Rapid activation of ARF6 after RAF inhibition augments BRAFV600E and promotes therapy resistance.

The intrinsic ability of cancer cells to evade death underpins tumorigenesis, progression, metastasis and the survival of drug-tolerant persister (DTP) cells. Herein, we discovered that when activated, the small GTPase ARF6 plays a central role in tumor survival by facilitating expression of the BRAF oncoprotein. Tumor-specific deletion caused a significant reduction in BRAF protein and MAPK signaling and prevented rapid tumor progression.

eIF4E Enriched Extracellular Vesicles Induce Immunosuppressive Macrophages through HMGCR-Mediated Metabolic Rewiring.

Tumor driven immune suppression poses a significant impediment to the success of immunotherapy in ovarian cancer. Among the various mechanisms contributing to immune suppression, intracellular communication facilitated by tumor-derived extracellular vesicles (EVs) within the tumor microenvironment emerges as a pivotal factor influencing tumor growth. Here, it is demonstrated that extracellular vesicle-packaged eIF4E from tumor cells alters protein translation in macrophages, contributing to antitumor immune response.

Primary renal neuroendocrine with lymph nodal metastasis occurring in a horseshoe kidney: Report of a rare case with discussion on grading issues.

Primary renal well-differentiated neuroendocrine tumors (WDNETs) are uncommon tumors that differ in histological pattern, biological behavior, and response to treatment. There is a considerable correlation between WDNETs and congenital or acquired renal anomalies. We report a WDNET in a horseshoe kidney with lymph nodal metastasis in a 35-year-old male.

Phenotypic and Genotypic Characterization of Clinical Isolates of Carbapenem-Resistant Acinetobacter baumannii: A Cross-Sectional Study From a Tertiary Care Hospital in Western Uttar Pradesh, India.

Introduction due to its recognition as a major cause of healthcare-associated infections, is posing a huge therapeutic challenge for clinicians globally. The present study aimed to study the phenotypic and genotypic characteristics of carbapenem-resistant (CRAB). Methods A total of 121 clinical isolates of were identified using VITEK 2 (bioMérieux, France) from January 2017 to June 2018.

Two-Dimensional Electronic Spectroscopy in the Condensed Phase Using Equivariant Transformer Accelerated Molecular Dynamics Simulations.

Two-dimensional electronic spectroscopy (2DES) provides rich information about how the electronic states of molecules, proteins, and solid-state materials interact with each other and their surrounding environment. Atomistic molecular dynamics simulations offer an appealing route to uncover how nuclear motions mediate electronic energy relaxation and their manifestation in electronic spectroscopies but are computationally expensive. Here we show that by using an equivariant transformer-based machine learning architecture trained with only 2500 ground state and 100 excited state electronic structure calculations, one can construct accurate machine-learned potential energy surfaces for both the ground-state electronic surface and excited-state energy gap.

A Rare Case of Ovarian Abscess Secondary to Infection in Women with MRKH: A Case Report and Review of Literature.

Most common clinical presentation of a woman with MRKH is primary amenorrhea. It is rare to have pelvic masses in women with MRKH. Only few cases have been reported in literature.

Therapeutic induction of ferroptosis in tumors using PD-L1 targeting antibody nanogel conjugates.

Although programmed cell death ligand 1 (PD-L1) is best known for its role in immune suppression, tumor-intrinsic functions are emerging. Here, we report that tumor cells that express PD-L1 are sensitive to ferroptosis inducers such as imidazole ketone erastin (IKE). PD-L1 promotes ferroptosis sensitivity because it suppresses SLC7A11 expression and diminishes glutathione levels.

Polymers for Disrupting Protein-Protein Interactions: Where Are We and Where Should We Be?

Protein-protein interactions (PPIs) are central to the cellular signaling and regulatory networks that underlie many physiological and pathophysiological processes. It is challenging to target PPIs using traditional small molecule or peptide-based approaches due to the frequent lack of well-defined binding pockets at the large and flat PPI interfaces. Synthetic polymers offer an opportunity to circumvent these challenges by providing unparalleled flexibility in tuning their physiochemical properties to achieve the desired binding properties.

Protocol for the isolation of tumor cell-derived extracellular vesicles followed by in vivo metastasis assessment in a murine ovarian cancer model.

Extracellular vesicles (EVs) play a crucial role in facilitating communication between cancer cells and their immediate or remote microenvironments, thereby promoting the extensive spread of cancer throughout the body. In this context, we present a protocol for the isolation of tumor cell-derived EVs followed by in vivo metastasis assessment in a murine ovarian cancer model. We describe steps for the isolation and characterization of EVs from ID8 cells, development of a metastatic mouse model, and sample preparation for flow cytometry.

Cinnamaldehyde attenuates TNF-α induced skeletal muscle loss in C2C12 myotubes via regulation of protein synthesis, proteolysis, oxidative stress and inflammation.

Inflammation is the primary driver of skeletal muscle wasting, with oxidative stress serving as both a major consequence and a contributor to its deleterious effects. In this regard, regulation of both can efficiently prevent atrophy and thus will increase the rate of survival [1]. With this idea, we hypothesize that preincubation of Cinnamaldehyde (CNA), a known compound with anti-oxidative and anti-inflammatory properties, may be able to prevent skeletal muscle loss.

Laparoscopic Cerclage in a Case of Unicornuate Uterus with Cervical Insufficiency and Previous Failed Mc Donald Cerclage with a Successful Outcome: A Case Report.

In this report, we describe a 28-year-old woman, with unicornuate uterus and multiple mid-trimester losses, with two failed Mc Donald's cerclage. She presented to us as a case of recurrent pregnancy losses with history suggestive of cervical incompetence and on detailed investigation was found to be ANA and anti-cardiolipin antibody positive and Rh negative. We performed an interval laparoscopic cervical cerclage for her and were able to successfully deliver her at 35 + 3 weeks with a healthy baby by caesarean section after previous five pregnancy losses and two failed Mc Donald's cerclage.

Beyond the Asylum Walls: Tracing the Tapestry of Mental Health Interventions Across Eras and Cultures.

This article offers an extensive review of the changing field of mental health therapies, charting a transformational path from traditional methods to modern breakthroughs and speculating on potential future developments. The story develops by investigating historical viewpoints while reflecting on the present and highlighting the lessons learned and their impact on contemporary practices. We have advanced from the stigmatized constraints of asylums to a paradigm that puts human rights, dignity, and individualized, culturally sensitive treatment first.

Systems analysis reveals differential expression of endocervical genes in African women randomized to DMPA-IM, LNG implant or cu-IUD.

Although effective contraceptives are crucial for preventing unintended pregnancies, evidence suggests that their use may perturb the female genital tract (FGT). A comparative analysis of the effects of the most common contraceptives on the FGT have not been evaluated in a randomized clinical trial setting. Here, we evaluated the effect of three long-acting contraceptive methods: depot medroxyprogesterone acetate(DMPA-IM), levonorgestrel(LNG) implant, and a copper intrauterine device (Cu-IUD), on the endocervical host transcriptome in 188 women from the Evidence for Contraceptive Options and HIV Outcomes Trial (ECHO) trial.

Elucidating the Role of Hydrogen Bonding in the Optical Spectroscopy of the Solvated Green Fluorescent Protein Chromophore: Using Machine Learning to Establish the Importance of High-Level Electronic Structure.

Hydrogen bonding interactions with chromophores in chemical and biological environments play a key role in determining their electronic absorption and relaxation processes, which are manifested in their linear and multidimensional optical spectra. For chromophores in the condensed phase, the large number of atoms needed to simulate the environment has traditionally prohibited the use of high-level excited-state electronic structure methods. By leveraging transfer learning, we show how to construct machine-learned models to accurately predict the high-level excitation energies of a chromophore in solution from only 400 high-level calculations.

Evaluation of cinnamaldehyde derivatives as potential protective agents against oxidative-stress induced myotube atrophy using chemical, biological and computational analysis.

Skeletal muscle atrophy, associated with increased morbidity, mortality and poor quality of life, is a metabolic disorder with no FDA approved drug. Oxidative stress is one of the key mediators of atrophy that influences various cell signaling molecules. The goal of this study is to identify potential antioxidant agents that could be used to treat atrophy.

Early Stimulation and Enhanced Preschool: A Randomized Trial.

Objectives: To estimate the impacts of 2 interventions, early stimulation (ES) for children aged <3 years and enhanced preschool (EP) for children aged 3+ years, and their interactions.

Methods: In Odisha, India, 192 villages were randomly assigned to ES or to no ES. Within each village, about 8 mothers with children initially aged 7 to 16 months were enrolled, receiving ES or no ES accordingly (n = 1449).

Metabolic Reprogramming in Tumor-Associated Macrophages in the Ovarian Tumor Microenvironment.

The interaction between tumor cells and macrophages in the tumor microenvironment plays an essential role in metabolic changes in macrophages and reprograms them towards a pro-tumorigenic phenotype. Increasing evidence indicates that macrophage metabolism is a highly complex process and may not be as simple as previously thought. Pro-inflammatory stimuli switch macrophages towards an M1-like phenotype and rely mainly on aerobic glycolysis and fatty acid synthesis, whereas anti-inflammatory stimuli switch macrophages towards an M2-like phenotype.

Systems Analysis Reveals Contraceptive-Induced Alteration of Cervicovaginal Gene Expression in a Randomized Trial.

Hormonal contraceptives (HCs) are vital in managing the reproductive health of women. However, HC usage has been linked to perturbations in cervicovaginal immunity and increased risk of sexually transmitted infections. Here, we evaluated the impact of three HCs on the cervicovaginal environment using high-throughput transcriptomics.

An enantio- and diastereoselective approach to indoloquinolizidines in continuous flow.

Merging polymer-supported asymmetric organocatalysis with continuous flow in a packed bed reactor has been used as the key, enantiodetermining step in a short synthesis of indoloquinolizidines. Using this approach, a highly enantioselective, solvent-free and rapid conjugate addition of dimethyl malonate to a diverse family of cinnamaldehydes in continuous flow, allowing the preparation of relevant oxodiesters in multigram amounts has been developed. The obtained Michael adducts have been used to complete an expedient diastereoselective synthesis of indoloquinolizidine cascade Pictet-Splengler cyclisation-lactamisation in continuous flow.

Extracellular vesicle contents as non-invasive biomarkers in ovarian malignancies.

Ovarian cancer most commonly presents at an advanced stage where survival is approximately 30% compared with >80% if diagnosed and treated before disease spreads. Diagnostic capabilities have progressed from surgical staging via laparotomy to image-guided biopsies and immunohistochemistry staining, along with advances in technology and medicine. Despite improvements in diagnostic capabilities, population-level screening for ovarian cancer is not recommended.

Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer.

SPHK1 (sphingosine kinase-1) catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P), is found to be highly expressed in solid tumors. Here, extracellular vesicles (EVs) are identified as the key transporters of SPHK1 to the tumor microenvironment. Consequently, SPHK1-packaged EVs elevate S1P levels in the tumor microenvironment, where S1P appears as an immunosuppressive agent.