Introduction: Itch is a distressing atopic dermatitis (AD) symptom that impacts quality of life. With the emergence of multiple new agents for the treatment of AD, the ability and speed with which an ...agent reduces itch may factor in agent selection.
Objective: In this study, the primary objective was to quantify the rate at which agents for AD provide itch reduction using the peak itch numerical rating scale (NRS) data from phase II and III clinical trials.
Methods: A PubMed literature search was performed in February 2020 to find phase II and III randomized clinical trials for the treatment of AD published from 2014 to 2020. A TIMEACLIR-Itch value was calculated from NRS data to represent the time to meaningful itch reduction.
Results: We find a shorter TIme to achieving a MEAningful CLInical Response for itch reduction (TIMEACLIR-Itch) for small molecule inhibitors when compared to biologic agents. We also observe that nemolizumab achieves TIMEACLIR-Itch more quickly than IL-4 or IL-4/13 agents.
Conclusion: These findings support the role that IL-31 has in producing itch and the role Janus kinase inhibitors (JAKinibs) play in itch reduction. This comparison of TIMEACLIR-Itch for different treatments may help guide therapy and management for AD patients.
While trimodality therapy for esophageal cancer has improved patient outcomes, surgical complication rates remain high. The goal of this study was to identify modifiable factors associated with ...postoperative complications after neoadjuvant chemoradiation.
From 1998 to 2011, 444 patients were treated at our institution with surgical resection after chemoradiation. Postoperative (pulmonary, gastrointestinal GI, cardiac, wound healing) complications were recorded up to 30 days postoperatively. Kruskal-Wallis tests and χ(2) or Fisher exact tests were used to assess associations between continuous and categorical variables. Multivariate logistic regression tested the association between perioperative complications and patient or treatment factors that were significant on univariate analysis.
The most frequent postoperative complications after trimodality therapy were pulmonary (25%) and GI (23%). Lung capacity and the type of radiation modality used were independent predictors of pulmonary and GI complications. After adjusting for confounding factors, pulmonary and GI complications were increased in patients treated with 3-dimensional conformal radiation therapy (3D-CRT) versus intensity modulated radiation therapy (IMRT; odds ratio OR, 2.018; 95% confidence interval CI, 1.104-3.688; OR, 1.704; 95% CI, 1.03-2.82, respectively) and for patients treated with 3D-CRT versus proton beam therapy (PBT; OR, 3.154; 95% CI, 1.365-7.289; OR, 1.55; 95% CI, 0.78-3.08, respectively). Mean lung radiation dose (MLD) was strongly associated with pulmonary complications, and the differences in toxicities seen for the radiation modalities could be fully accounted for by the MLD delivered by each of the modalities.
The radiation modality used can be a strong mitigating factor of postoperative complications after neoadjuvant chemoradiation.
Abstract Introduction The multinucleated syncytiotrophoblast is formed and maintained by cytotrophoblast cell fusion and serves multiple functions to ensure a successful pregnancy. We have previously ...reported that the proprotein convertase furin is required for trophoblast syncytialization by processing type 1 insulin-like growth factor receptor (IGF1R). Methods Utilizing trophoblast cell fusion models including induced fusion of choriocarcinoma BeWo cells and spontaneous fusion of primary cultured term cytotrophoblast cells, the expression of furin was evaluated by quantitative real-time PCR, Western blotting and immunofluorescence. The key transcription factor regulating the FUR gene promoter and critical responsive elements were identified by luciferase reporter assays, truncated mutants analysis, site-directed mutagenesis and ChIP. Results We demonstrated that the levels of FUR mRNA were significantly stimulated by cAMP/PKA signaling pathway during spontaneous fusion of cytotrophoblast cells and forskolin-induced fusion of BeWo cells. cAMP-responsive element binding protein (CREB) was proven to be the key transcription factor which regulated the FUR P1 promoter during forskolin-induced BeWo cell fusion, and two critical cAMP-responsive elements (CREs) in the P1 promoter were further identified. Finally, we showed that CREB mediated endogenous furin activation and that CREB siRNA attenuated forskolin-induced furin expression and cell fusion in BeWo cells. Discussion This provides the first evidence of the upstream regulator of furin during trophoblast cell fusion. Conclusions The above results suggest that the FUR transcription is activated by CREB-dependent stimulation of the FUR P1 promoter during human trophoblast syncytialization.
Zika virus (ZIKV) was first isolated in Africa; decades later, caused large outbreaks in the Pacific, and is considered endemic in Asia. We aim to describe ZIKV disease epidemiology outside the ...Americas, the importance of travelers as sentinels of disease transmission, and discrepancies in travel advisories from major international health organizations.
This descriptive analysis using GeoSentinel Surveillance Network records involves sixty-four travel and tropical medicine clinics in 29 countries. Ill returned travelers with a confirmed or probable diagnosis of ZIKV disease acquired in Africa, Asia and the Pacific seen between 1 January 2012 and 31 December 2016 are included, and the frequencies of demographic, trip, and diagnostic characteristics described. ZIKV was acquired in Asia (18), the Pacific (10) and Africa (1). For five countries (Indonesia, Philippines, Thailand, Vietnam, Cameroon), GeoSentinel patients were sentinel markers of recent Zika activity. Additionally, the first confirmed ZIKV infection acquired in Kiribati was reported to GeoSentinel (2015), and a probable case was reported from Timor Leste (April 2016), representing the only case known to date. Review of Zika situation updates from major international health authorities for country risk classifications shows heterogeneity in ZIKV country travel advisories.
Travelers are integral to the global spread of ZIKV, serving as sentinel markers of disease activity. Although GeoSentinel data are collected by specialized clinics and do not capture all imported cases, we show that surveillance of imported infections by returned travelers augments local surveillance system data regarding ZIKV epidemiology and can assist with risk categorization by international authorities. However, travel advisories are variable due to risk uncertainties.
Abstract
Aims
Despite being an essential therapy for breast cancer, trastuzumab has potential risks of cardiotoxicity. The incidence of trastuzumab-related major adverse cardiac and cerebrovascular ...event (MACCE) and its predictors remain unknown in Taiwan.
Methods and results
Through a three-hospital retrospective cohort study, we analyzed the incidence of MACCE in 386 breast cancer patients exposure to trastuzumab from 2010 to 2018. To further reconfirm our findings, in a nationwide study using the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified 13502 women diagnosed with breast cancer who received chemotherapy from 2010 to 2015 and found 6751 women who received initial treatment with trastuzumab. After 1:1 propensity score matching with trastuzumab nonusers, the incidence of MACCE was measured with a median follow-up of 36 months. In the hospital-based study, among 386 patients receiving trastuzumab, the 5-year incidences of MACCE and heart failure (HF) were 5.4% and 2.8%, respectively. In the national cohort, the crude incidences of MACCEs and HF were 4.67% and 3.21%, respectively. After adjustment for age and comorbidities, the hazard ratio of MACCE was 1.485 (95% CI 1.246–1.769). Notably, among the endpoints, only the hazard ratio of HF was significantly higher in patients receiving trastuzumab than in nonusers. In the subgroup analysis, except for patients also using taxanes, those receiving trastuzumab had a higher risk of MACCE than nonusers.
Conclusions
From clinical observations in a nationwide cohort, we found an increased risk of MACCE, especially HF, in patients receiving trastuzumab. Given that its cardiotoxicity is independent of traditional cardiovascular risks, our findings highlight critical concerns regarding the cardiac safety of trastuzumab use.
Funding Acknowledgement
Type of funding sources: Private hospital(s). Main funding source(s): Chi-Mei Medical Center, National Cheng Kung University Hospital
The physical properties of particles used in radiation therapy, such as protons, have been well characterized, and their dose distributions are superior to photon-based treatments. However, proton ...therapy may also have inherent biologic advantages that have not been capitalized on. Unlike photon beams, the linear energy transfer (LET) and hence biologic effectiveness of particle beams varies along the beam path. Selective placement of areas of high effectiveness could enhance tumor cell kill and simultaneously spare normal tissues. However, previous methods for mapping spatial variations in biologic effectiveness are time-consuming and often yield inconsistent results with large uncertainties. Thus the data needed to accurately model relative biological effectiveness to guide novel treatment planning approaches are limited. We used Monte Carlo modeling and high-content automated clonogenic survival assays to spatially map the biologic effectiveness of scanned proton beams with high accuracy and throughput while minimizing biological uncertainties. We found that the relationship between cell kill, dose, and LET, is complex and non-unique. Measured biologic effects were substantially greater than in most previous reports, and non-linear surviving fraction response was observed even for the highest LET values. Extension of this approach could generate data needed to optimize proton therapy plans incorporating variable RBE.
Abnormal proliferation, apoptosis repression and differentiation blockage of hematopoietic stem/progenitor cells have been characterized to be the main reasons leading to acute myeloid leukemia ...(AML). Previous studies showed that miR-29a and miR-29b could function as tumor suppressors in leukemogenesis. However, a comprehensive investigation of the function and mechanism of miR-29 family in AML development and their potentiality in AML therapy still need to be elucidated. Herein, we reported that the family members, miR-29a, -29b and -29c, were commonly downregulated in peripheral blood mononuclear cells and bone marrow (BM) CD34+ cells derived from AML patients as compared with the healthy donors. Overexpression of each miR-29 member in THP1 and NB4 cells markedly inhibited cell proliferation and promoted cell apoptosis. AKT2 and CCND2 mRNAs were demonstrated to be targets of the miR-29 members, and the role of miR-29 family was attributed to the decrease of Akt2 and CCND2, two key signaling molecules. Significantly increased Akt2, CCND2 and c-Myc levels in the AML cases were detected, which were correlated with the decreased miR-29 expression in AML blasts. Furthermore, a feed-back loop comprising of c-Myc, miR-29 family and Akt2 were found in myeloid leukemogenesis. Reintroduction of each miR-29 member partially corrected abnormal cell proliferation and apoptosis repression and myeloid differentiation arrest in AML BM blasts. An intravenous injection of miR-29a, -29b and -29c in the AML model mice relieved leukemic symptoms significantly. Taken together, our finding revealed a pivotal role of miR-29 family in AML development and rescue of miR-29 family expression in AML patients could provide a new therapeutic strategy.
High precision, L sub 2.3 -edge photoabsorption and magnetic circular dichroism spectra of iron and cobalt were measured in transmission with in situ grown thin films, eliminating experimental ...artifacts encountered by the indirect methods used in all previous measurements. The magnetic moments determined from the integrals of these spectra are found to be excellent agreement (within 3%) for the orbital to spin moment ratios, and in good agreement (within 7%) for the individual moments, with those obtained from Einstein-de Haas gyromagnetic ratio measurements, demonstrating decisively the applicability of the individual orbital and spin sum rules.
PDF
