Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma.

Resistance to standard cisplatin-based chemotherapies leads to worse survival outcomes for patients with esophageal squamous cell carcinoma (ESCC). Therefore, there is an urgent need to understand the aberrant mechanisms driving resistance in ESCC tumors. We hypothesized that ubiquilin-4 (UBQLN4), a protein that targets ubiquitinated proteins to the proteasome, regulates the expression of Meiotic Recombination 11 Homolog A (MRE11A), a critical component of the MRN complex and DNA damage repair pathways.

Texture analysis of iodine maps and conventional images for k-nearest neighbor classification of benign and metastatic lung nodules.

Background: The purpose of this study was to analyze if the use of texture analysis on spectral detector CT (SDCT)-derived iodine maps (IM) in addition to conventional images (CI) improves lung nodule differentiation, when being applied to a k-nearest neighbor (KNN) classifier.

Methods: 183 cancer patients who underwent contrast-enhanced, venous phase SDCT of the chest were included: 85 patients with 146 benign lung nodules (BLN) confirmed by either prior/follow-up CT or histopathology and 98 patients with 425 lung metastases (LM) verified by histopathology, F-FDG-PET-CT or unequivocal change during treatment. Semi-automatic 3D segmentation of BLN/LM was performed, and volumetric HU attenuation and iodine concentration were acquired.

An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities.

Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in , as well as copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a and -driven mouse model of ABC-DLBCL.

Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas.

Aberrant B-cell receptor/NF-κB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas, especially in diffuse large B-cell lymphoma (DLBCL). Recurrent mutations in this cascade, for example, in CD79B, CARD11, or NFKBIZ, and also in the Toll-like receptor pathway transducer MyD88, all deregulate NF-κB, but their differential impact on lymphoma development and biology remains to be determined. Here, we functionally investigate primary mouse lymphomas that formed in recipient mice of Eµ-myc transgenic hematopoietic stem cells stably transduced with naturally occurring NF-κB mutants.

Surgical resection of symptomatic brain metastases improves the clinical status and facilitates further treatment.

Background: Brain metastases (BM) frequently cause focal neurological deficits leading to a reduced Karnofsky performance score (KPS). Since KPS is routinely used to guide the choice of adjuvant therapy, we hypothesized that improving KPS by surgical resection may improve the chance for adjuvant treatment and ultimately result in better survival. We therefore analyzed the course of a large cohort undergoing resection of symptomatic brain metastases in the context of further treatment and clinical outcome.

Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints.

In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy.

A phase 1 dose-escalation study of checkpoint kinase 1 (CHK1) inhibitor prexasertib in combination with p38 mitogen-activated protein kinase (p38 MAPK) inhibitor ralimetinib in patients with advanced or metastatic cancer.

Purpose The primary objective was to determine the recommended Phase 2 dose (RP2D) of checkpoint kinase 1 inhibitor, prexasertib, in combination with the p38 mitogen-activated protein kinase inhibitor, ralimetinib, which may be safely administered to patients with advanced cancer. Methods This Phase 1, nonrandomized, open-label, dose-escalation study of prexasertib+ralimetinib included patients with advanced and/or metastatic cancer, followed by a planned cohort expansion in patients with colorectal or non-small-cell lung cancer with KRAS and/or BRAF mutations. Intravenous prexasertib was administered at 60 mg/m (days 1 and 15 of a 28-day cycle), together with oral ralimetinib every 12 h (days 1 to 14 at 100 mg [Cohort 1, n = 3] or 200 mg [Cohort 2, n = 6]).

ATM activity in T cells is critical for immune surveillance of lymphoma in vivo.

The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear.

Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia.

Exosome-dependent immune surveillance at the metastatic niche requires BAG6 and CBP/p300-dependent acetylation of p53.

Extracellular vesicles released by tumor cells contribute to the reprogramming of the tumor microenvironment and interfere with hallmarks of cancer including metastasis. Notably, melanoma cell-derived EVs are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. However, molecular insights into how vesicles are selectively packaged with cargo defining their specific functions remain elusive.

UBQLN4 promotes non-homologous end joining by repressing DNA end-resection.

Ataxia-telangiectasia-mutated (ATM) promotes homologous recombination (HR)-mediated DNA double-strand break repair. It was recently shown that the proteasomal shuttle factor UBQLN4 facilitates MRE11 degradation to repress HR. Surprisingly, the UBQLN4-MRE11 interaction is ATM-dependent, suggesting that the proximal DNA damage kinase ATM does not only initiate HR, but also limits excessive end resection.

DNA double-strand break repair pathway choice - from basic biology to clinical exploitation.

Mutations in genes encoding components of the DNA damage response (DDR) are among the most frequent aberrations in human tumors. Moreover, a large array of human syndromes is caused by mutations in genes involved in DDR pathways. Among others, homologous recombination repair (HR) of DNA double-strand breaks (DSB) is frequently affected by disabling mutations.

Vector uncoating limits adeno-associated viral vector-mediated transduction of human dendritic cells and vector immunogenicity.

AAV vectors poorly transduce Dendritic cells (DC), a feature invoked to explain AAV's low immunogenicity. However, the reason for this non-permissiveness remained elusive. Here, we performed an in-depth analysis using human monocyte-derived immature DC (iDC) as model.

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors.

Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair.

BRCA1 and BARD1 mediate apoptotic resistance but not longevity upon mitochondrial stress in .

Interventions that promote healthy aging are typically associated with increased stress resistance. Paradoxically, reducing the activity of core biological processes such as mitochondrial or insulin metabolism promotes the expression of adaptive responses, which in turn increase animal longevity and resistance to stress. In this study, we investigated the relation between the extended lifespan elicited by reduction in mitochondrial functionality and resistance to genotoxic stress.

Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities.

Oncogenic MYD88 mutations, most notably the Leu 265 Pro (L265P) mutation, were recently identified as potential driver mutations in various B-cell non-Hodgkin Lymphomas (NHLs). The L265P mutation is now thought to be common to virtually all NHLs and occurs in between 4 and 90% of cases, depending on the entity. Since it is tumor-specific, the mutation, and the pathways it regulates, might serve as advantageous therapeutic targets for both conventional chemotherapeutic intervention, as well as immunotherapeutic strategies.

HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types.

Processes like cellular senescence are characterized by complex events giving rise to heterogeneous cell populations. However, the early molecular events driving this cascade remain elusive. We hypothesized that senescence entry is triggered by an early disruption of the cells' three-dimensional (3D) genome organization.

Case Report: A Cryptosporidium infection in a patient with relapsed T-lymphoblastic lymphoma undergoing allogeneic stem cell transplantation.

Cryptosporidium infection is a rare cause of enterocolitis. In immunocompromised patients, cryptosporidiosis may lead to debilitating and life-threatening diarrhea and malabsorption, occasionally with multi-organ involvement. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) requires long-term immunosuppressive therapy, while cellular immunity is usually compromised due to intensive conditioning chemotherapy.

Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib.

Macrophage migration inhibitory factor promotes resistance to glucocorticoid treatment in EAE.

Objective: Glucocorticoids (GCs) are used as standard treatment for acute attacks of multiple sclerosis (MS). However, GCs eventually lose efficacy and do not prevent disease progression. Macrophage migration inhibitory factor (MIF) is the only known proinflammatory cytokine induced by GCs that inhibits their anti-inflammatory effects.

Transient antiangiogenic treatment improves delivery of cytotoxic compounds and therapeutic outcome in lung cancer.

Extensive oncologic experience argues that the most efficacious applications of antiangiogenic agents rely upon a combination with cytotoxic drugs. Yet there remains a lack of clarity about how to optimize scheduling for such drug combinations. Prudent antiangiogenic therapy might transiently normalize blood vessels to improve tumor oxygenation and drug exposure.

Erufosine, a novel alkylphosphocholine, induces apoptosis in CLL through a caspase-dependent pathway.

The alkylphosphocholine (APC) erufosine is a synthetic phospholipid analogue with antineoplastic activity. APC are known to interact with lipid metabolism and modulate cellular signaling pathways, particularly the phosphorylation of Akt. Here, in primary CLL cells induction of apoptosis was detected with an IC50 of 22muM whereas healthy donor PBMC were less sensitive towards erufosine.

Overexpression of the Fas-inhibitory molecule TOSO: a novel antiapoptotic factor in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterised by resistance to apoptotic stimuli, mediated by overexpression of anti-apoptotic factors or extracellular survival signals. In this context, TOSO, also known as Fas-inhibitory molecule 3, was identified as a candidate gene over-expressed in CLL. TOSO is a transmembrane protein that inhibits Fas-mediated apoptosis by binding Fas-associated death domain via its C-terminal intracellular domain.

Effects of the beta3-adrenergic agonist BRL 37344 on endothelial nitric oxide synthase phosphorylation and force of contraction in human failing myocardium.

Background: In nonfailing myocardium, beta(3)-adrenergic signaling causes a decrease in contractility via endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) release. This study investigates the hypothesis that beta(3)-adrenergic signaling undergoes alterations in failing myocardium.

Methods: We compared eNOS- and beta(3)-adrenoceptor expression using Western blot analysis in human nonfailing myocardium versus failing myocardium.