using the Surveillance, Epidemiology, and End Results database. The patients were stratified by lymph node involvement (N0 vs N+) and T stage (T1a–T1b vs T1c vs T2 vs T3 vs T4). The Kaplan–Meier method was used to estimate OS, and Cox regression analysis was used to compare survival between subgroups after adjustment for patient-specific factors.

Results

Lymph node involvement and T stage significantly interacted (p < 0.001). Among the patients with node-negative disease, 5-year OS decreased monotonically with increasing T stage (59.1%, 30.6%, 22.9%, 16.6%, and 8.0%, respectively; p < 0.001). In contrast, among the patients with node-positive disease, those with T1a–T1b tumors (< 10 mm) had worse 5-year OS than those with T1c tumors (7.4% vs 17.6%; adjusted hazard ratio, 0.70; 95% confidence interval, 0.50–0.97; p = 0.034) and similar survival compared with those who had T2, T3, or T4 tumors (9.7%, 8.2%, and 4.8%, respectively; p > 0.2 in all cases).

Conclusions

Among patients with lymph node-positive PDAC, very small primary tumors are associated with decreased OS. This finding raises the possibility that small tumors capable of lymph node metastasis might represent more biologically aggressive cancers.

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ASO Author Reflections: Towards Better Metrics for Judging Academic Productivity in Surgical Oncology

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ASO Author Reflections: The Evolution of Minimally Invasive Liver Surgery and the Future with Robotics

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CKD Due to a Novel Mitochondrial DNA Mutation: A Case Report

In human kidney disease, mitochondrial ultrastructural damage has long been recognized. Although the extent to which such mitochondrial changes contribute to human kidney disease is uncertain, experimental studies clearly demonstrate that mitochondrial damage can instigate pathogenetic processes that drive ongoing kidney disease. Clinical credence for this experimentally based hypothesis is provided by the development of kidney disease in patients with primary mitochondrial disorders. In this regard, substantial interest surrounds the occurrence of kidney disease in primary mitochondrial cytopathies, a heterogeneous group of conditions in which mutations in mitochondrial DNA (mtDNA) or nuclear DNA impair the functionality of components of the mitochondrial respiratory chain.

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Kidneys

The shyest of organs, kidneys hidebehind the peritoneumand do not join in abdominal rumblings.Blood flows through, creamy and thick, a velvet red.After a whirlwind of sifting and sorting,a storm of charged ions switching places,what leaves is watery and weak, reeking of rejection.The kidneys are completely without glamor.In their drab retro-peritoneal closetthey will never beat with valor like the heart,never give wind to songs like the lungs,never compose sonnets like the brain.Working silently backstage, they plumb away,unheralded for crafting our foul, vital wastesimply because it is hard to love a drain.

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Nephrotoxicity and Chinese Herbal Medicine

Chinese herbal medicine has been practiced for the prevention, treatment, and cure of diseases for thousands of years. Herbal medicine involves the use of natural compounds, which have relatively complex active ingredients with varying degrees of side effects. Some of these herbal medicines are known to cause nephrotoxicity, which can be overlooked by physicians and patients due to the belief that herbal medications are innocuous. Some of the nephrotoxic components from herbs are aristolochic acids and other plant alkaloids. In addition, anthraquinones, flavonoids, and glycosides from herbs also are known to cause kidney toxicity. The kidney manifestations of nephrotoxicity associated with herbal medicine include acute kidney injury, CKD, nephrolithiasis, rhabdomyolysis, Fanconi syndrome, and urothelial carcinoma. Several factors contribute to the nephrotoxicity of herbal medicines, including the intrinsic toxicity of herbs, incorrect processing or storage, adulteration, contamination by heavy metals, incorrect dosing, and interactions between herbal medicines and medications. The exact incidence of kidney injury due to nephrotoxic herbal medicine is not known. However, clinicians should consider herbal medicine use in patients with unexplained AKI or progressive CKD. In addition, exposure to herbal medicine containing aristolochic acid may increase risk for future uroepithelial cancers, and patients require appropriate postexposure screening.

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Microbiome and Cardiovascular Disease in CKD

Patients with CKD exhibit a disproportionate burden of cardiovascular mortality, which likely stems from the presence of unique, nontraditional risk factors that accompany deteriorating kidney function. Mounting evidence suggests that alterations to the intestinal microbiome in CKD may serve as one such risk factor. The human intestinal tract is home to >100 trillion micro-organisms made up of a collection of commensal, symbiotic, and pathogenic species. These species along with their local environment constitute the intestinal microbiome. Patients with CKD show intestinal dysbiosis, an alteration of the gut micro-organism composition and function. Recent evidence links byproducts of intestinal dysbiosis to vascular calcification, atherosclerosis formation, and adverse cardiovascular outcomes in CKD. CKD-associated intestinal dysbiosis may also be accompanied by defects in intestinal barrier function, which could further enhance the negative effects of pathogenic intestinal bacteria in the human host. Thus, intestinal dysbiosis, defective intestinal barrier function, and a reduced capacity for clearance by the kidney of absorbed bacterial byproducts may all potentiate the development of cardiovascular disease in CKD. This narrative review focuses on microbiome-mediated mechanisms associated with CKD that may promote atherosclerosis formation and cardiovascular disease. It includes (1) new data supporting the hypothesis that intestinal barrier dysfunction leads to bacterial translocation and endotoxemia that potentiate systemic inflammation, (2) information on the accumulation of dietary-derived bacterial byproducts that stimulate pathways promoting atheromatous changes in arteries and cardiovascular disease, and (3) potential interventions. Despite great scientific interest in and a rapidly growing body of literature on the relationship between the microbiome and cardiovascular disease in CKD, many important questions remain unanswered.

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Insights into the Role of Mucosal Immunity in IgA Nephropathy

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Minding the Missing Link: The Effect of Donor-Recipient Pairing on Kidney Transplant Outcomes

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Defining Hypertension: Role of New Trials and Guidelines

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Kidney Function Decline in Patients with CKD and Untreated Hepatitis C Infection

Background and objectives

Studies evaluating the role of hepatitis C viral (HCV) infection on the progression of CKD are few and conflicting. Therefore, we evaluated the association of untreated HCV on kidney function decline in patients with stage 3–5 CKD.

Design, setting, participants, & measurements

This retrospective cohort study included members of Kaiser Permanente Southern California and Kaiser Permanente Mid-Atlantic States aged ≥18 years, with incident HCV and CKD diagnoses from January 1, 2004 to December 31, 2014. We used generalized estimating equations to compare the rate of change in eGFR between those with HCV and CKD versus CKD alone, adjusting for covariates. Cox proportional hazards models compared the risk of 25% decrease in eGFR and ESKD (defined as progression to eGFR<15 ml/min per 1.73 m² on two or more occasions, at least 90 days apart) in those with HCV and CKD versus CKD alone, adjusting for covariates.

Results

We identified 151,974 patients with CKD only and 1603 patients with HCV and CKD who met the study criteria. The adjusted annual decline of eGFR among patients with HCV and CKD was greater by 0.58 (95% confidence interval [95% CI], 0.31 to 0.84) ml/min per 1.73 m², compared with that in the CKD-only population (HCV and CKD, –1.61; 95% CI, –1.87 to –1.35 ml/min; CKD only, –1.04; 95% CI, –1.06 to –1.01 ml/min). Adjusted for covariates, the hazard for a 25% decline in eGFR and for ESKD were 1.87 (95% CI, 1.75 to 2.00) and 1.93 (95% CI, 1.64 to 2.27) times higher among those with HCV and CKD, respectively, compared with those with CKD only.

Conclusions

Untreated HCV infection was associated with greater kidney function decline in patients with stage 3–5 CKD.

https://ift.tt/2CxCFl5

Effect of Treatment of Metabolic Acidosis on Vascular Endothelial Function in Patients with CKD: A Pilot Randomized Cross-Over Study

Background and objectives

We examined the effect of alkali replacement for metabolic acidosis on vascular endothelial function in patients with CKD.

Methods

We performed a pilot, prospective, open-label 14-week crossover study examining the effect of oral sodium bicarbonate treatment on vascular function in 20 patients with an eGFR of 15–44 ml/min per 1.73 m² with low serum bicarbonate levels (16–21 mEq/L). Each period was 6 weeks in duration with a 2-week washout period in between. Patients were treated to goal serum bicarbonate of ≥23 mEq/L. The primary end point was change in brachial artery flow-mediated dilation (FMD) between treatment and control conditions. Secondary end points included changes in markers of inflammation, bone turnover, mineral metabolism, and calcification.

Results

Eighteen patients completed the study and were included in the primary efficacy analysis. The mean (SD) age and eGFR were 59 (12) years and 26 (8) ml/min per 1.73 m², respectively. Serum bicarbonate increased significantly with sodium bicarbonate treatment (+2.7±2.9 mEq/L, P≤0.001), whereas there was no change in bicarbonate levels in the control group. FMD significantly improved after sodium bicarbonate therapy (mean±SD, FMD baseline: 4.1%±4.1%; 6 weeks: 5.2%±2.9%; P=0.04) There was no significant change in FMD in the control group (mean±SD, FMD baseline: 4.6%±3.1%; 6 weeks: 4.1%±3.4%; P=0.20). Compared with control, sodium bicarbonate treatment resulted in a significant increase in FMD (mean, 1.8%; 95% confidence interval, 0.3 to 3.3; P=0.02). There was no significant change in bone markers or serum calcification propensity with treatment. Serum phosphorus and intact fibroblast growth factor 23 increased significantly during treatment.

Conclusions

Treatment of metabolic acidosis with sodium bicarbonate significantly improved vascular endothelial function in patients with stages 3b and 4 CKD.

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Clinical Pharmacogenomics: Applications in Nephrology

Pharmacogenomics is a tool for practitioners to provide precision pharmacotherapy using genomics. All providers are likely to encounter genomic data in practice with the expectation that they are able to successfully apply it to patient care. Pharmacogenomics tests for genetic variations in genes that are responsible for drug metabolism, transport, and targets of drug action. Variations can increase the risk for drug toxicity or poor efficacy. Pharmacogenomics can, therefore, be used to help select the best medication or aid in dosing. Nephrologists routinely treat cardiovascular disease and manage patients after kidney transplantation, two situations for which there are several high-evidence clinical recommendations for commonly used anticoagulants, antiplatelets, statins, and transplant medications. Successful use of pharmacogenomics in practice requires that providers are familiar with how to access and use pharmacogenomics resources. Similarly, clinical decision making related to whether to use existing data, whether to order testing, and if data should be used in practice is needed to deliver precision medicine. Pharmacogenomics is applicable to virtually every medical specialty, and nephrologists are well positioned to be implementation leaders.

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Inching toward a Greater Understanding of Genetic Hypercalciuria: The Role of Claudins

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Metagenomic analysis and the functional profiles of traditional fermented pork fat ‘sa-um’ of Northeast India

Fermented pork fat (sa-um) is traditionally and extensively consumed in Northeast Indian region for several decades. However, no scientific reports are available regarding its nutritional value as well as its pot...

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ASO Author Reflections: A Novel Muscle Measure for Gastric Cancer

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ASO Author Reflections: Do Distinct Patterns of Recurrence Impact the Prognosis of Patients With Resected Pancreatic Ductal Adenocarcinoma?

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ASO Author Reflections: Biological Diversity of Histologic Subtypes

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Correction to: Phase 2 Open-Label Trial Investigating Percutaneous Laser Ablation for Treatment of Early-Stage Breast Cancer: MRI, Pathology, and Outcome Correlations

The article "Phase 2 Open-Label Trial Investigating Percutaneous Laser Ablation for Treatment of Early-Stage Breast Cancer: MRI, Pathology, and Outcome Correlations", written by Barbara Schwartzberg et al., was originally published electronically on the publisher's internet portal (currently SpringerLink) on July 9, 2018, without open access.

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ASO Author Reflections: Survival Trends in Gastric Adenocarcinoma

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Intraoperative Dexamethasone Decreases Infectious Complications After Pancreaticoduodenectomy and is Associated with Long-Term Survival in Pancreatic Cancer

Abstract

Background

Dexamethasone is administered intraoperatively to prevent anesthesia-related nausea and vomiting and to reduce postoperative opioid administration. However, the adverse effects of corticosteroids on anastomotic healing and wound infection as well as oncologic outcomes remain unclear. We analyzed the effect of intraoperative dexamethasone administration on surgical outcomes after pancreaticoduodenectomy and on long-term survival in pancreatic cancer patients.

Methods

A total of 679 pancreaticoduodenectomies from a prospectively maintained database were analyzed. Surgical outcomes were compared between patients who received intraoperative dexamethasone and those who did not. Kaplan–Meier curves and Cox-regression survival analysis were performed in patients with pancreatic cancer. A propensity analysis was done to reduce the inherent bias of retrospective design.

Results

Patients who received dexamethasone (117, 17.2%) were younger and more likely to be female than those who did not (p = 0.001). Overall and 30-day major morbidity were similar among all resected patients, although there were fewer infectious complications in the dexamethasone group (18.8% vs. 28.5%, p = 0.032). In pancreatic cancer patients, dexamethasone was associated with significantly improved median overall survival (46 vs. 22 months, p = 0.017). This effect occurred independently of stage, pathologic characteristics, or adjuvant therapy, with adjusted hazard ratios, derived from pre-propensity and post-propensity analysis, of 0.67 (0.47–0.97) and 0.57 (0.37–0.87), respectively.

Conclusions

A single intraoperative dose of dexamethasone did not increase morbidity after pancreaticoduodenectomy and, in fact, was associated with a decrease in infectious complications. The treatment was independently associated with improved overall survival in patients with pancreatic adenocarcinoma, an effect that cannot be explained and needs further validation in a prospective setting.

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Men 65 years of age or younger received more chemotherapy and had improved OS, but not BCSS, compared with men older than 65 years. For all BCM, SPC is a risk, and appropriate screening may be warranted.

https://ift.tt/2E6Jpb9

Seasonal variation of extracellular enzymatic activity in marine snow-associated microbial communities and their impact on the surrounding water

Abstract

Seasonal changes of microbial abundance and associated extracellular enzymatic activity in marine snow and in seawater were studied in the northern Adriatic during a three year period. Marine snow was present during the entire investigated period, although with higher concentrations during summer than during winter. Microorganisms densely colonized marine snow and aggregate-associated enzymatic activity was substantially higher (up to 10⁵ times) than in seawater. Alkaline phosphatase activity (APA) and aminopeptidase activity in marine snow showed seasonal variation with higher activities in late spring-summer than in autumn-winter, probably in response to changes in the quantity and quality of organic matter. The highest cell-specific bacterial activity was found for phosphatase, followed by peptidase, and the lowest for glucosidases. Differential hydrolysis of marine snow-derived organic matter points to the well-known P-limitation of the northern Adriatic and indicates preferential utilization of phosphorus- and nitrogen-rich organic compounds by microbes, while hydrolysis of polysaccharides seemed to be less important. In oligotrophic conditions during summer, organic matter released from marine snow might represent a significant source of substrate for free-living bacteria in seawater. For the first time microorganisms producing APA in marine snow were identified revealing that dense populations of bacteria expressed APA, while cyanobacteria did not. Cyanobacteria proliferating in marine snow could benefit from phosphorus release by bacteria and nanoflagellates.

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Friends or foes in the rhizosphere: traits of fluorescent Pseudomonas that hinder Azospirillum brasilense growth and root colonization

Abstract

Bacteria of the Azospirillum and Pseudomonas genera are ubiquitous members of the rhizosphere, where they stimulate plant growth. Given the outstanding capacity of pseudomonads to antagonize other microorganisms, we analyzed the interaction between these two bacterial groups to identify determinants of their compatibility. We could establish that, when in direct contact, certain Pseudomonas strains produce lethality on Azospirillum brasilense cells using an antibacterial type 6 secretion system. When analyzing the effect of Pseudomonas spp. diffusible metabolites on A. brasilense growth on King's B medium, we detected strong inhibitory effects, mostly mediated by siderophores. On Congo Red medium, both inhibitory and stimulatory effects were induced by unidentified compounds. Under this condition, P. protegens CHA0 produced a Gac/Rsm-regulated antibiotic which specifically inhibited A. brasilense Sp7 but not Sp245. This effect was not associated to the production of 2,4-diacetylphloroglucinol. The three identified antagonism determinants were also active in vivo, resulting in a reduction of viable cells of A. brasilense in the roots of wheat seedlings when co-inoculated with pseudomonads. These results are relevant to the understanding of social dynamics in the rhizosphere and might aid in the selection of strains for mixed inoculants.

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Modeling Tuberculosis in Mycobacterium marinum Infected Adult Zebrafish

Here, we present a protocol to model human tuberculosis in an adult zebrafish using its natural pathogen Mycobacterium marinum. Extracted DNA and RNA from the internal organs of infected zebrafish can be used to reveal the total mycobacterial loads in the fish and the host's immune responses with qPCR.

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Evaluation of Escherichia coli pathotypes associated with Irritable Bowel Syndrome

Abstract

Irritable Bowel Syndrome (IBS) affects 10–20% of people. Increased numbers of Escherichia coli (E. coli) correlate with symptoms, and patients respond to antimicrobials targeting E. coli. We examined whether specific E. coli strains, phylogroups and pathotypes are associated with IBS. We evaluated 218 E. coli isolates from 33 IBS patients and 23 healthy controls. RAPD analysis revealed 89 E. coli strains (29 controls, 60 IBS), spanning the A, B1, B2, D phylogroups. Strains were similarly enriched in virulence genes associated with extraintestinal pathogenic E.coli (ExPEC) and/or adherent-invasive E.coli (AIEC). Three strains harbored a diarrheagenic virulence gene (2 IBS, 1 control). E. coli capable of invading epithelial cells or replicating in macrophages were detected in 53% of IBS and 50% controls, and 67% IBS and 45% controls respectively (P>0.05). AIEC were identified in 33% of IBS patients vs. 20% of controls (P=0.35). Virulence genes ibeA, ColV and pduC were associated with intramacrophage persistence; ibeA and ColV were associated with epithelial invasion and AIEC pathotype (P<0.05). IBS patients and controls are commonly colonized by E. coli that resemble ExPEC and display pathogen-like behavior in vitro, similar to CD-associated AIEC. The relationship of these resident pathosymbiont E. coli to IBS warrants further investigation.

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Quantitative proteomic analysis of xylose fermentation strain Pichia stipitis CBS 5776 to lignocellulosic inhibitors acetic acid, vanillin, and 5-hydroxymethylfurfural

Abstract

To obtain a global insight into the dynamic protein expression pattern in Pichia stipitis during xylose fermentation in the presence of three representative inhibitors (acetic acid, vanillin, and 5-hydroxymethylfurfural), proteins were extracted for quantitative proteomic analysis using 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) on a liquid chromatography-mass/mass spectrometry (LC-MS/MS) instrument. Interestingly, aconitase (Aco1p) and NAD-isocitrate dehydrogenase (Idh1p), were upregulated during the middle exponential phase in the presence of the three inhibitors during tricarboxylic acid (TCA) cycle. We speculated that yeast cells adaptively increased the expression of the TCA cycle proteins to compensate for low NADH derived from glycolysis in the presence of the three inhibitors. Proteins related to amino acid metabolism, aminoacyl tRNA synthesis, and stress response were also significantly affected in the presence of the three inhibitors. Taken together, quantitative proteomic analysis is capable of monitoring P. stipitis xylose fermentation under inhibitor conditions and identifying physiological changes, such as stress response.

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Streptomyces protein secretion and its application in biotechnology

Abstract

Bacteria are of tremendous importance in the pharma- and bio-industry as producers of a broad range of economically interesting metabolites and proteins. Gram-positive bacteria are valuable hosts for the production of heterologous proteins for obvious reasons. Contrary to Gram-negative bacteria, Gram-positive bacteria release their secreted proteins immediately into the spent culture broth as they are not hindered by an outer membrane. Secretory protein production also avoids the formation of inclusion bodies, hence facilitating downstream processing. Eight protein secretion pathways have been described in Gram-positive bacteria, but solely the general secretion or Sec pathway, and to a lesser extent, the Twin-arginine pathway are used for the recombinant protein production. This process is not always successful, but might be hampered by inefficient secretion, misfolding of the recombinant protein, its degradation by proteases and metabolic burden by the host hindering proper growth and diminishing product yield. In this review, the different protein export avenues will be briefly discussed, and the potential means to optimize protein secretion and yields for the Streptomyces lividans model presented. The proposed approaches are largely applicable for other Streptomyces host systems.

https://ift.tt/2NsuaJ2

Multifocal/Multicentric Ipsilateral Invasive Breast Carcinomas with Similar Histology: Is Multigene Testing of All Individual Foci Necessary?

Abstract

Background

Multiple synchronous ipsilateral invasive breast carcinomas (BCs) with similar histology usually have concordant receptor status. It is unknown whether individual foci with similar histology also share molecular and biological similarities or are heterogenous. This study examined the concordance of the 21-gene recurrence score (RS) in multiple synchronous morphologically similar ipsilateral BCs.

Patients and Methods

We identified patients with multiple ipsilateral BCs and available RS treated at our institution from 1/2014 to 6/2018. BCs were divided into three groups based on RS: (1) RS in same risk category, (2) RS in different risk categories but within 2-unit difference (e.g., RS 17 and RS 19), and (3) RS in different risk categories and a change of > 2 units. BCs in groups 1 and 2 were considered as concordant (no significant clinical impact) and BCs in group 3 as discordant (variation affects management).

Results

A total of 53 patients met the study criteria. RS was concordant in 46 (87%) cases. Seven (13%) cases were discordant (group 3). Of these, three (43%, 3/7) had biopsy cavity changes (BXC) adjacent to the BC with highest RS. In two cases the focus with higher RS had a lower percentage of progesterone receptor-positive tumor cells. In two cases, extensive ductal carcinoma in situ was associated with the BC focus with lower RS.

Conclusions

Morphologically similar multifocal ipsilateral BCs have concordant RS in 87% (46/53) of cases. Our results suggest that, in cases of morphologically similar multifocal BCs, testing of a single focus provides accurate prognostic and predictive information.

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ASO Author Reflections: Benefit of Adjuvant Radiotherapy for Clinical Outcome in Patients with Soft Tissue Sarcoma

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Should anti-EGFR mAbs be discontinued for conversion surgery in untreated right-sided metastatic colorectal cancer? A systematic review and meta-analysis

Abstract

Background

Previous studies have demonstrated that left-sided tumors have better prognoses than right-sided tumors in RAS wild-type mCRC (metastatic colorectal cancer) patients, while anti-EGFR mAbs appear to have no advantage compared with bevacizumab for right-sided tumors in these patients. Nevertheless, it remains unclear whether primary tumor location affects patients' options for potentially curative resection.

Methods

PubMed, the Cochrane Library, Embase, ASCO, and ESMO conference abstracts were searched. The inclusion criteria were RCT (randomized controlled trials) studies that evaluated the efficacy of anti-EGFR mAbs based on primary tumor location. The outcomes included ORR, ETS, and DpR. ORs for ORR were calculated with 95% confidence intervals by Comprehensive Meta-Analysis, version 2.0.

Result

Nine studies including nine RCTs were analyzed. Regardless of left- or right-sided tumors, the ORRs for anti-EGFR mAb (left-sided: 80.2%, 95% CI, 47–95%; I² = 76.9%; right-sided: 46.1%, 95% CI, 39.4–53.0%; I² = 18.9%) were both higher than the control arm including chemotherapy with or without bevacizumab. The ORs for anti-EGFR mAbs have a significant benefit compared with chemotherapy with or without bevacizumab in left-sided tumors (OR = 2.19, 95% CI, 1.41–3.38; P < 0.001). For right-sided tumors, anti-EGFR mAbs still significantly improved the ORR compared with chemotherapy alone (OR = 1.75, 95% CI, 1.05–2.90; P = 0.03), and the OR numerically favored the anti-EGFR mAbs compared with bevacizumab (OR = 1.281, 95% CI, 0.77–2.12; P = 0.335). The data of ETS and DpR from three RCTs also favored the EGFR antibody irrespective of tumor location. Resection data on differentiating tumor locations is inconclusive. For right-sided tumors, it should be noted that median PFS and OS were comparable for patients who achieved ETS in both treatment arms.

Conclusions

Anti-EGFR mAbs have advantages in the tumor shrinkage regardless of left- or right-sided tumors, which is important for conversion therapy. For right-sided tumors, anti-EGFR mAbs should remain the first choice for potentially curative resection in RAS wild-type mCRC patients. ETS may represent a subgroup of patients with right-sided tumors who might benefit from the anti-EGFR mAb.

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An In Vitro Assay to Detect tRNA-Isopentenyl Transferase Activity

Here, we describe a protocol for the biochemical characterization of the yeast RNA-modifying enzyme, Mod5, and discuss how this protocol could be applied to other RNA-modifying enzymes.

https://ift.tt/2yc6mnT

Tox and Hound – The Dantastic Mr. Tox & Howard – S02E04 – The Bloody Mess

17F58B0C-8AEA-442B-A787-9174998C4174.jpe

The synthetic cannabinoid / brodifacoum outbreak with Dr. Steve Aks Join Dan (@drusyniak) &Howard (@heshiegreshie) as they chat with Dr. Steve Aks as they talk about one of the more concerning toxicologic outbreaks in recent memory – the exposure to brodifacoum through synthetic cannabinoid use. Although still ongoing, this crisis highlights the importance of teamwork […]

EMCrit Project by Tox & Hound.

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Tight junction proteins in gastrointestinal and liver disease

Over the past two decades a growing body of evidence has demonstrated an important role of tight junction (TJ) proteins in the physiology and disease biology of GI and liver disease. On one side, TJ proteins exert their functional role as integral proteins of TJs in forming barriers in the gut and the liver. Furthermore, TJ proteins can also be expressed outside TJs where they play important functional roles in signalling, trafficking and regulation of gene expression. A hallmark of TJ proteins in disease biology is their functional role in epithelial-to-mesenchymal transition. A causative role of TJ proteins has been established in the pathogenesis of colorectal cancer and gastric cancer. Among the best characterised roles of TJ proteins in liver disease biology is their function as cell entry receptors for HCV—one of the most common causes of hepatocellular carcinoma. At the same time TJ proteins are emerging as targets for novel therapeutic approaches for GI and liver disease. Here we review our current knowledge of the role of TJ proteins in the pathogenesis of GI and liver disease biology and discuss their potential as therapeutic targets.

Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Δευτέρα 8 Οκτωβρίου 2018

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