Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells.

Background And Aims: Oncogenic KRAS mutations are present in approximately 90% of pancreatic ductal adenocarcinoma (PDAC). However, Kras mutation alone is insufficient to transform precancerous cells into metastatic PDAC. This study investigates how KRAS-mutated epithelial cells acquire the capacity to escape senescence or even immune clearance, thereby progressing to advanced PDAC.

V-ATPase in glioma stem cells: a novel metabolic vulnerability.

Background: Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth.

The diagnostic dilemma of adrenal vascular tumors: analysis of 21 cases and systematic review of the literature.

Purpose: Adrenal vascular tumors are mainly represented by adrenal cavernous hemangiomas (ACHs) and adrenal cystic lymphangiomas (ACLs). Their radiological features often overlap with malignant tumors, therefore ruling out malignancy becomes mandatory. We analyzed clinical, radiological, and histopathological data to identify specific characteristics of these tumors.

Simplified acid extraction and quantification of histones in human tumor cells.

Histones are essential nuclear proteins that package eukaryotic DNA into chromosomes, play a vital role in gene regulation, DNA replication, DNA repair and chromosome condensation. Understanding histone modifications is crucial for grasping biological and disease-related processes. Specific alterations in histone modifications serve as sensitive and selective biomarkers for conditions like cancer, impacting both tumor and immune cells and affecting their interactions.

Preclinical models of soft tissue sarcomas - generation and applications to enhance translational research.

Soft tissue sarcomas (STS) represent a large group of rare and ultra-rare tumors distinguished by unique morphological, molecular and clinical features. Patients with such rare cancers are generally underrepresented in clinical trials which has limited the introduction of new treatment options and subsequent improvement of patient outcomes. Preclinical models of STS that recapitulate the human disease can aid progress in identifying new effective treatments.

AN IMMUNOHISTOCHEMICAL AND MOLECULAR GENETIC STUDY OF 60 COLORECTAL CARCINOMA BRAIN METASTASES IN PURSUIT OF PREDICTIVE BIOMARKERS FOR CANCER THERAPY.

Colorectal carcinoma brain metastases (n=60) were studied using next-generation sequencing and immunohistochemistry. RAS and BRAF mutations were detected in 58.2% and 7.

Exploring treatment-driven subclonal evolution of prognostic triple biomarkers: Dual gene fusions and chimeric RNA variants in novel subtypes of acute myeloid leukemia patients with KMT2A rearrangement.

Chromosomal rearrangements (CR) initiate leukemogenesis in approximately 50 % of acute myeloid leukemia (AML) patients; however, limited targeted therapies exist due to a lack of accurate molecular and genetic biomarkers of refractory mechanisms during treatment. Here, we investigated the pathological landscape of treatment resistance and relapse in 16 CR-AML patients by monitoring cytogenetic, RNAseq, and genome-wide changes among newly diagnosed, refractory, and relapsed AML. First, in FISH-diagnosed KMT2A (MLL gene, 11q23)/AFDN (AF6, 6q27)-rearrangement, RNA-sequencing identified an unknown CCDC32 (15q15.

Phosphodiesterase 4D inhibition improves the functional and molecular outcome in a mouse and human model of Charcot Marie Tooth disease 1 A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited peripheral neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. It is primarily marked by Schwann cell dedifferentiation and demyelination, leading to motor and sensory deficits. Cyclic adenosine monophosphate (cAMP) is crucial for Schwann cell differentiation and maturation.

Dogs are a susceptible species to human adenovirus 36 infection: New insights into the host range of the virus causing infectious obesity.

The prevalence of obesity within the human population is escalating globally yearly. Obesity constitutes a complex ailment with diverse etiological factors. Recently, the infectious side of obesity aetiology, implicating pathogens such as human adenovirus 36 (HAdV-D36), has gained attention.

Amniotic fluid stem cell extracellular vesicles as a novel fetal therapy for pulmonary hypoplasia: a review on mechanisms and translational potential.

Disruption of developmental processes affecting the fetal lung leads to pulmonary hypoplasia. Pulmonary hypoplasia results from several conditions including congenital diaphragmatic hernia (CDH) and oligohydramnios. Both entities have high morbidity and mortality, and no effective therapy that fully restores normal lung development.

Neuroendocrine prostate cancer drivers SOX2 and BRN2 confer differential responses to imipridones ONC201, ONC206, and ONC212 in prostate cancer cell lines.

Objectives: Prostate cancer (PCa) is a leading cause of cancer death in men worldwide. Approximately 30% of castrate-resistant PCa becomes refractory to therapy due to neuroendocrine differentiation (NED) that is present in <1% of de-novo tumors. First-in-class imipridone ONC201/TIC10 therapy has shown clinical activity against midline gliomas, neuroendocrine tumors, and PCa.

Concurrent RB1 and P53 pathway disruption predisposes to the development of a primitive neuronal component in high-grade gliomas depending on MYC-driven EBF3 transcription.

The foremost feature of glioblastoma (GBM), the most frequent malignant brain tumours in adults, is a remarkable degree of intra- and inter-tumour heterogeneity reflecting the coexistence within the tumour bulk of different cell populations displaying distinctive genetic and transcriptomic profiles. GBM with primitive neuronal component (PNC), recently identified by DNA methylation-based classification as a peculiar GBM subtype (GBM-PNC), is a poorly recognized and aggressive GBM variant characterised by nodules containing cells with primitive neuronal differentiation along with conventional GBM areas. In addition, the presence of a PNC component has been also reported in IDH-mutant high-grade gliomas (HGGs), and to a lesser extent to other HGGs, suggesting that regardless from being IDH-mutant or IDH-wildtype, peculiar genetic and/or epigenetic events may contribute to the phenotypic skewing with the emergence of the PNC phenotype.

Metabolomics identifies plasma biomarkers of localized radiation injury.

A radiological accident may result in the development of a local skin radiation injury (LRI) which may evolve, depending on the dose, from dry desquamation to deep ulceration and necrosis through unpredictable inflammatory waves. Therefore, early diagnosis of victims of LRI is crucial for improving medical care efficiency. This preclinical study aims to identify circulating metabolites as biomarkers associated with LRI using a C57BL/6J mouse model of hind limb irradiation.

Organization of the chromosomal passenger complex clusters at inner centromeres in mitosis.

Stable transmission of the genome during cell division is crucial for all life forms and is universally achieved by Aurora B-mediated error correction of the kinetochore-microtubule attachments. Aurora B is the enzymatic subunit of the tetrameric protein complex called the chromosomal passenger complex (CPC), and its centromeric enrichment is required for Aurora B to ensure accurate chromosome segregation. How cells enrich the CPC at centromeres is therefore an outstanding question to be elucidated.

Single cell derived multicellular meristem: insights into male-to-hermaphrodite conversion and de novo meristem formation in ceratopteris.

Land plants alternate between asexual sporophytes and sexual gametophytes. Unlike seed plants, ferns develop free-living gametophytes. Gametophytes of the model fern Ceratopteris exhibit two sex types: hermaphrodites with pluripotent meristems and males lacking meristems.

Predictive Role of Soluble B-Cell Maturation Antigen in Short-Term Monitoring of Differently Treated Multiple Myeloma Patients: A Prospective Study.

Background: The management of multiple myeloma is challenging because the disease is incurable and unexpected relapses can threaten a patient's survival. Several assessment systems are currently available, but they often require invasive or costly procedures (e.g.

Acylglycerol kinase inhibits macrophage anti-tumor activity via limiting mtDNA release and cGAS-STING-type I IFN response.

: Tumor associated macrophages (TAMs) are critical components in regulating the immune statuses of the tumor microenvironments. Although TAM has been intensively studied, it is unclear how mitochondrial proteins such as AGK regulate the TAMs' function. : We investigated the AGK function in TAMs using macrophage-specific deficient mice with B16 and LLC syngeneic tumor models.

A machine learning-based strategy to elucidate the identification of antibiotic resistance in bacteria.

Microorganisms, crucial for environmental equilibrium, could be destructive, resulting in detrimental pathophysiology to the human host. Moreover, with the emergence of antibiotic resistance (ABR), the microbial communities pose the century's largest public health challenges in terms of effective treatment strategies. Furthermore, given the large diversity and number of known bacterial strains, describing treatment choices for infected patients using experimental methodologies is time-consuming.

Intranasally administrated fusion-inhibitory lipopeptides block SARS-CoV-2 infection in mice and enable long-term protective immunity.

We have assessed antiviral activity and induction of protective immunity of fusion-inhibitory lipopeptides derived from the C-terminal heptad-repeat domain of SARS-CoV-2 spike glycoprotein in transgenic mice expressing human ACE2 (K18-hACE2). The lipopeptides block SARS-CoV-2 infection in cell lines and lung-derived organotypic cultures. Intranasal administration in mice allows the maintenance of homeostatic transcriptomic immune profile in lungs, prevents body-weight loss, decreases viral load and shedding, and protects mice from death caused by SARS-CoV-2 variants.

The impact of neoadjuvant therapy in patients with left-sided resectable pancreatic cancer: an international multicenter study.

Purpose: To assess the association between neoadjuvant therapy and overall survival (OS) in patients with left-sided resectable pancreatic cancer (RPC) compared to upfront surgery.

Background: Left-sided pancreatic cancer is associated with worse OS compared to right-sided pancreatic cancer. Although neoadjuvant therapy is currently seen as not effective in patients with RPC, current randomized trials included mostly patients with right-sided RPC.

Single-cell analysis reveals ESX-1-mediated accumulation of permissive macrophages in infected mouse lungs.

(MTB) ESX-1, a type VII secretion system, is a key virulence determinant contributing to MTB's survival within lung mononuclear phagocytes (MNPs), but its effect on MNP recruitment and differentiation remains unknown. Here, using multiple single-cell RNA sequencing techniques, we studied the role of ESX-1 in MNP heterogeneity and response in mice and murine bone marrow-derived macrophages (BMDM). We found that ESX-1 is required for MTB to recruit diverse MNP subsets with high MTB burden.

Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.

Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation.

Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis.

Background: Clonal myeloproliferation and fibrotic transformation of the bone marrow (BM) are the pathogenetic events most commonly occurring in myelofibrosis (MF). There is great evidence indicating that tumor microenvironment is characterized by high lactate levels, acting not only as an energetic source, but also as a signaling molecule.

Methods: To test the involvement of lactate in MF milieu transformation, we measured its levels in MF patients' sera, eventually finding a massive accumulation of this metabolite, which we showed to promote the expansion of immunosuppressive subsets.

Schlafen 11 Expression in Patients With Small Cell Lung Cancer and Its Association With Clinical Outcomes.

Background: Schlafen 11 (SLFN-11) has been identified as a sensitizer of tumor cells to DNA-damaging agents. However, the relationship between SLFN-11 expression and clinical outcomes in patients with small cell lung cancer (SCLC) remains unexplored. Thus, we aimed to evaluate the impact of SLFN-11 expression on survival in patients with limited-stage (LS) SCLC.

Clonally expanded, targetable, natural killer-like NKG7 T cells seed the aged spinal cord to disrupt myeloid-dependent wound healing.

Spinal cord injury (SCI) increasingly affects aged individuals, where functional impairment and mortality are highest. However, the aging-dependent mechanisms underpinning tissue damage remain elusive. Here, we find that natural killer-like T (NKLT) cells seed the intact aged human and murine spinal cord and multiply further after injury.