The COVID-19 pandemic caused by the SARS-CoV-2 virus continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either Boceprevir or Telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro with IC50 values ranging from 7.6 to 748.5 nM. The co-crystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a SARS-CoV-2 infection transgenic mouse model, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

BackgroundPrimary gastric adenosquamous carcinoma (ASC) is a rare subset of ASC. This study aims to investigate the clinicopathological features, diagnosis, treatment, and outcomes of primary gastric ASC.MethodsThe medical records of 13 consecutive patients with primary gastric ASC between January 2010 and July 2014 from a single institutional database were reviewed.ResultsMale predominance was observed (M/F = 10/3) among the patients, and their median age was 62 years (range: 43 to 79 years). The primary lesions were most often found in the upper third of the stomach, with a median tumor size of 5 cm (range: 2.25 cm to 10.5 cm). Ten patients underwent radical resections (R0 resection, 76.9%), while three patients had palliative resections (R1/R2 resection, 23.1%). Twelve patients had lymph node metastasis at the time of surgery. Adenocarcinoma and squamous cell carcinoma components in lymph node were found in eight and two cases, respectively, while two patients had both squamous cell carcinoma and adenocarcinoma components. In terms of the TNM staging system, stages IIB, IIIA, IIIB, IIIC, and IV were detected in 2 (15.4%), 2 (15.4%), 1 (7.7%), 5 (38.5%), and 3 (23.1%) patients, respectively. The median follow-up period was 22 months (range: 5 to 52 months); during which, four patients were still alive and eight patients died because of tumor progression. The 1-, 2-, and 3-year survival rates were 76.9%, 46.2%, and 15.4%, respectively.ConclusionsPrimary gastric ASC has a very poor prognosis, and both squamous cell carcinoma and adenocarcinoma components have distant metastasis potential.

Minimally invasive surgery for gastric GISTs ≤5 cm is safe and feasible. The final choice regarding a minimally invasive approach should be based on the tumor size, tumor location, pattern of tumor growth, and experience of laparoscopic surgeons.

BackgroundDuodenal gastrointestinal stromal tumors (DGIST) are rare, and data on their management is limited. We here report the clinicopathological characteristics, different surgical treatments, and long-term prognosis of DGIST.MethodsData of 74 consecutive patients with DGIST in a single institution from June 2000 to June 2014 were retrospectively analyzed. The overall survival (OS) and recurrence/metastasis-free survival rates of 74 cases were calculated using Kaplan–Meier method.ResultsOut of 74 cases, 42 cases were female (56.76 %) and 32 cases (43.24 %) were male. Approximately 22.97, 47.30, 16.22, and 13.51 % of the tumors originated in the first to fourth portion of the duodenum, respectively, with a tumor size of 5.08 ± 2.90 cm. Patients presented with gastrointestinal bleeding (n = 37, 50.00 %), abdominal pain (n = 25, 33.78 %), mass (n = 5, 6.76 %), and others (n = 7, 9.76 %). A total of 18 patients (24.3 %) underwent wedge resection (WR); 39 patients (52.7 %) underwent segmental resection (SR); and 17 cases (23 %) underwent pancreaticoduodenectomy (PD). The median follow-up was 56 months (1–159 months); 19 patients (25.68 %) experienced tumor recurrence or metastasis, and 14 cases (18.92 %) died. The 1-, 3-, and 5-year recurrence/metastasis-free survival rates were 93.9, 73.7, and 69 %, respectively. The 1-, 3- and 5-year OS were 100, 92.5, and 86 %, respectively. The recurrence/metastasis-free survival rate in the PD group within 5 years was lower than that in the WR group (P = 0.047), but was not different from that in the SR group (P = 0.060). No statistically significant difference was found among the three operation types (P = 0.294).ConclusionsDGIST patients have favorable prognosis after complete tumor removal, and surgical procedures should be determined by the DGIST tumor location and size.

BackgroundGastric neuroendocrine neoplasms (G-NENs) are uncommon, and data on their management is limited. We here investigated the clinicopathological characteristics, surgical and survival outcomes in G-NENs among Chinese. Moreover, we will discuss their prognostic value.MethodsFrom existing databases of the West China Hospital, we retrospectively identified 135 consecutive patients who were surgically treated and pathologically diagnosed as G-NENs from January 2009 to August 2015.ResultsThis entire cohort comprised 98 males and 37 females, with a median age of 60 years. Twenty-five patients underwent endoscopic resection, while 110 patients underwent open/laparoscopic surgery. Thirty-nine patients had neuroendocrine tumor G1 (NET G1), seven patients had neuroendocrine tumor G2 (NET G2), 69 patients had neuroendocrine carcinoma G3 (NEC G3) and 20 patients had mixed adenoneuroendocrine carcinoma (MANEC). The median survival was not achieved for both NET G1 and NET G2 versus 19 months (range 3–48) for NEC G3 and 10.5 months (range 3–45) for MANEC. The 3-year survival rates for stage I, II, III, and IV were 91.1 %, 78.6 %, 51.1 % and 11.8 %, respectively (P < 0.001). As for the prognostic analysis, both surgical margin and the newly updated World Health Organization (WHO) classification were independent predictors of overall survival (OS).ConclusionsG-NENs are a kind of rare tumors, and patients with NET G3 and MANEC have unfavorable prognosis even surgically treated. Moreover, surgical margin and the new 2010 WHO criteria are closely associated with OS for G-NENs.

Traditional therapeutic methods for skin wounds have many disadvantages, and new wound dressings that can facilitate the healing process are thus urgently needed. Platelet-rich plasma (PRP) contains multiple growth factors (GFs) and shows a significant capacity to heal soft tissue wounds. However, these GFs have a short half-life and deactivate rapidly; we therefore need a sustained delivery system to overcome this shortcoming. In this study, poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA: PLEL) hydrogel was successfully created as delivery vehicle for PRP GFs and was evaluated systematically. PLEL hydrogel was injectable at room temperature and exhibited a smart thermosensitive in situ gel-formation behavior at body temperature. In vitro cell culture showed PRP-loaded PLEL hydrogel (PRP/PLEL) had little cytotoxicity, and promoted EaHy926 proliferation, migration and tube formation; the factor release assay additionally indicated that PLEL realized the controlled release of PRP GFs for as long as 14 days. When employed to treat rodents’ full-thickness skin defects, PRP/PLEL showed a significantly better ability to raise the number of both newly formed and mature blood vessels compared to the control, PLEL and PRP groups. Furthermore, the PRP/PLEL-treated group displayed faster wound closure, better reepithelialization and collagen formation. Taken together, PRP/PLEL provides a promising strategy for promoting angiogenesis and skin wound healing, which extends the potential of this dressing for clinical application.

Background:The choice of anastomosis methods including Billroth I, Billroth II, and Roux-en-Y after a distal gastrectomy is still controversial. The conventional meta-analyses assessing 2 alternative treatments were not powered to compare differences in clinical outcomes. To guide treatment decisions in patients with gastric cancer (GC) after distal gastrectomy, we did a systematic review and network meta-analysis to identify the best reconstruction method.Methods:We systematically searched PubMed, EMBASE, the Cochrane Library for randomized controlled trials comparing the outcomes of Billroth I, Billroth II, or Roux-en-Y reconstruction after distal subtotal gastrectomy for patients with GC, then we performed a direct meta-analysis and Bayesian network meta-analysis to pooled odds ratios (OR) or weighted mean differences (WMD) with 95% credible intervals (CrI) with random effects model. The node-splitting method was used to assess the inconsistency. We estimated the potential ranking probability of treatments by calculating the surface under the cumulative ranking curve for each intervention.Results:Nine studies involving 1161 patient were included in the network meta-analysis. Statistical significance was reached for the comparisons of Roux-en-Y versus Billroth I reconstruction (WMD 37, 95% Crl: 22–51) and Billroth II versus Billroth I reconstruction (WMD 25, 95% Crl: 5.8–43) for operation time; and Roux-en-Y versus Billroth I reconstruction (WMD 26, 95% Crl: 2.1–68) for intraoperative blood loss; and Roux-en-Y versus Billroth I reconstruction (OR 3.4, 95% Crl: 1.1–13) for delayed gastric emptying. Roux-en-Y reconstruction was superior to Billroth I and Billroth II reconstruction in terms of frequency of bile reflux (OR 0.095, 95% Crl: 0.010–0.63; OR 0.064, 95% Crl: 0.0037–0.84, respectively) and the incidence of remnant gastritis (OR 0.33, 95% Crl: 0.16–0.58; OR 0.40, 95% Crl: 0.17–0.92, respectively).Conclusion:Roux-en-Y reconstruction is superior to Billroth I and Billroth II reconstruction in terms of preventing bile reflux and remnant gastritis, Billroth I and Billroth II anastomosis could be considered as the substitute in consideration of technical simplicity. As for postoperative morbidity and the advantage of physiological food passage, Billroth I method is the choice.

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