BMP2-ERK-ATF4 Axis-Based 6-methoxybenzofuran Compound I-9 Acts as Candidate Drug for Bone Formation and Anti-Osteoporosis.

As the global population ages, the number of patients with osteoporosis is rapidly rising. The existing first-line clinical drugs are bone resorption inhibitors that have difficulty restoring the bone mass of elderly patients to the safe range. The range and period of use of existing peptides and monoclonal antibodies are limited, and small-molecule bone formation-promoting drugs are urgently required. We established an I-9 synthesis route with high yield, simple operation, and low cost that was suitable for future large-scale production. I-9 administration promoted bone formation and increased bone mass in mice with low bone mass in an aged C57 mouse model. Our findings revealed a hitherto undescribed pathway involving the BMP2-ERK-ATF4 axis that promotes osteoblast differentiation; I-9 has favorable biosafety in mice. This study systematically investigated the efficacy, safety, and mechanism of I-9 for treating osteoporosis and positions this drug for preclinical research in the future. Thus, this study has promoted the development of small-molecule bone-promoting drugs.

Design and synthesis of dabigatran etexilate derivatives with inhibiting thrombin activity for hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.

Nestin overexpression reduces the sensitivity of gastric cancer cells to trastuzumab.

Background: Trastuzumab (TRA) shows significant efficacy in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). While TRA can help treat HER2-positive breast cancer, TRA resistance is a key clinical challenge. Nestin reportedly regulates the cellular redox homeostasis in lung cancer. This study aimed at identifying the functions of Nestin on the TRA sensitivity of HER2-positive GC cells. Methods: Real-time polymerase chain reaction (PCR) and Western blotting (WB) were performed to explore the association between the mRNA and protein expression profiles, respectively, of Nestin and the Keap1-Nrf2 pathway. The influence of Nestin overexpression on the in vitro sensitivity of GC cells to TRA was explored by Cell Counting Kit-8 (CCK-8) assay, colony formation assay, reactive oxygen species (ROS) detection, and flow cytometry. Results: TRA treatment caused Nestin downregulation in two HER2-positive GC cell lines (MKN45 and NCI-N87). Nestin overexpression reduced the sensitivity of GC cells to TRA. The expression and activity of Nrf2 and relevant downstream antioxidant genes were increased by Nestin overexpression. Nestin overexpression also significantly suppressed TRA-induced apoptosis and ROS generation. In vivo tumor growth experiment with female BALB/c nude mice indicated that Nestin upregulation restored the tumor growth rate which was inhibited by TRA treatment. Conclusions: Collectively, the inhibitory effect of Nestin on the TRA sensitivity of cells to TRA was confirmed in this study. These results imply that the antioxidant Nestin-Nrf2 axis may play a role in the mechanism underlying the resistance of GC cells to TRA.

Comparison of long-term outcomes of stereotactic body radiotherapy (SBRT) via Helical tomotherapy for early-stage lung cancer with or without pathological proof.

BACKGROUND: Stereotactic body radio therapy (SBRT) has emerged as a standard treatment option for nonsurgical candidates with early-stage non-small cell lung cancer (NSCLC). Pathological proof is sometimes difficult to obtain in patients with solitary pulmonary nodules (SPNs). We aimed to compare the clinical outcomes of stereotactic body radiotherapy via helical tomotherapy (HT-SBRT) for early-stage lung cancer patients with or without a pathological diagnosis. METHODS: Between June 2011 and December 2016, we treated 119 lung cancer patients with HT-SBRT, including 55 with a clinical diagnosis and 64 with a pathological diagnosis. Survival outcomes, including local control (LC), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were compared between two cohorts with and without a pathological diagnosis. RESULTS: The median follow-up for the whole group was 69 months. Patients with a clinical diagnosis were significantly older (p = 0.002). No significant differences were observed between the clinical and pathological diagnosis cohorts in terms of the long-term outcome, with 5-year LC, PFS, CSS, and OS of 87% versus 83% (p = 0.58), 48% versus 45% (p = 0.82), 87% versus 84% (p = 0.65), and 60% versus 63% (p = 0.79), respectively. Recurrence patterns and toxicity were also similar. CONCLUSIONS: Empiric SBRT appears to be a safe and effective treatment option in a multidisciplinary setting when patients with SPNs highly suggestive of malignancy are unable/refuse to obtain a definitive pathological diagnosis.

Pre-procedure oral administration of pronase improves efficacy of lugol chromoendoscopy in esophageal squamous cell carcinoma screening: a prospective, double-blinded, randomized, controlled trial.

BACKGROUND AND AIMS: Chromoendoscopy with Lugol's staining is used to screen for early esophageal squamous cell carcinoma (ESCC). Its efficacy is greatly limited by unstandardized defoaming preparation. This study aimed to confirm whether pre-procedure oral administration of pronase could improve the diagnostic performance of Lugol chromoendoscopy in high-risk patients being screened for early ESCC. METHODS: A total of 955 patients at-risk were prospectively recruited for screening for ESCC. Patients were randomly assigned (1:1) to groups with or without (control group) pronase administration. Endoscopic diagnosis of early ESCC was based on the presence of pink-color sign in Lugol's unstained area, and a biopsy was routinely conducted if the Lugol's unstained lesion was larger than 0.5 cm. The early cancer detection rate was used as the primary endpoint. RESULTS: Pre-procedure oral administration of pronase improved mucosal visibility during Lugol chromoendoscopy (P = 0.008). There were no differences in the number of Lugol's unstained lesions between the 2 groups (23.27% [111/477] vs. 25.11% [120/478], P = 0.508). Meaningfully, the detection rate of ESCC (confirmed by histopathology) was significantly higher in the pronase group than in the control group (27.03% [30/111] vs. 17.50% [21/120], P = 0.041), as well as the detection rate of lesions with pink-color sign during chromoendoscopy (35.14% [39/111] vs. 13.33% [16/120], P < 0.001). The diagnostic performance of Lugol chromoendoscopy had improved with the use of pronase (area under the curve = 0.85 vs. 0.69, P = 0.019), accompanied by an increased sensitivity (86.67% vs. 47.62%, P = 0.004). There was no difference in the adverse events between the 2 groups (P = 0.793). CONCLUSIONS: Pre-procedure oral administration of pronase significantly increased the detection rate of early ESCC and optimized the diagnostic performance of Lugol chromoendoscopy, which should be recommended during routine endoscopic screening for early ESCC in high-risk patients. TRIAL REGISTRATION: Pronase improves efficacy of Lugol chromoendoscopy screening on esophageal cancerous lesions (NCT02030769).

Morbidity and Mortality of Patients Who Underwent Minimally Invasive Esophagectomy After Neoadjuvant Chemoradiotherapy vs Neoadjuvant Chemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial.

Importance: Safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) vs neoadjuvant chemotherapy (nCT) for treatment of locally advanced esophageal squamous cell carcinoma (ESCC) remain uncertain given lack of high-level clinical evidence. Objective: To compare safety and long-term survival of nCRT followed by minimally invasive esophagectomy (MIE) with that of nCT followed by MIE for patients with locally advanced ESCC. Design, Setting, and Participants: A prospective, multicenter, open-label, randomized clinical trial that compared safety and efficacy of nCRT vs nCT followed by MIE for patients with locally advanced ESCC. From January 1, 2017, to December 31, 2018, 264 patients with ESCC of clinical stages from cT3 to T4aN0 to 1M0 were enrolled. Analysis was performed on an intention-to-treat basis from January 1, 2017, to August 30, 2020. Interventions: Eligible patients were randomized to the nCRT group (n = 132) or the nCT group (n = 132) by a computer-generated random system. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while 40 Gy of concurrent radiotherapy was added for the nCRT group. At about 6 weeks after neoadjuvant therapy, MIE via thoracoscopy and laparoscopy was performed for the patients in both groups. Main Outcomes and Measures: The primary outcome was 3-year overall survival. Secondary outcomes included postoperative complications, mortality, postoperative pathologic outcome, recurrence-free survival time, and quality of life. Results: Among 264 patients (226 men [85.6%]; mean [SD] age, 61.4 [6.8] years), postoperative morbidity was 47.4% in the nCRT group (54 of 114) and 42.6% in the nCT group (46 of 108), with no significant difference between groups (difference, 4.8%; 95% CI, -8.2% to 17.5%; P = .48). Distribution of the severity of complications was similar between the 2 groups based on Clavien-Dindo classification. The 90-day perioperative mortality rate was 3.5% for the nCRT group (4 of 114) and 2.8% for the nCT group (3 of 108) (P = .94). The R0 resection rates were similar between groups (109 of 112 [97.3%] vs 100 of 104 [96.2%]; P = .92). However, patients in the nCRT group had a higher pathologic complete response (residual tumor, 0%) rate (40 of 112 [35.7%] vs 4 of 104 [3.8%]; P < .001) and a higher rate of negative lymph nodes (ypN0, 74 of 112 [66.1%] vs 48 of 104 [46.2%]; P = .03) than those in the nCT group. One-year overall survival using intention-to-treat analysis was 87.1% in the nCRT group (115 of 132) and 82.6% in the nCT group (109 of 132) (P = .30). Furthermore, deaths caused by tumor progression or recurrence were significantly less in the nCRT group than in the nCT group (9 of 132 [6.8%] vs 19 of 132 [14.4%]; P = .046); however, deaths from nontumor causes were similar (8 of 132 [6.1%] vs 4 of 132 [3.0%]; P = .24). Conclusions and Relevance: Initial results of the trial showed that nCRT followed by MIE has similar safety to and better histopathologic outcome than nCT followed by MIE for treatment of locally advanced ESCC. Trial Registration: ClinicalTrials.gov Identifier: NCT03001596.

Residual tumor characteristics of esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy.

OBJECTIVE: The study was to investigate the characteristics of residual tumors of esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy. METHODS: The resection specimens of 187 patients undergoing surgery after neoadjuvant chemoradiotherapy in Zhongshan Hospital of Fudan University were reevaluated. Tumor regression grade determined by residual tumor ratios was scored for each specific layer of the esophageal wall and all removed lymph nodes for 4 grades as tumor regression grade 1, 0% residual tumors, tumor regression grade 2, less than 10%; tumor regression grade 3, 10% to 50%; tumor regression grade 4, greater than 50%. The pretreatment pathologic tumor stage and pretreatment pathologic lymph node stage before neoadjuvant chemoradiotherapy were recorded reflecting the original depth of primary tumor and number of originally involved lymph nodes, respectively. According to regression directionality, regression pattern was classified into 4 categories as type I: regression toward the lumen, type II: regression toward the invasive front, type III: concentric regression, and type IV: scattered regression. Statistical analyses were performed using Mann-Whitney, chi-square, Cochran Q tests, and Kendall τ-b coefficient, appropriately. RESULTS: A total of 138 patients have residual tumors, and 97 patients (70.3%), 100 patients (72.5%), 89 patients (64.5%), 63 patients (45.7%), and 68 patients (49.3%) have malignant cells in mucosa, submucosa, muscularis propria, adventitia/surrounding stroma, and lymph nodes, respectively. A total of 115 patients (83.3%) had residual tumors in the mucosa or submucosa, but 63 (54.8%) were graded as tumor regression grade 2 with small amounts of tumors in these 2 layers, 9 patients (6.5%) had residual tumors only in the deep 2 layers, and 14 patients (10.1%) had residual tumors only in lymph nodes. Overall, 86 patients (62.7%) with residual tumors are difficult to identify via present techniques. In patients with tumors that involved all esophageal layers before neoadjuvant chemoradiotherapy, only muscularis propria contained residual tumors significantly more frequently than the adventitia/surrounding stroma (P < .001). The random type IV and nonrandom regression patterns of type I to III were comparable with 48.9% and 51.1%, respectively. In patients with positive lymph node before neoadjuvant chemoradiotherapy, only a small portion of patients (29.2%, 28/96) achieved ypN0 status (nodes pathological complete response), even worse than the primary lesions (33.6%, 63/187) in esophageal squamous cell carcinoma. CONCLUSIONS: The small amount of viable tumor cells in the superficial layers, low pathological complete response rate of lymph nodes, and diverse regression patterns lead to difficulty of detecting residual tumors in esophageal squamous cell carcinoma.

Clinical efficacy of TACE combined with Apatinib in the treatment of advanced hepatocellular carcinoma.

PURPOSE: To explore the therapeutic efficacy and clinical safety of transcatheter arterial chemoembolization (TACE) combined with Apatinib in patients with advanced hepatocellular carcinoma (HCC). METHODS: 88 patients with advanced HCC admitted to our hospital from March 2015 to March 2016 were randomly assigned into group A (TACE) or B (TACE combined with Apatinib). Therapeutic efficacy and adverse events were recorded by follow-up data every three months after treatment. Disease control rate (DCR) and objective response rate (ORR) in both groups were calculated based on 18-month follow-up records. RESULTS: Nine months after treatment, DCR and ORR in group A were 81.82% and 36.36%, respectively, and 95.45% and 63.64% in group B. Disease-free survival (DFS) in group A and B was 11.15 and 16.5 months, respectively. No significant differences in the adverse event incidence (fever, abdominal pain, nausea and vomiting) after embolization were found between the two groups (p>0.05). The incidence of hypertension, hand-foot syndrome, and proteinuria in group B was significantly higher than those in group A (p<0.05). Adverse events were all alleviated after symptomatic treatment. CONCLUSIONS: The therapeutic efficacy of TACE combined with Apatinib in HCC treatment is higher compared to TACE alone, which may be related to the inhibition of tumor angiogenesis. TACE combined with Apatinib can improve the prognosis and prolong the overall survival (OS) of HCC patients.

[Research of relationship between antiviral efficacy on chronic hepatitis C and the application time and dose of ribavirin].

OBJECTIVE: To perform a preliminarily study on the relationship between the duration and dosage of ribavirin treatment and its antiviral effect against chronic hepatitis C. METHODS: A total of 69 patients with chronic hepatitis C whose hemogloblin (HGB) level had decreased to 100 g/L were divided into two groups for receiving a reduced dosage of ribavirin when their HGB level fell to less than or equal to 100 g/L or for withdrawal of the ribavirin treatment when their HGB level fell to less than or equal to 80 g/L (restricted group), or for receiving a reduced dosage when the HGB level fell to less than or equal to 80 g/L or for withdrawal of the ribavirin treatment when the HGB level fell below less than or equal to 60 g/L (adjusted group).The rates of sustained virological response (SVR), relapse, and incidence of adverse effects were statistically compared between the two groups. RESULTS: The adjusted group had a significantly higher SVR rate than the restricted group (91.17% vs.74.29%, P = 0.049). At the 2-year follow-up after treatment withdrawal, there were significantly less cases of relapse in the adjusted group than in the restricted group (23.07% vs.6.45%, P = 0.038).The adjusted group had lower incidence rates of severe anemia and cardiovascular events but there was no significant difference from these rates in the restricted group (P more than 0.05).Subgroup analysis of the adjusted group showed that the patients with HCV-RNA baseline level of less than 5 lg copy/ml had a significantly higher SVR rate than the patients with HCV-RNA baseline level of more than 5 lg copy/ml (100% vs.76.92%, P = 0.021), and that the patients infected with non genotype-1 had a significantly higher SVR rate than patients infected with genotype-1 (100% vs.70.00%, P = 0.005). CONCLUSION: When patients with chronic hepatitis C develop anemia during the course of anti-HCV ribavirin therapy with Peg-IFNat2a, adjustment of the ribavirin treatment duration and dosage can increase the likelihood of achieving and sustaining SVR and decrease the rate of relapse; these treatment adjustments are not associated with changes in severe adverse effects.The adjustment approach, however, shows more benefit for patients with lower viral load and non genotype-1 infection.

Observation on therapeutic efficacy of ursodeoxycholic acid in Chinese patients with primary biliary cirrhosis: a 2-year follow-up study.

The efficacy of ursodeoxycholic acid (UDCA) on long-term outcome of primary biliary cirrhosis (PBC) has been less documented in Chinese cohort. We aimed to assess the therapeutic effect of UDCA on Chinese patients with PBC. In the present study, 67 patients with PBC were treated with UDCA (13-15 mg·kg(-1)·day(-1)) and followed up for 2 years to evaluate the changes of symptoms, laboratory values and histological features. As the results indicated, fatigue and pruritus were obviously improved by UDCA, particularly in patients with mild or moderate symptoms. The alkaline phosphatase and γ-glutamyl transpetidase levels significantly declined at year 2 comparing to baseline values, with the most profound effects achieved in patients at stage 2. The levels of alanine aminotransferase and aspartate aminotransferase significantly decreased whereas serum bilirubin and immunoglobulin M levels exhibited no significant change. Histological feature was stable in patients at stages 1-2 but still progressed in patients at stages 3-4. The biochemical response of patients at stage 2 was much better than that of patients at stages 3-4. These data suggest that, when treated in earlier stage, patients in long-term administration of UDCA can gain favorable results not only on symptoms and biochemical responses but also on histology. It is also indicated that later histological stage, bad biochemical response and severe symptom may be indicators of poor prognosis for UDCA therapy.

[Observation on therapeutic alliance with UDCA and glucocorticoids in AIH-PBC overlap syndrome].

OBJECTIVE: To observe the efficacy of ursodeoxycholic acid (UDCA) combined with glucocorticoids in the treatment of autoimmune hepatitis-primary biliary cirrhosis (AIH-PBC) overlap syndrome. METHODS: 19 patients with AIH-PBC overlap syndrome were divided randomly into two groups: initiate combined group and initiate UDCA-monotherapy group. Biochemical responses and pathological features before and after treatment were analyzed retrospectively with student's t test, Wilcoxon rank sum test and Fisher's exact method. RESULTS: In the initiate combination group, biochemical responses in terms of AIH features (ALT decline to normal, IgG is less than or equal to 16 g/L) and PBC features (ALP decline ≥ 40% or to normal) were achieved. In UDCA-monotherapy group, no statistical difference existed in biochemical responses before adding glucocorticoids, whereas the levels of ALT, AST, GLB and IgG decreased significantly when combined with glucocorticoids. No statistical difference of rates of biochemical responses eixted between the two groups, whereas variance could be seen in different pathological stages. Alleviation of inflammatory infiltration after therapy appeared in 3 patients. CONCLUSION: Combination therapy of UDCA with glucocorticoids could be suitable for AIH-PBC overlap syndrome. Early treatment is of benefit for achieving better biochemical response and pathological improvement.

[Comparison between two diagnostic criteria for PBC-AIH overlap syndrome].

Not Abstract.

[A two-year follow-up study on the efficacy of ursodeoxycholic acid on primary biliary cirrhosis in different stages].

OBJECTIVE: To assess the therapeutic effect of primary biliary cirrhosis(PBC) in different stages with ursodeoxycholic acid (UDCA). METHODS: 91 patients with PBC were divided into 4 periods based on levels of liver test and symptoms. Clinical manifestations, biochemical changes and pathological changes were observed for 2 years on UDCA therapy. RESULTS: The levels of alkaline phosphatase (ALP) and glutamyltranspetidase (GGT) at the second PBC period were declined by 51.9% and 67.3% respectively after a 6-month UDCA therapy. The biochemical responses were 81.25% (Paris criteria) and 93.75% (Barcelona criteria). The levels of ALP and GGT at the third PBC period were declined by 48.8% and 46.6% after 6 months of UDCA therapy, and the biochemical responses were 36.84% (Paris criteria) and 57.89% (Barcelona criteria). Symptoms like fatigue, pruritus and jaundice after UDCA therapy were better than before. Same results also appeared at the fourth period. 11 patients in different periods underwent pathological examinations before and after UDCA therapy and no progression found in the first and the second periods, however difference found in the third and the fourth periods with the lymphocyte infiltration was less than before UDCA treatment. CONCLUSION: Good biochemical responds appear in patients at the second, third and forth periods after UDCA therapy, in which the second period is best. Symptoms could be improved after UDCA treatment. Early UDCA therapy is benefit for slowing down the progression of liver pathology.