Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.

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The proteasome inhibitors lactacystin and AcLLNal induced p53-independent apoptosis in two human glioma cell lines, and the apoptosis was accompanied by up-regulation of immunoreactive wild-type p53, p21 fI , Mdm2, and p27 uipI . Pretreatment with cycloheximide decreased the induction of cell death independently of p53 protein status, suggesting that the upregulation of short-lived proteins is associated with proteasome inhibitor-induced apoptosis. Caspase-3-like proteases were activated in the proteasome inhibitor-mediated apoptosis, and the induction of cell death was inhibited more effectively in the presence of z-VAD.fmk than in the presence of Ac-DEVD.fmk, suggesting that caspases other than caspase-3 are involved. Nonetheless, there were no significant alterations in levels of immunoreactive Bcl-2, Bcl-x v , Bax, Bad, and Bak, nor any evidence of cytochrome c release into cytosol and dissipation of v v8 8 m . Thus, the proteasome inhibitor-induced apoptosis is mediated by a mitochondria-independent mechanism, and the once activated caspase-3 does not cause the cytochrome c release and the v v8 8 m disruption. z 1999 Federation of European Biochemical Societies.

Apoptosis was induced in human glioma cell lines by exposure to 100 nM calphostin C, a specific inhibitor of protein kinase C. Calphostin C-induced apoptosis was associated with synchronous down-regulation of Bcl-2 and Bcl-x L as well as activation of caspase-3 but not caspase-1. The exposure to calphostin C led to activation of stress-activated protein kinase/c-Jun NH 2 -terminal kinase (SAPK/JNK) and p38 kinase and concurrent inhibition of extracellular signal-regulated kinase (ERK). Upstream of ERK, Shc was shown to be activated, but its downstream Raf1 and ERK were inhibited. The pretreatment with acetyl-Tyr-Val-Ala-Asp-aldehyde, a relatively selective inhibitor of caspase-3, or benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.fmk), a broad spectrum caspase inhibitor, similarly inhibited calphostin C-induced activation of SAPK/JNK and p38 kinase as well as apoptotic nuclear damages (chromatin condensation and DNA fragmentation) and cell shrinkage, suggesting that caspase-3 functions upstream of SAPK/JNK and p38 kinase, but did not block calphostin C-induced surface blebbing and cell death. On the other hand, the inhibition of SAPK/JNK by transfection of dominant negative SAPK/JNK and that of p38 kinase by SB203580 induced similar effects on the calphostin Cinduced apoptotic phenotypes and cell death as did z-VAD.fmk and acetyl-Tyr-Val-Ala-Asp-aldehyde, but the calphostin C-induced PARP cleavage was not changed, suggesting that SAPK/JNK and p38 kinase are involved in the DNA fragmentation pathway downstream of caspase-3. The present findings suggest, therefore, that the activation of SAPK/JNK and p38 kinase is dispensable for calphostin C-mediated and z-VAD.fmk-resistant cell death.It has been expected that signal transduction pathways involving specific protein kinases are involved in mediating apoptosis. Extracellular signal-regulated kinase (ERK) 1 is most strongly stimulated by activation of protein-tyrosine kinase receptors (1) and also activated by both Ras-dependent (2-4) and Ras-independent signalings (5) in response to activation of G protein-coupled receptors, and common intermediates in intracellular signaling cascades are involved in diverse cellular functions including growth and differentiation (6). Activation of PKC by 12-O-tetradecanoylphorbol-13-acetate results in the activation of Raf1 (7) and ERK (8 -11) within minutes, suggesting the involvement of PKC in the signaling pathway leading to ERK activation. In addition, Ras functions as an essential transducer of various physiological signals leading to cell growth and proliferation in a PKC-dependent or PKC-independent manner (12), and activated Ras also renders cells susceptible to apoptosis after depression of PKC activity (13,14).SAPK/JNK and p38 kinase have been proposed to mediate apoptosis, but a number of reports have challenged the notion that the activation of SAPK/JNK and/or p38 kinase is sufficient to induce apoptosis (15-21), and the integration and balance of SAPK/JNK and p38 pathways probably contribute to commitment to a...

Background This study evaluated the prognostic value of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) together with host-related factors in patients with unresectable advanced gastric cancer. Methods The study enrolled 262 patients who received chemotherapy for unresectable advanced gastric cancer at Kochi Medical School from 2007 to 2015. Clinicopathological information and systemic inflammatory response data were analyzed for associations between baseline cancer-related prognostic variables and survival outcomes. Results The median survival time was significantly lower for patients with high ALP, high LDH, high total bilirubin, high aspartate aminotransferase, high alanine transaminase, high gamma-glutamyltransferase, high creatinine, a Glasgow prognostic score (GPS) of 1 or 2 score compared to GPS 0, higher compared to lower neutrophil to lymphocyte ratio (NLR) 3.9, lower compared to higher prognostic nutrition index 36.1, T3-4 compared to T1-2 tumor and diffuse-type compared to intestinaltype histology. Multivariate survival analysis identified high ALP 322 (HR 1.808; 95% CI 1.015-3.220; P = 0.044), T2-3 (HR 2.622; 95% CI 1.224-5.618; P = 0.013), and diffuse-type gastric cancer (HR 2.325; 95% CI 1.341-4.032; P = 0.003) as significant independent predictors of worse prognosis in the studied group of cancer patients. Conclusions High level of ALP is an independent, worse prognosis factor for patients receiving chemotherapy for unresectable and recurrent gastric cancer.