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Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection. Systemic sepsis is a potentially life-threatening illness and immunocompromised individuals are especially vulnerable. Here, using a cohort of patients with intra-abdominal origin sepsis, the authors show an important role for the NLRP3 inflammasome in establishing a host response, and NLRP3 dysfunction is a common feature of sepsis mortality.

Barrett's esophagus (BE) is a premalignant lesion that can lead to an invasive esophageal adenocarcinoma (EAC), a type of cancer that usually has a poor outcome. We have previously described a set of four microRNAs (miR‐192, 194, 196a and b) that are markers of the disease's progression. To determine whether these miRNAs might also be drivers of invasive EAC development, their overexpression in EAC cells was analyzed. Only the overexpression of miR‐196a and miR‐196b induced a phenotype switch in non‐invasive EAC cells, resembling epithelial‐to‐mesenchymal transition (EMT). The overexpression of miR‐196a promoted EMT and increased cell motility and NFκB signaling. Mechanistically, miR‐196a targets the inhibitor of NFκB alpha NFKBIa and also leads to c‐MYC protein accumulation by down‐regulating VCP expression. This in turn up‐regulated TERT expression and reinforced NFκB signaling. NFκB signaling, TERT, and c‐MYC inhibition resulted in a reversed‐EMT phenotype, with decreased EMT hallmarks and cell motility in miR‐196a overexpressing cells. Finally, an immunohistochemical analysis of BE tissue samples showed that c‐MYC, TERT, and NFκB signaling increased in BE patients who developed EAC, more so than in patients that did not. The high expression of miR‐196a induces aggressive features in non‐invasive EAC cells. These effects are dependent on the c‐MYC/TERT/NFκB signaling molecular axis. BE patients and non‐invasive EAC patients with high miR‐196a expression could benefit from therapeutic interventions to prevent EMT or activation of the molecular pathway described in this study. mir‐196a promotes Esophagus Adenocarcinoma aggressiveness. On one hand, mir‐196a targets the valosin‐containing protein (VCP) mRNA, causing the accumulation of c‐MYC protein that leads to high amounts of TERT. On the other hand, mir‐196a targets the inhibitor of NFκB (NFKBIA). This, along with TERT, increases NFKB signaling and SNAIL1 transcription, provoking an epithelial‐to‐mesenchymal transition (EMT) and tumor aggressiveness.

Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage hepatectomy technique which can be associated with a hypertrophic stimulus on the future liver remnant (FLR) stronger than other techniques--such as portal vein ligation (PVL). However, the reason of such hypertrophy is still unclear, but it is suggested that liver transection combined with portal vein ligation (ALPPS) during the first stage of this technique may play a key role. The aim of this study is to compare the hypertrophic stimulus on the FLR and the clinical changes associated with both ALPPS and PVL in a rat surgical model. For this purpose, three groups of SD rats were used, namely ALPPS (n = 30), PVL (n = 30) and sham-treated (n = 30). The second stage of ALPPS (hepatectomy of the atrophic lobes), was performed at day 8. Blood and FLR samples were collected at 1, 24, 48 hours, 8 days and 12 weeks after the surgeries. ALPPS provoked a greater degree of hypertrophy of the FLR than the PVL at 48 hours and 8 days (p<0.05). The molecular pattern was also different, with the highest expression of IL-1β at 24h, IL-6 at 8 days, and HGF and TNF-α at 48 hours and 8 days (p<0.05). ALPPS also brought about a mild proliferative stimulus at 12 weeks, with a higher expression of HGF and TGF-β (p<0.05) than PVL. Clinically, ALPPS caused a significant liver damage during the first 48 hours, with a recovery of liver function at day 8. In conclusion, ALPPS seems to induce higher functional hypertrophy on the FLR than PVL at day 8. Such regenerative response seems to be leaded by a complex interaction between pro-mitogenic (IL-6, HGF, TNF-α) and antiproliferative (IL1-β and TGF-β) cytokines.

Poly‐(ADP‐ribose) polymerase‐2 (PARP‐2) belongs to a large family of enzymes that synthesize and transfer ADP‐ribose polymers to acceptor proteins, modifying their functional properties. PARP‐2‐deficient (Parp‐2 −/− ) cells, similar to Parp‐1 −/− cells, are sensitive to both ionizing radiation and alkylating agents. Here we show that inactivation of mouse Parp‐2, but not Parp‐1, produced a two‐fold reduction in CD4 + CD8 + double‐positive (DP) thymocytes associated with decreased DP cell survival. Microarray analyses revealed increased expression of the proapoptotic Bcl‐2 family member Noxa in Parp‐2 −/− DP thymocytes compared to littermate controls. In addition, DP thymocytes from Parp‐2 −/− have a reduced expression of T‐cell receptor (TCR)α and a skewed repertoire of TCRα toward the 5′ Jα segments. Our results show that in the absence of PARP‐2, the survival of DP thymocytes undergoing TCRα recombination is compromised despite normal amounts of Bcl‐x L . These data suggest a novel role for PARP‐2 as an important mediator of T‐cell survival during thymopoiesis by preventing the activation of DNA damage‐dependent apoptotic response during the multiple rounds of TCRα rearrangements preceding a positively selected TCR.

Background Pheochromocytoma occurs in nearly 50% of MEN 2A (multiple endocrine neoplasia, type 2A) cases. Many issues related to this tumor are still the subject of debate: the diagnostic management in patients who have had positive genetic study results (RET mutation), variations related to mutation, the best surgical option, and the real relapse rate during long-term follow-up. The aim of this study is to present our experience with this unusual disease, looking for answers to some of these questions. Patients and methods Of 169 patients belonging to 19 MEN 2A families, 54 (32%) presented with pheochromocytoma. The following variables have been studied: (1) clinical and diagnostic data [age, mutation, clinical features, results of catecholamines and catabolites in a 24-h urine sample, computerized tomography (CT) scan and iodine-131 meta-iodobenzylguanidine (MIBG) scintigraphy results, and the means of diagnostic, clinical, or genetic screening]; (2) surgical treatment; and (3) follow-up and recurrence. The mean follow-up time was 92.5 months (range: 12–120 months). Results The mean age of the 54 patients was 37.9 years (range: 14–71 years); 33 were women. Most (96.3%) mutations were found in exon 11. The most frequent mutations were Cys634Tyr (in 33 cases [61.1%]) and Cys634Arg (in 14 [25.9%]). The diagnosis of pheocromocytoma was made after the diagnosis of MTC in 26 cases (48.2%), simultaneously in 21 (38.9%), and prior in the 7 remaining cases (12.9%). At the time of diagnosis 28 patients (51.8%) were asymptomatic and 26 (48.2%) had clinical features related to pheochromocytoma. In 6 patients (11.1%), the values of catecholamines and catabolites in urine were normal. In the cases with high values, the most useful isolated determination was that of metanephrines (82%), followed by adrenaline (76%). The CT scan did not provide a correct diagnosis in 6 patients with bilateral lesions, and one patient with a bilateral tumor was not diagnosed by MIBG. The combination of CT scan and MIBG diagnosed 100% of cases. The pheochromocytoma was bilateral in 27 cases, with a total number of 81 pathological glands detected. A laparascopic approach was used in 30 cases and a laparotomy in 24. The mean tumor size was 4.5 cm (range: 1–18 cm). Five patients with unilateral resection relapsed (18.5%), and the mean relapse time was 43.2 months (range: 12–120 months). There was a greater frequency of pheochromocytoma in those subjects who had the Cys634Arg mutation ( p  < 0.03). In addition, the Cys634Arg mutation is more frequent in bilateral cases. There are no prognostic factors for recurrence. Conclusions Pheochromocytoma in MEN 2A is related to the type of mutation, which can be early onset and is frequently asymptomatic. Its diagnosis requires catecholamines determinations as well as a CT scan. Correct diagnosis of bilaterality is established by CT and MIBG. Laparoscopic adrenalectomy is the treatment of choice.

Background The best type of laparoscopic approach in solid liver tumours (SLTs), whether total laparoscopic surgery or hand-assisted laparoscopic surgery (HALS), has not yet been established. Our objective is to present our experience with laparoscopic liver resections in SLTs performed by HALS using a new approach. Methods We performed 35 laparoscopic resections in SLTs, of which 26 were carried out using HALS (in 25 patients) and 21 patients had liver metastases of a colorectal origin (LMCRC) (1 patient had 2 resections), 1 metastasis from a neuroendocrine tumour of the pancreas, 1 hepatocarcinoma on a healthy liver, 1 primary hepatic leiomyosarcoma and 1 giant haemangioma. Mean follow-up was 22 months. Operation One right hemihepatectomy, one left hemihepatectomy, five bisegmentectomies II–III, three bisegmentectomies VI–VII and 16 segmentectomies (five of S. VI, three of S. VIII; three of S. V; two of S. IVb; one of S. II; one of S. IV; and in the remaining case resection of S. III and VI plus resection of a metastasis in S. VIII). Main outcome measures Morbidity and mortality, conversion to open procedure, intraoperative blood loss, intra- and postoperative transfusion, length of stay and survival. Results There were no intra- or postoperative deaths, nor were there any conversions. One patient presented with morbidity (3.8%) (liver abscess). Mean blood loss was 200 ml (range 0–600 ml). One patient required transfusion (3.8%). Mean operative time was 180 min (range 120–360 min). Mean length of hospital stay was 4 days (range 2–5 days). The actuarial survival rate of the patients at 36 months with liver metastases from colorectal carcinoma (LMCRC) was 80%. Conclusions Liver resection with HALS reproduces the low morbidity and mortality rates and effectiveness (3-year survival) of open surgery in SLTs when indicated selectively.

Background/Aims: The management of locally advanced rectal cancer has changed substantially over the last few decades with neoadjuvant chemoradiotherapy. The aim of the present study is to compare the results between neoadjuvant post-treatment rectoscopy and the anatomopathological findings of the surgical specimen. Patients and Methods: We conducted a prospective study of 67 patients with locally advanced adenocarcinoma of the rectum (stages II and III). Two groups were established: One with complete clinical response (cCR) and one without (non-cCR), based on the findings at rectoscopy. Assessment of tumor regression grade in the surgical specimen was determined using Mandard's tumor regression scale. Results: Seventeen patients showed a cCR. Thirty-five biopsies were negative and 32 were positive for mailgnancy. All the cCR patients had a negative biopsy (P < 0.0001). All 32 positive biopsies revealed the presence of adenocarcinoma, and of the 35 negative biopsies, 18 had no malignancy and 17 were diagnosed with adenocarcinoma (P < 0.0001). Sixteen of the 17 cCR patients showed a complete pathological response and one patient showed the presence of adenocarcinoma. Of the 50 non-cCR patients 48 revealed the presence of adenocarcinoma and two had absence of malignancy. According to the Mandard classification, 16 of the 17 cCR patients were grade I and 1 grade II; 2 non-cCR patients were grade I, 7 grade II, 13 grade III, 19 grade IV, and 9 grade V. Conclusions: Endoscopic and histological findings could be determinants in the assessment of response to neoadjuvant treatment.

ObjectiveTo present surgical and oncological outcomes using a prospective and randomized trial (LapOpHuva, NCT02727179) comparing minimally invasive liver resection (LLR) versus open liver resection (OLR) in patients with colorectal liver metastases (CRLM).MethodsBetween February 2005 and March 2016, 204 selected patients with CRLM were randomized and 193 were included: LLR (n = 96) and OLR (n = 97). The primary endpoint was to compare postoperative morbidity. Other secondary endpoints were oncological outcomes, use of the Pringle maneuver, surgical time, blood losses, transfusions, hospital stay, mortality and OS, and disease-free survival (DFS) at 3, 5, and 7 years.ResultsLLR presented with lower global morbidity (11.5% vs. 23.7%, p = 0.025) but with similar severe complications. Long-term survival outcomes were similar in both groups. The cumulative 1-, 3-, 5-, 7-year OS for LLR and OLR were 92.5%, 71.5%, 49.3%, 35.6% versus 93.6%, 69.7%, 47.4%, 35.5%, respectively (log-rank = 0.047, p = 0.82). DFS for LLR and OLR was 72.7%, 33.5%, 22.7%, and 20.8% versus 61.6%, 27.2%, 23.9%, and 17.9%, respectively (log-rank = 1.427, p = 0.23). LLR involved more use of the Pringle maneuver (15.5% vs. 30.2%, p = 0.025) and a shorter hospital stay (4 vs. 6 days, p < 0.001). There were no differences regarding surgical time, blood losses, transfusion, and mortality.ConclusionsIn selected patients with CRLM, LLR presents similar oncological outcomes with the advantages of the short-term results associated with LLR.

The severity of acute pancreatitis results from the transmigration and activation of leukocytes within the pancreas and the local synthesis and release of proinflammatory-soluble mediators that transform a local injury into a systemic inflammatory response. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear DNA-binding protein that has been shown to play a relevant role in cell necrosis and organ failure in various diseases associated with inflammation. Therefore, we set out to investigate whether the genetic deletion of PARP-1 or PARP-2 (a new member of the PARP family) genes, or pharmacological inhibition of PARP activity might affect the development and severity of acute pancreatitis and pancreatitis-associated lung injury. Secretagogue-induced acute pancreatitis was achieved by 12 hourly intraperitoneal injections of cerulein in mice deficient in PARP-1 or PARP-2 genes, and wild-type (WT) littermate mice untreated or treated with PARP activity inhibitors. The severity of pancreatitis was assessed by measurements of serum amylase, lipase, interleukin-1β and IL-6, pancreatic water content, histologic grading and pancreas myeloperoxidase (MPO) activity. Lung injury was evaluated by quantifying MPO activity and morphological changes. We found that the severity of acute pancreatitis and pancreatitis-associated lung injury was significantly attenuated in mice lacking PARP-1, but not PARP-2, compared with WT mice. Interestingly, administration of PARP inhibitors, 3-aminobenzamide or PJ34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethyacetamide HCl), in WT mice markedly decreased acute pancreatitis severity and pulmonary-associated injury in a larger extension than genetic deletion of PARP-1. Our results support the potential therapeutic application of PARP inhibitors in the development and severity of acute pancreatitis and associated lung injury.

BackgroundRight hemicolectomy is a very common surgery. Many studies compare different options for laparoscopic ileocolic anastomoses: intra- or extracorporeal; handsewn or stapled; side-to-side or end-to-side. However, there are no studies about the influence that peristalsis could have on this anastomosis. The aim of this study is to compare safety and feasibility of isoperistaltic and antiperistaltic anastomosis in terms of postoperative morbidity and mortality between both groups. The secondary endpoint is to compare long-term functional outcomes (chronic diarrhoea) and quality of life (GIQLI questionnaire) after a 1-year follow-up period.MethodsA double-blind, randomised, prospective trial in patients undergoing scheduled surgery for right colon cancer with laparoscopic right hemicolectomy and isoperistaltic (ISO) or antiperistaltic (ANTI) ileocolic anastomoses.ResultsHundred and eight patients were included in the study. Patients were randomised either to isoperistaltic or antiperistaltic configuration (54 ISO/ANTI). No significant differences in baseline variables were found. No differences in surgical time (130 [120–150] min ISO vs. 140 [127–160] ANTI, p = 0.481), nor in anastomotic time (19 [17–22] vs. 20 [16–25], p = 0.207) and nor in postoperative complications: 37.0% ISO versus 40.7% ANTI, (p = 0.693) were found. There were no differences in postoperative ileus (p = 0.112) nor in anastomotic leakage (3.7% vs. 5.56%, p = 1.00). Differences in “time to first flatus” and “time to first deposition” were found in favour of the antiperistaltic group (p = 0.004 and p = 0.017). Anastomotic configuration did not influence hospital stay (3 days [2–6] isoperistaltic vs. 3 [2–4] antiperistaltic, p = 0.236). During follow-up, there were no differences between the two groups at 1, 6 and 12 months (p = 0.154, p = 0.498 and p = 0.683), nor in chronic diarrhoea rates in GIQLI scores (24% ISO vs. 31.4% ANTI, p = 0.541).ConclusionsThe isoperistaltic and antiperistaltic ileocolic anastomosis present similar results in terms of performance, safety and functionality. However, further studies must be carried out in order to assess relationship between postoperative ileus and anastomosis configuration.Trial registrationRandomised Clinical trial (Identifier: NCT02309931).