The MAGIC algorithm probability predicts treatment response and long-term outcomes to second-line therapy for acute GVHD.

The significance of biomarkers in second-line treatment for acute graft-versus-host disease (GVHD) has not been well characterized. We analyzed clinical data and serum samples at the initiation of second-line systemic treatment of acute GVHD from 167 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC) between 2016 and 2021. Sixty-two patients received ruxolitinib-based therapy, whereas 102 received other systemic agents.

Third-party fecal microbiota transplantation for high-risk treatment-naïve acute GVHD of the lower GI tract.

Disruption of the intestinal microbiome is observed with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (LGI) tract, and fecal microbiota transplantation (FMT) has successfully cured steroid-refractory cases. In this open-label, single-arm, pilot study, third-party, single-donor FMT was administered in combination with systemic corticosteroids to participants with high-risk acute LGI GVHD, with a focus on treatment-naïve cases. Participants were scheduled to receive 1 induction dose (15 capsules per day for 2 consecutive days), followed by 3 weekly maintenance doses, consisting of 15 capsules per dose.

The New NCI Precision Medicine Trials.

Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target.

Clinical response to belumosudil in bronchiolitis obliterans syndrome: a combined analysis from 2 prospective trials.

Chronic graft-versus-host disease (cGVHD) of the lung, or bronchiolitis obliterans syndrome (BOS), is a high-risk disease manifestation associated with poor outcomes. Currently available treatments have demonstrated limited clinical efficacy in this setting. Belumosudil is a novel oral selective rho-associated coiled-coil-containing protein kinase-2 inhibitor that was recently approved by the US Food and Drug Administration in the treatment of cGVHD.

mirTarRnaSeq: An R/Bioconductor Statistical Package for miRNA-mRNA Target Identification and Interaction Analysis.

We introduce mirTarRnaSeq, an R/Bioconductor package for quantitative assessment of miRNA-mRNA relationships within sample cohorts. mirTarRnaSeq is a statistical package to explore predicted or pre-hypothesized miRNA-mRNA relationships following target prediction.We present two use cases applying mirTarRnaSeq.

Defibrotide: real-world management of veno-occlusive disease/sinusoidal obstructive syndrome after stem cell transplant.

Hepatic veno-occlusive disease or sinusoidal obstructive syndrome (VOD/SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Defibrotide is the only medication approved by the US Food and Drug Administration for the management of severe VOD/SOS after HSCT. We report our center's experience with commercially available defibrotide as treatment of patients with VOD/SOS.

Integrated spatial genomics reveals global architecture of single nuclei.

Identifying the relationships between chromosome structures, nuclear bodies, chromatin states and gene expression is an overarching goal of nuclear-organization studies. Because individual cells appear to be highly variable at all these levels, it is essential to map different modalities in the same cells. Here we report the imaging of 3,660 chromosomal loci in single mouse embryonic stem (ES) cells using DNA seqFISH+, along with 17 chromatin marks and subnuclear structures by sequential immunofluorescence and the expression profile of 70 RNAs.

Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins.

Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex.

Inter-Eye Association of Visual Field Defects in Glaucoma and Its Clinical Utility.

Purpose: To investigate intereye associations of visual field (VF) defects.

Methods: We selected 24-2 VF pairs of both eyes from 63,604 patients tested on the same date with mean deviation (MD) ≥ -12 dB. VFs were decomposed into one normal and 15 defect patterns previously identified using archetypal analysis.

Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer.

The paucity of genetically informed, immunocompetent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high-grade serous tubo-ovarian cancer (HGSC) models exhibiting mutational combinations seen in patients with HGSC. Detailed analysis of homologous recombination (HR)-proficient ( ), HR-deficient ( ), and unclassified ( ) organoids revealed differences in properties (proliferation, differentiation, and "secretome"), copy-number aberrations, and tumorigenicity.

CRISP-view: a database of functional genetic screens spanning multiple phenotypes.

High-throughput genetic screening based on CRISPR/Cas9 or RNA-interference (RNAi) enables the exploration of genes associated with the phenotype of interest on a large scale. The rapid accumulation of public available genetic screening data provides a wealth of knowledge about genotype-to-phenotype relationships and a valuable resource for the systematic analysis of gene functions. Here we present CRISP-view, a comprehensive database of CRISPR/Cas9 and RNAi screening datasets that span multiple phenotypes, including in vitro and in vivo cell proliferation and viability, response to cancer immunotherapy, virus response, protein expression, etc.

Author Correction: Molecular architecture of lineage allocation and tissue organization in early mouse embryo.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme.

An integrative ENCODE resource for cancer genomics.

ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types.

Penetrance of Breast and Ovarian Cancer in Women Who Carry a Mutation and Do Not Use Risk-Reducing Salpingo-Oophorectomy: An Updated Meta-Analysis.

Background: Use of risk-reducing Salpingo-oophorectomy (RRSO) substantially reduces the risk of ovarian and breast cancer for women who carry a mutation. It is important to adjust for RRSO use in the estimation of penetrance of breast and ovarian cancer.

Methods: We searched PubMed for penetrance estimates of breast and ovarian cancer from studies that genotyped individual patients and explicitly adjusted for RRSO use by censoring follow-up at the age of RRSO.

ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells.

Programmed DNA recombination in mammalian cells occurs predominantly in a directional manner. While random DNA breaks are typically repaired both by deletion and by inversion at approximately equal proportions, V(D)J and class switch recombination (CSR) of immunoglobulin heavy chain gene overwhelmingly delete intervening sequences to yield productive rearrangement. What factors channel chromatin breaks to deletional CSR in lymphocytes is unknown.

Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development.

Repair of DNA double-stranded breaks (DSBs) during lymphocyte development is essential for V(D)J recombination and forms the basis of immunoglobulin variable region diversity. Understanding of this process in lymphogenesis has historically been centered on the study of RAG1/2 recombinases and a set of classical non-homologous end-joining factors. Much less has been reported regarding the role of chromatin modifications on this process.

Lisa: inferring transcriptional regulators through integrative modeling of public chromatin accessibility and ChIP-seq data.

We developed Lisa (http://lisa.cistrome.org/) to predict the transcriptional regulators (TRs) of differentially expressed or co-expressed gene sets.

Two faces of bivalent domain regulate VEGFA responsiveness and angiogenesis.

The bivalent domain (BD) at promoter region is an unique epigenetic feature poised for activation or repression during cell differentiation in embryonic stem cell. However, the function of BDs in already differentiated cells remains exclusive. By profiling the epigenetic landscape of endothelial cells during VEGFA (vascular endothelial growth factor A) stimulation, we discovered that BDs are widespread in endothelial cells and preferentially marked genes responsive to VEGFA.

Author Correction: Molecular architecture of lineage allocation and tissue organization in early mouse embryo.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Transcriptional network dynamics during the progression of pluripotency revealed by integrative statistical learning.

The developmental potential of cells, termed pluripotency, is highly dynamic and progresses through a continuum of naive, formative and primed states. Pluripotency progression of mouse embryonic stem cells (ESCs) from naive to formative and primed state is governed by transcription factors (TFs) and their target genes. Genomic techniques have uncovered a multitude of TF binding sites in ESCs, yet a major challenge lies in identifying target genes from functional binding sites and reconstructing dynamic transcriptional networks underlying pluripotency progression.