No abstract available
https://ift.tt/2PkWSRS
Παρασκευή 9 Νοεμβρίου 2018
Functional Trajectories Before and After Major Surgery in Older Adults
Objectives: We hypothesized that distinct sets of functional trajectories can be identified in the year before and after major surgery, with unique transition probabilities from pre to postsurgical functional trajectories, and that outcomes would be better among participants undergoing elective versus nonelective surgery. Background: Major surgery is common and can be highly morbid in older persons. The relationship between the course of disability (ie, functional trajectory) before and after surgery in older adults has not been well-studied for most operations. Methods: Prospective cohort study of 754 community-living persons 70 years or older. The analytic sample included 250 participants who underwent their first major surgery during the study period. Results: Before surgery, 4 functional trajectories were identified: no disability (n = 60, 24.0%), and mild (n = 84, 33.6%), moderate (n = 73, 29.2%), and severe (n = 33, 13.2%) disability. After surgery, 4 functional trajectories were identified: rapid (n = 39, 15.6%), gradual (n = 76, 30.4%), partial (n = 70, 28.0%), and little (n = 57, 22.8%) improvement. Rapid improvement was seen for n = 31 (51.7%) participants with no disability before surgery, but was uncommon among those with mild disability (n = 8, 9.5%) and was not observed in the moderate and severe trajectory groups. For participants with mild to moderate disability before surgery, gradual improvement (n = 46, 54.8%) and partial improvement (n = 36, 49.3%) were most common. Most participants with severe disability (n = 27, 81.8%) before surgery exhibited little improvement. Outcomes were better for participants undergoing elective versus nonelective surgery. Conclusions: Functional prognosis in the year after major surgery is highly dependent on premorbid function.https://ift.tt/2QyE3XO
Response: “Which is the True Role of Bridging Therapies for HCC Patients Waiting for Liver Transplantation?”
No abstract availablehttps://ift.tt/2PlfWj2
The Challenge of Measuring Surgeon Spending for Payment Policies
Objective: Our objective was to understand the reliability of profiling surgeons on average health care spending. Summary of Background Data: Under its Merit-based Incentive Payment System (MIPS), Medicare will measure surgeon spending and tie performance to payments. Although the intent of this cost-profiling is to reward low-cost surgeons, it is unknown whether surgeons can be accurately distinguished from their peers. Methods: We used Michigan Medicare and commercial payer claims data to construct episodes of surgical care and to calculate average annual spending for individual surgeons. We then estimated the "reliability" (ie, the ability to distinguish surgeons from their peers) of these cost-profiles and the case-volume that surgeons would need in order to achieve high reliability [intraclass correlation coefficient (ICC) >0.8]. Finally, we calculated the reliability of 2 alternative methods of profiling surgeons (ie, using multiple years of data and grouping surgeons by hospitals). Results: We found that annual cost-profiles of individual surgeons had poor reliability; the ICC ranged fromhttps://ift.tt/2PnmgGu
Developing Safe Opioid Prescribing Practices Through Medical Student Education
No abstract availablehttps://ift.tt/2QxThwm
Succeeding in New Cardiac Bundles: Lessons from History, Directions for the Future
No abstract availablehttps://ift.tt/2QxmI1C
WWP2 Is One Promising Novel Oncogene
Abstract
WWP2 is an E3 ubiquitin ligase and plays an important role in regulation of many cellular biological activities through ubiquitination and degradation of its substrates. Recently accumulating evidences indicate that WWP2 plays a crucial part in the pathogenesis in different types of tumors. In this report, the role of this gene especially in tumorigenesis was reviewed. WWP2 is dysregulated in various of tumors, and it promotes carcinogenesis mainly through PTEN/Akt signaling pathway. WWP2 also participates in anti-cancer agents' sensitivity, indicating WWP2 may be a novel target for cancer treatment. WWP2 is one promising novel oncogene.
https://ift.tt/2Pk4qo7
Clinical and patient-reported outcomes after image-guided intra-articular therapeutic hip injections for osteoarthritis-related hip pain: a retrospective study
Abstract
Objective
To evaluate change in patient-reported outcomes following image-guided intra-articular therapeutic steroid hip injections for pain and assess correlations of outcomes with patient- and injection-specific factors.
Materials and methods
We retrospectively reviewed consecutive patients treated for hip pain who completed outcomes assessments from October 2011 to September 2017 at an outpatient orthopedic surgery clinic. Only patients with radiographic hip osteoarthritis (Tönnis grade ≥ 1) who underwent steroid hip injections were included. Outcomes assessments included EuroQol-5 domain (EQ5D), EQ5D-visual analog scale (VAS), and hip disability and osteoarthritis outcome score (HOOS), obtained before and within 1–6 months post-injection. Among 113 patients who completed surveys, the mean age was 59 years (±13.7 years), including 77 women (68%) and 36 men (32%). Time to repeat injection or arthroplasty was recorded. Exact Wilcoxon signed rank test assessed score differences and Spearman correlation, Kruskal–Wallis, and Mann–Whitney tests assessed correlations.
Results
Of 113 patients, 34 had outcomes measured at <8 weeks and 79 at ≥8 weeks. There was no significant change among any of the patients, short- or long-term follow-up subgroups in EQ5D (p = 0.450, 0.770, 0.493 respectively), EQ5D-VAS (p = 0.581, 0.915, 0.455), average-HOOS (p = 0.478, 0.696, 0.443) or total-HOOS (p = 0.380, 0.517, 0.423) scores. Forty-nine patients underwent hip arthroplasty within 1 year. Positive correlation was found between days from injection to surgery and change in EQ5D (r = 0.29, p = 0.025), average-HOOS (r = 0.33, p = 0.019), and total-HOOS (r = 0.37, p = 0.008).
Conclusion
We demonstrated no significant change in patient-reported outcomes measured at short- and long-term intervals up to 6 months after therapeutic steroid hip injections.
https://ift.tt/2OBsU74
Early-Onset Neonatal Pneumococcal Infection: A Problem Deserving More RecognitionA Case Report and Review of the Literature
Streptococcus pneumoniae (SP) is a major cause of morbidity in childhood but has accounted for only a few reported cases of early-onset neonatal sepsis. Over the past decade, there have been increasing reports of early-onset neonatal sepsis due to SP associated with fulminant systemic disease and high mortality rates. Simultaneous maternal and neonatal sepsis with SP is relatively unusual. The literature reports rare cases of vaginal carriage and/or endometritis with this organism resulting in neonatal sepsis. We present a case of neonatal pneumococcal serotype 1 sepsis and cellulitis occurring concurrently with puerperal pneumococcal bacteremia. A male neonate was born at 38 weeks' gestation after a normal pregnancy. Although he was administered the appropriate antibiotics, the baby developed nape cellulitis and sepsis on the second day of life with SP that progressed to abscess formation requiring surgical drainage. The mother simultaneously developed pneumococcal bacteremia and endometritis 2 hours after delivery. Blood culture isolates from the mother and child were both serogroup 1. Transmission to the neonate may have been ascending or hematogenous. In addition, we summarize the neonate and maternal characteristics, clinical courses, and outcomes of published case reports of early-onset neonatal pneumococcal sepsis in the peer-reviewed literature. Our case highlights the need to consider SP as a cause of neonatal sepsis that can mimic early-onset group B streptococcal infection. Recognition of resistant strains in cases of bacteremia and meningitis is critical, and should be considered in choice of antibiotic therapy. Enhanced surveillance for the maternal carriage of SP and invasive pneumococcal disease during the neonatal period would help to define the epidemiology. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Correspondence to: Sarah S. Alsubaie, MD, Department of Pediatrics, College of Medicine, King Saud University, King Saud University Medical City, PO Box 2925, Riyadh 11461, Saudi Arabia. E-mail: salsubaie@ksu.edu.sa. The author has no funding or conflicts of interest to disclose. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2yX3Nqf
https://ift.tt/2yX3Nqf
How right hemisphere damage after stroke can impair speech comprehension
Abstract
Acquired language disorders after stroke are strongly associated with left hemisphere damage. When language difficulties are observed in the context of right hemisphere strokes, patients are usually considered to have atypical functional anatomy. By systematically integrating behavioural and lesion data from brain damaged patients with functional MRI data from neurologically normal participants, we investigated when and why right hemisphere strokes cause language disorders. Experiment 1 studied right-handed patients with unilateral strokes that damaged the right (n = 109) or left (n = 369) hemispheres. The most frequently impaired language task was: auditory sentence-to-picture matching after right hemisphere strokes; and spoken picture description after left hemisphere strokes. For those with auditory sentence-to-picture matching impairments after right hemisphere strokes, the majority (n = 9) had normal performance on tests of perceptual (visual or auditory) and linguistic (semantic, phonological or syntactic) processing. Experiment 2 found that these nine patients had significantly more damage to dorsal parts of the superior longitudinal fasciculus and the right inferior frontal sulcus compared to 75 other patients who also had right hemisphere strokes but were not impaired on the auditory sentence-to-picture matching task. Damage to these right hemisphere regions caused long-term speech comprehension difficulties in 67% of patients. Experiments 3 and 4 used functional MRI in two groups of 25 neurologically normal individuals to show that within the regions identified by Experiment 2, the right inferior frontal sulcus was normally activated by (i) auditory sentence-to-picture matching; and (ii) one-back matching when the demands on linguistic and non-linguistic working memory were high. Together, these experiments demonstrate that the right inferior frontal cortex contributes to linguistic and non-linguistic working memory capacity (executive function) that is needed for normal speech comprehension. Our results link previously unrelated literatures on the role of the right inferior frontal cortex in executive processing and the role of executive processing in sentence comprehension; which in turn helps to explain why right inferior frontal activity has previously been reported to increase during recovery of language function after left hemisphere stroke. The clinical relevance of our findings is that the detrimental effect of right hemisphere strokes on language is (i) much greater than expected; (ii) frequently observed after damage to the right inferior frontal sulcus; (iii) task dependent; (iv) different to the type of impairments observed after left hemisphere strokes; and (v) can result in long-lasting deficits that are (vi) not the consequence of atypical language lateralization.https://ift.tt/2RJ5KNO
DNA Sliding Clamps as Therapeutic Targets.
 | Related Articles |
DNA Sliding Clamps as Therapeutic Targets.
Front Mol Biosci. 2018;5:87
Authors: Altieri AS, Kelman Z
Abstract
Chromosomal DNA replication is achieved by an assembly of multi-protein complexes at the replication fork. DNA sliding clamps play an important role in this assembly and are essential for cell viability. Inhibitors of bacterial (β-clamp) and eukaryal DNA clamps, proliferating cell nuclear antigen (PCNA), have been explored for use as antibacterial and anti-cancer drugs, respectively. Inhibitors for bacterial β-clamps include modified peptides, small molecule inhibitors, natural products, and modified non-steroidal anti-inflammatory drugs. Targeting eukaryotic PCNA sliding clamp in its role in replication can be complicated by undesired effects on healthy cells. Some success has been seen in the design of peptide inhibitors, however, other research has focused on targeting PCNA molecules that are modified in diseased states. These inhibitors that are targeted to PCNA involved in DNA repair can sensitize cancer cells to existing anti-cancer therapeutics, and a DNA aptamer has also been shown to inhibit PCNA. In this review, studies in the use of both bacterial and eukaryotic sliding clamps as therapeutic targets are summarized.
PMID: 30406112 [PubMed]
https://ift.tt/2SZMOfi
Vaccine adjuvant ARNAX promotes mucosal IgA production in influenza HA vaccination.
 | Related Articles |
Vaccine adjuvant ARNAX promotes mucosal IgA production in influenza HA vaccination.
Biochem Biophys Res Commun. 2018 Nov 04;:
Authors: Takeda Y, Takaki H, Fukui-Miyazaki A, Yoshida S, Matsumoto M, Seya T
Abstract
Adjuvant stimulates pattern-recognition receptors (PRRs) expressed by dendritic cells, which causes immune-enhancing of T lymphocytes. Adjuvant also induces innate immune response in whole-body cells via PRRs to evoke cytokinemia. A cytokine-mediated immune response is important for the systemic protection of a host from microbial infections. Using an influenza subcomponent vaccine in a mouse model, we intranasally administered a TLR3-specific adjuvant ARNAX + HA split vaccine to mice. ARNAX efficiently induced mucosal IgA and systemic IgG production by nasal drop. Moreover, ARNAX + HA simultaneously induced CD8 and CD4 T cell activation. We have previously shown that ARNAX does not induce harmful systemic cytokine production. Thus, our findings indicate that the ARNAX + HA vaccine is a harmless prophylactic vaccine for flu that induces HA-specific T cell activation and IgA/IgG production. These results suggested that ARNAX + antigen enhanced the immune response without inducing inflammatory toxicity for vaccination against infectious diseases.
PMID: 30404733 [PubMed - as supplied by publisher]
https://ift.tt/2z2Oufv
Gender Bias Produces Gender Gaps in STEM Engagement
Abstract
We explored whether the existence of gender bias causes gender gaps in STEM engagement. In Experiment 1 (n = 322), U.S. women projected less sense of belonging, positivity toward, and aspirations to participate in STEM than did men when exposed to the reality of STEM gender bias. These gender differences disappeared when participants were told that STEM exhibits gender equality, suggesting that gender bias produces STEM gender gaps. Experiment 2 (n = 429) explored whether results generalized to a specific STEM department, and whether organizational efforts to mitigate gender bias might shrink gender gaps. U.S. women exposed to a biased chemistry department anticipated more discrimination and projected less sense of belonging, positive attitudes and trust and comfort than did men. These gender differences vanished when participants read about an unbiased department, again suggesting that gender bias promotes STEM gender gaps. Further, moderated mediation analyses suggested that in the presence of gender bias (but not gender equality), women projected less positive attitudes and trust and comfort than did men because they experienced less sense of belonging and anticipated more discrimination. Results were largely unaffected by whether departments completed a diversity training, suggesting that knowledge of diversity initiatives alone cannot close STEM gender gaps.
https://ift.tt/2Qzlpzk
The Relationship Between Sexualized Appearance and Perceptions of Women’s Competence and Electability
Abstract
Women do not have a uniform or standardized "suit" to wear in the workplace so they must make daily decisions about what to wear. Some propose that women should dress in a sexualized way to gain power and influence, but sexy attire is related to lower perceptions of competence for women in leadership positions. We explored the effect of revealing or conservative attire on perceptions of women's leadership competence. We also used eye-tracker technology to determine whether looking at sexualized body parts (i.e., breasts, hemline) was related to lower perceptions of leadership competence and electability. A female candidate for a student senate presidency at a U.S. university wearing revealing clothing was perceived by 191 college students as less honest and trustworthy, electable, and competent than one wearing conservative clothing. Sexualized body parts were looked at longer when the candidate was wearing revealing clothing compared to conservative clothing. Furthermore, mediation analyses indicated that the revealing clothing led participants to gaze at sexualized body parts, which, in turn, led to perceiving the candidate as less honest/trustworthy, which lowered their evaluations of her competence and electability. These findings suggest that viewing a woman in a sexy outfit can lead others to stare more at her body and make negative evaluations of her personal attributes. This finding has implications for the choices women make in workplace and leadership contexts.
https://ift.tt/2Pi3ZKR
Expression of Concern to IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation
Expression of Concern to IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation
Expression of Concern to IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation, Published online: 09 November 2018; doi:10.1038/s41419-018-1175-8
Expression of Concern to IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiationhttps://ift.tt/2OAUEbD
Eribulin in the treatment of advanced breast cancer: real-world scenario from 39 Italian centers – ESEMPiO study
Future Oncology, Ahead of Print.
https://ift.tt/2QtEOS5
Combination immunotherapy in metastatic renal cell carcinoma. Are we leaving something back?
Future Oncology, Ahead of Print.
https://ift.tt/2PltTNX
Breast microcalcifications: biological and diagnostic perspectives
Future Oncology, Ahead of Print.
https://ift.tt/2PhdhXo
Two-Drug Cocktail Active against RCC [News in Brief]
Avelumab and axitinib boosted progression-free survival by 64% over sunitinib.
https://ift.tt/2RGxXF8
SPRED1 Is a Tumor Suppressor in Mucosal Melanoma [Research Watch]
Targeted sequencing identifies biallelic SPRED1 inactivation in 16 of 43 patients with mucosal melanoma.
https://ift.tt/2RM8Ctf
MITF Synchronizes UV-Protection Programs in the Skin [Research Watch]
MITF controls the balance between the skin stress response and pigmentation in response to UV.
https://ift.tt/2RGSgCe
ALKBH1 Promotes N6-methyladenine DNA Modifications in Glioblastoma [Research Watch]
The DNA demethylase ALKBH1 promotes glioblastoma stem cell (GSC) growth and tumorigenesis.
https://ift.tt/2DvOkBd
Alpelisib Extends PFS in PIK3CA-Mutant Breast Cancer [News in Brief]
PI3Kα inhibitor improves outcomes for biomarker-defined subset of patients.
https://ift.tt/2DyYfpZ
A Screen of C2H2 Zinc Fingers Reveals Degrons Targeted by Thalidomide [Research Watch]
A screen identified 15 C2H2 zinc finger degrons that are degraded by thalidomide analogues.
https://ift.tt/2RRLx8T
FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma
In October 2017, the U.S. Food and Drug Administration granted regular approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor (CAR) T cell therapy, for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Efficacy was based on complete remission (CR) rate and duration of response (DOR) in 101 adult patients with relapsed or refractory large B-cell lymphoma (median 3 prior systemic regimens) treated on a single-arm trial. Patients received a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine. The objective response rate per independent review committee was 72% (95% CI: 62, 81) with a CR rate of 51% (95% CI: 41, 62). With a median follow-up of 7.9 months, the median DOR was not reached in patients achieving CR (95% CI: 8.1 months, not estimable [NE]), whereas patients with partial remission had an estimated median DOR of 2.1 months (95% CI: 1.3, 5.3). Among 108 patients evaluated for safety, serious adverse reactions occurred in 52%. Cytokine release syndrome and neurologic toxicities occurred in 94% and 87% of patients, respectively, leading to implementation of a Risk Evaluation and Mitigation Strategy.
https://ift.tt/2zGsBlL
Treatment-induced tumor cell apoptosis and secondary necrosis drive tumor progression in the residual tumor microenvironment through MerTK and IDO-1
Efferocytosis [phagocytic apoptotic cell (AC) clearance] removes AC before they undergo secondary necrosis and leak inflammation-inducing intracellular contents. Efferocytosis concurrently increases immunosuppressive cytokines and leukocytes, limiting tissue damage, promoting tolerance to AC-derived antigens, and maintaining tissue homeostasis. Thus, tumor cell efferocytosis following cytotoxic cancer treatments could have deleterious consequences in tumor residual disease (RD). We report here that efferocytosis clears tumor AC in RD of lapatinib-treated HER2+ mammary tumors, increasing immunosuppressive cytokines, myeloid-derived suppressor cells (MDSC), regulatory T cells (TRegs), and metastasis. Although efferocytosis blockade caused secondary AC necrosis and induced interferon (IFN)-γ, tumor MDSC, TRegs, and immunosuppressive cytokines remained prevalent due to IFNγ-induced indoleamine-2,3-dioxegenase (IDO)-1, an immune regulator known for driving maternal-fetal antigen tolerance. Combined inhibition of efferocytosis and IDO-1 in tumor RD decreased AC-induced and NC-induced immunosuppressive phenotypes, blocked tumor metastasis, and caused tumor regression in 60% of cases. This suggests that AC and NC promote tumor 'homeostasis' and progression via efferocytosis.
https://ift.tt/2T0btQP
Loss of the BCR-FGFR1 GEF domain suppresses RHOA activation and enhances B-lymphomagenesis in mice
Transformation of hematopoietic stem cells by the BCR-FGFR1 fusion kinase found in a variant of Stem Cell Leukemia/Lymphoma (SCLL) syndrome leads to development of B-lymphomas in syngeneic mice and humans. In this study, we show that the relatively rapid onset of this leukemia is potentially related to oncogenic domains within the BCR component. BCR recruited a guanidine nucleotide exchange factor (GEF) domain to the fusion kinase to facilitate activation of small GTPases such as RHOA. Deletion of this GEF domain increased leukemogenesis, enhanced cell survival and proliferation, and promoted stem cell expansion and lymph node metastasis. This suggests that, in an SCLL context, the presence of the endogenous GEF motif leads to reduced leukemogenesis. Indeed, loss of the GEF domain suppressed activation of RHOA and PTEN, leading to increased activation of AKT. Loss of the GEF domain enhanced cell proliferation and invasion potential, which was also observed in cells in which RHOA is knocked down, supported by the observation that overexpression of RHOA leads to reduced viability and invasion. In vivo, depletion of RHOA in SCLL cells significantly increased disease progression and shortened latency. Collectively, these data show that the BCR GEF domain affects phenotypes associated with progression of SCLL through suppression of RHOA signaling.
https://ift.tt/2zGapJ8
The reciprocity between radiotherapy and cancer immunotherapy
The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in treating locally advanced diseases, thus requiring them to be combined with standard treatments in hope to produce synergistic antitumor responses. Radiotherapy in particular, has long been hypothesized to have actions complementary to those of immune checkpoint blockade, and a growing body of evidence indicates that cancer immunotherapy may also have radiosensitizing effects, which would provide unique benefit for locoregional treatments. Recent studies have demonstrated that when immune cells are activated by immunotherapeutics, they can reprogram the tumor microenvironment in ways that may potentially increase the radiosensitivity of the tumor. In this review, we highlight the evidence that supports reciprocal interactions between cancer immunotherapy and radiotherapy, where in addition to the traditional notion that radiation serves to enhance the activation of antitumor immunity, an alternative scenario also exists in which T-cell activation by cancer immunotherapy may sensitize tumors to radiation treatment through mechanisms that include normalization of the tumor vasculature and tissue hypoxia. We describe the empirical observations from preclinical models that support such effects and discuss their implications for future research and trial design.
https://ift.tt/2T0ZhPJ
Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody-Drug Conjugate Mirvetuximab Soravtansine
Purpose: Reversible, low-grade ocular adverse events (AEs) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeted antibody-drug conjugate undergoing Phase III clinical evaluation in platinum-resistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine. Experimental Design: Target expression in the human eye was determined by immunohistochemistry. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a Phase I clinical study, ovarian cancer patients were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle. Results: FRα expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients respectively; no grade 3/4 ocular events were observed. Compared to those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% versus 15%) and none discontinued due to ocular AEs. Conclusions: Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend towards symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine.
https://ift.tt/2T0ZgLF
Predicting Outcome in Head and Neck Cancer: miRNAs with potentially big effects
A five-microRNA signature for HPV negative head and neck squamous cell carcinoma (HNSCC) identifies patients at risk for inferior outcomes. Combining established clinical variables with this novel microRNA signature affords an opportunity to personalize and intensify treatment strategies in this high-risk patient population.
https://ift.tt/2zGArMj
Frequent homologous recombination deficiency in high-grade endometrial carcinomas.
Purpose The elevated levels of somatic copy number alterations (SCNA) in a subset of high-risk endometrial cancers (EC) are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in EC and its association with histopathological and molecular characteristics. Experimental Design Fresh tumor tissue was prospectively collected from 36 EC, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars-a surrogate marker for HRD-was determined in the TCGA EC cohort. Results Most EC included in the final analysis (n=25) were of non-endometrioid (52%), grade 3 (60%) histology and FIGO-stage I (72%). HRD was observed in 24% (n=6) of cases and was restricted to non-endometrioid EC (NEEC), with 46% of NEEC being HRD compared to none of the endometrioid EC (EEC, P=0.014). All but one of the HRD cases harboured either a pathogenic BRCA1 variant or high somatic copy number losses of HR genes. Analysis of TCGA cases supported these results, with BRCA-associated genomic scars present in up to 48% (63/132) of NEEC vs. 12% (37/312) of EEC (P<0.001). Conclusions HRD occurs in EC, and is largely restricted to non-endometrioid, TP53-mutant EC. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors.
https://ift.tt/2T0bsML
Domain Requirements and Genetic Interactions of the Mud1 Subunit of the Saccharomyces cerevisiae U1 snRNP
Mud1 is an inessential 298-amino acid protein subunit of the Saccharomyces cerevisiae U1 snRNP. Mud1 consists of N-terminal and C-terminal RRM domains (RRM1 and RRM2) separated by a linker domain. Synthetic lethal interactions of mud1 with deletions of inessential spliceosome components Nam8, Mud2, and Msl1, or missense mutations in the branchpoint-binding protein Msl5 enabled us to dissect genetically the domain requirements for Mud1 function. We find that the biological activities of Mud1 can be complemented by co-expressing separately the RRM1 (aa 1-127) and linker-RRM2 (aa 128-298) modules. Whereas RRM1 and RRM2 (aa 197-298) per se are inactive in all tests of functional complementation, the linker-RRM2 by itself partially complements a subset of synthetic lethal mud1 interactions. Linker segment aa 155 to 196 contains a nuclear localization signal rich in basic amino acids that is necessary for RRM2 activity in mud1 complementation. Alanine scanning mutagenesis indicates that none of the individual RRM1 amino acid contacts to U1 snRNA in the cryo-EM model of the yeast U1 snRNP is necessary for mud1 complementation activity.
https://ift.tt/2QtueKY
American Academy of Pediatrics, Nov. 2-6
The American Academy of Pediatrics National Conference and Exhibition The annual meeting of the American Academy of Pediatrics was held from Nov. 2 to 6 in Orlando, Florida, and attracted approximately 12,000 participants from around the world,...
https://ift.tt/2PQDJqr
Many Women Have Not Heard of Ovarian Cancer Before Dx
FRIDAY, Nov. 9, 2018 -- Many women are not knowledgeable about ovarian cancer before diagnosis despite most women experiencing prediagnosis symptoms, according to a report published online Oct. 18 by the World Ovarian Cancer Coalition. Researchers...
https://ift.tt/2DcTAJ7
FDA to Ban Most Flavored Electronic Cigarettes
FRIDAY, Nov. 9, 2018 -- As part of the U.S. Food and Drug Administration's efforts to reduce teens' use of flavored electronic cigarettes, a ban on sales of most flavored e-cigarettes in retail stores and gas stations across the United States is to...
https://ift.tt/2PRVw0c
CDC: Gun Deaths on the Rise in the United States
FRIDAY, Nov. 9, 2018 -- Homicides and suicides involving guns are on the rise in the United States, according to a federal government study. The study revealed that in 2015 to 2016, there were 27,394 homicides involving a gun and 44,955 suicides...
https://ift.tt/2DeZfP3
Quick New Ebola Test Approved by FDA
FRIDAY, Nov. 9, 2018 -- A fast, single-use fingerstick test for infection with the Ebola virus has been approved by the U.S. Food and Drug Administration. The emergency use authorization (EUA) is for the DPP Ebola Antigen System. It analyzes blood...
https://ift.tt/2PScY50
Simultaneous transabdominal preperitoneal hernia repair and laparoscopic cholecystectomy: A report of 17 cases
Abstract
Introduction
Inguinal hernia repair and cholecystectomy are frequently performed in the field of gastrointestinal surgery. However, reports describing surgical procedures that involve simultaneous transabdominal preperitoneal hernia repair (TAPP) and laparoscopic cholecystectomy (LC), as well as the safety and usefulness of this combination, are limited. Herein, we report a surgical procedure involving simultaneous TAPP and LC (TAPP + LC) and present the outcomes of patients who have undergone this combined surgical procedure, with a particular focus on its safety and usefulness.
Methods
We simultaneously performed TAPP + LC in 17 patients (mean age, 66.5 ± 8.1 years) with concomitant inguinal hernia and gallbladder stones. We assessed surgical outcomes.
Results
The mean operative time was 157 ± 39 min, and mean postoperative hospital stay was 3.2 ± 0.6 days. The median cost was $7673 for TAPP + LC. The mean postoperative length of hospital stay was 1.1 ± 0.6 day for TAPP alone and 3.4 ± 1.4 days for LC alone. The median costs of TAPP alone and LC alone were $4932 and $5453, respectively. Regarding intraoperative complications, the inferior epigastric vessels were damaged in two patients, and seroma was detected as a postoperative complication in one; these complications were spontaneously resolved. No mesh‐ or infection‐related complications were noted.
Conclusion
Simultaneous TAPP + LC is safe and can be regarded as a standard surgical procedure for patients with concomitant inguinal hernia and gallbladder stones. The TAPP + LC combination appears to help prevent the need for two hospitalizations and, thereby, reduces hospital stay and economic burden.
https://ift.tt/2PivwMe
Successful single‐stage laparoscopic surgery using a preoperative self‐expanding metallic stent in patients with obstructive colorectal cancer
Abstract
Introduction
Although a self‐expanding metallic stent (SEMS) or a transnasal or transanal decompression tube is sometimes used as a bridge to surgery in patients with obstructive colorectal cancer, the optimal decompression procedure to achieve successful laparoscopic surgery remains unclear.
Methods
Forty‐two patients with obstructive colorectal cancer who were preoperatively decompressed by using SEMS (the SEMS group, n = 20) or a decompression tube (the DT group, n = 22) between January 2010 and February 2017 were included in this retrospective study.
Results
In the SEMS group, 20 patients (100%) were able to eat and 17 patients (85%) were able to undergo total colonoscopy preoperatively, but no patients could do so in the DT group (P < 0.01 and P < 0.01, respectively). The serum albumin level increased in the time between admission and just before surgery in five patients in the SEMS groups (25%), whereas it decreased in all patients in the DT group (P = 0.037). Laparoscopic surgery was performed more frequently in the SEMS groups (19 patients, 95%) than in the DT group (13 patients, 59.1%) (P = 0.018). Primary anastomosis without stoma was also achieved more frequently in the SEMS groups (19 patients, 95%) than in the DT group (15 patients, 68.2%) (P = 0.047). Anastomotic leakage did not occur in the SEMS group, but it did occur in one patient in the DT group. The recurrence‐free survival rate did not differ between the groups (median follow‐up period: 21 months).
Conclusion
In patients with obstructive colorectal cancer, SEMS appears to be more effective than a decompression tube as a preoperative treatment to achieve successful laparoscopic resection without stoma.
https://ift.tt/2QxOFXd
Laparoscopic para‐aortic lymphadenectomy for colorectal cancer with clinically suspected lymph node metastasis
Abstract
Introduction
The optimal surgical management strategy for isolated para‐aortic lymph node (PALN) metastases from colorectal cancer (CRC) remains unclear. However, the complication rates for open approaches remain high. In this study, the outcomes of laparoscopic para‐aortic lymphadenectomy in patients with clinically suspected PALN metastasis were evaluated.
Methods
Between April 2013 and April 2018, we performed laparoscopic primary resection and para‐aortic lymphadenectomy in 11 patients with advanced colorectal cancer and clinically suspected PALN metastasis. This study was a single‐center, retrospective, case series analysis, and the surgical outcomes were reviewed.
Results
There were no cases of perioperative mortality, and conversion to open surgery was necessary in only one patient (9%) because of invasion into a rib. One patient (9%) required a blood transfusion. Postoperative complications occurred in three patients, and the morbidity rate was 27% (3/11). Pathologically, PALN metastasis was confirmed in five patients (45%), all of whom received postoperative chemotherapy. The median survival time for all patients was 25 months, and one patient died of recurrence at 25 months after the initial surgery. Two other patients were alive with recurrence after 47 and 36 months, and two patients were alive without recurrence after 17 and 2 months.
Conclusion
Laparoscopic para‐aortic lymphadenectomy for advanced colorectal cancer with clinically suspected PALN is technically feasible and may be beneficial in selected patients. It is necessary to investigate the feasibility of this procedure in a future case series, and information regarding true oncologic outcome will require long‐term follow‐up.
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Operative outcomes after laparoscopic splenectomy with special reference to prophylactic antibiotics
Abstract
Introduction
We conducted a retrospective study to investigate the progress of the operative outcome after laparoscopic splenectomy (LS), with a special reference to the administration of prophylactic antibiotics (PA).
Methods
The study included 123 patients who underwent elective LS. Operative outcomes before and after the operative procedure was standardized and the impact of treatment with PA on surgical‐site infection were investigated.
Results
With regard to complications, wound infection developed in one (0.8%), portal trunk thrombosis in one (0.8%), pancreatic fistula in one (0.8%), postoperative bleeding in two (1.6%), pleural effusion in one (0.8%), and reoperation because of bowel injury in one (0.8%). Although morbidity did not differ between patients in the early (until the end of 2010) and late (after the beginning of 2011) periods, intraoperative blood loss was lower in patients in the late period. During the late period, no patients required conversion to open surgery. The proportion of patients with surgical‐site infection did not differ between those who received PA 1 h before the start of surgery and every 3 h during surgery and those who received PA 1 h before the start of surgery, every 3 h during surgery, and twice a day for 24–72 h after surgery.
Conclusion
Operative outcomes after LS improved after the standardization of the operative procedure. The administration of PA 1 h before surgery and every 3 h during surgery seems to be sufficient to prevent surgical‐site infection during LS.
https://ift.tt/2Qyc7mU
Mediastinoscopic salvage esophagectomy for recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy in a previously pneumonectomized patient
Abstract
We herein report a case of mediastinoscopic salvage esophagectomy for recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy in a previously pneumonectomized patient. A 66‐year‐old man with a medical history of left‐sided pneumonectomy for lung cancer was diagnosed with local recurrence of lower esophageal squamous cell carcinoma (cT3N0M0 cStage II) 9 years after definitive chemoradiotherapy. The mediastinoscopic cervical approach and laparoscopic transhiatal approach were combined, and the thoracic esophagus was safely mobilized to separate the esophagus from the stump of the left bronchus and to divide dense adhesions between the esophagus and fibrotic tissue at the site of the previous left mediastinal pleural resection. The esophagectomy was uneventful and followed by reconstruction with a gastric conduit via the retrosternal route. The pathological diagnosis was esophageal squamous cell carcinoma (pT3‐AD, pN1, M0, pStage III), indicating R0 resection. Even as salvage surgery, mediastinoscopic esophagectomy is a safe and curative treatment strategy for esophageal cancer patients who have previously undergone pneumonectomy.
https://ift.tt/2PorvGh
Laparoscopic rectal tumor surgery after administration of a new sclerosing therapy (aluminum potassium sulfate and tannic acid injection) for internal hemorrhoids: A report of three cases
Abstract
Aluminum potassium sulfate and tannic acid (ALTA) injection is a new sclerosing therapy for internal hemorrhoids that has been gaining widespread use. However, there have been few reports about rectal cancer after ALTA injection. We performed laparoscopic surgery for three patients who had underwent ALTA therapy 6 months or 1 year earlier: (i) a 51‐year‐old man with neuroendocrine tumor; (ii) a 44‐year‐old woman with rectal cancer; and (iii) 77‐year‐old man with rectal cancer. All three patients had sclerosis of the resected rectal wall stump, making transection of the rectum difficult. Histological examination of the specimens also showed an inflammatory reaction and/or fibrosis of the resection stump. Although laparoscopic low anterior resection was planned for all three patients, we had to construct a diverting stoma for two patients and could not perform sphincter‐preserving surgery for the other. We must be well prepared for laparoscopic rectal surgeries after ALTA therapy, and these cases suggest sigmoidoscopy before ALTA therapy should be recommended.
https://ift.tt/2QECkQI
Distribution of disease courses in familial versus sporadic multiple sclerosis
Abstract
Objectives
The overall distribution of disease courses in multiple sclerosis (MS) is well established, but little is known about the distribution among familial MS cases. We examine the frequency of the different MS courses among familial and sporadic MS cases and determine whether MS cases within the same family had the same age at diagnosis and have experienced the same disease course.
Materials and methods
This is a nationwide register study, based on data from the Danish MS Registry, the Danish Civil Registration System and the Danish National Patient Registry. The main variables are MS diagnosis, MS course and 1st degree relatives with MS. The statistical analyses were carried out using logistic regression analysis, Kappa coefficient and intraclass correlations coefficient.
Results
In total 7,402 MS cases where included in the study, of which 531 have an affected first‐degree relatives, and 6,871 are sporadic. We found that relapsing remitting MS including secondary progressive MS was more common among familial MS cases than among sporadic MS cases (Odds ratio=1.64, 95% CI: 1.20‐2.24, p=0.002).
We subsequently analysed data on 133 MS families and found that MS courses correlate between the first and the second MS case diagnosed, while age at diagnosis does not.
Conclusion
Familial MS cases are more likely to have relapsing‐remitting MS than a progressive course compared to sporadic MS cases. Secondly, we find that within MS families, first‐degree relatives are likely to have the same MS course, but we do not find that they are diagnosed at the same age.
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Marked response to nivolumab combined with external radiation therapy for metastatic renal cell carcinoma: report of two cases
Abstract
Although nivolumab has been regarded as a standard agent for patients with previously treated advanced renal cell carcinoma (RCC), a significant proportion of these patients fail to achieve a response to nivolumab. In recent years, several studies have reported the favorable therapeutic impact of combined therapy with immune checkpoint inhibitors and radiotherapy on a wide variety of advanced malignant tumors, such as melanoma and lung cancer; however, the significance of this combined treatment for advanced RCC patients has not been well characterized. Here, we report two patients with metastatic RCC showing a marked response to nivolumab and external radiation therapy, including one with an abscopal response, after progression on prior treatment with multiple targeted agents. Based on the clinical courses of these two patients suggesting additive or synergistic efficacies on combining radiation with nivolumab, it might be worthwhile to consider the addition of radiotherapy for metastatic RCC patients treated with nivolumab.
https://ift.tt/2FpeeIX
Yeast ( Saccharomyces cerevisiae ) and its effect on production indices of livestock and poultry—a review
Abstract
Improved feed efficiency is the current drive of today's livestock enterprise and this may be actualized using feed supplementation. The use of natural growth promoting products in livestock feed is on the increase because of the ban on the use of antibiotics in feed by the European Union (EU). The use of antibiotics in animal feed has been reported to increase antimicrobial resistance and this has made animal nutritionist search for natural alternatives to antibiotics. Yeast, one of such natural alternatives in animal production, has received great attention in the last couple of decades. Research has shown that about 2500 yeast species exist in nature of which Saccharomyces cerevisiae is prominent. This paper reviews the current body of knowledge on production and physiological indices of livestock and poultry fed yeast diets. The chemical composition, nutritional analysis, and mechanism of actions of yeast were also discussed.
https://ift.tt/2DcqREd
Pathological tumor infiltrative pattern and sites of initial recurrence in stage II/III gastric cancer: Propensity score matching analysis of a multi‐institutional dataset
A multicenter database analysis using propensity score matching revealed that the pathological tumor infiltrative pattern was closely correlated with postoperative recurrence patterns in patients with stage II/III gastric cancer.
Abstract
Background
Advanced gastric cancer frequently recurs even after radical resection followed by adjuvant chemotherapy. The aim of this study was to evaluate the relationship between pathological infiltrative pattern (INF) and initial recurrence patterns in patients with stage II/III gastric cancer using a large multicenter database.
Methods
We retrospectively analyzed 1098 eligible patients who underwent curative gastrectomy for stage II/III gastric cancer at nine institutions between 2010 and 2014. Patients were categorized into the INF‐a/b and INF‐c groups and adjusted using propensity score matching.
Results
After propensity score matching, 686 patients (343 for each) were classified in the INF‐a/b and INF‐c groups. There were no significant differences in overall and disease‐free survival between the two groups. In the INF‐a/b group, frequencies of recurrence at the peritoneum, lymph node, and liver were equivalent. In contrast, the peritoneum was the most frequent site and accounted for 60% of the total recurrences in the INF‐c group. The cumulative peritoneal recurrence rate was significantly higher in the INF‐c group than in the INF‐a/b group (hazard ratio 2.47). INF‐c was a significant risk factor for peritoneal recurrences in most subgroups including age, sex, macroscopic type, tumor differentiation, and disease stage, and whether the postoperative treatment was given. Multivariate analysis identified INF‐c as an independent risk factor for peritoneal recurrences. The cumulative liver recurrence rate was significantly higher in the INF‐a/b group than in the INF‐c group (hazard ratio 3.44).
Conclusions
INF may represent an important predictor of recurrence patterns after curative resection of stage II/III gastric cancer.
https://ift.tt/2PPCE29
Risk factors for brain metastases in patients with non–small‐cell lung cancer
Abstract
Brain metastases (BM) are severe incidents in patients with non–small‐cell lung cancer (NSCLC). The controversial value of prophylactic cranial irradiation (PCI) in NSCLC in terms of survival benefit prompted us to explore the possible risk factors for BM in NSCLC and identify the potential population most likely to benefit from PCI. Risk factors for brain metastases in NSCLC are reviewed in this article. Identifying patients with a higher risk of BM could possibly increase the benefit of PCI while reducing the discomfort and risks caused by unnecessary invasive procedures in the NSCLC patient population. Future studies might focus on finding a solid basis for the prediction of the occurrence of brain metastases and for the therapeutic decision on the use of PCI.
https://ift.tt/2DaYSow
Biallelic COLGALT1 variants are associated with cerebral small vessel disease
Abstract
Objective
Approximately 5% of cerebral small vessel diseases are hereditary, which include COL4A1/COL4A2‐related disorders. COL4A1/COL4A2 encode type IV collagen α1/2 chains in the basement membranes of cerebral vessels. COL4A1/COL4A2 mutations impair the secretion of collagen to the extracellular matrix, thereby resulting in vessel fragility. The diagnostic yield for COL4A1/COL4A2 variants is around 20%–30%, suggesting other mutated genes might be associated with this disease. This study aimed to identify novel genes that cause COL4A1/COL4A2‐related disorders.
Methods
Whole exome sequencing was performed in two families with suspected COL4A1/COL4A2‐related disorders. We validated the role of COLGALT1 variants by constructing a 3D structural model, evaluating ColGalT1 protein expression and ColGalT activity by western blotting and collagen galactosyltransferase assays, and performing in vitro RNA interference and rescue experiments.
Results
Exome sequencing demonstrated biallelic variants in COLGALT1 encoding collagen β (1‐O) galactosyltransferase 1, which was involved in the post‐translational modification of type IV collagen in two unrelated patients: c.452T>G (p.Leu151Arg) and c.1096delG (p.Glu366Argfs*15) in Patient 1, and c.460G>C (p.Ala154Pro) and c.1129G>C (p.Gly377Arg) in Patient 2. 3D model analysis suggested that p.Leu151Arg and p.Ala154Pro destabilized protein folding, which impaired enzymatic activity. ColGalT1 protein expression and ColGalT activity in Patient 1 were undetectable. RNA interference studies demonstrated that reduced ColGalT1 altered COL4A1 secretion, and rescue experiments showed that mutant COLGALT1 insufficiently restored COL4A1 production in cells compared with wild‐type.
Interpretation
Biallelic COLGALT1 variants cause cerebral small vessel abnormalities through a common molecular pathogenesis with COL4A1/COL4A2‐related disorders.
This article is protected by copyright. All rights reserved.
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Magnetic resonance T1w/T2w ratio: A parsimonious marker for Parkinson's disease
Abstract
Objective
Newer MRI techniques have shown promise in capturing early Parkinson's disease (PD)‐related changes in the substantia nigra pars compacta (SNc), the key pathological loci. Their translational value, however, is hindered by technical complexity and inconsistent results.
Methods
A novel yet simple MRI contrast, the T1w/T2w ratio, was used to study 76 PD patients and 70 controls. The T1w/T2w ratio maps were analyzed using both voxel‐based and region‐of‐interest approaches in normalized space. The sensitivity and specificity of the SN T1w/T2w ratio in discriminating between PD and controls also were assessed. In addition, its diagnostic performance was tested in a subgroup of PD patients with disease duration ≤2 years (PDE). A second independent cohort of 73 PD and 49 controls was used for validation.
Results
Compared to controls, PD patients showed a higher T1w/T2w ratio in both the right (cluster size=164 mm3, p<0.0001) and left (cluster size=213 mm3, p<0.0001) midbrain that was located ventrolateral to the red nucleus and corresponded to the SNc. The region‐of‐interest approach confirmed the group difference in the SNc T1w/T2w ratio between PD and controls (p<0.0001). The SNc T1w/T2w ratio had high sensitivity (0.908) and specificity (0.80) to separate PD and controls (AUC=0.926), even for PDE patients (AUC=0.901, sensitivity=0.857, specificity=0.857). These results were validated in the second cohort.
Interpretation
The T1w/T2w ratio can detect PD‐related changes in the SN and may be used as a novel, parsimonious in vivo biomarker for the disease, particularly early stage patients, with high translational value for clinical practice and research.
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Tocilizumab treatment for new‐onset refractory status epilepticus
Abstract
We investigated the therapeutic potential of the interleukin‐6 receptor inhibitor tocilizumab in 7 patients with new‐onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n=5) or without rituximab (n=2). Status epilepticus (SE) was terminated after 1‐2 doses of tocilizumab in six patients with a median interval of three days from the initiation. They had no recurrence of SE during the observation. However, two patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE.
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Brain‐State Dependent Stimulation boosts functional recovery following stroke
Abstract
Objective
Adjuvant protocols devised to enhance motor recovery in subacute stroke patients have failed to show benefits with respect to classic therapeutic interventions. Here we evaluate the efficacy of a novel brain‐state dependent intervention based on known mechanisms of memory and learning, that is integrated as part of the weekly rehabilitation program in subacute stroke patients.
Methods
Twenty‐four hospitalized subacute stroke patients were randomly assigned to two intervention groups; 1. The associative group received thirty pairings of a peripheral electrical nerve stimulus (ES) such that the generated afferent volley arrived precisely during the most active phase of the motor cortex as patients attempted to perform a movement; 2. In the control group the ES intensity was too low to generate a stimulation of the nerve. Functional (including the lower extremity Fugl‐Meyer assessment (LE‐FM; primary outcome measure)) and neurophysiological (changes in motor evoked potentials (MEPs)) assessments were performed prior to and following the intervention period.
Results
The associative group significantly improved functional recovery with respect to the control group (median (interquartile range) LE‐FM improvement: 6.5 (3.5‐8.25) and 3 (0.75‐3), respectively; p=0.029). Significant increases in MEP amplitude were seen following all sessions in the associative group only (p's≤0.006).
Interpretation
This is the first evidence of a clinical effect of a neuromodulatory intervention in the subacute phase of stroke. This was evident with relatively few repetitions in comparison to available techniques, making it a clinically‐viable approach. The results indicate the potential of the proposed neuromodulation system in daily clinical routine for stroke rehabilitation.
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Deep brain stimulation: potential for neuroprotection
Abstract
Over the last two decades there has been an exponential rise in the number of patients receiving deep brain stimulation (DBS) to manage debilitating neurological symptoms in conditions such as Parkinson's disease, essential tremor, and dystonia. Novel applications of DBS continue to emerge including treatment of various psychiatric conditions (e.g. obsessive‐compulsive disorder, major depression) and cognitive disorders such as Alzheimer's disease. Despite widening therapeutic applications, our understanding of the mechanisms underlying DBS remains limited. In addition to modulation of local and network‐wide neuronal activity, growing evidence suggests that DBS may also have important neuroprotective effects in the brain by limiting synaptic dysfunction and neuronal loss in neurodegenerative disorders. In this review, we consider evidence from preclinical and clinical studies of DBS in Parkinson's disease, Alzheimer's disease, and epilepsy that suggest chronic stimulation has the potential to mitigate neuronal loss and disease progression.
https://ift.tt/2AW9AgY
Ductal obstruction promotes formation of pre‐neoplastic lesions from the pancreatic ductal compartment
Pancreatitis is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice have demonstrated that pancreatitis contributes to oncogenic Kras‐driven carcinogenesis, probably initiated in acinar cells; however, oncogenic Kras alone or in combination with caerulein‐induced pancreatitis is not sufficient in initiating PDAC from the ductal compartment. We thus introduced ductal obstruction – which induces a more severe form of pancreatitis – by pancreatic ductal ligation in mice harbouring oncogenic Kras. This induced a particular phenotype with highly proliferative non‐mucinous cells with nuclear atypia. Around these lesions, there was a significant proliferation of activated fibroblasts and infiltration of immune cells, corroborating the pathological features of pre‐neoplastic lesions. Lineage‐tracing experiments revealed that these pre‐neoplastic cells derived from two distinctive cellular sources: acinar and ductal cells. Phenotypic characterisation revealed that the duct‐derived pre‐neoplastic lesions show a high proliferative potential with persistent activation of tumour‐promoting inflammatory pathways while the acinar‐derived ones were less proliferative with persistent p53 activation. Furthermore, the duct‐derived pre‐neoplastic cells have a particularly high nuclear‐to‐cytoplasmic ratio. These data demonstrate that ductal obstruction promotes pre‐neoplastic lesion formation from the pancreatic ductal compartment.
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Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR‐133/PRDM16 pathway
Cancer‐related cachexia is a metabolic syndrome characterized by a wasting disorder of adipose and skeletal muscle and is accompanied by body weight loss and systemic inflammation. The treatment options for cancer cachexia are limited, and the molecular mechanism remains poorly understood. Circular RNAs (circRNAs) are a novel family of endogenous noncoding RNAs that have been proposed to regulate gene expression in mammals. Exosomes are small vesicles derived from cells, and recent studies have shown that circRNAs are stable in exosomes. However, little is known about the biological role of circRNAs in exosomes. In this study, we showed that circRNAs in plasma exosomes have specific expression features in gastric cancer (GC), and ciRS‐133 is linked with the browning of white adipose tissue (WAT) in GC patients. Exosomes derived from GC cells deliver ciRS‐133 into pre‐adipocytes, promoting the differentiation of pre‐adipocytes into brown‐like cells by activating PRDM16 and suppressing miR‐133. Moreover, knockdown of ciRS‐133 reduced cancer cachexia in tumor‐implanted mice, decreasing oxygen consumption and heat production. Thus, exosome‐delivered circRNAs are involved in WAT browning and play a key role in cancer‐associated cachexia.
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Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial
Human papillomavirus (HPV)‐based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case‐control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25‐65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from 257 women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50 <CIN2); Group 2: 103 HPV+, normal cytology with HPV persistence at 12 mo. (53 CIN2/3; 50 <CIN2); Group 3: 50 HPV+, normal cytology with HPV clearance at 12 mo. (assumed <CIN2). For the combined groups, S5 risk score CIN2/3 relative sensitivity, specificity and positive predictive value (PPV) were compared with other triage approaches. Methylation showed a highly significant increasing trend with disease severity. For CIN3, S5 relative sensitivity and specificity were: 93.2% (95%CI: 81.4‐98.0) and 41.8% (35.2‐48.8), compared to 86.4% (75.0‐95.7) and 49.8% (43.1‐56.6) respectively for combined abnormal cytology/HPV16/18 positivity (differences not significant); adjusted PPVs were 18.2% (16.2‐20.4) and 19.3% (16.6‐22.2) respectively. S5 was also positive in baseline specimens from eight cancers detected during or after trial participation. The S5 methylation score had high sensitivity and PPV for CIN3, compatible with US and European thresholds for colposcopy referral. Methylation signatures can identify most HPV positive women at increased risk of cervical cancer from their baseline screening specimens.
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Mutated EPHA2 is a target for combating lymphatic metastasis in intrahepatic cholangiocarcinoma
Exploring the genetic aberrations favoring metastasis is important for understanding and developing novel strategies to combat cancer metastasis. It is still lack of effective treatment for the dismal prognosis of intrahepatic cholangiocarcinoma (ICC). Here, we aimed to study genetic alternations during lymph node metastasis of ICC and investigate potential mechanisms and clinical strategy focused on mutations. We performed whole‐exome sequencing and transcriptome sequencing on samples from 30 ICC patients, including lymph node metastases from five of the patients. We identified the alterations of genetic pattern related to lymph node metastases of ICC. EPHA2, a member of the tyrosine kinase family, was found to be frequently mutated in ICC. Correlation analysis indicated that EPHA2 mutations were closely associated with lymph node metastasis of ICC. In vitro and in vivo experiments revealed that EPHA2 mutations could lead to ligand independent phosphorylation of Ser897, and promote lymphatic metastasis of ICC, in which NOTCH1 signaling pathway played an important role. In both in vitro assays and patient‐derived xenografts, an inhibitor of Ser897 phosphorylation effectively suppressed the metastasis of ICC with mutated EPHA2. Our findings demonstrated that EPHA2 mutants may be an attractive therapeutic target for lymphatic metastasis of ICC.
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Assessing the Time Dependence of Prognostic Values of Cytology and Human Papillomavirus Testing in Cervical Cancer Screening
Accurate assessment of risks for developing cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) following a given set of screening test results is instrumental to reaching valid conclusions and informing cervical cancer screening recommendations. Using data from the Canadian Cervical Cancer Screening Trial (CCCaST), we assessed prognostic values of enrollment screening test results to predict CIN2+ among women attending routine cervical screening using multivariable Cox proportional hazards (PH) regression and its flexible extension during each of two follow‐up periods (protocol‐defined and extended). Non‐proportional (time‐dependent (TD)) and/or non‐linear effects were modeled, as appropriate. Women with abnormal cytology had hazard ratios (HRs) for CIN2+ detection of 17.61 (95% CI: 11.25‐27.57) and 10.46 (95% CI: 5.41‐20.24) relative to women with normal cytology during the protocol‐defined and extended follow‐up periods, respectively. High‐risk human papillomavirus (HR‐HPV) positivity was an even stronger predictor of CIN2+ risk, with significant TD effects during both follow‐up periods (p<0.001 for both TD effects). Risks among women co‐testing HR‐HPV+ with and without abnormal cytology (relative to women co‐testing negative) were highest immediately following baseline, and decreased significantly thereafter (p<0.001 for both TD effects). HRs for HPV16+ and HPV18+ women (relative to those testing HR‐HPV‐) did not vary significantly over time (HR=182.96; 95% CI: 95.16‐351.77 and HR=111.81; 95% CI: 44.60‐280.31, respectively). Due to TD effects, conventional Cox model estimates considerably underestimated adjusted HRs associated with positive HR‐HPV testing results early on in the follow‐up periods.
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Circulating 25‐hydroxyvitamin D, vitamin D binding protein, and risk of advanced and lethal prostate cancer
We previously found that higher total 25‐hydroxyvitamin D [25(OH)D] levels were associated with lower risk of lethal prostate cancer. However, the relationships of bioavailable 25(OH)D and vitamin D binding protein (VDBP) with risk of advanced and lethal prostate cancer are unclear. In a prospective case‐control study of 156 pairs of advanced prostate cancer cases and controls, we directly measured prediagnostic circulating 25(OH)D and VDBP and calculated bioavailable 25(OH)D using a validated formula. We examined the association of bioavailable 25(OH)D and VDBP levels with risk of advanced and lethal prostate cancer and whether total 25(OH)D levels interacted with VDBP levels to affect the risk. Conditional logistic models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to total 25(OH)D (P trend=0.02), bioavailable 25(OH)D levels were not more strongly associated with risk of advanced prostate cancer (P trend=0.14). Although VDBP levels were not associated with risk of advanced prostate cancer (P trend=0.16), we observed an interaction between total 25(OH)D levels and VDBP levels in relation to risk of advanced prostate cancer (P interaction=0.03). Compared to those with total 25(OH)D levels below the median and VDBP levels above the median (at highest risk), men with both levels above the median had a multivariable‐adjusted OR of 0.31 (95% CI, 0.15‐0.65) for advanced prostate cancer. We observed similar results when we restricted the analyses to 116 lethal prostate cancer cases and their controls. Our data suggest that VDBP levels may modify the association between total 25(OH)D levels and risk of advanced and lethal prostate cancer.
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New use for old drugs: the protective effect of atypical antipsychotics on hepatocellular carcinoma
It has been encouraged to use large existing data like insurance claims data to investigate the new indications of old drugs. New strategies of research are warranted to identify feasible drugs. We conducted a dual research model with a population‐based case‐control study using Taiwan's National Health Insurance Research Database and an in‐vitro study to investigate the association between atypical antipsychotic and Hepatocellular carcinoma (HCC) risk.
The study herein consists of two components. The first is a population‐based case‐control study using existing data from the Taiwan National Health Insurance Research Database. The second component was an in‐vitro study in which HCC cell lines (Huh7 and Hep G2) were treated with risperidone, quetiapine, and clozapine. Following treatment of the foregoing antipsychotics, the HCC cell lines were assessed for cell proliferation, invasion, and apoptosis. Multivariate conditional logistic regression analysis revealed that antipsychotic use was independently and inversely associated with HCC risk (adjusted odds‐ratio [aOR]:0.85, 95% CI: 0.81‐0.89). The protective effect was dose‐dependent: compared to the low cumulative defined daily dose (cDDD) group (0‐29 cDDD), the 30‐89 cDDD and ≥90 cDDD groups were associated with significantly reduced risk for HCC (aOR: 0.56, 95% CI: 0.41‐0.76; aOR: 0.37, 95% CI: 0.27‐0.50, respectively). In‐vitro study results indicated that risperidone, quetiapine and clozapine significantly inhibited cell proliferation, invasion and induced apoptosis in human HCC cell lines.
Our results herein suggested that antipsychotic use might reduce the risk of HCC and may provide evidence for new uses of old drugs.
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Factors Associated with False Positive Fecal Immunochemical Tests in a Large German Colorectal Cancer Screening Study
In recent years fecal immunochemical tests (FITs) have been offered as a primary screening test for colorectal cancer (CRC) in a growing number of countries. This study aims to identify factors associated with apparently false positive results of FITs.
In this cross‐sectional study within the German population‐based screening colonoscopy program, participants were invited to provide a stool sample for FIT prior to colonoscopy. 4656 participants aged 50‐79 years with no known history of CRC or inflammatory bowel disease (IBD) and no findings of neoplasms at screening colonoscopy were included in the current analyses. Main outcome measures were rates and factors associated with apparently false positive FIT results.
Apparently false positive FIT results were found for 378 participants (8.1%). Male sex (OR=1.30, 95%CI 1.03, 1.62), age ≥ 65 years (OR=1.27, 95%CI 1.01, 1.59), a BMI ≥ 30 kg/m2 (OR=1.81, 95%CI 1.36, 2.40), current smoking (OR=1.63, 95%CI 1.18, 2.25), use of aspirin (OR=1.36, 95%CI 1.02, 1.82) and a new diagnosis of IBD (OR=9.13, 95%CI 2.18, 38.19) or other non‐neoplastic findings (OR=1.86, 95%CI 1.37, 2.51) at screening colonoscopy were independently associated with significantly increased odds of a positive FIT.
Although considered false‐positive in the context of CRC screening, the identified factors associated with apparently false positive FIT results are known risk factors for and may point to conditions other than colorectal neoplasms that may be potential sources of gastrointestinal bleeding, potentially requiring further medical follow up.
The study was registered in the German Clinical Trials Register (DRKS‐ID: DRKS00008737).
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Comprehensive analysis of HPV infection, EGFR exon 20 mutations and LINE1 hypomethylation as risk factors for malignant transformation of sinonasal inverted papilloma to squamous cell carcinoma
Different risk factors are suspected to be involved in malignant transformation of sinonasal papillomas and include HPV infection, tobacco smoking, occupational exposure, EGFR/KRAS mutations and DNA methylation alterations. In this study, 25 inverted sinonasal papillomas (ISPs), 5 oncocytic sinonasal papillomas (OSP) and 35 squamous cell carcinomas (SCCs) from 54 patients were genotyped for ten genes involved in EGFR signalling. . HPV‐DNA detection was performed by in‐situ hybridisation and LINE‐1 methylation was quantitatively determined by bisulphite‐pyrosequencing.
High‐risk HPV was observed only in 13% of ISP‐associated SCC and in 8% of de novo‐SCC patients. EGFR mutations occurred in 72% of ISPs, 30% of ISP‐associated SCCs and 17% of de novo‐SCCs. At 5‐year follow‐up, SCC arose in only 30% (6/20) of patients with EGFR‐mutated ISPs compared with 76% (13/17) of patients with EGFR‐wild‐type ISP (p=0.0044). LINE‐1 hypomethylation significantly increased from papilloma/early stage SCC to advanced stage SCC (p=0.03) and was associated with occupational exposure (p=0.01) and worse prognosis (p=0.09). In conclusion, our results suggest that a small subset of these tumours could be related to HPV infection; EGFR mutations characterise those ISPs with a lower risk of developing into SCC; LINE‐1 hypomethylation is associated with occupational exposure and could identify more aggressive nasal SCC.
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Basal biomarkers Nestin and INPP4B predict gemcitabine benefit in metastatic breast cancer: samples from the phase III SBG0102 clinical trial
In a formal prospective‐retrospective analysis of the phase III SBG0102 clinical trial randomizing metastatic breast cancer patients to gemcitabine‐docetaxel or to single agent docetaxel, patients with basal‐like tumors by PAM50 gene expression had significantly better overall survival in the gemcitabine arm. By immunohistochemistry (IHC), triple negative status was not predictive, but more specific biomarkers have since become available defining basal‐like by nestin positivity or loss of inositol‐polyphosphate‐4‐phosphate (INPP4B). Here, we evaluate their capacity to identify which patients benefit from gemcitabine in the metastatic setting.
Nestin and INPP4B staining and interpretation followed published methods. A prespecified statistical plan evaluated the primary hypothesis that patients with basal‐like breast cancer, defined as "nestin+ or INPP4B‐", would have superior overall survival on gemcitabine‐docetaxel when compared to docetaxel. Interaction tests, Kaplan‐Meier curves and forest plots were used to assess prognostic and predictive capacities of biomarkers relative to treatment.
Among 239 cases evaluable for this study, 36 (15%) had been classified as basal‐like by PAM50. "Nestin+ or INPP4B‐" was observed in 41 (17%) of the total cases and was significantly associated with PAM50 basal‐like subtype. Within an estimated median follow‐up of 13 years, patients assigned as IHC basal "nestin+ or INPP4B‐" had significantly better overall survival on gemcitabine‐docetaxel versus docetaxel monotherapy (HR=0.31, 95%CI: 0.16‐0.60), whereas no differences were observed for other patients (HR=0.99), P‐interaction<0.01. In the metastatic setting, women with IHC basal breast cancers defined as "nestin+ or INPP4B‐" have superior overall survival when randomized to gemcitabine‐containing chemotherapy compared to docetaxel alone. These findings need to be validated using larger prospective‐retrospective phase III clinical trials series.
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Genetic variants in CCL5 and CCR5 genes and serum VEGF‐A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients
Early VEGF‐A reduction (EVR) by targeting abundant VEGF‐A is a potential predictive marker of bevacizumab (BEV). The CCL5/CCR5 axis modulates VEGF‐A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first‐line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n=48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR‐based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF‐A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression‐free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24‐0.83, P=0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26‐0.95, P=0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF‐A levels at baseline and a greater decrease in VEGF‐A levels at day 14 compared with the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first‐line treatment for mCRC.
This article is protected by copyright. All rights reserved.
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Vesicle‐bound EBV‐BART13‐3p miRNA in circulation distinguishes nasopharyngeal‐ from head & neck cancer and asymptomatic EBV‐infections
Cell‐free microRNA (miRNA) in biofluids released by tumors in either protein or vesicle‐bound form, represent promising minimally‐invasive cancer biomarkers. However, a highly abundant non‐tumor background in human plasma and serum complicates the discovery and detection of tumor‐selective circulating miRNAs.
We performed small RNA sequencing on serum and plasma RNA from Nasopharyngeal Carcinoma (NPC) patients. Collectively, Epstein Barr virus‐encoded miRNAs, more so than endogenous miRNAs, signify presence of NPC. However, RNAseq‐based EBV miRNA profiles differ between NPC patients, suggesting inter‐tumor heterogeneity or divergent secretory characteristics. We determined with sensitive qRT‐PCR assays that EBV miRNAs BART7‐3p, BART9‐3p and BART13‐3p are actively secreted by C666.1 NPC cells bound to extracellular vesicles (EVs) and soluble ribonucleoprotein complexes. Importantly, these miRNAs are expressed in all primary NPC tumor biopsies and readily detected in nasopharyngeal brushings from both early and late‐stage NPC patients. Increased levels of BART7‐3p, BART9‐3p and particularly BART13‐3p, distinguish NPC patient sera from healthy controls. Receiver operating characteristic curve analysis using sera from endemic NPC patients, other head & neck cancers and individuals with asymptomatic EBV‐infections reveals a superior diagnostic performance of EBV miRNAs over anti‐EBNA1 IgA serology and EBV‐DNA load (AUC 0.87‐0.96 vs 0.86 and 0.66 respectively). The high specificity of circulating EBV‐BART13‐3p (97%) for NPC detection is in agreement with active secretion from NPC tumor cells. We conclude EV‐bound BART13‐3p in circulation is a promising, NPC‐selective, biomarker that should be considered as part of a screening strategy to identify NPC in endemic regions.
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Spin–Orbit Torque Switching in a Nearly Compensated Heusler Ferrimagnet
The epitaxial growth of ferrimagnetic Heusler thin films is reported, with magnetic properties optimized based upon concentration and thickness. Efficient current‐induced magnetic switching is demonstrated for a nearly compensated ferrimagnet that has a relatively large thickness and robust stability, opening the door for the possible use of compensated ferrimagnets for fast, energy‐efficient spintronic devices.
Abstract
Ferrimagnetic materials combine the advantages of the low magnetic moment of an antiferromagnet and the ease of realizing magnetic reading of a ferromagnet. Recently, it was demonstrated that compensated ferrimagnetic half metals can be realized in Heusler alloys, where high spin polarization, zero magnetic moment, and low magnetic damping can be achieved at the same time. In this work, by studying the spin–orbit torque induced switching in the Heusler alloy Mn2Ru1− xGa, it is found that efficient current‐induced magnetic switching can be realized in a nearly compensated sample with strong perpendicular anisotropy and large film thickness. This work demonstrates the possibility of employing compensated Heusler alloys for fast, energy‐efficient spintronic devices.
https://ift.tt/2QxEfXB
Improved Outcoupling Efficiency and Stability of Perovskite Light‐Emitting Diodes using Thin Emitting Layers
An important design principle for perovskite light‐emitting diodes is discovered regarding optimal perovskite thickness. Adopting a thinner perovskite layer is beneficial for both device efficiency and stability, with external quantum efficiency (EQE) as high as 17.6% being achieved. The improved EQE is primarily due to better light outcoupling, and the improved stability is correlated with reduced Joule heating.
Abstract
Hybrid organic–inorganic perovskite semiconductors have shown potential to develop into a new generation of light‐emitting diode (LED) technology. Herein, an important design principle for perovskite LEDs is elucidated regarding optimal perovskite thickness. Adopting a thin perovskite layer in the range of 35–40 nm is shown to be critical for both device efficiency and stability improvements. Maximum external quantum efficiencies (EQEs) of 17.6% for Cs0.2FA0.8PbI2.8Br0.2, 14.3% for CH3NH3PbI3 (MAPbI3), 10.1% for formamidinium lead iodide (FAPbI3), and 11.3% for formamidinium lead bromide (FAPbBr3)‐based LEDs are demonstrated with optimized perovskite layer thickness. Optical simulations show that the improved EQEs source from improved light outcoupling. Furthermore, elevated device temperature caused by Joule heating is shown as an important factor contributing to device degradation, and that thin perovskite emitting layers maintain lower junction temperature during operation and thus demonstrate increased stability.
https://ift.tt/2PmbPDh
Promoted Glycerol Oxidation Reaction in an Interface‐Confined Hierarchically Structured Catalyst
The confinement of Pt nanosheets is realized in a vertically erected graphene array with hierarchically porous architecture to address the mass‐diffusion limitation in interface‐confined catalysis. Such a confined 3D catalyst exhibits a much stronger oxidation and CC bond cleaving ability for the glycerol oxidation reaction, leading to a superior mass activity and selectivity toward C1 products than commercial Pt/C catalysts.
Abstract
Confined catalysis in a 2D system is of particular interest owing to the facet control of the catalysts and the anisotropic kinetics of reactants, which suppress side reactions and improve selectivity. Here, a 2D‐confined system consisting of intercalated Pt nanosheets within few‐layered graphene is demonstrated. The strong metal–substrate interaction between the Pt nanosheets and the graphene leads to the quasi‐2D growth of Pt with a unique (100)/(111)/(100) faceted structure, thus providing excellent catalytic activity and selectivity toward one‐carbon (C1) products for the glycerol oxidation reaction. A hierarchically porous graphene architecture, grown on carbon cloth, is used to fabricate the confined catalyst bed in order to enhance the mass‐diffusion limitation in interface‐confined reactions. Owing to its unique 3D porous structure, this graphene‐confined Pt catalyst exhibits an extraordinary mass activity of 2910 mA mgPt−1 together with a formate selectivity of 79% at 60 °C. This paves the way toward rational designs of heterogeneous catalysts for energy‐related applications.
https://ift.tt/2PhNbDL
Autonomous Ultrafast Self‐Healing Hydrogels by pH‐Responsive Functional Nanofiber Gelators as Cell Matrices
Tissue engineering requires biocompatible, dynamic materials mimicking the extracellular matrix. Hybrid hydrogels from albumin‐derived copolymers grafted with functional peptide nanofiber gelators are developed. pH‐induced intramolecular rearrangement of peptide grafts facilitates gelation at physiological conditions providing injectability and excellent biocompatibility for primary cells. The mechanically robust hybrids feature ultrafast autonomous self‐recovery and show promise in biomedical applications.
Abstract
The synthesis of hybrid hydrogels by pH‐controlled structural transition with exceptional rheological properties as cellular matrix is reported. "Depsi" peptide sequences are grafted onto a polypeptide backbone that undergo a pH‐induced intramolecular O–N–acyl migration at physiological conditions affording peptide nanofibers (PNFs) as supramolecular gelators. The polypeptide–PNF hydrogels are mechanically remarkably robust. They reveal exciting thixotropic behavior with immediate in situ recovery after exposure to various high strains over long periods and self‐repair of defects by instantaneous reassembly. High cytocompatibility, convenient functionalization by coassembly, and controlled enzymatic degradation but stability in 2D and 3D cell culture as demonstrated by the encapsulation of primary human umbilical vein endothelial cells and neuronal cells open many attractive opportunities for 3D tissue engineering and other biomedical applications.
https://ift.tt/2Qy1ZdS
Robust Tin‐Based Perovskite Solar Cells with Hybrid Organic Cations to Attain Efficiency Approaching 10%
Hybrid cation (guanidinium/formamidinium) tin‐based perovskites that give a new performance record for lead‐free perovskite solar cells (power conversion efficiency = 9.6%)are demonstrated. The fabricated devices show an incredible light‐soaking stability for continuous 1 sun illumination for 1 h, and the device passes all harsh verification steps to attain a certified efficiency of 8.3% for a fresh cell.
Abstract
The stability of a tin‐based perovskite solar cell is a major challenge. Here, hybrid tin‐based perovskite solar cells in a new series that incorporate a nonpolar organic cation, guanidinium (GA+), in varied proportions into the formamidinium (FA+) tin triiodide perovskite (FASnI3) crystal structure in the presence of 1% ethylenediammonium diiodide (EDAI2) as an additive, are reported. The device performance is optimized at a precursor ratio (GAI:FAI) of 20:80 to attain a power conversion efficiency (PCE) of 8.5% when prepared freshly; the efficiencies continuously increase to attain a record PCE of 9.6% after storage in a glove‐box environment for 2000 h. The hybrid perovskite works stably under continuous 1 sun illumination for 1 h and storage in air for 6 days without encapsulation. Such a tin‐based perovskite passes all harsh standard tests, and the efficiency of a fresh device, 8.3%, is certified. The great performance and stability of the device reported herein attains a new milestone for lead‐free perovskite solar cells on a path toward commercial development.
https://ift.tt/2PmrLoQ
Liquid‐Alloy‐Assisted Growth of 2D Ternary Ga2In4S9 toward High‐Performance UV Photodetection
High‐quality 2D ternary n‐type Ga2In4S9 flakes are synthesized through a liquid‐metal‐alloy‐assisted chemical vapor deposition method. Photodetectors based on the Ga2In4S9 flakes display outstanding UV detection ability with fast response speed. In addition, under the synergistic effect of the back gate and illumination, Ga2In4S9‐based phototransistors exhibit a responsivity up to ≈104 A W−1.
Abstract
2D ternary systems provide another degree of freedom of tuning physical properties through stoichiometry variation. However, the controllable growth of 2D ternary materials remains a huge challenge that hinders their practical applications. Here, for the first time, by using a gallium/indium liquid alloy as the precursor, the synthesis of high‐quality 2D ternary Ga2In4S9 flakes of only a few atomic layers thick (≈2.4 nm for the thinnest samples) through chemical vapor deposition is realized. Their UV‐light‐sensing applications are explored systematically. Photodetectors based on the Ga2In4S9 flakes display outstanding UV detection ability (R λ = 111.9 A W−1, external quantum efficiency = 3.85 × 104%, and D* = 2.25 × 1011 Jones@360 nm) with a fast response speed (τring ≈ 40 ms and τdecay ≈ 50 ms). In addition, Ga2In4S9‐based phototransistors exhibit a responsivity of ≈104 A W−1@360 nm above the critical back‐gate bias of ≈0 V. The use of the liquid alloy for synthesizing ultrathin 2D Ga2In4S9 nanostructures may offer great opportunities for designing novel 2D optoelectronic materials to achieve optimal device performance.
https://ift.tt/2Pm7hgb
Lowering the Schottky Barrier Height by Graphene/Ag Electrodes for High‐Mobility MoS2 Field‐Effect Transistors
Contact resistance between the channel and electrodes in MoS2 devices is significantly reduced using a low work function metal (Ag) and graphene as an interfacial layer between MoS2 and Ag because the Schottky barrier height is lowered at the contacts. Using graphene/Ag contacts instead of Ti/Au improves the field‐effect mobility, on/off current ratio, and photoresponsivity of the devices.
Abstract
2D transition metal dichalcogenides (TMDCs) have emerged as promising candidates for post‐silicon nanoelectronics owing to their unique and outstanding semiconducting properties. However, contact engineering for these materials to create high‐performance devices while adapting for large‐area fabrication is still in its nascent stages. In this study, graphene/Ag contacts are introduced into MoS2 devices, for which a graphene film synthesized by chemical vapor deposition (CVD) is inserted between a CVD‐grown MoS2 film and a Ag electrode as an interfacial layer. The MoS2 field‐effect transistors with graphene/Ag contacts show improved electrical and photoelectrical properties, achieving a field‐effect mobility of 35 cm2 V−1 s−1, an on/off current ratio of 4 × 108, and a photoresponsivity of 2160 A W−1, compared to those of devices with conventional Ti/Au contacts. These improvements are attributed to the low work function of Ag and the tunability of graphene Fermi level; the n‐doping of Ag in graphene decreases its Fermi level, thereby reducing the Schottky barrier height and contact resistance between the MoS2 and electrodes. This demonstration of contact interface engineering with CVD‐grown MoS2 and graphene is a key step toward the practical application of atomically thin TMDC‐based devices with low‐resistance contacts for high‐performance large‐area electronics and optoelectronics.
https://ift.tt/2QuSgFe
An Ambipolar Superconducting Field‐Effect Transistor Operating above Liquid Helium Temperature
An ambipolar superconducting field‐effect transistor is developed using a strongly correlated molecular system laminated on a SiO2/Si substrate. The low‐temperature electronic state is fine tuned in the vicinity of the superconductor‐to‐Mott‐insulator transition, utilizing the negative pressure effect from the substrate, which allows a small dose of hole or electron injection by the SiO2 dielectric to control the superconductivity above 4.2 K.
Abstract
Superconducting (SC) devices are attracting renewed attention as the demands for quantum‐information processing, meteorology, and sensing become advanced. The SC field‐effect transistor (FET) is one of the elements that can control the SC state, but its variety is still limited. Superconductors at the strong‐coupling limit tend to require a higher carrier density when the critical temperature (T C) becomes higher. Therefore, field‐effect control of superconductivity by a solid gate dielectric has been limited only to low temperatures. However, recent efforts have resulted in achieving n‐type and p‐type SC FETs based on organic superconductors whose T C exceed liquid He temperature (4.2 K). Here, a novel "ambipolar" SC FET operating at normally OFF mode with T C of around 6 K is reported. Although this is the second example of an SC FET with such an operation mode, the operation temperature exceeds that of the first example, or magic‐angle twisted‐bilayer graphene that operates at around 1 K. Because the superconductivity in this SC FET is of unconventional type, the performance of the present device will contribute not only to fabricating SC circuits, but also to elucidating phase transitions of strongly correlated electron systems.
https://ift.tt/2QwM8MQ
Balancing Scattering Channels: A Panoscopic Approach toward Zero Temperature Coefficient of Resistance Using High‐Entropy Alloys
In the high‐entropy alloy system Al xCoCrFeNi, x is used as a "knob" to elucidate the connection between composition, electrical resistivity, Kondo scattering, and microstructure. Furthermore, x controls the type of microstructure formed inside a spinodal region, which in turn tunes the temperature coefficient of resistance from positive to negative over a wide temperature range though different scattering mechanisms.
Abstract
Designing alloys with an accurate temperature‐independent electrical response over a wide temperature range, specifically a low temperature coefficient of resistance (TCR), remains a big challenge from a material design point of view. More than a century after their discovery, Constantan (Cu–Ni) and Manganin (Cu–Mn–Ni) alloys remain the top choice for strain gauge applications and high‐quality resistors up to 473–573 K. Here, an average TCR is demonstrated that is up to ≈800 times smaller in the temperature range 5–300 K and >800 times smaller than for any of these standard materials over a wide temperature range (5 K < T < 1200 K). This is achieved for selected compositions of Al xCoCrFeNi high‐entropy alloys (HEAs), for which a strong correlation of the ultralow TCR is established with the underlying microstructure and its local composition. The exceptionally low electron–phonon coupling expected in these HEAs is crucial for developing novel devices, e.g., hot‐electron detectors, high‐Q resonant antennas, and materials in gravitational wave detectors.
https://ift.tt/2PpoSnC
Pseudoprogression of Melanoma Brain Metastases
Abstract
Purpose of Review
Immune checkpoint inhibitors are increasingly being used to treat melanoma brain metastases. One potential complication of immune checkpoint inhibitors is a phenomenon called pseudoprogression, in which a tumor transiently increases in size due to lymphocyte infiltration. This article reviews the characteristics of pseudoprogression and their clinical implications.
Recent Findings
Pseudoprogression can be challenging to differentiate from true progression noted clinically or radiographically, thereby complicating management decisions and potentially confusing patients and their families. The transient tumor enlargement can also cause symptoms that mimic true tumor progression.
Summary
Because the use of immunotherapy on melanoma brain metastases is a relatively new treatment paradigm, there is limited evidence to guide clinical decision-making and prognostication related to pseudoprogression.
https://ift.tt/2Qxgj6F
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
