Prolonged hospitalisation for immigrants and high risk patients with positive smear pulmonary tuberculosis.

Background and objective. Tuberculosis (TB) occurring in immigrants and resistance to drugs are major problems for TB control in Western countries. Directly observed therapy (DOT) reduces disease transmission, but this approach may have poor results among illegal immigrants. Our aim was to evaluate a prolonged hospitalisation programme to improve early outcome of TB treatment in high risk patients. Methods. All the consecutive adult patients with sputum smear-positive pulmonary TB admitted to 2 Italian referral TB Centres were evaluated. Hospital-based DOT was provided to high risk patients up-to smear conversion. Demographic, microbiological and clinical conditions, as potential factors associated with confirmed smear conversion at 60 and 90 days of anti-tuberculous therapy were evaluated. Results. 122 patients were studied, 45.9% of them were immigrants (20% illegal) from high-prevalence TB countries. HIV testing was negative in all cases. Twelve patients had M. tuberculosis resistant to ≥ 1 first-line anti-tuberculous agents. The rate of defaulting from TB treatment was 7.3%. Sputum smear became negative in 84.4% cases after 60 days and 93.3% cases after 90 days. At such time, smear conversion rates were similar among different high risk subgroups such as illegal immigrants (95.9%), legal foreign-born (92.5%) and Italian persons (94.8%). Persistent sputum smear positivity was independently correlated with the extent of pulmonary lesions at 60 (p<0.0001) and 90 days (p=0.038) of hospital-based DOT. Conclusions. These findings suggest that prolonged hospitalisation for illegal immigrants and high risk TB patients, may positively influence the early outcome of TB treatment despite of drug resistance and legal status

Polyphenol-mediated autophagy in cancer: Evidence of in vitro and in vivo studies

One of the hallmarks of cellular transformation is the altered mechanism of cell death. There are three main types of cell death, characterized by different morphological and biochemical features, namely apoptosis (type I), autophagic cell death (type II) and necrosis (type III). Autophagy, or self-eating, is a tightly regulated process involved in stress responses, and it is a lysosomal degradation process. The role of autophagy in cancer is controversial and has been associated with both the induction and the inhibition of tumor growth. Autophagy can exert tumor suppression through the degradation of oncogenic proteins, suppression of inflammation, chronic tissue damage and ultimately by preventing mutations and genetic instability. On the other hand, tumor cells activate autophagy for survival in cellular stress conditions. Thus, autophagy modulation could represent a promising therapeutic strategy for cancer. Several studies have shown that polyphenols, natural compounds found in foods and beverages of plant origin, can efficiently modulate autophagy in several types of cancer. In this review, we summarize the current knowledge on the effects of polyphenols on autophagy, highlighting the conceptual benefits or drawbacks and subtle cell-specific effects of polyphenols for envisioning future therapies employing polyphenols as chemoadjuvants

Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies.

One of the hallmarks of cellular transformation is the altered mechanism of cell death. There are three main types of cell death, characterized by different morphological and biochemical features, namely apoptosis (type I), autophagic cell death (type II) and necrosis (type III). Autophagy, or self-eating, is a tightly regulated process involved in stress responses, and it is a lysosomal degradation process. The role of autophagy in cancer is controversial and has been associated with both the induction and the inhibition of tumor growth. Autophagy can exert tumor suppression through the degradation of oncogenic proteins, suppression of inflammation, chronic tissue damage and ultimately by preventing mutations and genetic instability. On the other hand, tumor cells activate autophagy for survival in cellular stress conditions. Thus, autophagy modulation could represent a promising therapeutic strategy for cancer. Several studies have shown that polyphenols, natural compounds found in foods and beverages of plant origin, can efficiently modulate autophagy in several types of cancer. In this review, we summarize the current knowledge on the effects of polyphenols on autophagy, highlighting the conceptual benefits or drawbacks and subtle cell-specific effects of polyphenols for envisioning future therapies employing polyphenols as chemoadjuvants

Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo

Malignant mesothelioma (MM) is a rare orphan aggressive neoplasia with low survival rates. Among the other signaling pathways, ErbB receptors and Hh signaling are deregulated in MM. Thus, molecules involved in these signaling pathways could be used for targeted therapy approaches. The aim of this study was to evaluate the effects of inhibitors of Hh- (GANT-61) and ErbB receptors (Afatinib)-mediated signaling pathways, when used alone or in combination, on growth, cell cycle, cell death and autophagy, modulation of molecules involved in transduction pathways, in three human MM cell lines of different histotypes. The efficacy of the combined treatment was also evaluated in a murine epithelioid MM cell line both in vitro and in vivo. This study demonstrated that combined treatment with two inhibitors counteracting the activation of two different signaling pathways involved in neoplastic transformation and progression, such as those activated by ErbB and Hh signaling, is more effective than the single treatments in reducing MM growth in vitro and in vivo. This study may have clinical implications for the development of targeted therapy approaches for MM

GD2 redirected CAR T and activated NK-cell-mediated secretion of IFNγovercomes MYCN-dependent IDO1 inhibition, contributing to neuroblastoma cell immune escape

Immune escape mechanisms employed by neuroblastoma (NB) cells include secretion of immunosuppressive factors disrupting effective antitumor immunity. The use of cellular therapy to treat solid tumors needs to be implemented. Killing activity of anti-GD2 Chimeric Antigen Receptor (CAR) T or natural killer (NK) cells against target NB cells was assessed through coculture experiments and quantified by FACS analysis. ELISA assay was used to quantify interferon-gamma (IFN gamma) secreted by NK and CAR T cells. Real Time PCR and Western Blot were performed to analyze gene and protein levels modifications. Transcriptional study was performed by chromatin immunoprecipitation and luciferase reporter assays on experiments of mutagenesis on the promoter sequence. NB tissue sample were analyzed by IHC and Real Time PCR to perform correlation study. We demonstrate that Indoleamine-pyrrole 2,3-dioxygenase1 (IDO1), due to its ability to convert tryptophan into kynurenines, is involved in NB resistance to activity of immune cells. In NB, IDO1 is able to inhibit the anti-tumor effect displayed by of both anti-GD2 CAR (GD2.CAR) T-cell and NK cells, mainly by impairing their IFN gamma production. Furthermore, inhibition of MYCN expression in NB results into accumulation of IDO1 and consequently of kynurenines, which negatively affect the immune surveillance. Inverse correlation between IDO1 and MYCN expression has been observed in a wide cohort of NB samples. This finding was supported by the identification of a transcriptional repressive role of MYCN on IDO1 promoter. The evidence of IDO1 involvement in NB immune escape and its ability to impair NK and GD2.CAR T-cell activity contribute to clarify one of the possible mechanisms responsible for the limited efficacy of these immunotherapeutic approaches. A combined therapy of NK or GD2.CAR T-cells with IDO1 inhibitors, a class of compounds already in phase I/II clinical studies, could represent a new and still unexplored strategy capable to improve long-term efficacy of these immunotherapeutic approaches

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

sharma et al. define a new primary atopic disorder caused by heterozygous gain-of-function variants in STAT6. this results in severe, early-onset allergies, and is seen in 16 patients from 10 families. Anti-IL-4R & alpha; antibody and JAK inhibitor treatment were highly effective.STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. we have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. the cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). all patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and T(H)2 skewing. Precision treatment with the anti-IL-4R & alpha; antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. this study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder