Sherrillabbott1357

ding program targets and to take advantage of these sources of variation.Ovarian cancer (OCa) is the deadliest gynecologic cancer. Emerging studies suggest ovarian cancer stem cells (OCSCs) contribute to chemotherapy resistance and tumor relapse. C-176 clinical trial Recent studies demonstrated estrogen receptor beta (ERβ) exerts tumor suppressor functions in OCa. However, the status of ERβ expression in OCSCs and the therapeutic utility of the ERβ agonist LY500307 for targeting OCSCs remain unknown. OCSCs were enriched from ES2, OV90, SKOV3, OVSAHO, and A2780 cells using ALDEFLUOR kit. RT-qPCR results showed ERβ, particularly ERβ isoform 1, is highly expressed in OCSCs and that ERβ agonist LY500307 significantly reduced the viability of OCSCs. Treatment of OCSCs with LY500307 significantly reduced sphere formation, self-renewal, and invasion, while also promoting apoptosis and G2/M cell cycle arrest. Mechanistic studies using RNA-seq analysis demonstrated that LY500307 treatment resulted in modulation of pathways related to cell cycle and apoptosis. Western blot and RT-qPCR assays demonstrated the upregulation of apoptosis and cell cycle arrest genes such as FDXR, p21/CDKN1A, cleaved PARP, and caspase 3, and the downregulation of stemness markers SOX2, Oct4, and Nanog. Importantly, treatment of LY500307 significantly attenuated the tumor-initiating capacity of OCSCs in orthotopic OCa murine xenograft models. Our results demonstrate that ERβ agonist LY500307 is highly efficacious in reducing the stemness and promoting apoptosis of OCSCs and shows significant promise as a novel therapeutic agent in treating OCa.There is growing scientific evidence for the crucial role of post-transcriptional RNA modifications in carcinogenesis, progression, metastasis, and drug resistance across various cancer entities. N6-methyladenosine (m6A) is the most abundant type of RNA modification. m6A is coordinated by a dynamic interplay of 'writers' (METTL3, METTL4, METTL14, WTAP, KIAA1429), 'erasers' (FTO, ALKBH5), and 'readers' (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In this study, we comprehensively examined protein and mRNA expression levels of m6A writers, readers, and erasers in two cervical cancer (CC) cohorts (UHB CC cohort, N = 118; TCGA CC cohort, N = 307) with regard to clinical outcomes. In the UHB CC cohort, high protein expression levels of METTL14 (p = 0.016), WTAP (p = 0.007), KIAA1439 (p < 0.001), ALKBH5 (p < 0.001), HNRNPC (p = 0.012), YTHDC1 (p < 0.001), and YTHDF3 (p = 0.004) were significantly associated with a shorter overall survival (OS). In the TCGA CC cohort, mRNA expression levels of METTL14 (p = 0.012), WTAP (p = 0.041), KIAA1429 (p = 0.016), and YTHDC1 (p = 0.026) showed prognostic values. However, after correction for multiple testing, statistical significance remained only for m6A protein expression levels (q < 0.1). Our study points towards dysregulated m6A modification in CC. Hence, m6A might serve as a promising prognostic biomarker and therapeutical target in CC.Medical adhesives are used to secure wound care dressings and other critical devices to the skin. Without means of safe removal, these stronger adhesives are difficult to painlessly remove from the skin and may cause medical-adhesive-related skin injuries (MARSI), including skin tears and an increased risk of infection. Lower-adhesion medical tapes may be applied to avoid MARSI, leading to device dislodgement and further medical complications. This paper outlines the development of a high-adhesion medical tape designed for low skin trauma upon release. By warming the skin-attached tape for 10-30 s, a significant loss in adhesion was achieved. A C14/C18 copolymer was developed and combined with a selected pressure-sensitive adhesive (PSA) material. The addition of 1% C14/C18 copolymer yielded the largest temperature-responsive drop in surface adhesion. The adhesive film was characterized using AFM, and distinct nanodomains were identified on the exterior surface of the PSA. Our optimized formulation yielded 67% drop in adhesion when warmed to 45 °C, perhaps due to melting nanodomains weakening the adhesive-substrate boundary layer. Pilot clinical testing resulted in a significant decrease in pain when a heat pack was used for removal, giving an average pain reduction of 66%.Huntington's Disease (HD) is a fatal autosomal dominant neurodegenerative disease manifested through motor dysfunction and cognitive deficits. Decreased fertility is also observed in HD animal models and HD male patients, due to altered spermatogenesis and sperm function, thus resulting in reduced fertilization potential. Although some pharmaceuticals are currently utilized to mitigate HD symptoms, an effective treatment that remedies the pathogenesis of the disease is yet to be approved by the FDA. Identification of genes and relevant diagnostic biomarkers and therapeutic target pathways including glycolysis and mitochondrial complex-I-dependent respiration may be advantageous for early diagnosis, management, and treatment of the disease. This review addresses the HD pathway in neuronal and sperm metabolism, including relevant gene and protein expression in both neurons and spermatozoa, indicated in the pathogenesis of HD. Furthermore, zinc-containing and zinc-interacting proteins regulate and/or are regulated by zinc ion homeostasis in both neurons and spermatozoa. Therefore, this review also aims to explore the comparative role of zinc in both neuronal and sperm function. Ongoing studies aim to characterize the products of genes implicated in HD pathogenesis that are expressed in both neurons and spermatozoa to facilitate studies of future treatment avenues in HD and HD-related male infertility. The emerging link between zinc homeostasis and the HD pathway could lead to new treatments and diagnostic methods linking genetic sperm defects with somatic comorbidities.Wall-associated kinases (WAKs) are important receptor-like proteins that play major roles in plant defense against pathogens. Fusarium head blight (FHB), one of the most widespread and devastating crop diseases, reduces wheat yield and leads to quality deterioration. Although WAK gene families have been studied in many plants, systematic research on bread wheat (Triticum aestivum) and its role in FHB resistance, in particular, is lacking. In this study, we identified and characterized 320 genes of the TaWAK family in wheat distributed across all chromosomes except 4B and divided them into three phylogenetic groups. Duplication and synteny analyses provided valuable information on the evolutionary characteristics of the TaWAK genes. The gene expression pattern analysis suggested that TaWAK genes play diverse roles in plant biological processes and that at least 30 genes may be involved in the response to Fusarium infection in wheat spikes, with most of the genes contributing to pectin- and chitin-induced defense pathways. Furthermore, 45 TaWAK genes were identified within 17 hcmQTLs that are related to wheat FHB resistance. Our findings provide potential candidate genes for improving FHB resistance and insights into the future functional analysis of TaWAK genes in wheat.Cerebrovascular disease involves a range of conditions including ischemic and hemorrhagic stroke, vascular malformations, and vascular cognitive impairment and dementia (VCID) [...].We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody-drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA- PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.Endometrial cancer (EC) rates are rising annually. Additional prediction markers need to be evaluated because only 10-20% of EC cases show an objective response to immune-checkpoint inhibitors (ICIs). Our previous methylomic study found that BHLHE22 is hypermethylated in EC tissues and can be detected using a Pap-smear sample. BHLHE22, a basic helix loop helix transcription factor family member, is known as a transcriptional repressor and is involved in cell differentiation. However, the role of BHLHE22 in EC remains poorly understood. Herein, we analyzed BHLHE22 expression in 54 paired cancer and normal endometrial tissue samples, and confirmed with databases (TCGA, GTEx, and human protein atlas). We found that BHLHE22 protein expression was significantly downregulated in EC compared with normal endometrium. High BHLHE22 expression was associated with microsatellite-instable subtype, endometrioid type, grade, and age. It showed a significant favorable survival. BHLHE22 overexpression inhibited the proliferation and migration of EC cells. Functional enrichment analysis showed that BHLHE22 was significantly associated with immune-related pathways. Furthermore, BHLHE22 was positively correlated with proinflammatory leukocyte infiltration and expression of chemokine genes in EC. In conclusion, BHLHE22 regulates immune-related pathways and modulates the immune microenvironment of EC.We assessed SARS-CoV-2-specific CD4+ and CD8+ T cell responses in samples from 89 acute COVID-19 patients, utilizing blood samples collected during the first wave of COVID-19 in Italy. The goal of the study was to examine correlations between SARS-CoV-2-specific T cell responses in the early phase comparing mild, moderate, or severe COVID-19 disease outcomes. T cell responses to the spike (S) and non-S proteins were measured in a combined activation-induced marker (AIM) and intracellular cytokine staining (ICS) assay. Early CD4+ T cell responses to SARS-CoV-2 S correlated with milder disease by both AIM and IFNγ ICS readouts. The correlation of S-specific CD4+ T cell responses with milder disease severity was most striking within the first two weeks of symptom onset compared to later time points. Furthermore, donors with milder disease were associated with polyantigenic CD4+ T cell responses that recognized more prominently non-S proteins in addition to S, while severe acute COVID-19 was characterized by lower magnitudes of CD4+ T cell responses and a narrower repertoire.