NEMO is essential for directing the kinases IKKα and ATM to the sites of DNA damage.

The DNA damage repair kinase ATM is phosphorylated by the NF-κB pathway kinase IKKα, resulting in enhanced DNA damage repair through the nonhomologous end-joining pathway. Thus, inhibition of IKKα enhances the efficacy of cancer therapy based on inducing DNA damage. Here, we found a role for the IKK regulatory subunit NEMO in DNA damage repair mediated by ATM and IKKα.

Chromogenic mRNA ISH Expression Correlates with LMO2 Protein and Gene Expression and Captures Their Survival Impact in Diffuse Large B-Cell Lymphoma, NOS.

Background: is a relevant gene involved in B-cell ontogeny and a survival predictor of aggressive large B-cell lymphomas (aLBCL). Most studies assessing mRNA expression have relied on microarray platforms or qRT-PCR methods, overlooking tissue morphology. In this study, we evaluate RNA expression by chromogenic in situ hybridization (CISH) in normal tissue and in a series of 82 aLBCL.

Specific and shared biological functions of PARP2 - is PARP2 really a lil' brother of PARP1?

PARP2, that belongs to the family of ADP-ribosyl transferase enzymes (ART), is a discovery of the millennium, as it was identified in 1999. Although PARP2 was described initially as a DNA repair factor, it is now evident that PARP2 partakes in the regulation or execution of multiple biological processes as inflammation, carcinogenesis and cancer progression, metabolism or oxidative stress-related diseases. Hereby, we review the involvement of PARP2 in these processes with the aim of understanding which processes are specific for PARP2, but not for other members of the ART family.

Attenuation of Tumor Burden in Response to Rucaparib in Lung Adenocarcinoma: The Contribution of Oxidative Stress, Apoptosis, and DNA Damage.

In cancer, overactivation of poly (ADPribose) polymerases (PARP) plays a relevant role in DNA repair. We hypothesized that treatment with the PARP inhibitor rucaparib may reduce tumor burden via several biological mechanisms (apoptosis and oxidative stress) in mice. In lung tumors (LP07 lung adenocarcinoma) of mice treated/non-treated (control animals) with PARP inhibitor (rucaparib,150 mg/kg body weight/24 h for 20 day), PARP activity and expression, DNA damage, apoptotic nuclei, cell proliferation, and redox balance were measured using immunoblotting and immunohistochemistry.

Microvascular inflammation in the absence of human leukocyte antigen-donor-specific antibody and C4d: An orphan category in Banff classification with cytotoxic T and natural killer cell infiltration.

Isolated microvascular inflammation (iMVI) without HLA donor-specific antibodies or C4d deposition in peritubular capillaries remains an enigmatic phenotype that cannot be categorized as antibody-mediated rejection (ABMR) in recent Banff classifications. We included 221 kidney transplant recipients with biopsies with ABMR (n = 73), iMVI (n = 32), and normal (n = 116) diagnoses. We compared peripheral blood leukocyte distribution by flow cytometry and inflammatory infiltrates in kidney transplant biopsies among groups.

Severe perioperative anaphylaxis: Incidence in a tertiary hospital in Spain over a 20-year period. A historical cohort study.

Objective: To assess the incidence of severe perioperative anaphylaxis, the mechanisms involved, the value of laboratory/skin tests, and the most effective treatments.

Methods: A historical cohort study conducted in a tertiary public hospital in Spain. Patients that had undergone anaesthesia during the 20-year period were included.

Studying the Immunomodulatory Functions of PARP1 and PARP2 in Mouse Models of Cancer.

Poly-ADP-ribosylation of proteins, mediated by the two ADP-ribosyltransferases PARP1 and PARP2 in response to DNA damage, has emerged as a critical mediator of the DNA damage response (DDR). Accordingly, considering the critical role of DDR in cancer, PARP inhibitors (PARPi) have become an important class of therapeutics. PARPi have largely been considered for their intrinsic actions to tumor cells per se.

Current innovative engineered antibodies.

Antibody engineering has developed very intensively since the invention of the hybridoma technology in 1975, and it now can generate therapeutic agents with high specificity and reduced adverse effects. Indeed, antibodies have become one of the most innovative therapeutic agents in recent years, with some landing in the top 10 bestselling pharmaceutical drugs. New antibodies are being approved every year, in different formats and for treating various illnesses, including cancer, autoimmune inflammatory diseases, metabolic diseases and infectious diseases.

Attenuation of Muscle Damage, Structural Abnormalities, and Physical Activity in Respiratory and Limb Muscles following Treatment with Rucaparib in Lung Cancer Cachexia Mice.

Overactivation of poly (ADPribose) polymerases (PARPs) is involved in cancer-induced cachexia. We hypothesized that the PARP inhibitor rucaparib may improve muscle mass and reduce damage in cancer cachexia mice. In mouse diaphragm and gastrocnemius (LP07 lung adenocarcinoma) treated with PARP inhibitor (rucaparib,150 mg/kg body weight/24 h for 20 days) and in non-tumor control animals, body, muscle, and tumor weights; tumor area; limb muscle strength; physical activity; muscle structural abnormalities, damage, and phenotype; PARP activity; and proteolytic and autophagy markers were quantified.

Impact of DNA Damage Response-Targeted Therapies on the Immune Response to Tumours.

The DNA damage response (DDR) maintains the stability of a genome faced with genotoxic insults (exogenous or endogenous), and aberrations of the DDR are a hallmark of cancer cells. These cancer-specific DDR defects present new therapeutic opportunities, and different compounds that inhibit key components of DDR have been approved for clinical use or are in various stages of clinical trials. Although the therapeutic rationale of these DDR-targeted agents initially focused on their action against tumour cells themselves, these agents might also impact the crosstalk between tumour cells and the immune system, which can facilitate or impede tumour progression.

Long-Term Evolution of the Adaptive NKG2C NK Cell Response to Cytomegalovirus Infection in Kidney Transplantation: An Insight on the Diversity of Host-Pathogen Interaction.

Human CMV infection is frequent in kidney transplant recipients (KTR). Pretransplant Ag-specific T cells and adaptive NKG2C NK cells associate with reduced incidence of infection in CMV KTR. Expansions of adaptive NKG2C NK cells were reported in posttransplant CMV-infected KTR.

Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice.

Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage.

ADP-ribosyltransferases, an update on function and nomenclature.

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases.

Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer.

Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway.

Reduced expansion of CD94/NKG2C NK cells in chronic lymphocytic leukemia and CLL-like monoclonal B-cell lymphocytosis is not related to increased human cytomegalovirus seronegativity or NKG2C deletions.

Introduction: Dysregulated NK cell-mediated immune responses contribute to tumor evasion in chronic lymphocytic leukemia (CLL), although the NK cell compartment in CLL-like monoclonal B-cell lymphocytosis (MBL) is poorly understood. In healthy individuals, human cytomegalovirus (HCMV) induces the expansion of NK cells expressing high levels of CD94/NKG2C NK cell receptor (NKR) specific for HLA-E.

Methods: We analyzed the expression of NKG2A, NKG2C, ILT2, KIR, CD161, and CD57 in 24 MBL and 37 CLL.

Increased PARP Activity and DNA Damage in NSCLC Patients: The Influence of COPD.

(1) : Lung cancer (LC) is a major leading cause of death worldwide. Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 are key players in cancer. We aimed to assess PARP-1 and PARP-2 expression and activity and DNA damage in tumors and non-tumor lungs from patients with/without chronic obstructive pulmonary disease (COPD).

Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ.

The alternative non-homologous end-joining (NHEJ) pathway promotes DNA double-strand break (DSB) repair in cells deficient for NHEJ or homologous recombination, suggesting that it operates at all stages of the cell cycle. Here, we use an approach in which DNA breaks can be induced in G1 cells and their repair tracked, enabling us to show that joining of DSBs is not functional in G1-arrested XRCC4-deficient cells. Cell cycle entry into S-G2/M restores DSB repair by Pol θ-dependent and PARP1-independent alternative NHEJ with repair products bearing kilo-base long DNA end resection, micro-homologies and chromosome translocations.

Impact of cytomegalovirus infection on B cell differentiation and cytokine production in multiple sclerosis.

Background: Human cytomegalovirus (HCMV) infection has been recently associated with a low risk of multiple sclerosis (MS), yet the basis behind this observation remains uncertain. In this study, we aimed to determine in MS patients whether HCMV induces modifications in the peripheral B cell compartment.

Methods: HCMV serostatus was determined in 73 MS patients (55 relapsing-remitting MS (RRMS); 18 progressive MS (PMS)) and 30 healthy controls, assessing their B cell immunophenotype and cytokine production (GM-CSF, IL-6, IL-10, and TNFα) by flow cytometry.

Long-Term Redistribution of Peripheral Lymphocyte Subpopulations after Switching from Calcineurin to mTOR Inhibitors in Kidney Transplant Recipients.

Classical immunosuppression based on steroids, calcineurin inhibitors, and mycophenolate results in several unwanted effects and unsatisfactory long-term outcomes in kidney transplantation (KT). New immunosuppressors search for fewer adverse events and increased graft survival but may have a distinct impact on graft function and immunological biomarkers according to their mechanism of action. This prospective study evaluates the immunological effect of tacrolimus to serine/threonine protein kinase mechanistic target of rapamycin inhibitors (mTORi) conversion in 29 KT recipients compared with 16 controls maintained on tacrolimus.

Exploring Health Science Students' Notions on Organ Donation and Transplantation: A Multicenter Study.

Unlabelled: The knowledge acquired during university education about organ donation and transplantation (ODT) decisively influences the information future health professionals transmit. This is important in ODT where the participation of the general public is essential to obtain organs.

Objective: To determine notions of Spanish medicine and nursing students on ODT and its relationship with attitude toward ODT.

Adaptive NKG2C+ natural killer cells are related to exacerbations and nutritional abnormalities in COPD patients.

Unlabelled: Chronic obstructive pulmonary disease (COPD) is a chronic and often progressive disorder with a heterogeneous presentation and frequent systemic manifestations. Several aspects like persistence in smoking habit, continuous exacerbations, alpha-1-antitrypsin deficiency and inflammatory-immune response, are involved in the pathophysiology and progression of the disease. However, the role of natural killer (NK) cells remains controversial.