Interferon-ε loss is elusive 9p21 link to immune-cold tumors, resistant to immune-checkpoint therapy and endogenous CXCL9/10 induction.

Introduction: Copy-number (CN) loss of chromosome 9p, or parts thereof, impair immune response and confer ICT resistance by direct elimination of immune-regulatory genes on this arm, notably IFNγ genes at 9p24.1, and type-I interferon (IFN-I) genes at 9p21.3.

Donor selection in allogeneic stem cell transplantation.

Purpose Of Review: Recent progress in human leukocyte antigen (HLA) characterization, increased accrual of unrelated donors and cord blood units, and a new platform for haploidentical transplantation have resulted in the widespread availability of donors for allogeneic hematopoietic stem cell transplantation.

Recent Findings: Advances in HLA typing have identified an increasing number of loci and alleles that are crucial for successful transplantation. Newer HLA A, B, C, DRB1, and DQB1 alleles, DPB1 mismatches, and HLA B leader sequence matching are incorporated into donor selection algorithms.

Natural language processing analysis of the psychosocial stressors of mental health disorders during the pandemic.

Over the past few years, the COVID-19 pandemic has exerted various impacts on the world, notably concerning mental health. Nevertheless, the precise influence of psychosocial stressors on this mental health crisis remains largely unexplored. In this study, we employ natural language processing to examine chat text from a mental health helpline.

Metastatic site influences driver gene function in pancreatic cancer.

Driver gene mutations can increase the metastatic potential of the primary tumor, but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation of - a transcriptional effector of TGFβ signaling - which is a hallmark of multiple gastrointestinal malignancies. inactivation mediates TGFβ's remarkable anti- to pro-tumorigenic switch during cancer progression and can thus influence both tumor initiation and metastasis.

Long-term remission of infantile Takayasu arteritis associated with germline CBL syndrome after allogeneic hematopoietic stem cell transplantation: A case report and literature review.

Takayasu arteritis (TA) is a large-vessel vasculitis that rarely presents in infancy. Casitas B-lineage lymphoma (CBL) syndrome is a rare genetic disorder due to heterozygous CBL gene germline pathogenic variants that is characterized by a predisposition to develop juvenile myelomonocytic leukemia (JMML). Vasculitis, including TA, has been reported in several patients.

Engineering megabase-sized genomic deletions with MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements).

The elimination of large genomic regions has been enabled by the advent of site-specific nucleases. However, as the intended deletions get larger, the efficiency of successful engineering decreases to a point where it is not feasible to retrieve edited cells due to the rarity of on-target events. To address this issue, we developed a system called molecular alteration of chromosomes with engineered tandem elements (MACHETE).

Individualized dose of anti-thymocyte globulin based on weight and pre-transplantation lymphocyte counts in pediatric patients: a single center experience.

Anti-thymocyte globulin (ATG) has become a standard in preventing GVHD in related and unrelated donor transplantation, but there is no consensus on the best administration schedule. The PARACHUTE trial reported excellent CD4 immune reconstitution (CD4 IR) using a dosing schedule based on the patient's weight and pre-conditioning absolute lymphocyte count (ALC). In 2015 we introduced the PARACHUTE dosing schedule for pediatric patients at our center.

Genetic Findings of Potential Donor Origin following Hematopoietic Cell Transplantation: Recommendations on Donor Disclosure and Genetic Testing from the World Marrow Donor Association.

Following hematopoietic cell transplantation (HCT), recipients are subjected to extensive genetic testing to monitor the efficacy of the transplantation and identify relapsing malignant disease. This testing is increasingly including the use of large gene panels, which may lead to incidental identification of genetic and molecular information of potential donor origin. Deciphering whether variants are of donor origin, and if so, whether there are clinical implications for the donor can prove challenging.

5 years DKMS Chile: approach, results and impact of the first unrelated stem cell donor center in Chile.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed worldwide to treat blood cancer and other life-threatening blood disorders. As successful transplantation requires an HLA-compatible donor, unrelated donor centers and registries have been established worldwide to identify donors for patients without a family match. Ethnic minorities are underrepresented in large donor registries.

The Use of the Oxygenation Stretch Index to Predict Outcomes in Mechanically Ventilated Patients With COVID-19 ARDS.

Background: In ARDS caused by COVID-19 pneumonia, appropriate adjustment of physiologic parameters based on lung stretch or oxygenation may optimize the ventilatory strategy. This study aims to describe the prognostic performance on 60-d mortality of single and composite respiratory variables in subjects with COVID-19 ARDS who are on mechanical ventilation with a lung-protective strategy, including the oxygenation stretch index combining oxygenation and driving pressure (ΔP).

Methods: This single-center observational cohort study enrolled 166 subjects on mechanical ventilation and diagnosed with COVID-19 ARDS.

HLA allele and haplotype frequencies of registered stem cell donors in Chile.

Patients in need of hematopoietic stem cell transplantation often rely on unrelated stem cell donors matched in certain human leukocyte antigen (HLA) genes. Donor search is complicated by the extensive allelic variability of the HLA system. Therefore, large registries of potential donors are maintained in many countries worldwide.

Liver-Intestinal Involvement in Graft Versus Host Disease in Pediatric Hematopoietic Stem Cell Transplantation Patients: Ten Years of Experience in 2 Centers of Latin America.

Unlabelled: To describe the behavior and characteristics of children with diagnosis of graft versus host disease (GVHD) with liver-intestinal involvement.

Methods: Retrospective cohort study of pediatric patients with history of hematopoietic stem cell transplantation for diagnosis of GVHD with gastrointestinal (GI) or liver involvement, from 2 pediatric centers.

Results: Between 2007 and 2017, 57 pediatric patients presented with liver or intestinal GVHD; 74% with GI GVHD, 11% with liver GVHD, and 15% with liver-intestinal involvement.

Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis.

The response to tumor-initiating inflammatory and genetic insults can vary among morphologically indistinguishable cells, suggesting as yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we performed single-cell analyses on normal, inflamed, premalignant, and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identified heterogeneous cell states that are primed for diverse, late-emerging neoplastic fates and linked these to chromatin remodeling at cell-cell communication loci.

Post-transcriptional control of a stemness signature by RNA-binding protein MEX3A regulates murine adult neurogenesis.

Neural stem cells (NSCs) in the adult murine subependymal zone balance their self-renewal capacity and glial identity with the potential to generate neurons during the lifetime. Adult NSCs exhibit lineage priming via pro-neurogenic fate determinants. However, the protein levels of the neural fate determinants are not sufficient to drive direct differentiation of adult NSCs, which raises the question of how cells along the neurogenic lineage avoid different conflicting fate choices, such as self-renewal and differentiation.

An immunocompetent rectal cancer model to study radiation therapy.

We describe a mouse model of rectal cancer (RC) involving rapid tumor organoid engraftment via orthotopic transplantation in an immunocompetent setting. This approach uses simple mechanical disruption to allow engraftment, avoiding the use of dextran sulfate sodium. The resulting RC tumors invaded from the mucosal surface and metastasized to distant organs.

Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy.

Colorectal cancer (CRC) patient-derived organoids predict responses to chemotherapy. Here we used them to investigate relapse after treatment. Patient-derived organoids expand from highly proliferative LGR5 tumor cells; however, we discovered that lack of optimal growth conditions specifies a latent LGR5 cell state.

KRAS Mutants Upregulate Integrin β4 to Promote Invasion and Metastasis in Colorectal Cancer.

Unlabelled: KRAS mutation in colorectal cancer is associated with aggressive tumor behavior through increased invasiveness and higher rates of lung metastases, but the biological mechanisms behind these features are not fully understood. In this study, we show that KRAS-mutant colorectal cancer upregulates integrin α6β4 through ERK/MEK signaling. Knocking-out integrin β4 (ITGB4) specifically depleted the expression of integrin α6β4 and this resulted in a reduction in the invasion and migration ability of the cancer cells.

Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants.

Base editing can be applied to characterize single nucleotide variants of unknown function, yet defining effective combinations of single guide RNAs (sgRNAs) and base editors remains challenging. Here, we describe modular base-editing-activity 'sensors' that link sgRNAs and cognate target sites in cis and use them to systematically measure the editing efficiency and precision of thousands of sgRNAs paired with functionally distinct base editors. By quantifying sensor editing across >200,000 editor-sgRNA combinations, we provide a comprehensive resource of sgRNAs for introducing and interrogating cancer-associated single nucleotide variants in multiple model systems.

Sequential lateral positioning as a new lung recruitment maneuver: an exploratory study in early mechanically ventilated Covid-19 ARDS patients.

Background: A sequential change in body position from supine-to-both lateral positions under constant ventilatory settings could be used as a postural recruitment maneuver in case of acute respiratory distress syndrome (ARDS), provided that sufficient positive end-expiratory pressure (PEEP) prevents derecruitment. This study aims to evaluate the feasibility and physiological effects of a sequential postural recruitment maneuver in early mechanically ventilated COVID-19 ARDS patients.

Methods: A cohort of 15 patients receiving lung-protective mechanical ventilation in volume-controlled with PEEP based on recruitability were prospectively enrolled and evaluated in five sequentially applied positions for 30 min each: Supine-baseline; Lateral-1st side; 2nd Supine; Lateral-2nd side; Supine-final.

Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease.

The viral nucleocapsid protein and the human RNA-binding protein Mex3A promote translation of the Andes orthohantavirus small mRNA.

The capped Small segment mRNA (SmRNA) of the Andes orthohantavirus (ANDV) lacks a poly(A) tail. In this study, we characterize the mechanism driving ANDV-SmRNA translation. Results show that the ANDV-nucleocapsid protein (ANDV-N) promotes in vitro translation from capped mRNAs without replacing eukaryotic initiation factor (eIF) 4G.

KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix.

Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix.

A gene-environment-induced epigenetic program initiates tumorigenesis.

Tissue damage increases the risk of cancer through poorly understood mechanisms. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution.