ProstaMine: a bioinformatics tool for identifying subtype-specific co-alterations associated with aggressiveness in prostate cancer.

Background: Prostate cancer is a leading cause of cancer-related deaths among men, marked by heterogeneous clinical and molecular characteristics. The complexity of the molecular landscape necessitates tools for identifying multi-gene co-alteration patterns that are associated with aggressive disease. The identification of such gene sets will allow for deeper characterization of the processes underlying prostate cancer progression and potentially lead to novel strategies for treatment.

Continuous evolution of compact protein degradation tags regulated by selective molecular glues.

Conditional protein degradation tags (degrons) are usually >100 amino acids long or are triggered by small molecules with substantial off-target effects, thwarting their use as specific modulators of endogenous protein levels. We developed a phage-assisted continuous evolution platform for molecular glue complexes (MG-PACE) and evolved a 36-amino acid zinc finger (ZF) degron (SD40) that binds the ubiquitin ligase substrate receptor cereblon in complex with PT-179, an orthogonal thalidomide derivative. Endogenous proteins tagged in-frame with SD40 using prime editing are degraded by otherwise inert PT-179.

Scalable Multipollutant Exposure Assessment Using Routine Mobile Monitoring Platforms.

Introduction: The absence of spatially resolved air pollution measurements remains a major gap in health studies of air pollution, especially in disadvantaged communities in the United States and lower-income countries. Many urban air pollutants vary over short spatial scales, owing to unevenly distributed emissions sources, rapid dilution away from sources, and physicochemical transformations. Primary air pollutants from traffic have especially sharp spatial gradients, which lead to disparate effects on human health for populations who live near air pollution sources, with important consequences for environmental justice.

Multi-season mobile monitoring campaign of on-road air pollution in Bengaluru, India: High-resolution mapping and estimation of quasi-emission factors.

Mobile monitoring can supplement regulatory measurements, particularly in low-income countries where stationary monitoring is sparse. Here, we report results from a ~ year-long mobile monitoring campaign of on-road concentrations of black carbon (BC), ultrafine particles (UFP), and carbon dioxide (CO) in Bengaluru, India. The study route included 150 unique kms (average: ~22 repeat measurements per monitored road segment).

Proteolysis-targeting chimeras with reduced off-targets.

Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation.

Urban Air-Quality Estimation Using Visual Cues and a Deep Convolutional Neural Network in Bengaluru (Bangalore), India.

Mobile monitoring provides robust measurements of air pollution. However, resource constraints often limit the number of measurements so that assessments cannot be obtained in all locations of interest. In response, surrogate measurement methodologies, such as videos and images, have been suggested.

SIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma.

Ewing sarcoma (ES), which is characterized by the presence of oncogenic fusion proteins such as EWS/FLI1, is an aggressive pediatric malignancy with a high rate of early dissemination and poor outcome after distant spread. Here we demonstrate that the SIX1 homeoprotein, which enhances metastasis in most tumor types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes. Like EWS/FLI1, SIX1 promotes cell growth/transformation, yet dramatically inhibits migration and invasion, as well as metastasis in vivo.

A harmonized resource of integrated prostate cancer clinical, -omic, and signature features.

Genomic and transcriptomic data have been generated across a wide range of prostate cancer (PCa) study cohorts. These data can be used to better characterize the molecular features associated with clinical outcomes and to test hypotheses across multiple, independent patient cohorts. In addition, derived features, such as estimates of cell composition, risk scores, and androgen receptor (AR) scores, can be used to develop novel hypotheses leveraging existing multi-omic datasets.

FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity.

Cellular exposure to free fatty acids (FFAs) is implicated in the pathogenesis of obesity-associated diseases. However, there are no scalable approaches to comprehensively assess the diverse FFAs circulating in human plasma. Furthermore, assessing how FFA-mediated processes interact with genetic risk for disease remains elusive.

Photoswitchable Molecular Glues Enable Optical Control of Transcription Factor Degradation.

Immunomodulatory drugs (IMiDs), which include thalidomide and its derivatives, have emerged as the standard of care against multiple myeloma. They function as molecular glues that bind to the E3 ligase cereblon (CRBN) and induce protein interactions with neosubstrates, including the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). The subsequent ubiquitylation and degradation of these transcription factors underlies the antiproliferative activity of IMiDs.

A molecular glue approach to control the half-life of CRISPR-based technologies.

Cas9 is a programmable nuclease that has furnished transformative technologies, including base editors and transcription modulators (e.g., CRISPRi/a), but several applications of these technologies, including therapeutics, mandatorily require precision control of their half-life.

FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity.

Unlabelled: Cellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA- mediated processes interact with genetic risk for disease remains elusive.

curatedPCaData: Integration of clinical, genomic, and signature features in a curated and harmonized prostate cancer data resource.

Genomic and transcriptomic data have been generated across a wide range of prostate cancer (PCa) study cohorts. These data can be used to better characterize the molecular features associated with clinical outcomes and to test hypotheses across multiple, independent patient cohorts. In addition, derived features, such as estimates of cell composition, risk scores, and androgen receptor (AR) scores, can be used to develop novel hypotheses leveraging existing multi-omic datasets.

A general approach to identify cell-permeable and synthetic anti-CRISPR small molecules.

The need to control the activity and fidelity of CRISPR-associated nucleases has resulted in a demand for inhibitory anti-CRISPR molecules. The small-molecule inhibitor discovery platforms available at present are not generalizable to multiple nuclease classes, only target the initial step in the catalytic activity and require high concentrations of nuclease, resulting in inhibitors with suboptimal attributes, including poor potency. Here we report a high-throughput discovery pipeline consisting of a fluorescence resonance energy transfer-based assay that is generalizable to contemporary and emerging nucleases, operates at low nuclease concentrations and targets all catalytic steps.

Antigens Expressed by Breast Cancer Cells Undergoing EMT Stimulate Cytotoxic CD8 T Cell Immunity.

Antigenic differences formed by alterations in gene expression and alternative splicing are predicted in breast cancer cells undergoing epithelial to mesenchymal transition (EMT) and the reverse plasticity known as MET. How these antigenic differences impact immune interactions and the degree to which they can be exploited to enhance immune responses against mesenchymal cells is not fully understood. We utilized a master microRNA regulator of EMT to alter mesenchymal-like EO771 mammary carcinoma cells to a more epithelial phenotype.

Bias in PM measurements using collocated reference-grade and optical instruments.

Optical PM measurements are sensitive to aerosol properties that can vary with space and time. Here, we compared PM measurements from collocated reference-grade (beta attenuation monitors, BAMs) and optical instruments (two DustTrak II and two DustTrak DRX) over 6 months. We performed inter-model (two different models), intra-model (two units of the same model), and inter-type (two different device types: optical vs.

Characteristics and health risk assessment of fine particulate matter and surface ozone: results from Bengaluru, India.

Urban air pollution is a complex problem, which requires a multi-pronged approach to understand its dynamics. In the current study, various aspects of air pollution over Bengaluru city were studied utilizing simultaneous reference-grade measurements (during the period July 2019 to June 2020) of fine particulate matter mass concentration (PM), aerosol black carbon mass concentrations (BC), and surface ozone (O) concentrations. The study period mean PM, BC, and O were observed to be 26.

CRISPR-based therapeutics: current challenges and future applications.

The discovery, only a decade ago, of the genome editing power of clustered regularly interspaced short palindromic repeats (CRISPR)-associated nucleases is already reinventing the therapeutic process, from how new drugs are discovered to novel ways to treat diseases. CRISPR-based screens can aid therapeutic development by quickly identifying a drug's mechanism of action and escape mutants. Additionally, CRISPR-Cas has advanced emerging ex vivo therapeutics, such as cell replacement therapies.

IL13Rα2 Promotes Proliferation and Outgrowth of Breast Cancer Brain Metastases.

Purpose: The survival of women with brain metastases (BM) from breast cancer remains very poor, with over 80% dying within a year of their diagnosis. Here, we define the function of IL13Rα2 in outgrowth of breast cancer brain metastases (BCBM) and , and postulate IL13Rα2 as a suitable therapeutic target for BM.

Experimental Design: We performed IHC staining of IL13Rα2 in BCBM to define its prognostic value.

Self-assembled supramolecular nanomicelles from a bile acid-docetaxel conjugate are highly tolerable with improved therapeutic efficacy.

Herein, we present the engineering of a supramolecular nanomicellar system that is composed of self-assembled units of the PEGylated lithocholic acid (LCA)-docetaxel (DTX) conjugate (LCA-DTX-PEG). We tethered a short polyethylene glycol unit to LCA and used an esterase-sensitive ester linkage between DTX and LCA. The LCA-DTX-PEG conjugate formed nanomicelles (LCA-DTX-PEG NMs) with ∼160 nm hydrodynamic diameter that are sensitive to cellular esterases and maximized the release of DTX under high esterase exposure.

Impact of COVID-19 lockdown on the fine particulate matter concentration levels: Results from Bengaluru megacity, India.

Leveraging the COVID-19 India-wide lockdown situation, the present study attempts to quantify the reduction in the ambient fine particulate matter concentrations during the lockdown (compared with that of the pre-lockdown period), owing to the highly reduced specific anthropogenic activities and thereby pollutant emissions. The study was conducted over Bengaluru (India), using PM (mass concentration of particulate matter having size less than or equal to 2.5 µm) and Black Carbon mass concentration (BC) data.

Chemogenetic System Demonstrates That Cas9 Longevity Impacts Genome Editing Outcomes.

Prolonged Cas9 activity can hinder genome engineering as it causes off-target effects, genotoxicity, heterogeneous genome-editing outcomes, immunogenicity, and mosaicism in embryonic editing-issues which could be addressed by controlling the longevity of Cas9. Though some temporal controls of Cas9 activity have been developed, only cumbersome systems exist for modifying the lifetime. Here, we have developed a chemogenetic system that brings Cas9 in proximity to a ubiquitin ligase, enabling rapid ubiquitination and degradation of Cas9 by the proteasome.

Bile Acid Tethered Docetaxel-Based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes.

In this study, we describe the engineering of sub-100 nm nanomicelles (DTX-PC NMs) derived from phosphocholine derivative of docetaxel (DTX)-conjugated lithocholic acid (DTX-PC) and poly(ethylene glycol)-tethered lithocholic acid. Administration of DTX-PC NMs decelerate tumor progression and increase the mice survivability compared to Taxotere (DTX-TS), the FDA-approved formulation of DTX. Unlike DTX-TS, DTX-PC NMs do not cause any systemic toxicity and slow the decay rate of plasma DTX concentration in rodents and non-rodent species including non-human primates.