Immunohistochemical Analysis of Myenteric Ganglia and Interstitial Cells of Cajal in Ulcerative Colitis

Ulcerative colitis (UC) is an inflammatory bowel disease with alterations of colonic motility, which influence clinical symptoms. Although morpho-functional abnormalities in the enteric nervous system have been suggested, in UC patients scarce attention has been paid to possible changes in the cells that control colonic motility, including myenteric neurons, glial cells, and interstitial cells of Cajal (ICC). This study evaluated the neural-glial components of myenteric ganglia and ICC in the colonic neuromuscular compartment of UC patients by quantitative immunohistochemical analysis. Full-thickness archival samples of the left colon were collected from 10 patients with UC (5 M, 5 F; age range, 45-62 years) who underwent elective bowel resection. The colonic neuromuscular compartment was evaluated immunohistochemically in paraffin cross-sections. The distribution and number of neurons, glial cells and ICC were assessed by anti-HuC/D, -S100β and -c-Kit antibodies, respectively. Data were compared with findings on archival samples of normal left colon from 10 sex- and age-matched control patients, who underwent surgery for uncomplicated colon cancer. Compared to controls, patients with UC showed: (a) reduced density of myenteric HuC/D-positive neurons and S100β-positive glial cells, with a loss over 61% and 38%, respectively, and increased glial cell/neuron ratio; (b) ICC decrease in the whole neuromuscular compartment. The quantitative variations of myenteric neuro-glial cells and ICC indicate considerable alterations of the colonic neuromuscular compartment in the setting of mucosal inflammation associated with UC, and provide a morphological basis for better understanding the motor abnormalities often observed in UC patients

Salmonella typhimurium and Escherichia coli dissimilarity: closely related bacteria with distinct metabolic profiles

Live attenuated strains of Salmonella typhimurium have been extensively investigated as vaccines for a number of infectious diseases. However, there is still little information available concerning aspects of their metabolism. S. typhimurium and Escherichia coli show a high degree of similarity in terms of their genome contents and metabolic networks. However, this work presents experimental evidence showing that significant differences exist in their abilities to direct carbon fluxes to biomass and energy production. It is important to study the metabolism of Salmonella in order to elucidate the formation of acetate and other metabolites involved in optimizing the production of biomass, essential for the development of recombinant vaccines. The metabolism of Salmonella under aerobic conditions was assessed using continuous cultures performed at dilution rates ranging from 0.1 to 0.67 h1, with glucose as main substrate. Acetate assimilation and glucose metabolism under anaerobic conditions were also investigated using batch cultures. Chemostat cultivations showed deviation of carbon towards acetate formation, starting at dilution rates above 0.1 h1. This differed from previous findings for E. coli, where acetate accumulation was only detected at dilution rates exceeding 0.4 h1, and was due to the lower rate of acetate assimilation by S. typhimurium under aerobic conditions. Under anaerobic conditions, both microorganisms mainly produced ethanol, acetate, and formate. A genome-scale metabolic model, reconstructed for Salmonella based on an E. coli model, provided a poor description of the mixed fermentation pattern observed during Salmonella cultures, reinforcing the different patterns of carbon utilization exhibited by these closely related bacteria. This article is protected by copyright. All rights reserved.Special thanks to Amadeus Azevedo for the HPLC analyses and technical assistance. The authors acknowledge the national funding received from CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil), the international cooperation project CAPES-FCT (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/Brazil-Fundacao para a Ciencia e a Tecnologia/Portugal-Process 315/11), CAPES (Atracao de Jovens Talentos-Process 064922/2014-01) and to Fundacao para a Ciencia e Tecnologia the strategic funding of UID/BIO/04469/2013 unit

Patient-reported Quality of Life outcomes in patients treated for muscle-invasive bladder cancer with radiotherapy ± chemotherapy in the BC2001 Phase III Randomised Controlled Trial

BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer, demonstrated improvement of local control and bladder cancer-specific survival from the addition of concomitant 5-fluorouracil and mitomycin C to radiotherapy.This article is available via Open Access. Click on the Publisher URL to access the full-text

Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

Background Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. Methods This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. Results Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). Conclusions Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. METHODS: This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. RESULTS: Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). CONCLUSIONS: Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival

Toward a quantitative approach to migrants integration

Migration phenomena and all the related issues, like integration of different social groups, are intrinsically complex problems since they strongly depend on several competitive mechanisms as economic factors, cultural differences and many others. By identifying a few essential assumptions, and using the statistical mechanics of complex systems, we propose a novel quantitative approach that provides a minimal theory for those phenomena. We show that the competitive interactions in decision making among a population of $N$ host citizens and $P$ immigrants, a bi-partite spin-glass, give rise to a "social consciousness" inside the host community in the sense of the associative memory of neural networks. The theory leads to a natural quantitative definition of migrant's "integration" inside the community. From the technical point of view this minimal picture assumes, as control parameters, only general notions like strength of the random interactions, the ratio among the two party sizes and the cultural influence. Few steps forward, toward more refined models, which include some structure on the random interaction topology (as dilution to avoid the plain mean field approach) and correlations of experiences felt among the two parties (biasing the distribution of the coupling) are discussed at the end, where we show the robustness of our approach

Transarterial Chemoembolization for Hepatocellular Carcinoma in Clinical Practice: Temporal Trends and Survival Outcomes of an Iterative Treatment

Background: Transarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE application and repetition, as well as the related outcome, have changed over the last three decades in Italy. Methods: Data of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988–1993), P2 (1994–1998), P3 (1999–2004), P4 (2005–2009), P5 (2010–2014), and P6 (2015–2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment. Results: The proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p < 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p < 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC). Conclusions: Despite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis

Expression of interleukin 6 (IL-6) correlates with oestrogen receptor in human breast carcinoma

Multifunctional cytokines play important and only partially defined roles in mammary tumour development and progression. Normal human mammary epithelial cells constitutively produce interleukin 6 (IL-6), IL-8 and a non-secreted form of tumour necrosis factor. Transformation of mammary epithelial cells by different oncogenes is frequently associated with alterations of cytokine/growth factor production and responsiveness. In the present study we analysed the expression of IL-6 in 149 cases of invasive breast carcinoma and the data have been correlated with clinico-pathological variables including tumour size, histological grade, nodal status, and oestrogen and progesterone receptors, Ki67 and p53, protein expression. Though the majority of breast carcinomas expressed at least low levels of immunoreactive IL-6, we found that expression of this cytokine was inversely associated with histological tumour grade (P = 0.0017), but not with tumour size and nodal status. Ki67 positivity was inversely correlated with IL-6 expression (P = 0.027). Among biological parameters analysed, a direct association was found between the percentage of IL-6-positive cells and that of oestrogen (P = 0.00005) and progesterone (P = 0.025) receptor-positive cells. No correlation was observed between IL-6 and p53 protein expression. These data indicate that down regulation of IL-6 is associated with highly malignant mammary carcinomas. It will be of interest to evaluate whether alterations of cytokines that are constitutively produced by mammary cells are also associated with high-grade tumours