Comprehensive whole-genome sequencing reveals origins of mutational signatures associated with aging, mismatch repair deficiency and temozolomide chemotherapy.

In a comprehensive study to decipher the multi-layered response to the chemotherapeutic agent temozolomide (TMZ), we analyzed 427 genomes and determined mutational patterns in a collection of ∼40 isogenic DNA repair-deficient human TK6 lymphoblast cell lines. We first demonstrate that the spontaneous mutational background is very similar to the aging-associated mutational signature SBS40 and mainly caused by polymerase zeta-mediated translesion synthesis (TLS). MSH2-/- mismatch repair (MMR) knockout in conjunction with additional repair deficiencies uncovers cryptic mutational patterns.

-Acyl Homoserine Lactone Production by the Marine Isolate, .

(isolate SD1D, with 98.5% sequence similarity to DMS 21967 KOPRI 20902) is a marine bacterium that was isolated from ballast tank fluids as part of a biofilm study in 2014. Our previous work indicated that although this strain produced no detectable biofilm, it was the only isolate to produce -acyl homoserine lactones (AHLs) in assays using the broad-range reporter strain, KYC55.

Leeches Predate on Fast-Escaping and Entangling Blackworms by Spiral Entombment.

We investigate how the Helobdella sp. freshwater leeches capture and consume Lumbriculus variegatus blackworms despite the blackworm's ultrafast helical swimming escape reflex and ability to form large tangled "blobs." We describe a spiral "entombment" predation strategy, where Helobdellid leeches latch onto blackworms with their anterior sucker and envelop them in a spiral cocoon.

Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury.

We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury.

Leeches Predate on Fast-Escaping and Entangling Blackworms by Spiral Entombment.

We investigate how the spp. freshwater leeches capture and consume blackworms despite the blackworm's ultrafast helical swimming escape reflex and ability to form large tangled 'blobs'. We describe our discovery of a unique spiral 'entombment' strategy used by these leeches to overcome the blackworms' active and collective defenses.

Germline biallelic BRCA2 pathogenic variants and medulloblastoma: an international cohort study.

Constitutional heterozygous pathogenic variants in genes coding for some components of the Fanconi anemia-BRCA signaling pathway, which repairs DNA interstrand crosslinks, represent risk factors for common cancers, including breast, ovarian, pancreatic and prostate cancer. A high cancer risk is also a main clinical feature in patients with Fanconi anemia (FA), a rare condition characterized by bone marrow failure, endocrine and physical abnormalities. The mainly recessive condition is caused by germline pathogenic variants in one of 21 FA-BRCA pathway genes.

Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.

Methods: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries.

Deletion Modulates Cytokine and Extracellular Matrix Expression in Chronic Spinal Cord Injury, Leading to Improved Secondary Damage and Functional Recovery.

Toll-like receptors (TLRs) play an important role in the innate immune response after CNS injury. Although TLR4 is one of the best characterized, its role in chronic stages after spinal cord injury (SCI) is not well understood. We examined the role of TLR4 signaling in injury-induced responses at 1 d, 7 d, and 8 weeks after spinal cord contusion injury in adult female TLR4 null and wild-type mice.

Financial Performance is Associated With PPE Shortages in Chain-Affiliated Nursing Homes During the COVID-19 Pandemic: A Longitudinal Study.

Many nursing homes operated at thin profit margins prior to the COVID-19 pandemic. This study examines the role of nursing homes' financial performance and chain affiliation in shortages of personal protection equipment (PPE) during the first year of the COVID-19 pandemic. We constructed a longitudinal file of 79 868 nursing home-week observations from 10 872 unique facilities.

Association of serum testosterone with chronic obstructive pulmonary disease (COPD) in a nationally representative sample of White, Black, and Hispanic men.

Background: The association between total testosterone (T) and chronic obstructive pulmonary disease (COPD), remains poorly understood. We aim to investigate this association and how it varies by smoking status, body fatness, and race/ethnicity in a nationally representative sample of American men.

Methods: Data included a full sample (NHANES 1988-1991, 1999-2004, 2011-2012) and subset sample (excluding 2011-2012, no estradiol and SHBG levels available) of 2748 and 906 men (≥20 years), respectively.

Alterations of neural activity in the prefrontal cortex associated with deficits in working memory performance.

Working memory (WM), a core cognitive function, enables the temporary holding and manipulation of information in mind to support ongoing behavior. Neurophysiological recordings conducted in nonhuman primates have revealed neural correlates of this process in a network of higher-order cortical regions, particularly the prefrontal cortex (PFC). Here, we review the circuit mechanisms and functional importance of WM-related activity in these areas.

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

Unlabelled: Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.

Autoclaving-induced dimensional changes of three-dimensional printed surgical guides: An in vitro study.

Objectives: Surgical guides are frequently used for dental implant placement. The aim of this study was to evaluate the impact of the 3D printing process itself and subsequent steam autoclaving on the dimensional stability of five different resin/printer combinations (RPCs).

Materials And Methods: Fifty identical surgical guides (10 per group) were produced consisting of five RPCs.

Drug screening in zebrafish larvae reveals inflammation-related modulators of secondary damage after spinal cord injury in mice.

Prolonged inflammation after spinal cord injury is detrimental to recovery. To find pharmacological modulators of the inflammation response, we designed a rapid drug screening paradigm in larval zebrafish followed by testing of hit compounds in a mouse spinal cord injury model. We used reduced linked green fluorescent protein (GFP) reporter gene expression as a read-out for reduced inflammation in a screen of 1081 compounds in larval zebrafish.

Disparities in refusal of surgery for gynecologic cancer.

Objective: To identify sociodemographic and clinical factors associated with refusal of gynecologic cancer surgery and to estimate its effect on overall survival.

Methods: The National Cancer Database was surveyed for patients with uterine, cervical or ovarian/fallopian tube/primary peritoneal cancer treated between 2004 and 2017. Univariate and multivariate logistic regression were used to assess associations between clinico-demographic variables and refusal of surgery.

Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature.

Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing.

Ceruloplasmin-Deficient Mice Show Dysregulation of Lipid Metabolism in Liver and Adipose Tissue Reduced by a Protein Replacement.

Ceruloplasmin is a ferroxidase that plays a role in iron homeostasis; its deficiency fosters inter alia iron accumulation in the liver, which expresses the soluble form of the protein secreted into the bloodstream. Ceruloplasmin is also secreted by the adipose tissue, but its role in adipocytes has been poorly investigated. We hypothesized that ceruloplasmin might have a role in iron/lipid interplay.

Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type.