In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα ...positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.
Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its ...antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.
The integration of an organic electrochemical transistor with human barrier tissue cells provides a novel method for assessing toxicology of compounds in vitro. Minute variations in paracellular ...ionic flux induced by toxic compounds are measured in real time, with unprecedented temporal resolution and extreme sensitivity.
Relatively little is known about the effects of hemodialysis frequency on the disability of patients with ESRD.
This study examined changes in physical performance and self-reported physical health ...and functioning among subjects randomized to frequent (six times per week) compared with conventional (three times per week) hemodialysis in both the Frequent Hemodialysis Network daily (n=245) and nocturnal (n=87) trials. The main outcome measures were adjusted change in scores over 12 months on the short physical performance battery (SPPB), RAND 36-item health survey physical health composite (PHC), and physical functioning subscale (PF) based on the intention to treat principle.
Overall scores for SPPB, PHC, and PF were poor relative to population norms and in line with other studies in ESRD. In the Daily Trial, subjects randomized to frequent compared with conventional in-center hemodialysis experienced no significant change in SPPB (adjusted mean change of -0.20±0.19 versus -0.41±0.21, P=0.45) but experienced significant improvement in PHC (3.4±0.8 versus 0.4±0.8, P=0.009) and a relatively large change in PF that did not reach statistical significance. In the Nocturnal Trial, there were no significant differences among subjects randomized to frequent compared with conventional hemodialysis in SPPB (adjusted mean change of -0.92±0.44 versus -0.41±0.43, P=0.41), PHC (2.7±1.4 versus 2.1±1.5, P=0.75), or PF (-3.1±3.5 versus 1.1±3.6, P=0.40).
Frequent in-center hemodialysis compared with conventional in-center hemodialysis improved self-reported physical health and functioning but had no significant effect on objective physical performance. There were no significant effects of frequent nocturnal hemodialysis on the same physical metrics.
Ion flow across polarized epithelia is a tightly regulated process. Measurement of the transepithelial resistance is a highly relevant parameter for assessing the function or health of the tissue. ...Dynamic, electrical measurements of transepithelial ion flow are preferred as they provide the most accurate snapshot of effects of external stimuli. Enteric pathogens such as Salmonella typhimurium are known to disrupt ion flow in gastrointestinal epithelia. Here, for the first time, the use of organic transistors as a powerful potential alternative for front‐line, disposable, high‐throughput diagnostics of enteric pathogens is demonstrated. The transistors' ability to detect early and subtle changes in transepithelial ion flow is capitalized upon to develop a highly sensitive detector of epithelial integrity. Stable operation of the organic devices under physiological conditions is shown, followed by dynamic, pathogen‐specific diagnosis of infection of epithelia. Further, operation of the device is possible in complex matrices, showing particular promise for food and safety applications.
Organic electronic materials have opened the door for the development of low‐cost, disposable sensors for cell‐based in vitro diagnostics. Here, for the first time, the feasibility of using an organic transistor integrated with a human intestinal cell line for detecting a food‐borne enteric pathogen, Salmonella typhimurium, is shown by dynamically measuring changes in ion flow provoked by the bacteria.
In colon cancer, downregulation of the transmembrane heparan sulfate proteoglycan syndecan‐1 (Sdc‐1) is associated with increased invasiveness, metastasis, and dedifferentiation. As Sdc‐1 modulates ...signaling pathways relevant to stem cell function, we tested the hypothesis that it may regulate a tumor‐initiating cell phenotype. Sdc‐1 small‐interfering RNA knockdown in the human colon cancer cell lines Caco2 and HT‐29 resulted in an increased side population (SP), enhanced aldehyde dehydrogenase 1 activity, and higher expression of CD133, LGR5, EPCAM, NANOG, SRY (sex‐determining region Y)‐box 2, KLF2, and TCF4/TCF7L2. Sdc‐1 knockdown enhanced sphere formation, cell viability, Matrigel invasiveness, and epithelial‐to‐mesenchymal transition‐related gene expression. Sdc‐1‐depleted HT‐29 xenograft growth was increased compared to controls. Decreased Sdc‐1 expression was associated with an increased activation of β1‐integrins, focal adhesion kinase (FAK), and wingless‐type (Wnt) signaling. Pharmacological FAK and Wnt inhibition blocked the enhanced stem cell phenotype and invasive growth. Sequential flow cytometric SP enrichment substantially enhanced the stem cell phenotype of Sdc‐1‐depleted cells, which showed increased resistance to doxorubicin chemotherapy and irradiation. In conclusion, Sdc‐1 depletion cooperatively enhances activation of integrins and FAK, which then generates signals for increased invasiveness and cancer stem cell properties. Our findings may provide a novel concept to target a stemness‐associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence.
Databases
The GEO accession number of the Affymetrix transcriptomic screening is GSE58751.
Loss of Sdc‐1 in colon cancer cells activates β1‐integrin and focal adhesion kinase, which in turn induces TCF4 expression, promoting a FAK: Wnt signaling axis. This enhances the cancer stem cell phenotype and drives an epithelial–mesenchymal transition‐like state with an increase in invasion, tumor growth in vivo, and enhanced resistance to chemo‐ and radiation therapy.
Preterm birth, defined as birth before 37 weeks of gestation, is a leading cause of perinatal and infant mortality throughout the world. Preterm birth is also associated with long-term neurological ...disabilities and other significant health issues in children. A short cervix in the second trimester has been noted to be one of the strongest predictors of subsequent spontaneous preterm birth in both singleton and multiple pregnancies. Some studies have shown that cervical support in the form of an Arabin pessary lowers the risk of preterm birth in women with a singleton gestation and short cervical length; however, other studies have conflicting results. Our objective was to form an international collaborative of planned or ongoing randomized trials of pessary in singleton and twin gestations with a short cervix.
In November 2014, an international group of investigators, who had initiated or were planning randomized trials of pessary for pregnant people with a short cervix and singleton or twin gestation to prevent preterm birth, formed a collaboration to plan a prospective individual patient data (IPD) meta-analysis of randomized trials (PROspective Meta-analysis of Pessary Trials PROMPT). The PROMPT investigators agreed on meta-analysis IPD hypotheses for singletons and twins, eligibility criteria, and a set of core baseline and outcome measures. The primary outcome is a composite of fetal death or preterm delivery before 32 weeks' gestation. Secondary outcomes include maternal and neonatal morbidities. The PROMPT protocol may be viewed as a written agreement among the study investigators who make up the PROMPT consortium (PROSPERO ID# CRD42018067740).
Results will be published in phases as the individual participating studies are concluded and published. Results of the first phase of singleton and twin pessary trials are expected to be available in late 2022. Updates are planned as participating trials are completed and published.
· Short cervical length predicts preterm birth.. · Results of prior cervical pessary trials are mixed.. · Meta-analysis of pessary trials protocol..
End-stage renal disease patients experience significant impairments in health-related quality of life (HRQOL). Testing various strategies to improve patient HRQOL in multicenter clinical trials, such ...as the Frequent Hemodialysis Network (FHN) trials is vitally important.
The aim of this paper is to describe the design and conduct of HRQOL and patient-reported outcomes (PRO) assessment in the FHN trials.
In the FHN trials, HRQOL was examined as a multidimensional concept, and the SF-36 RAND Physical Health Composite score was one of the co-primary outcomes. The instruments completed to assess HRQOL included the Medical Outcomes Study Short Form SF-36, Health Utilities Index 3, Sleep Problems Index, Beck Depression Inventory and feeling thermometer. These instruments have been shown to have high reliability, validity and responsiveness to change in the end-stage renal disease population. Additional items evaluating PRO including sexual function, time to recovery after dialysis and patients' self-perceived burden to caregiver were also assessed. All questionnaires were administered by trained interviewers using computer-assisted telephone interviewing to ensure blinding and minimizing selection bias. Interim analysis reveals that these instruments can be used to collect a comprehensive set of HRQOL measures with minimal patient burden.
Accurate measurement of HRQOL and PRO can help us test whether hemodialysis interventions improve the health and well-being of this compromised patient population. We have shown that a comprehensive set of HRQOL measures can be centrally collected through telephone interviews in a blinded fashion, in a way that is well tolerated with minimum respondent burden.
Ceramics are currently widely used in various defense industries. Among them are the purposes of body armor (vests and helmets), vehicle protection, and ballistic protection. This review aims to ...provide insight into ceramic armor materials including their manufacture, use, and application as protective materials. The method used is a literature review and describes the results of the analysis related to the application of ceramic materials in the form of ceramic armor. The use of ceramic armor materials in defense industry products is proven to provide good performance compared to metal materials, especially in increasing the mobility capabilities of defense personnel. In addition, the use of ceramic armor has initiated the development of lightweight protective materials so that various technologies have been developed to maximize the use of ceramics in the defense industry.
Keramik saat ini banyak digunakan dalam berbagai industri pertahanan. Diantaranya untuk keperluan bahan pelindung tubuh (rompi dan helm), pelindung kendaraan, dan pelindung balistik. Review ini bertujuan untuk memberikan wawasan tentang material armor keramik yang meliputi pembuatan, penggunaan, dan aplikasinya sebagai bahan pelindung. Metode yang digunakan adalah literatur review dan mendeskripsikan hasil analisa terkait aplikasi material keramik dalam bentuk ceramic armor. Pemanfaatan material armor keramik pada produk industri pertahanan terbukti dapat memberikan performa yang baik dibandingkan dengan material logam terutama dalam meningkatkan kemampuan mobilitas dari personil pertahanan. Selain itu penggunaan armor keramik telah menginisiasi pengembangan material pelindung ringan sehingga berbagai macam teknologi dikembangkan untuk dapat memaksimalkan penggunaan keramik dalam industri pertahanan.
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