mVOC 4.0: a database of microbial volatiles.

Metabolomic microbiome research has become an important topic for understanding agricultural, ecological as well as health correlations. Only the determination of both the non-volatile and the volatile organic compound (mVOC) production by microorganisms allows a holistic view for understanding the complete potential of metabolomes and metabolic capabilities of bacteria. In the recent past, more and more bacterial headspaces and culture media were analyzed, leading to an accumulation of about 3500 mVOCs in the updated mVOC 4.

Inhibition of the Rho/MRTF pathway improves the response of BRAF-resistant melanoma to PD1/PDL1 blockade.

Metastatic cutaneous melanoma is a fatal skin cancer. Resistance to targeted and immune therapies limits the benefits of current treatments. Identifying and adding anti-resistance agents to current treatment protocols can potentially improve clinical responses.

Withdrawn 2.0-update on withdrawn drugs with pharmacovigilance data.

One challenge in the development of novel drugs is their interaction with potential off-targets, which can cause unintended side-effects, that can lead to the subsequent withdrawal of approved drugs. At the same time, these off-targets may also present a chance for the repositioning of withdrawn drugs for new indications, which are potentially rare or more severe than the original indication and where certain adverse reactions may be avoidable or tolerable. To enable further insights into this topic, we updated our database Withdrawn by adding pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS), as well as mechanism of action and human disease pathway prediction features for drugs that are or were temporarily withdrawn or discontinued in at least one country.

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis.

The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics. The role of the KEAP1/NRF2 pathway as pro-tumorigenic or anti-tumorigenic throughout stages of carcinogenesis (including initiation, promotion, progression, and metastasis) is complex.

Exploring structural effects in a new class of NRF2 inhibitors.

NRF2 is a transcription factor that controls the cellular response to various stressors, such as reactive oxygen and nitrogen species. As such, it plays a key role in the suppression of carcinogenesis, but constitutive NRF2 expression in cancer cells leads to resistance to chemotherapeutics and promotes metastasis. As a result, inhibition of the NRF2 pathway is a target for new drugs, especially for use in conjunction with established chemotherapeutic agents like carboplatin and 5-fluorouracil.

SuperNatural 3.0-a database of natural products and natural product-based derivatives.

Natural products (NPs) are single chemical compounds, substances or mixtures produced by a living organism - found in nature. Evolutionarily, NPs have been used as healing agents since thousands of years and still today continue to be the most important source of new potential therapeutic preparations. Natural products have played a key role in modern drug discovery for several diseases.

SuperPred 3.0: drug classification and target prediction-a machine learning approach.

Since the last published update in 2014, the SuperPred webserver has been continuously developed to offer state-of-the-art models for drug classification according to ATC classes and target prediction. For the first time, a thoroughly filtered ATC dataset, that is suitable for accurate predictions, is provided along with detailed information on the achieved predictions. This aims to overcome the challenges in comparing different published prediction methods, since performance can vary greatly depending on the training dataset used.

BRAF Inhibitor Resistance Confers Increased Sensitivity to Mitotic Inhibitors.

Single agent and combination therapy with BRAF and MEK inhibitors have remarkable efficacy against melanoma tumors with activating BRAF mutations, but in most cases BRAF inhibitor (BRAFi) resistance eventually develops. One resistance mechanism is reactivation of the ERK pathway. However, only about half of BRAFi resistance is due to ERK reactivation.

A Comparative Analysis of COVID-19 Vaccines Based on over 580,000 Cases from the Vaccination Adverse Event Reporting System.

Background: The COVID-19 pandemic is being battled via the largest vaccination campaign in history, with more than eight billion doses administered thus far. Therefore, discussions about potentially adverse reactions, and broader safety concerns, are critical. The U.

Ibrutinib Blocks YAP1 Activation and Reverses BRAF Inhibitor Resistance in Melanoma Cells.

Most B-Raf proto-oncogene (BRAF)-mutant melanoma tumors respond initially to BRAF inhibitor (BRAFi)/mitogen-activated protein kinase kinase 1 inhibitor (MEKi) therapy, although few patients have durable long-term responses to these agents. The goal of this study was to use an unbiased computational approach to identify inhibitors that reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we found that ibrutinib effectively reverses this signature, and we demonstrate experimentally that ibrutinib resensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib.

SuperTCM: A biocultural database combining biological pathways and historical linguistic data of Chinese Materia Medica for drug development.

Aim Of The Study: Botanicals used in Traditional Chinese Medicine (TCM) are a rich source for drug discovery and provide models for multi-component drug development. To facilitate the studies of the actions of TCM drugs and expand their applications, a comprehensive database is urgently required.

Methods: One online resource connects all the relevant data from multiple scientific sources and languages.

Prediction of oral squamous cell carcinoma based on machine learning of breath samples: a prospective controlled study.

Background: The aim of this study was to evaluate the possibility of breath testing as a method of cancer detection in patients with oral squamous cell carcinoma (OSCC).

Methods: Breath analysis was performed in 35 OSCC patients prior to surgery. In 22 patients, a subsequent breath test was carried out after surgery.

Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in -Mutant Melanoma Cell Lines.

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% V600 mutations and ≈30% mutations). While drugs targeting the MAPK pathway have yielded success in V600 mutant melanoma patients, such therapies have been ineffective in patients with mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of mutant melanoma cell lines.

PROMISCUOUS 2.0: a resource for drug-repositioning.

The development of new drugs for diseases is a time-consuming, costly and risky process. In recent years, many drugs could be approved for other indications. This repurposing process allows to effectively reduce development costs, time and, ultimately, save patients' lives.

Apigenin by targeting hnRNPA2 sensitizes triple-negative breast cancer spheroids to doxorubicin-induced apoptosis and regulates expression of ABCC4 and ABCG2 drug efflux transporters.

Acquired resistance to doxorubicin is a major hurdle in triple-negative breast cancer (TNBC) therapy, emphasizing the need to identify improved strategies. Apigenin and other structurally related dietary flavones are emerging as potential chemo-sensitizers, but their effect on three-dimensional TNBC spheroid models has not been investigated. We previously showed that apigenin associates with heterogeneous ribonuclear protein A2/B1 (hnRNPA2), an RNA-binding protein involved in mRNA and co-transcriptional regulation.

Oestrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation.

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.

Therapeutic potential of targeting mixed lineage kinases in cancer and inflammation.

Dysregulation of intracellular signaling pathways is a key attribute of diseases associated with chronic inflammation, including cancer. Mitogen activated protein kinases have emerged as critical conduits of intracellular signal transmission, yet due to their ubiquitous roles in cellular processes, their direct inhibition may lead to undesired effects, thus limiting their usefulness as therapeutic targets. Mixed lineage kinases (MLKs) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that interact with scaffolding proteins and function upstream of p38, JNK, ERK, and NF-kappaB to mediate diverse cellular signals.

E2F1 Drives Breast Cancer Metastasis by Regulating the Target Gene FGF13 and Altering Cell Migration.

In prior work we demonstrated that loss of E2F transcription factors inhibits metastasis. Here we address the mechanisms for this phenotype and identify the E2F regulated genes that coordinate tumor cell metastasis. Transcriptomic profiling of E2F1 knockout tumors identified a role for E2F1 as a master regulator of a suite of pro-metastatic genes, but also uncovered E2F1 target genes with an unknown role in pulmonary metastasis.

Whole-Genome Multi-omic Study of Survival in Patients with Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) has been recognized as the most lethal type of malignant brain tumor. Despite efforts of the medical and research community, patients' survival remains extremely low. Multi-omic profiles (including DNA sequence, methylation and gene expression) provide rich information about the tumor.

EGFR Signals through a DOCK180-MLK3 Axis to Drive Glioblastoma Cell Invasion.

A hallmark of glioblastoma (GBM) tumors is their highly invasive behavior. Tumor dissemination into surrounding brain tissue is responsible for incomplete surgical resection, and subsequent tumor recurrence. Identification of targets that control GBM cell dissemination is critical for developing effective therapies to treat GBM.

Simulation for Operational Readiness in a New Freestanding Emergency Department: Strategy and Tactics.

Simulation in multiple contexts over the course of a 10-week period served as a core learning strategy to orient experienced clinicians before opening a large new urban freestanding emergency department. To ensure technical and procedural skills of all team members, who would provide care without on-site recourse to specialty backup, we designed a comprehensive interprofessional curriculum to verify and regularize a wide range of competencies and best practices for all clinicians. Formulated under the rubric of systems integration, simulation activities aimed to instill a shared culture of patient safety among the entire cohort of 43 experienced emergency physicians, physician assistants, nurses, and patient technicians, most newly hired to the health system, who had never before worked together.

MLK3 Signaling in Cancer Invasion.

Mixed-lineage kinase 3 (MLK3) was first cloned in 1994; however, only in the past decade has MLK3 become recognized as a player in oncogenic signaling. MLK3 is a mitogen-activated protein kinase kinase kinase (MAP3K) that mediates signals from several cell surface receptors including receptor tyrosine kinases (RTKs), chemokine receptors, and cytokine receptors. Once activated, MLK3 transduces signals to multiple downstream pathways, primarily to c-Jun terminal kinase (JNK) MAPK, as well as to extracellular-signal-regulated kinase (ERK) MAPK, P38 MAPK, and NF-κB, resulting in both transcriptional and post-translational regulation of multiple effector proteins.

Structural empowerment of clinical nurse managers.

Objective: The purpose of this study was to describe perceptions of structural empowerment of clinical nurse managers (CNMs) in 1 large healthcare system.

Background: The recruitment and retention of CNMs are crucial to the future of healthcare institutions. Understanding the extent to which CNMs feel supported in the work environment and have access to resources, information, support, and opportunities to learn and develop will be beneficial to organizational effectiveness.

The 18-kDa translocator protein (TSPO) disrupts mammary epithelial morphogenesis and promotes breast cancer cell migration.

Mitochondria play important roles in cancer progression and have emerged as viable targets for cancer therapy. Increasing levels of the outer mitochondrial membrane protein, 18-kDa translocator protein (TSPO), are associated with advancing breast cancer stage. In particular, higher TSPO levels are found in estrogen receptor (ER)-negative breast tumors, compared with ER-positive tumors.

Targeting mixed lineage kinases in ER-positive breast cancer cells leads to G2/M cell cycle arrest and apoptosis.

Estrogen receptor (ER)-positive tumors represent the most common type of breast cancer, and ER-targeted therapies such as antiestrogens and aromatase inhibitors have therefore been widely used in breast cancer treatment. While many patients have benefited from these therapies, both innate and acquired resistance continue to be causes of treatment failure. Novel targeted therapeutics that could be used alone or in combination with endocrine agents to treat resistant tumors or to prevent their development are therefore needed.