On-chip fabrication of tailored 3D hydrogel scaffolds to model cancer cell invasion and interaction with endothelial cells.

The high mortality associated with certain cancers can be attributed to the invasive nature of the tumor cells. Yet, the complexity of studying invasion hinders our understanding of how the tumor spreads. This work presents a microengineered three-dimensional (3D) model for studying cancer cell invasion and interaction with endothelial cells.

Hidden secrets of the cancer genome: unlocking the impact of non-coding mutations in gene regulatory elements.

Discoveries in the field of genomics have revealed that non-coding genomic regions are not merely "junk DNA", but rather comprise critical elements involved in gene expression. These gene regulatory elements (GREs) include enhancers, insulators, silencers, and gene promoters. Notably, new evidence shows how mutations within these regions substantially influence gene expression programs, especially in the context of cancer.

Long non-coding intergenic RNA, LINC00273 induces cancer metastasis and stemness via miRNA sponging in triple negative breast cancer.

LncRNAs and miRNAs, being the master regulators of gene expression, are crucial functional mediators in cancer. Our study unveils the critical regulatory role of the metastatic long non-coding RNA LINC00273 as the master regulator of oncogenes involved in cancer metastasis, stemness, and chemoresistance via its miRNA sponging mechanism. M2 (a salt of bis-Schiff base) mediated G quadruplex (G4) stabilization at the LINC00273 gene promoter remarkably inhibits LINC00273 transcription.

Air Quality and Health Impacts of Onshore Oil and Gas Flaring and Venting Activities Estimated Using Refined Satellite-Based Emissions.

Emissions from flaring and venting (FV) in oil and gas (O&G) production are difficult to quantify due to their intermittent activities and lack of adequate monitoring and reporting. Given their potentially significant contribution to total emissions from the O&G sector in the United States, we estimate emissions from FV using Visible Infrared Imaging Radiometer Suite satellite observations and state/local reported data on flared gas volume. These refined estimates are higher than those reported in the National Emission Inventory: by up to 15 times for fine particulate matter (PM), two times for sulfur dioxides, and 22% higher for nitrogen oxides (NO).

Evaluating the sensitivity of mortality attributable to pollution to modeling Choices: A case study for Colorado.

We evaluated the sensitivity of estimated PM and NO health impacts to varying key input parameters and assumptions including: 1) the spatial scale at which impacts are estimated, 2) using either a single concentration-response function (CRF) or using racial/ethnic group specific CRFs from the same epidemiologic study, 3) assigning exposure to residents based on home, instead of home and work locations for the state of Colorado. We found that the spatial scale of the analysis influences the magnitude of NO, but not PM, attributable deaths. Using county-level predictions instead of 1 km predictions of NO resulted in a lower estimate of mortality attributable to NO by ∼ 50 % for all of Colorado for each year between 2000 and 2020.

Switchable tetraplex elements in the heterogeneous nuclear ribonucleoprotein K promoter: micro-environment dictated structural transitions of G/C rich elements.

We have elucidated the hnRNP K promoter as a hotspot for tetraplex-based molecular switches receptive to micro-environmental stimuli. We have characterised the structural features of four tetraplex-forming loci and identified them as binding sites of transcription factors. These segments form either G-quadruplex or i-motif structures, the structural dynamicity of which has been studied in depth several biophysical techniques.

Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: Extended 41-month follow-up in the clear cell renal cell carcinoma cohort.

Background: Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented.

Ethnoracial Disparities in Nitrogen Dioxide Pollution in the United States: Comparing Data Sets from Satellites, Models, and Monitors.

In the United States (U.S.), studies on nitrogen dioxide (NO) trends and pollution-attributable health effects have historically used measurements from in situ monitors, which have limited geographical coverage and leave 66% of urban areas unmonitored.

Unraveling the structural aspects of the G-quadruplex in SMO promoter and elucidating its contribution in transcriptional regulation.

We located a 25 nt G-rich sequence in the promoter region of SMO oncogene. We performed an array of biophysical and biochemical assays and confirmed the formation of a parallel G quadruplex (SMO1-GQ) by the identified sequence. SMO1-GQ is highly conserved in primates.

Using evolutionary constraint to define novel candidate driver genes in medulloblastoma.

Current knowledge of cancer genomics remains biased against noncoding mutations. To systematically search for regulatory noncoding mutations, we assessed mutations in conserved positions in the genome under the assumption that these are more likely to be functional than mutations in positions with low conservation. To this end, we use whole-genome sequencing data from the International Cancer Genome Consortium and combined it with evolutionary constraint inferred from 240 mammals, to identify genes enriched in noncoding constraint mutations (NCCMs), mutations likely to be regulatory in nature.

Noncoding RNA as an influential epigenetic modulator with promising roles in cancer therapeutics.

The epigenetic landscape has an important role in cellular homeostasis and its deregulation leads to cancer. Noncoding (nc)RNA networks function as major regulators of cellular epigenetic hallmarks via regulation of vital processes, such as histone modification and DNA methylation. They are integral intracellular components affecting multiple oncogenic pathways.

Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study.

Background: Few treatment options are available for patients with advanced renal cell carcinoma who have received previous anti-PD-1-based or anti-PD-L1-based immunotherapy. Combining belzutifan, an HIF-2α inhibitor, with cabozantinib, a multitargeted tyrosine-kinase inhibitor of VEGFR, c-MET, and AXL, might provide more antitumoural effects than either agent alone. We aimed to investigate the antitumour activity and safety of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy.

Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease.

Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.

Identification and characterization of a flexile G-quadruplex in the distal promoter region of stemness gene REX1.

We have identified a parallel G-quadruplex (R1WT) in the distal promoter region (-821 base-pairs upstream of the TSS) of the pluripotent gene REX1. Through biophysical and biochemical approach, we have characterized the G-quadruplex (GQ) as a potential molecular switch that may control REX1 promoter activity to determine the transcriptional fate. Small- molecule interactive study of the monomeric form of R1WT (characterized as R1mut2) with TMPyP4 and BRACO-19 revealed GQ destabilization upon interaction with TMPyP4 and stabilization upon interaction with BRACO-19.

Insights from Application of a Hierarchical Spatio-Temporal Model to an Intensive Urban Black Carbon Monitoring Dataset.

Existing regulatory pollutant monitoring networks rely on a small number of centrally located measurement sites that are purposefully sited away from major emission sources. While informative of general air quality trends regionally, these networks often do not fully capture the local variability of air pollution exposure within a community. Recent technological advancements have reduced the cost of sensors, allowing air quality monitoring campaigns with high spatial resolution.

A deep reinforcement learning-based intelligent intervention framework for real-time proactive road safety management.

We propose a variable speed limit (VSL) system for improving the safety of urban expressways in real time. The system has two main functions: monitoring traffic data and then using the data to assess crash risk through a real-time crash prediction model (RTCPM). When the risk is high, the system triggers VSL control to restore traffic conditions to normal.

Mortality Risk from : A Comparison of Modeling Approaches to Identify Disparities across Racial/Ethnic Groups in Policy Outcomes.

Background: Regulatory analyses of air pollution policies require the use of concentration-response functions and underlying health data to estimate the mortality and morbidity effects, as well as the resulting benefits, associated with policy-related changes in fine particulate matter ()]. Common practice by U.S.

Three-year review of a capacity building pilot for a sustainable regional network on food, nutrition and health systems education in India.

Background: In Kolkata (India), there are high rates of malnourished children (45.9%) under the age of three, impacting growth, organ development, function, and cognition. Mothers have a major role to play during this crucial development stage, with research showing nutrition knowledge, attitudes and practices (KAP) of mothers are important determinants of childhood malnutrition.