Immune complex deposition promotes NK cell accumulation in the kidney.

In systemic lupus erythematosus, immune complexes deposited in the kidney vasculature represent a potent inflammatory trigger with a high potential to progress to glomerulonephritis and organ failure. These immune complexes can be recognized by multiple effector cells via complement and Fcγ receptors. The transcriptome of CD16-bearing NK cells has been documented in kidneys from patients with SLE.

Sepsis Impairs IFN-γ Production in CD8 T Cells through Changes in Local Chromatin Landscape.

Sepsis is a complex condition of inflammatory and immune dysregulation, triggered by severe infection. In survivors, chronic inflammation and immune dysregulation linger, facilitating the emergence of infections. CD8 dysfunction contributes to immunosuppression in sepsis survivors.

CD8 is down(regulated) for tolerance.

Activated CD8 T cells directly kill target cells. Therefore, the regulation of their function is central to avoiding immunopathology. Mechanisms that curb effector functions in CD4 and CD8 T cells are mostly shared, yet important differences occur.

Relevance of acquired T cell molecular defects in the immunopathogenesis of SLE.

Systemic lupus erythematosus (SLE) and other autoimmune diseases are thought to develop in genetically predisposed individuals when triggered by environmental factors. This paradigm does not fully explain disease development, as it fails to consider the delay between birth and disease expression. In this review, we discuss observations described in T cells from patients with SLE that are not related to hereditary factors and have therefore been considered secondary to the disease process itself.

Transient inhibition of sodium-glucose cotransporter 2 after ischemia/reperfusion injury ameliorates chronic kidney disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (Dapa), exhibited nephroprotective effects in patients with chronic kidney disease (CKD). We assessed the efficacy of short-term Dapa administration following acute kidney injury (AKI) in preventing CKD. Male Wistar rats were randomly assigned to Sham surgery, bilateral ischemia for 30 minutes (abbreviated as IR), and IR + Dapa groups.

Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial.

Introduction: Adding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC.

Methods: Eligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone.

Sirtuin 7 Deficiency Reduces Inflammation and Tubular Damage Induced by an Episode of Acute Kidney Injury.

Acute kidney injury (AKI) is a public health problem worldwide. Sirtuins are a family of seven NAD+-dependent deacylases, Overexpression of Sirtuin 1, 3, and 5 protect against AKI. However, the role of Sirtuin 7 (Sirt7) in AKI is not known.

Regulation of activated T cell survival in rheumatic autoimmune diseases.

Adaptive immune responses rely on the proliferation of T lymphocytes able to recognize and eliminate pathogens. The magnitude and duration of the expansion of activated T cell clones are finely regulated to minimize immunopathology and avoid autoimmunity. In patients with rheumatic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, activated lymphocytes survive and exert effector functions for prolonged periods, defying the mechanisms that normally curb their capacities during acute and chronic infections.

UNWINDING THE LONG ROAD THAT LEADS TO UNDERSTANDING AUTOIMMUNITY.

Systemic autoimmune diseases are complex clinical conditions that arise in genetically predisposed individuals as a result of the interplay between their immune system and their environment. In this perspective, we briefly discuss our current understanding of the pathogenesis of autoimmunity and indicate four research avenues whose exploration will bring us closer to resolving fundamental questions that remain unanswered in this enigmatic field.

FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity.

Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8 T cell-dependent anti-tumor immunity in mice.

Identification of regulatory T cell molecules associated with severity of multiple sclerosis.

Background: Regulatory CD4 T cells (Tregs) exhibit functional alterations in patients with multiple sclerosis (MS). Transforming growth factor (TGF)-β is a key regulator of Treg development and function.

Objective: The objective of this study is to determine whether the expression of functionally relevant TGF-β-regulated molecules is altered in Tregs from patients with MS.

Protein phosphatase 2A B55β limits CD8+ T cell lifespan following cytokine withdrawal.

How T cells integrate environmental cues into signals that limit the magnitude and length of immune responses is poorly understood. Here, we provide data that demonstrate that B55β, a regulatory subunit of protein phosphatase 2A, represents a molecular link between cytokine concentration and apoptosis in activated CD8+ T cells. Through the modulation of AKT, B55β induced the expression of the proapoptotic molecule Hrk in response to cytokine withdrawal.

TCR-α/β CD4 CD8 double negative T cells arise from CD8 T cells.

The cellular origin of CD4 CD8 (double negative, DNT) TCR-α/β T cells remains unknown. Available evidence indicates that they may derive from CD8 T cells, but most published data have been obtained using cells that bear an invariant transgenic T cell receptor that recognizes an Ag that is not present in normal mice. Here, we have used complementary fate mapping and adoptive transfer experiments to identify the cellular lineage of origin of DNT cells in wild-type mice with a polyclonal T cell repertoire.

Differential Treatments Based on Drug-induced Gene Expression Signatures and Longitudinal Systemic Lupus Erythematosus Stratification.

Systemic lupus erythematosus (SLE) is a heterogeneous disease with unpredictable patterns of activity. Patients with similar activity levels may have different prognosis and molecular abnormalities. In this study, we aimed to measure the main differences in drug-induced gene expression signatures across SLE patients and to evaluate the potential for clinical data to build a machine learning classifier able to predict the SLE subset for individual patients.

PPP2R2B hypermethylation causes acquired apoptosis deficiency in systemic autoimmune diseases.

Chronic inflammation causes target organ damage in patients with systemic autoimmune diseases. The factors that allow this protracted response are poorly understood. We analyzed the transcriptional regulation of PPP2R2B (B55ß), a molecule necessary for the termination of the immune response, in patients with autoimmune diseases.

The helminth-derived peptide GK-1 induces an anti-tumoral CD8 T cell response associated with downregulation of the PD-1/PD-L1 pathway.

CD8 T cells can kill malignant cells in an antigen-specific manner. However, anti-tumoral responses are usually limited by suppressive factors that curb the effector responses of tumor-infiltrating CD8 T cells. Therapeutic strategies to overcome intra-tumoral T cell suppression, for example immune checkpoint inhibition, have been clinically effective in patients with cancer.

Effect on quality of life of cisplatin added to single-agent chemotherapy as first-line treatment for elderly patients with advanced non-small cell lung cancer: Joint analysis of MILES-3 and MILES-4 randomised phase 3 trials.

Objectives: To evaluate the effect on quality of life (QOL) of the addition of cisplatin to single-agent chemotherapy in the treatment of elderly patients with advanced non-small cell lung cancer (NSCLC) enrolled in two parallel phase 3 trials, MILES-3 and MILES-4.

Patients And Methods: Advanced NSCLC pts, >70 years old, performance status (PS) 0-1, were eligible. Patients were randomly assigned to chemotherapy without or with cisplatin.

From Diagnostic-Therapeutic Pathways to Real-World Data: A Multicenter Prospective Study on Upfront Treatment for -Positive Non-Small Cell Lung Cancer (MOST Study).

Introduction: Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor ()-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice.

Methods: MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous -mutant NSCLC.

Gene-function studies in systemic lupus erythematosus.

Purpose Of Review: The aim of this review is to discuss recent developments in our understanding of how systemic lupus erythematosus (SLE)-associated genes contribute to autoimmunity.

Recent Findings: Gene-function studies have revealed mechanisms through which SLE-associated alleles of IFIH1, TNFAIP3, IRF5, and PRDM1 likely contribute to the development of autoimmunity. Novel research has identified Mac-1 (encoded by ITGAM), CaMK4, and iRhom2 as plausible therapeutic targets in lupus nephritis.

Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial.

Purpose: To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC).

Methods: Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m + cyclophosphamide (C) 600 mg/m × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS).

Cis interaction between sialylated FcγRIIA and the αI-domain of Mac-1 limits antibody-mediated neutrophil recruitment.

Vascular-deposited IgG immune complexes promote neutrophil recruitment, but how this process is regulated is still unclear. Here we show that the CD18 integrin Mac-1, in its bent state, interacts with the IgG receptor FcγRIIA in cis to reduce the affinity of FcγRIIA for IgG and inhibit FcγRIIA-mediated neutrophil recruitment under flow. The Mac-1 rs1143679 lupus-risk variant reverses Mac-1 inhibition of FcγRIIA, as does a Mac-1 ligand and a mutation in Mac-1's ligand binding αI-domain.

Metronomic oral vinorelbine for the treatment of advanced non-small cell lung cancer: a multicenter international retrospective analysis.

Purpose: Metronomic oral vinorelbine (MOV) could be a treatment option for unfit patients with advanced non-small cell lung cancer (NSCLC) based on its safety profile and high patient compliance.

Methods: We retrospectively collected data on 270 patients [median age 76 (range 48-92) years, M/F 204/66, PS 0 (27)/1 (110)/≥ 2 (133), median of 3 serious comorbidities] with stage IIIB-IV NSCLC treated with MOV as first (T1) (67%), second (T2) (19%) or subsequent (T3) (14%) line. Schedules consisted of vinorelbine 50 mg (138), 40 mg (68) or 30 mg (64) three times a week continuously.