Few studies have evaluated the impact of risk factors such as performance status (PS) and comorbidities on overall survival (OS) in patients with metastatic pancreatic cancer (mPC). We investigated ...the influence of comorbidity, PS and age on nab-paclitaxel and gemcitabine (NabGem) effectiveness profile in naive patients with mPC. 153 patients with mPC treated with NabGem upfront was divided in three groups (score 0 to 3) based on the absence or the presence of one or more risk factors among: age ≥ 70 years, PS 1 and comorbidities and the clinical outcomes was compared. Fifty-five patients were elderly (≥ 70 years), 80 patients have PS 1, whereas the other have PS 0. Patients with no risk factors (score 0) had an overall survival higher (20 months) than patients with one or two risk factors (score 1-2) (OS 11 months) and with three risk factors (score 3) (OS 8 months) (p < 0.01). The difference in OS was also statistically significant in patients without comorbidities (OS 15 months) compared to those with ≥ 1 comorbidity (OS 10 months) (p < 0.001). NabGem chemotherapy represent an effective treatment in naive patients. Age, PS, and comorbidities were prognostic factors in patients with metastatic pancreatic cancer.
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of ...monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.
NOD2 polymorphisms may affect sensing of the bacterial muramyl dipeptide (MDP) and trigger perturbed inflammatory responses. Genetic screening of a patient with immunodeficiency and enteropathy ...revealed a rare homozygous missense mutation in the first CARD domain of NOD2 (ENST00000300589; c.160G > A, p.E54K). Biochemical assays confirmed impaired NOD2-dependent signaling and proinflammatory cytokine production in patient's cells and heterologous cellular models with overexpression of the NOD2 mutant. Immunoprecipitation-coupled mass spectrometry unveiled the ATPase valosin-containing protein (VCP) as novel interaction partner of wildtype NOD2, while the binding to the NOD2 variant p.E54K was abrogated. Knockdown of VCP in coloncarcinoma cells led to impaired NF-κB activity and IL8 expression upon MDP stimulation. In contrast, tunicamycin-induced ER stress resulted in increased IL8, CXCL1, and CXCL2 production in cells with knockdown of VCP, while enhanced expression of these proinflammatory molecules was abolished upon knockout of NOD2. Taken together, these data suggest that VCP-mediated inflammatory responses upon ER stress are NOD2-dependent.
Cutaneous basal cell carcinoma (BCC) is the most common type of human tumor, and its incidence rate is increasing worldwide. Up until a few years ago, therapeutic options have been limited for ...patients with advanced BCC (including metastatic and locally-advanced BCC). Over the last few years, promising systemic therapies have been investigated for the treatment of advanced BCC. In particular, the Hedgehog signaling inhibition has shown remarkable results for this population. Hedgehog inhibitors, represented by vismodegib and sonidegib, have been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of both locally advanced and metastatic BCC, with, generally, a good safety profile. Notwithstanding the late onset of BCC in the global population, associated with life expectancy increase, only a few clinical trials have evaluated the efficacy and safety profile of Hedgehog inhibitors in this complex and neglected population. Herein, we review the major mechanisms implicated in the pathogenesis of BCC focusing on the Hedgehog signaling pathway and its therapeutic role in the elderly population. Finally, we report two case reports of BCC elderly patients in order to demonstrate both efficacy and safety of the Hedgehog inhibitors.
Lung cancer has been historically considered a poorly immunogenic disease because of the few evidence of immune responses in affected patients and the limited efficacy of immunomodulating strategies. ...Recent understanding of the molecular mechanisms leading to cancer immune evasion has allowed the development of a new class of drugs called immune checkpoint inhibitors, which reactivate host responses with outstanding clinical benefits in a portion of patients with non-small-cell lung cancer. In this review, we briefly summarize the basis of immunogenicity and immune escape of cancer, with specific focus on non-small-cell lung cancer, mechanisms underlying immune checkpoint inhibitors efficacy and the most updated results on potential biomarkers, with the final aim of defining current unmet needs of immunotherapy in clinical practice.
HIV-1 infection exhibits a significant sex bias. This study aimed at identifying and examining lymphocyte associated sex differences in HIV-1 pathogenesis using a data-driven approach. To select ...targets for investigating sex differences in lymphocytes, data of microarray experiments and literature mining were integrated. Data from three large-scale microarray experiments were obtained from NCBI/GEO and screened for sex differences in gene expression. Literature mining was employed to identify sex biased genes in the microarray data, which were relevant to HIV-1 pathogenesis and lymphocyte biology. Sex differences in gene expression of selected genes were investigated by RT-qPCR and flowcytometry in healthy individuals and persons living with HIV-1. A significant and consistent sex bias was identified in 31 genes, the majority of which were related to immunity and expressed at higher levels in women. Using literature mining, three genes (DPP4, FCGR1A and SOCS3) were selected for analysis by qPCR because of their relevance to HIV, as well as, B and T cell biology. DPP4 exhibited the most significant sex bias in mRNA expression (p = 0.00029). Therefore, its expression was further analyzed on B and T cells using flowcytometry. In HIV-1 infected controllers and healthy individuals, frequencies of CD4+DPP4+ T cells were higher in women compared to men (p = 0.037 and p = 0.027). In women, CD4 T cell counts correlated with a predominant decreased in DPP4+CD4+ T cells (p = 0.0032). Sex differences in DPP4 expression abrogated in progressive HIV-1 infection. In conclusion, we found sex differences in the pathobiology of T cells in HIV-1 infection using a data-driven approach. Our results indicate that DPP4 expression on CD4+ T cells might contribute to the immunological sex differences observed in chronic HIV-1 infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neutropenia is a common side effect associated with nab-paclitaxel gemcitabine (Nab-Gem) therapy. We retrospectively investigated the association between neutropenia induced by first-line Nab-Gem and ...survival in metastatic pancreatic carcinoma patients. Metastatic pancreatic patients treated with first-line Nab-Gem were included in this retrospective analysis. Neutropenia was categorized using the National Cancer Institute Common Toxicity Criteria scale. Outcome measures were overall survival (OS), progression-free survival (PFS) and response rate. 115 patients were analyzed. Median PFS was 7 months (95% CI 5-8) for patients with grade ≥ 3 neutropenia and 6 months (95% CI 5-6) for patients with grade < 3 neutropenia p = 0.08; hazard ratio (HR 0.68). Median OS was 13 months (95% CI 10-18) for patients with grade ≥ 3 neutropenia and 10 months (95% CI 8-13) for patients with grade < 3 neutropenia (p = 0.04; HR 0.44). In multivariate analysis, the occurrence of grade ≥ 3 neutropenia showed a statistically significant association with OS (HR 0.62; 95% CI 0.09-0.86; p = 0.05). Nab-Gem-induced neutropenia is associated with longer survival in metastatic pancreatic cancer patients.
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