Multiplexed mosaic tumor models reveal natural phenotypic variations in drug response within and between populations.

Many agents that show promise in preclinical cancer models lack efficacy in patients due to patient heterogeneity that is not captured in traditional assays. To address this problem, we have developed GENEVA, a platform that measures the molecular and phenotypic consequences of drug perturbations within diverse populations of cancer cells at single-cell resolution, both and . Here, we apply GENEVA to study the KRAS G12C inhibitors, recapitulating known properties of these drugs and uncovering a previously unknown role for mitochondrial activation in cell death induced by KRAS inhibition.

β-1,3-glucan from : a promising epidrug targeting epigenetic regulators PRMTs and SIRTs for therapeutic applications in ovarian cancer.

Natural products serve as a valuable resource in drug discovery and the identification of bioactive molecules in the field of epimedicine, which targets epigenetic regulator enzymes through epidrugs. In this study, β-1,3-glucan (BG), a natural storage polysaccharide in a well-known immunostimulatory agent, is propounded as a promising epidrug. To elucidate the therapeutic efficacy of BG against ovarian cancer, the molecular interactions between BG and epigenetic regulators, Protein Arginine Methyltransferases (PRMTs) and Sirtuins (SIRTs) were investigated using computational methods followed by gene expression studies in SKOV-3 ovarian cancer cell line.

Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling.

Non-small cell lung cancers (NSCLC) harboring common mutations in EGFR and KRAS characteristically respond transiently to targeted therapies against those mutations, but invariably, tumors recur and progress. Resistance often emerges through mutations in the therapeutic target or activation of alternative signaling pathways. Mechanisms of acute tumor cell resistance to initial EGFR (EGFRi) or KRAS (G12Ci) pathway inhibition remain poorly understood.

Systematic identification of post-transcriptional regulatory modules.

In our cells, a limited number of RNA binding proteins (RBPs) are responsible for all aspects of RNA metabolism across the entire transcriptome. To accomplish this, RBPs form regulatory units that act on specific target regulons. However, the landscape of RBP combinatorial interactions remains poorly explored.

Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer.

Cancer cells frequently alter their lipids to grow and adapt to their environment. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion.

Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint.

2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and likely the only other metazoan cGAMP hydrolase under homeostatic conditions.

Nanophytosome formulation of β-1,3-glucan and extract for drug delivery applications.

(EG) is a unicellular freshwater alga known for its high β-1,3-glucan (BG) content with well-known biological properties and immune response. The high molecular weight structure of BG traditionally poses a challenge in terms of its size and absorption. Therefore, the aim of this study was to develop a novel drug delivery mechanism of BG and EG to nanophytosomes (NPs) by converting the heavy molecular weight of BG and EG into lipid phosphatidylcholine (PC), which plays an important role in improving their bioavailability and entrapment in captivity.

Mobile colistin resistance (mcr) genes and recent developments in colistin resistance detection.

The peptide antibiotic colistin has been reserved as a last resort antibiotic treatment option for cases where other antibiotics including carbapenems have failed. Recent emergence of colistin resistance and discovery of mobile colistin resistance (mcr) genes, which encode the cell wall modifying phosphoethanolamine transferase enzyme, complicates the issue. The mcr genes have been associated with conjugative plasmids and can be horizontally transferred between different bacterial species.

Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin.

Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAIT cells are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. Here, we present a MAIT cell-centered profiling of hepatocellular carcinoma (HCC) using scRNA-seq, flow cytometry, and co-detection by indexing (CODEX) imaging of paired patient samples.

Comparative evaluation of the efficacy of nicotine chewing gum and nicotine patches as nicotine replacement therapy using salivary cotinine levels as a biochemical validation measure.

Background: Nicotine replacement therapy (NRT) and habit cessation counseling are considered the mainstay treatment for high nicotine dependence smokers. However, adherence to NRT is very poor. Among the NRTs, nicotine gums and nicotine patches are the most widely available.

Improved psychosocial measures associated with physical activity may be explained by alterations in brain-gut microbiome signatures.

Obesity contributes to physical comorbidities and mental health consequences. We explored whether physical activity could influence more than metabolic regulation and result in psychological benefits through the brain-gut microbiome (BGM) system in a population with high BMI. Fecal samples were obtained for 16 s rRNA profiling and fecal metabolomics, along with psychological and physical activity questionnaires.

ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway.

ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), we show that ENPP1 overexpression drives primary breast tumor growth and metastasis by synergistically dampening extracellular cGAMP-STING mediated antitumoral immunity and activating immunosuppressive extracellular adenosine (eADO) signaling.

How Discrimination Gets Under the Skin: Biological Determinants of Discrimination Associated With Dysregulation of the Brain-Gut Microbiome System and Psychological Symptoms.

Background: Discrimination is associated with negative health outcomes as mediated in part by chronic stress, but a full understanding of the biological pathways is lacking. Here we investigate the effects of discrimination involved in dysregulating the brain-gut microbiome (BGM) system.

Methods: A total of 154 participants underwent brain magnetic resonance imaging to measure functional connectivity.

SYF2 suppression mitigates neurodegeneration in models of diverse forms of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS.

A multi-omic brain gut microbiome signature differs between IBS subjects with different bowel habits.

Alterations of the brain-gut-microbiome system (BGM) have been implicated in the pathophysiology of irritable bowel syndrome (IBS), yet bowel habit-specific alterations have not been elucidated. In this cross-sectional study, we apply a systems biology approach to characterize BGM patterns related to predominant bowel habit. Fecal samples and resting state fMRI were obtained from 102 premenopausal women (36 constipation-predominant IBS (IBS-C), 27 diarrhea-predominant IBS (IBS-D), 39 healthy controls (HCs)).

WEE1 kinase inhibitor MK-1775 sensitizes oral tongue squamous cell carcinoma cells to radiation irrespective of TP53 status.

Objective: Oral tongue squamous cell carcinoma (OTSCC) frequently harbors non-functional p53 and depends on G2/M checkpoint mediated by WEE1. WEE1 suppression has been identified as a promising anti-tumor strategy. This study investigated the capacity of WEE1 kinase inhibitor (MK-1775) and its underlying mechanisms in enhancing radiation responses of OTSCC cells in vitro.

Association of haematological biomarkers with severity of COVID-19 pneumonia.

Background: Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China in December 2019. It is caused by SARS-CoV-2, a beta coronavirus. In this study, we assessed the association of biomarkers such as neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and lymphocyte monocyte ratio (LMR) with the severity of COVID-19 in patients.

Lessons Learned from COVID-19: The Youth Sports World Going Forward.

The coronavirus disease 2019 pandemic profoundly impacted athletes and organizations of all ages and calibers. As optimism grows and restrictions lift, the mindset of youth sports shifts to prospection. Using the lessons learned during the cancelled, postponed, or modified 2020-2021 season, stakeholders should envision a different playing field moving forward.