A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron in vivo

The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.

Correlation analysis between abundance of K-ras mutation in plasma free DNA and its correlation with clinical outcome and prognosis in patients with metastatic colorectal cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To detect K-ras gene mutations in plasma free DNA by peptide nucleic acid clamp PCR assay (PNA-PCR) and nested primer PCR, and to analyze the correlation between K-ras mutations and prognosis in patients with metastatic colorectal cancer (mCRC).</p><p><b>METHODS</b>Peripheral blood was collected and free DNA was extracted from plasma in 106 patients with mCRC. Nested primer PCR and PNA-PCR were used to detect K-ras gene mutation in the plasma free DNA. The patients were divided into three groups by K-ras status: wild-type group (wild-type determined by both methods), low mutation group (mutation by PNA-PCR method, wild-type by nested primer PCR method) and high mutation group (mutation by two methods). The correlation between K-ras mutations and prognosis was analyzed.</p><p><b>RESULTS</b>The mutation rate of K-ras in tumor tissues of the 106 patients was 40.6%. The Mutation rate of K-ras in plasma free DNA detected by PNA-PCR was 31.1%, significantly higher than that of 15.1% detected by nested primer PCR (P = 0.006). The consistent rate of the K-ras status in plasma free DNA detected by PNA-PCR and that in tumor tissue detected by traditional method was up to 83.0%. The median overall survival (OS) of patients of the wild type, low mutation and high mutation groups was 23.5 months, 17.3 months and 13.9 months, respectively (P = 0.002). The median progression-free survival (PFS) of the K-ras wild-type, low mutation and high mutation groups with first-line chemotherapy was 6.8 months, 6.1 months and 3.2 months, respectively (P = 0.002), and the median OS of them were 23.0 months, 15.5 months and 13.9 months, respectively (P = 0.036). The overall response rate (ORR) was improved in the K-ras wide-type patients who received cetuximab combined with chemotherapy as first-line therapy (75.0% vs. 23.4%, P = 0.058). Cetuximab combined with in second-line therapy chemotherapy led to a significant improvement in disease control rate (DCR) ( 100% vs. 35.7%, P < 0.001) as compared with those of chemotherapy alone. COX regression model showed that K-ras status detected by PNA-PCR, ECOG PS, number of surgery and initially metastatic site were independent factors for prognosis.</p><p><b>CONCLUSIONS</b>PNA-PCR for the detection of K-ras mutation in plasma free DNA can be used to substitute the traditional method for detection of K-ras mutation in tumor tissues. The abundance of K-ras mutation in plasma free DNA is an independent prognostic factor for patients with metastatic colorectal cancer.</p>

Resveratrol induces apoptosis and autophagy in T-cell acute lymphoblastic leukemia cells by inhibiting Akt/mTOR and activating p38-MAPK / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia (T-ALL) cells and potential molecular mechanisms.</p><p><b>METHODS</b>The anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTT test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK.</p><p><b>RESULTS</b>Resveratrol inhibited the proliferation and induced apoptosis and autophagy in T-ALL cells in a dose and time-dependent manner. It also induced cell cycle arrest at G0/G1 phase via up regulating cyclin-dependent kinase (CDK) inhibitors p21 and p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins (Mcl-1 and Bcl-2) and increased the expression of proapoptotic proteins (Bax, Bim, and Bad), and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-II/LC3-I and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced.</p><p><b>CONCLUSION</b>Our findings have suggested that resveratrol induces cell cycle arrest, apoptosis, and autophagy in T-ALL cells through inhibiting Akt/mTOR/p70S6K/4E-BP1 and activating p38-MAPK signaling pathways. Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol. Therefore, the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.</p>

Analysis of therapeutic effect and prognosis in patients with metastatic colorectal cancer and different K-ras status / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To evaluate the correlation of clinical effect and prognosis between patients with metastatic colorectal cancer (mCRC) and different K-ras status.</p><p><b>METHODS</b>The clinical characteristics, chemotherapeutic regimens and survival of 153 mCRC patients with different K-ras status were analyzed retrospectively.</p><p><b>RESULTS</b>The median overall survival (OS) in patients without K-ras mutation were 31.7 months, significantly longer than 21.3 months in the patients with K-ras mutation (P = 0.037). The median progression-free survival (PFS) and OS in patients who received chemotherapy followed by anti-EGFR antibody treatment were 11.5 and 39.3 months, respectively, significantly longer as compared with the PFS and OS in those received chemotherapy in combination with anti-EGFR antibody concomitantly (5.7, P = 0.02, and 28.7 months, P = 0.034, respectively).</p><p><b>CONCLUSIONS</b>K-ras status is a prognostic biomarker for mCRC patients treated with anti-EGFR antibody. The combination settings of anti-EGFR in combination with chemotherapy may improve survival of mCRC patients with wild-type K-ras status.</p>

Clinical analysis of the current treatment status of gastric cancer in 636 patients / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To evaluate the current clinical treatment status of gastric cancer in China.</p><p><b>METHODS</b>A retrospective analysis of clinicopathological characteristics of 636 patients with gastric cancer was conducted. Tumor response was evaluated using RECIST version 1.1 criteria.</p><p><b>RESULTS</b>Six hundred and thirty-six patients were included in this retrospective cohort: 479 men and 157 women. The median age was 57 years (14 to 86). The tumor site was: proximal (41.4%), distal (46.4%) or unknown (12.2%). The histology was: adenocarcinoma (85.8%), signet ring cell carcinoma (6.9%), or other and unknown (7.2%). The differentiation of the adenocarcinomas was: well differentiated (31.0%), moderately differentiated (13.4%), poorly differentiated (37.0%), or unknown (18.7%). The pTNM stage was: 0 (0.3%), I (3.6%), II (10.1%), III (36.8%), IV (45.6%), or unknown (3.6%). In 284 patients who underwent radical resection, the ratio of examined ten and/or more lymph nodes was higher in hospitals at or above provincial level than in hospitals at regional level (57.9% vs. 39.6%, P = 0.009). The disease-free survival was longer (21.7 m vs. 14.6 m, P = 0.005), and the overall survival was longer too (52.9 m vs. 33.8 m, P = 0.040). In 205 patients who received adjuvant chemotherapy, the ratio of administered six and/or more cycles chemotherapy was 42.1% vs. 35.2% (P = 0.318), and the disease-free survival was 22.7 m vs. 16.3 m (P = 0.005) between hospitals at or above provincial level and hospitals at regional level. In 387 patients with metastatic or unresectable gastric cancer who received palliative chemotherapy, the overall survival was 11.1 m (95%CI 9.9 - 12.3 m). Among them, 198 patients received second and/or more line chemotherapy, and the overall survival was longer (12.5 m vs. 7.7 m, P < 0.001). Except a longer progression-free survival (10.2 m, P < 0.05) and a longer overall survival (16.9 m, P < 0.05) were corresponded with the regimen containing trastuzumab, no other significant difference was observed among regimens in first line chemotherapy.</p><p><b>CONCLUSION</b>Chinese doctors working in different level hospitals have a different understanding of the treatment standard of gastric cancer, which resulted in different outcomes.</p>

HER-2 expression in advanced gastric cancer and its correlation with clinical features, outcome and prognosis / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To assess the HER-2 status in Chinese advanced gastric cancer patients and explore its correlation with clinical features, treatment response and prognosis.</p><p><b>METHODS</b>A total of 107 patients with advanced gastric cancer treated in our hospital from December 2005 to November 2008 were included in this retrospective analysis. HER-2 status was determined by immunohistochemisty (IHC) and/or fluorescence in situ hybridization (FISH). The correlations of HER-2 status with tumor location, pathology, treatment response and prognosis were analyzed and the efficacy of different chemottherapy regimens was compared.</p><p><b>RESULTS</b>The overall positive rate of HER-2 expression was 14.7% (15/102). The HER-2 status was detected by both methods in 102 patients, and the concordance of the two methods was 66.5%. The tumor site distribution was gastroesophageal junction (GEJ) 28.0%, proximal stomach 19.4%, gastric corpus 16.1%, antrum 26.9% and whole stomach 9.7%, respectively. There was no significant difference of HER-2 status among different tumor sites (P = 0.726), and no significant correlation between HER-2 expression and differentiation (P = 0.110). Among the evaluable 51 patients treated by first-line chemotherapy, the total objective effective rate was 23.5%. The median time-to-progression was 7.47 months, and median overall survival time was 11.07 months. The effective rate was 43.8% in patients who received XP regimen chemotherapy (cisplatin + capecitabine), significantly higher than the 14.3% in patients treated with other regimens (P = 0.033). Their overall survival was 14.17 months and 9.53 months, respectively (P = 0.059). The TTP was 6.63 months in HER-2 positive patients and 7.47 months in HER-2 negative patients, with a non-significant difference (P = 0.510). However, there was a improving tendency in the efficacy and OS, showing a effective rate of 45.5% and 17.5% (P = 0.102) and OS of 14.17 months and 10.63 months, respectively (P = 0.205).</p><p><b>CONCLUSIONS</b>HER-2-positivity rate in Chinese patients with advanced gastric cancer is similar to those reported in the literature. Along with the increasing use of targeted therapy and targeted agents, the efficacy and survival of gastric cancer patients is improving. HER-2-positive patients may benefit from it.</p>

Study on the correlation between induced abortion and reproductive tract infections / 中华流行病学杂志

Objective To explore the correlation between induced abortion and reproductive tract infections (RTIs). Methods On the basis of keeping the representation of cities under study,53 652 fertile women aged 15-49 were surveyed by using a stratified-cluster-random sampling.Investigation and gynecological examination were conducted by two steps - firstly converging at the clinics, and then visiting those households for someone who did not show up at the clinics. Results Among all the 32.0% (n=16 800) women ever having experienced the history of induced abortion,21.1%(n= 11 090) of them had one, 7.6%(n=3976) women had two, and 4.1%(n=1734) women had at least three events. 59.0%(n=30 959) women among our studied samples had ever had RTI,with 30.9% ( n = 16 215 ) of them had only one 20.0% (n = 10 494 ) women had two and 8.1% (n =4250) had three or more RTIs. Data from x2 text and ordinal regression analysis revealed that the rural married women who underwent more induced abortions were more likely to suffer from RTIs,especially cervical infection and PID. Conclusion Our study showed that the rates of induced abortion and reproductive tract infections among married women in Anhui province were both high.Women who underwent induced abortions had a higher prevalence rate of reproductive tract infections.

Evaluation of bevacizumab combined with irinotecan-based regimen as the first-line treatment for patients with metastatic colorectal cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To assess the efficacy and safety of bevacizumab plus irinotecan-based regimen for the first line treatment in metastatic colorectal cancer (mCRC) patients, and to investigate the correlation between serum tumor markers including CEA and CA19-9 and response as well as prognosis.</p><p><b>METHODS</b>From May 2007 to July 2008, 67 previously untreated mCRC patients received treatment of IFL (n = 25), IFL plus Bevacizumab (n = 20) or FOLFIRI (n = 22). The treatment continued until disease progression or unacceptable toxicity. The data were retrospectively analyzed.</p><p><b>RESULTS</b>All patients were evaluable for response, survival and toxicity analysis. The objective response rate of IFL, IFL plus Bevacizumab or FOLFIRI regimen groups was 16.0% (4/25), 35.0% (7/20) and 18.2% (4/22), respectively (χ(2) = 6.026, P = 0.049). The median progression-free survival (PFS) of IFL plus bevacizumab group was 7.5 months, significantly improved as compared with 3.7 months in the IFL group and 4 months in FOLFIRI group (χ(2) = 11.97, P = 0.003). Of all 67 cases, the one-year survival rate was 47.0%, two-year survival rate was 27.0%, and the median overall survival (OS) was 13.0 months, with no significant difference among the three treatment groups (χ(2) = 3.42, P = 0.18). The serum CEA and CA19-9 levels were decreased after treatment, but with no significant difference among the three groups (P > 0.05). The common toxicity profiles of IFL and FOLFIRI regimens were diarrhea and neutropenia, while the toxicity related to bevacizumab was consistent with that documented in previous literature, such as hypertension, hemorrhage, cardiac toxicity and delayed wound healing.</p><p><b>CONCLUSION</b>The addition of bevacizumab to irinotecan-based regimen significantly improves the response rate and PFS in first-line treatment for patients with mCRC and its toxicity is well tolerated.</p>