[Reflections on supervision strategies of new Tibetan drug registration].

Tibetan medicine is an essential part of Chinese medicine and has unique theoretical experience and therapeutic advantages. According to the development principle of inheriting the essence, sticking to the truth, and keeping innovative, the supervision department should give clear and reasonable guidance considering the characteristics of Tibetan medicine, establish a standard system for quality control, clinical verification and evaluation, and accelerate the research and commercialization of new drugs. In view of the needs of drug supply-side reform and the current situation of Tibetan medicine and new pharmaceutical research, we ponder and provide suggestions on the confusion faced by the current supervision of Tibetan drug registration, hoping to contribute to the supervision strategy of Tibetan drug registration and the high-quality development of Tibetan medicine industry.

Reconstruction of paralyzed arm function in patients with hemiplegia through contralateral seventh cervical nerve cross transfer: a multicenter study and real-world practice guidance.

BACKGROUND: A previous randomized controlled trial showed contralateral seventh cervical nerve (CC7) cross transfer to be safe and effective in restoring the arm function of spastic arm paralysis patients in a specified population. Guidance on indications, safety and expected long-term improvements of the surgery are needed for clinical practice. METHODS: This is a retrospective, multicenter, propensity score-matched cohort study. All patients registered between 2013 and 2019 with unilateral spastic arm paralysis over 1 year who were registered at one of five centers in China and South Korea were included. Patients received CC7 cross transfer or rehabilitation treatment in each center. Primary outcome was the change in the upper-extremity Fugl-Meyer (UEFM) score from baseline to 2-year follow-up; larger increase indicated better functional improvements. FINDINGS: The analysis included 425 eligible patients. After propensity score matching, 336 patients who were 1:1 matched into surgery and rehabilitation groups. Compared to previous trial, patient population was expanded on age (< 12 and > 45 years old), duration of disease (< 5 years) and severity of paralysis (severe disabled patients with UEFM < 20 points). In matched patients, the overall increases of UEFM score from preoperative evaluation to 2-year follow-up were 15.14 in the surgery group and 2.35 in the rehabilitation group (difference, 12.79; 95% CI: 12.02-13.56, p < 0.001). This increase was 16.58 at 3-year and 18.42 at 5-year follow-up compared with the surgery group baseline. Subgroup analysis revealed substantial increase on UEFM score in each subgroup of age, duration of disease, severity of paralysis and cause of injury. No severe complication or disabling sequela were reported in the surgery group. INTERPRETATION: This study showed that CC7 cross transfer can provide effective, safe and stable functional improvements in long-term follow-up, and provided evidences for expanding the indications of the surgery to a wider population of patients with hemiplegia.

Importance of applying Mixed Generalized Additive Model (MGAM) as a method for assessing the environmental health impacts: Ambient temperature and Acute Myocardial Infarction (AMI), among elderly in Shanghai, China.

Association between acute myocardial infarction (AMI) morbidity and ambient temperature has been examined with generalized linear model (GLM) or generalized additive model (GAM). However, the effect size by these two methods might be biased due to the autocorrelation of time series data and arbitrary selection of degree of freedom of natural cubic splines. The present study analyzed how the climatic factors affected AMI morbidity for older adults in Shanghai with Mixed generalized additive model (MGAM) that addressed these shortcomings mentioned. Autoregressive random effect was used to model the relationship between AMI and temperature, PM10, week days and time. The degree of freedom of time was chosen based on the seasonal pattern of temperature. The performance of MGAM was compared with GAM on autocorrelation function (ACF), partial autocorrelation function (PACF) and goodness of fit. One-year predictions of AMI counts in 2011 were conducted using MGAM with the moving average. Between 2007 and 2011, MGAM adjusted the autocorrelation of AMI time series and captured the seasonal pattern after choosing the degree of freedom of time at 5. Using MGAM, results were well fitted with data in terms of both internal (R2 = 0.86) and external validity (correlation coefficient = 0.85). The risk of AMI was relatively high in low temperature (Risk ratio = 0.988 (95% CI 0.984, 0.993) for under 12°C) and decreased as temperature increased and speeded up within the temperature zone from 12°C to 26°C (Risk ratio = 0.975 (95% CI 0.971, 0.979), but it become increasing again when it is 26°C although not significantly (Risk ratio = 0.999 (95% CI 0.986, 1.012). MGAM is more appropriate than GAM in the scenario of response variable with autocorrelation and predictors with seasonal variation. The risk of AMI was comparatively higher when temperature was lower than 12°C in Shanghai as a typical representative location of subtropical climate.

Morbidity and Mortality of Laparoscopic vs Open Total Gastrectomy for Clinical Stage I Gastric Cancer: The CLASS02 Multicenter Randomized Clinical Trial.

Importance: The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains uncertain given the lack of high-level clinical evidence. Objective: To compare the safety of LTG for clinical stage I gastric cancer with that of conventional open total gastrectomy (OTG). Design, Setting, and Participants: The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group CLASS02 study was a prospective, multicenter, open-label, noninferiority, randomized clinical trial that compared the safety of LTG vs OTG with lymphadenectomy for patients with clinical stage I gastric cancer. From January 2017 to September 2018, a total of 227 patients were enrolled. Final follow-up was in October 2018. Interventions: Eligible patients were randomized to LTG (n = 113) or OTG (n = 114) by an interactive web response system. Main Outcomes and Measures: The primary outcome was the morbidity and mortality within 30 days following surgeries between LTG and OTG with a noninferiority margin of 10%. The secondary outcomes were recovery courses and postoperative hospital stays. Results: A total of 214 patients were analyzed for morbidity and mortality (105 patients in the LTG group and 109 patients in the OTG group). The mean (SD) age was 59.8 (9.4) years in the LTG group and 59.4 (9.2) years in the OTG group, and most were male (LTG group, 75 of 105 [71.4%]; OTG group, 80 of 109 [73.4%]). The overall morbidity and mortality rates were not significantly different between the groups (rate difference, -1.1%; 95% CI, -11.8% to 9.6%). Intraoperative complications occurred in 3 patients (2.9%) in the LTG group and 4 patients (3.7%) in the OTG group (rate difference, -0.8%; 95% CI, -6.5% to 4.9%). In addition, there was no significant difference in the overall postoperative complication rate of 18.1% in the LTG group and 17.4% in the OTG group (rate difference, 0.7%; 95% CI, -9.6% to 11.0%). One patient in the LTG group died from intra-abdominal bleeding secondary to splenic artery hemorrhage. However, there was no significant difference in mortality between the LTG group and the OTG group (rate difference, 1.0%; 95% CI, -2.5% to 5.2%), and the distribution of complication severity was similar between the 2 groups. Conclusions and Relevance: The results of the CLASS02 trial showed that the safety of LTG with lymphadenectomy by experienced surgeons for clinical stage I gastric cancer was comparable to that of OTG. Trial Registration: ClinicalTrials.gov Identifier: NCT03007550.

Etanercept biosimilar (recombinant human tumor necrosis factor-α receptor II: IgG Fc fusion protein) and methotrexate combination therapy in Chinese patients with moderate-to-severe plaque psoriasis: a multicentre, randomized, double-blind, placebo-controlled trial.

Etanercept biosimilar recombinant human tumour necrosis factor-α receptor II: IgG Fc fusion protein (rhTNFR-Fc, trade name Yisaipu) has shown good efficacy in the treatment of moderate-to-severe plaque psoriasis. To compare the efficacy and safety of rhTNFR-Fc plus methotrexate (MTX) and rhTNFR-Fc plus placebo in Chinese patients with moderate-to-severe plaque psoriasis. In this multicentre, randomized, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned in a 1:1 ratio to receive rhTNFR-Fc plus MTX or rhTNFR-Fc plus placebo. The primary endpoint was the proportion of patients achieving Psoriasis Area and Severity Index improvement of at least 75% (PASI 75) from baseline at week 24. Adverse events (AEs) were recorded to evaluate safety. Efficacy analysis was performed using the intent-to-treat principle. A total of 466 patients were enrolled and randomly received rhTNFR-Fc plus MTX (combination group, n = 233) or rhTNFR-Fc plus placebo (monotherapy group, n = 233). PASI 75 at week 24 was significantly higher in the combination group than in the monotherapy group (81.86% vs. 65.50%, p < 0.001). Similar results were observed in other PASI improvement scores at week 12 [PASI 75, 62.39% vs. 44.54% (p < 0.001); PASI 50, 87.17% vs. 75.55% (p = 0.001); and PASI 90, 34.07% vs. 18.78% (p < 0.001)] and week 24 [PASI 50, 92.48% vs. 85.59% (p = 0.019); and PASI 90, 64.16% vs. 42.36% (p < 0.001)]. Significantly more patients had a static Physicians' Global Assessment of clear or almost clear in the combination group than in the monotherapy group at week 12 (26.46% vs. 12.50%, p < 0.001) and week 24 (62.38% vs. 40.83%, p < 0.001). The most common AEs in the two groups were upper respiratory tract infection and abnormal liver function. The combination therapy of rhTNFR-Fc plus MTX was an effective therapy for moderate-to-severe plaque psoriasis with an acceptable safety and tolerability profile, indicating that it was feasible and well tolerated for patients.

Individual Patient Data Meta-Analysis from 16 Trials for Safety Factors in Cytokine Release Syndrome After CAR-T Therapy in Patients with Non-Hodgkin Lymphoma (NHL) and Acute Lymphoblastic Leukemia.

INTRODUCTION: Chimeric antigen receptor T cells (CAR-T) with anti-CD19 have shown great promise in the treatment of relapsed and refractory non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is the most significant and life-threatening side effect. This individual patient data (IPD) meta-analysis is to investigate the association of severe CRS with CAR-T dose and baseline factors. METHODS: We collected the individual patient-level data of 237 patients with NHL or ALL from 16 published papers. A logistic model was used to analyze the association of severe CRS incidence with CAR-T dose and baseline factors including age and baseline tumor burden. A generalized additive model (GAM) with logit link function was used to estimate the nonlinear response for severe CRS incidence with CAR-T dose and baseline factors. RESULTS: Severe CRS incidence was positively associated with current proposed CAR-T treatment infusion dose at a range of 0.2 × 106-5.0 × 106 T cells per kg of body weight in patients less than or equal to 25 years old. For patients over 25 years old the association was not significant. Significant association between severe CRS incidence and baseline tumor burden was also shown in this study. CONCLUSIONS: Our results provide novel insights that association between CAR-T treatment dose and severe CRS incidence only exists in patients less than or equal to 25 years old. Severe CRS incidence is associated with baseline tumor burden which indicates that tumor burden needs to be controlled with induced chemotherapy before CAR-T treatment.

Sublingual immunotherapy of atopic dermatitis in mite-sensitized patients: a multi-centre, randomized, double-blind, placebo-controlled study.

Allergen-specific immunotherapy is widely used for allergic rhinitis and asthma treatment worldwide. This study explored the efficacy and safety of sublingual immunotherapy (SLIT) with the extracts of Dermatophagoides Farinae (D. farinae Drops) on house dust mites (HDM)-induced atopic dermatitis (AD). 239 patients with HDM-induced AD were recruited and exposure to a multi-centre, randomized, double-blind, and placebo-controlled clinical trials for 36 weeks, which were randomly divided into placebo and sublingual D. farinae Drops groups (high-dose, medium-dose and low-dose), respectively. Statistical analysis was performed in three groups: Full Analysis Set, Per Protocol Set and Safety Set. 48 cases have withdrawn from the study before the end of study. As primary outcomes, significant decreases in scoring atopic dermatitis and total medication score were showed in medium-dose and high-dose D. farinae Drops groups. In the sixth visit, the skin lesion area showed a statistically significant difference between high-dose/medium-dose D. farinae Drops group and placebo group (p < .05). Most adverse events are slight, and no life-threatening adverse drug reaction happened. Our research demonstrates the beneficial effect of SLIT with high or medium dose D. farinae Drops on AD, and the treatment was well tolerated.

The major causes and risk factors of total and cause-specific mortality during 5.4-year follow-up: the Shanghai Changfeng Study.

To investigate the major causes and predictive factors of death in a middle-aged and elderly Chinese population. A total of 6591 residents aged ≥ 45 years from Shanghai Changfeng community were followed up for an average of 5.4 years. The causes of death were coded according to the 10th Revision of International Classification of Diseases. The mortality rate was calculated by person-years of follow up and age-standardized according to the 2010 Chinese census data. Multivariable-adjusted Cox proportional hazards model was performed to investigate the predictors of all-cause and cause-specific mortality. During the total follow-up of 35,739 person-years, 370 deaths were documented (157 from malignant neoplasms, 70 from heart diseases, 68 from cerebrovascular diseases, 75 from other causes). The age-standardized all-cause mortality rate was 798.2 per 100,000 person-years (927.9 among men and 716.7 among women). Results from multivariable analyses showed that aging, diabetes, and osteoporosis at baseline were independent predictors of all-cause mortality, with hazard ratios (HR) of 1.11 (95% CI 1.10-1.13), 1.91 (1.51-2.42), and 1.71 (1.24-2.35), respectively. The population attributable risk percent of diabetes and osteoporosis was 19.7% and 11.7%, respectively. Cigarette smoking was associated with a higher risk of all-cause mortality in men (HR and 95%CI 1.44, 1.01-2.06). In women, diabetes and osteoporosis were related to a higher risk of cardiovascular mortality (3.27, 1.82-5.88 and 1.89, 1.04-3.46, respectively). While in men, osteoporosis was related to a higher risk of malignant neoplasms mortality (2.39, 1.07-5.33). Malignant neoplasms, heart diseases, and cerebrovascular diseases are the leading causes of death. Aging, smoking, underweight, diabetes, and osteoporosis are independent predictors of premature death among middle-aged and elderly Chinese community population. Moreover, there may have been some differences in the causes and predictors of premature death between men and women.

AAA: triple adaptive Bayesian designs for the identification of optimal dose combinations in dual-agent dose finding trials.

We propose a flexible design for the identification of optimal dose combinations in dual-agent dose finding clinical trials. The design is called AAA, standing for three adaptations: adaptive model selection, adaptive dose insertion and adaptive cohort division. The adaptations highlight the need and opportunity for innovation for dual-agent dose finding and are supported by the numerical results presented in the proposed simulation studies. To our knowledge, this is the first design that allows for all three adaptations at the same time. We find that AAA enhances the chance of finding the optimal dose combinations and shortens the trial duration. A clinical trial is being planned to apply the AAA design and a Web tool is being developed for both statisticians and non-statisticians.

Serum ferritin levels are associated with insulin resistance in Chinese men and post-menopausal women: the Shanghai Changfeng study.

Associations between ferritin and insulin sensitivity have been described in recent studies. The possible association showed conflicting results by sex and menopausal status. We aimed to investigate the cross-sectional association of ferritin levels with insulin resistance and ß-cell function. A total of 2518 participants (1033 men, 235 pre-menopausal women and 1250 post-menopausal women) were enrolled from the Changfeng Study. A standard interview was conducted, as well as anthropometric measurements and laboratory analyses, for each participant. The serum ferritin level was measured using electrochemiluminescence immunoassay. Insulin resistance and ß-cell function indices were derived from a homeostasis model assessment. The results showed that the serum ferritin levels were 250·4 (sd 165·2), 94·6 (sd 82·0) and 179·8 (sd 126·6) ng/ml in the men, pre-menopausal and post-menopausal women, respectively. In fully adjusted models (adjusting for age, current smoking, BMI, waist:hip ratio, systolic blood pressure, diastolic blood pressure, TAG, HDL-cholesterol, LDL-cholesterol, log urine albumin:creatinine ratio, leucocytes, alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transpeptidase), serum ferritin concentrations are significantly associated with insulin resistance in men and post-menopausal females, and the null association was observed in pre-menopausal females. Interestingly, an increased ß-cell function associated with higher ferritin was observed in post-menopausal participants, but not in male participants. In conclusion, these results suggested that elevated serum ferritin levels were associated with surrogate measures of insulin resistance among the middle-aged and elderly male and post-menopausal women, but not in pre-menopausal women.

Body mass index and cancer risk among Chinese patients with type 2 diabetes mellitus.

BACKGROUND: Obesity and diabetes are two risk factors for cancer. To evaluate the association of body mass index (BMI) with cancer risk in diabetic patients may improve current understanding of potential mechanisms. METHODS: A retrospective cohort study was conducted in 51,004 newly diagnosed T2DM patients derived from an electronic health record (EHR) database of Minhang district in Shanghai, China. Incident cancer cases and all-cause deaths occurred before September 30, 2015 were identified by linking with the Shanghai Cancer Registry and the Shanghai Vital Statistics. To examine the potential non-linear and linear relationships of BMI and cancer risk, Cox proportional hazard models with and without restricted cubic spline functions were used, respectively. RESULTS: A non-linear association was observed between BMI and overall cancer incidence in men younger than 60 years old (p for non-linearity = 0.009). Compared with those having BMI of 25.0 kg/m2, the cancer risk increased in those with either lower or higher BMI. In women older than 60 years old, linear dose-response relationships were observed between BMI and the risk of both overall cancer and breast cancer. As each unit increase in BMI, the overall cancer risks elevated by 3% (95%CI: 1-5%) and the breast cancer risks increased by 7% (95%CI: 1-13%). No significant association was observed between BMI and other common cancer sites. CONCLUSIONS: Our results show that the effect of BMI on cancer risk in Chinese patients with T2DM may vary by gender, age and cancer subtypes, suggesting different underlying biological mechanisms.

Recent Advances in Drug Development and Regulatory Science in China.

As the second largest pharmaceutical market with a great potential for future growth, China has drawn much attention from the global pharmaceutical community. With an increasing government investment in biomedical research, the domestic biopharmaceutical (biotechnological) companies in China are turning their attention to the development of innovative medicines and targeting the global market. To introduce innovative products to Chinese patients sooner, to improve the efficiency of its review and approval processes, and to harmonize its regulatory science with international standards, the China Food and Drug Administration (CFDA) has initiated a series of major changes to its policies and regulations. This paper presents a snapshot of China's pharmaceutical market, and research and development status, and introduces technical guidelines pertaining to clinical trials and new drug applications. The recent wave of ground-breaking reforms in CFDA's regulatory science is discussed. Examples of clinical trials and new drug applications are provided throughout the discussion.

Modeling the relationship between baseline lactate dehydrogenase and prognosis in patients with extensive-disease small cell lung cancer: a retrospective cohort study.

BACKGROUND: Elevated pretreatment lactate dehydrogenase (LDH) has been reported to be associated with poor survival in small cell lung cancer (SCLC). The present study aimed to investigate the continuous relationship between baseline LDH level and survival in patients with extensive-disease SCLC (ED-SCLC). METHODS: Data were retrospectively collected from Shanghai Health Information Network. Patients primarily diagnosed as ED-SCLC from April 2011 to August 2014 were eligible for our study. Patients' survival status was checked in March 2016. A multivariate Cox proportional hazard model was used to detect the association between baseline serum LDH and overall survival. The corresponding continuous relationship was analyzed by using natural spline functions in the Cox model. RESULTS: A total of 132 eligible ED-SCLC patients were analyzed. Elevated LDH at baseline was associated with poor survival (HR =1.92; 95% CI, 1.29-2.86). An increment of LDH would still raise the risk of death even in abnormal range. Among patients with elevated LDH, those who had relatively higher LDH levels (>370 U/L) would have a poorer prognosis than those with moderately elevated LDH levels (245-370 U/L; median survival time, 114 vs. 274 days; P value of log rank test, 0.007). CONCLUSIONS: LDH is a significant prognostic biomarker for ED-SCLC patients. The interpretation of continuous relationship between LDH and patients' survival can provide more accurate information for clinical practice.

Atomic Layer Co3 O4 Nanosheets: The Key to Knittable Zn-Air Batteries.

Flexible, wearable, and portable energy storage devices with high-energy density are crucial for next-generation electronics. However, the current battery technologies such as lithium ion batteries have limited theoretical energy density. Additionally, battery materials with small scale and high flexibility which could endure the large surface stress are highly required. In this study, a yarn-based 1D Zn-air battery is designed, which employs atomic layer thin Co3 O4 nanosheets as the oxygen reduction reaction/oxygen evolution reaction catalyst. The ultrathin nanosheets are synthesized by a high-yield and facile chemical method and show a thickness of only 1.6 nm, corresponding to few atomic layers. The 1D Zn-air battery shows high cycling stability and high rate capability. The battery is successfully knitted into clothes and it shows high stability during the large deformation and knotting conditions.

Trial of Contralateral Seventh Cervical Nerve Transfer for Spastic Arm Paralysis.

BACKGROUND: Spastic limb paralysis due to injury to a cerebral hemisphere can cause long-term disability. We investigated the effect of grafting the contralateral C7 nerve from the nonparalyzed side to the paralyzed side in patients with spastic arm paralysis due to chronic cerebral injury. METHODS: We randomly assigned 36 patients who had had unilateral arm paralysis for more than 5 years to undergo C7 nerve transfer plus rehabilitation (18 patients) or to undergo rehabilitation alone (18 patients). The primary outcome was the change from baseline to month 12 in the total score on the Fugl-Meyer upper-extremity scale (scores range from 0 to 66, with higher scores indicating better function). Results The mean increase in Fugl-Meyer score in the paralyzed arm was 17.7 in the surgery group and 2.6 in the control group (difference, 15.1; 95% confidence interval, 12.2 to 17.9; P<0.001). With regard to improvements in spasticity as measured on the Modified Ashworth Scale (an assessment of five joints, each scored from 0 to 5, with higher scores indicating more spasticity), the smallest between-group difference was in the thumb, with 6, 9, and 3 patients in the surgery group having a 2-unit improvement, a 1-unit improvement, or no change, respectively, as compared with 1, 6, and 7 patients in the control group (P=0.02). Transcranial magnetic stimulation and functional imaging showed connectivity between the ipsilateral hemisphere and the paralyzed arm. There were no significant differences from baseline to month 12 in power, tactile threshold, or two-point discrimination in the hand on the side of the donor graft. RESULTS: The mean increase in Fugl-Meyer score in the paralyzed arm was 17.7 in the surgery group and 2.6 in the control group (difference, 15.1; 95% confidence interval, 12.2 to 17.9; P<0.001). With regard to improvements in spasticity as measured on the Modified Ashworth Scale (an assessment of five joints, each scored from 0 to 5, with higher scores indicating more spasticity), the smallest between-group difference was in the thumb, with 6, 9, and 3 patients in the surgery group having a 2-unit improvement, a 1-unit improvement, or no change, respectively, as compared with 1, 6, and 7 patients in the control group (P=0.02). Transcranial magnetic stimulation and functional imaging showed connectivity between the ipsilateral hemisphere and the paralyzed arm. There were no significant differences from baseline to month 12 in power, tactile threshold, or two-point discrimination in the hand on the side of the donor graft. CONCLUSIONS: In this single-center trial involving patients who had had unilateral arm paralysis due to chronic cerebral injury for more than 5 years, transfer of the C7 nerve from the nonparalyzed side to the side of the arm that was paralyzed was associated with a greater improvement in function and reduction of spasticity than rehabilitation alone over a period of 12 months. Physiological connectivity developed between the ipsilateral cerebral hemisphere and the paralyzed hand. (Funded by the National Natural Science Foundation of China and others; Chinese Clinical Trial Registry number, 13004466 .).

Corilagin sensitizes epithelial ovarian cancer to chemotherapy by inhibiting Snail­glycolysis pathways.

We identified that corilagin is a major component extracted from a well-known hepatoprotective and antiviral medicinal herb, Phyllanthus niruri L with antitumor activity. Our previous study found that corilagin inhibited the growth of ovarian cancer cells via the TGF-ß/AKT/ERK signaling pathways. Recently, we demonstrated that corilagin enhanced the sensitivity of ovarian cancer cells to chemotherapy. Ovarian cancer cell lines, SKOv3ip, Hey and HO-8910PM-Snail, were treated with different concentrations of corilagin in combination with paclitaxel and carboplatin. Corilagin distinctly enhanced the inhibitory effects of paclitaxel and carboplatin. To understand the mechanisms involved in the chemo-sensitization by corilagin, we performed reverse phase protein array analysis to determine the signaling networks induced by corilagin. We observed that both paclitaxel and carboplatin upregulated the expression levels of several apoptotic and death-related proteins, such as caspase 3, caspase 7 and PDCD4, which were further enhanced when combined with corilagin. Meanwhile, corilagin induced distinct pathways to paclitaxel and carboplatin treatment. We also performed isobaric tags for relative and absolute quantitation proteomics analysis in corilagen-treated ovarian cancer cells. This analysis indicated that corilagin is mainly involved in the glycolysis pathway. Seahorse XF96 extracellular acidification rate analysis confirmed that corilagin inhibited glycolysis by downregulation of CD44 and STAT3. In summary, our observations indicate that corilagin sensitized epithelial ovarian cancer cells to paclitaxel and carboplatin treatment by primarily inhibiting Snail-glycolysis pathways. Corilagin is a herbal medicine with low toxic effects to normal cells, particularly hepatoprotective, and may be an ideal complimentary medicine when combined with highly toxic chemotherapeutic agents.

The Anti-Inflammatory Effects of Invigorating Kidney and Supplementing Qi Chinese Herbal Formulae in Asthma Patients.

BACKGROUND: The theories of Shen-reinforcement and Qi-supplementation are important in asthma treatment based on traditional Chinese medicine theories. Early studies suggested that Invigorating Kidney and Supplementing Qi herbal formulae, Bu Shen Fang Chuan (BSFC) and Bu Shen Yi Qi (BSYQ), conveyed promising results in asthma treatment. However, the efficacy and safety of the formulae need to be further investigated by a randomized double-blind clinical trial. METHODS: 328 eligible patients were randomly sent to BSFC, BSYQ, and placebo group. The two formulae were received as add-on therapy. The primary endpoints were rate of asthma exacerbation and Hamilton Rating Scale for Depression (HAM-D) score. The secondary endpoints included HPA axis function and inflammatory cytokine production profile. All indexes were measured before and after treatment. RESULTS: The primary endpoints were not improved in both groups; however, the depression levels of subgroup patients with HAM-D score > 5 were improved in BSFC group. HPA axis functions and inflammatory cytokines level were also improved by two formulae. The incidences of adverse events were similar among groups. CONCLUSIONS: The two formulae had multiple advantage effects on neuroendocrine-immune system. They are worth used as a replacement therapy in asthma. TRIAL REGISTRATION: This trial is registered with clinical trial number ChiCTR-PRC-09000529.

Assessing the adequacy of lymph node yield for different tumor stages of colon cancer by nodal staging scores.

BACKGROUND: According to the current official guidelines, at least 12 lymph nodes (LNs) are qualified as an adequate sampling for colon cancer patients. However, patients evaluated with less nodes were still common in the United States, and the prevalence of positive nodal disease may be under-estimated because of the false-negative assessment. In this study, we present a statistical model that allows preoperative determination of the minimum number of lymph nodes needed to confirm a node-negative disease with certain confidence. METHODS: Adenocarcinoma colon cancer patients with stage T1-T3, diagnosed between 2004 and 2013, who did not receive neoadjuvant therapies and had at least one lymph node pathologically examined, were extracted from the Surveillance, Epidemiology and End Results (SEER) database. A beta binomial distribution was used to estimate the probability of an occult nodal disease is truly node-negative as a function of total number of LNs examined and T stage. RESULTS: A total of 125,306 patients met study criteria; and 47,788 of those were node-positive. The probability of falsely identifying a patient as node-negative decreased with an increasing number of nodes examined for each stage, and was estimated to be 72% for T1 and T2 patients with a single node examined and 57% for T3 patients with a single node examined. To confirm an occult nodal disease with 90% confidence, 3, 8, and 24 nodes need to be examined for patients from stage T1, T2, and T3, respectively. CONCLUSIONS: The false-negative rate of diagnosed node negative, together with the minimum number of examined nodes for adequate staging, depend preoperatively on the clinical T stage. Predictive tools can recommend a threshold on the minimum number of examined nodes regarding to the favored level of confidence for each T stage.

CMISG1701: a multicenter prospective randomized phase III clinical trial comparing neoadjuvant chemoradiotherapy to neoadjuvant chemotherapy followed by minimally invasive esophagectomy in patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) (NCT03001596).

BACKGROUND: Neoadjuvant chemoradiation is not recommended as an approach for treatment of esophageal squamous cell carcinoma due to its significant postoperative mortality. However, it is assumed the combination of neoadjuvant chemoradiation with minimally invasive esophagectomy (MIE) may reduce postoperative mortality, which can revive preoperative chemoradiation. No randomized controlled studies comparing neoadjuvant chemoradiation plus MIE with neoadjuvant chemotherapy plus MIE have been performed so far. The present trial is initiated to obtain valid information whether neoadjuvant chemoradiation plus MIE yields better survival without worse postoperative morbidity and mortality in the treatment of locally advanced resectable esophageal squamous cell carcinoma(cT3-4aN0-1M0). METHODS/DESIGN: CMISG1701 is a multicenter, prospective, randomized, phase III clinical trial, investigating the safety and efficacy of neoadjuvant chemoradiation plus MIE compared with neoadjuvant chemotherapy plus MIE. Patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) are eligible for the study. A total of 264 patients are randomly assigned to neoadjuvant chemoradiation (arm A) or neoadjuvant chemotherapy (arm B) with a 1:1 allocation ratio. The primary outcome is overall survival assessed with a minimum follow-up of 36 months. Secondary outcomes are progression-free survival, recurrence-free survival, postoperative pathologic stage, treatment-related complications, postoperative mortality as well as quality of life. DISCUSSION: The objective of this trial is to identify the superior protocol with regard to patient survival, treatment morbidity/mortality and quality of life between neoadjuvant chemoradiation plus MIE and neoadjuvant chemotherapy plus MIE. TRIAL REGISTRATION: NCT03001596 (December 17, 2016).

Association of Mortality With the Death of a Sibling in Childhood.

Importance: The death of a close relative is associated with an increased mortality risk among the bereaved, but much less is known about the potential association of the death of a sibling in childhood with mortality in this population. Objective: To examine the association between sibling death in childhood and subsequent mortality risk. Design, Setting, and Participants: This population-based cohort study of 5 005 029 participants evaluated linked national registers in Denmark (January 1, 1973, through December 31, 2009) and Sweden (January 1, 1973, through December 31, 2008). A total of 2 060 354 Danish and 2 944 675 Swedish children who survived the first 6 months of their life were included. We excluded 14 children who died of the same external cause as their siblings within 30 days. Data were analyzed from November 2, 2015, through October 14, 2016. Exposures: Participants were classified as exposed if a sibling died in childhood (age <18 years). Main Outcomes and Measures: Poisson regression was used to estimate mortality rate ratio (MRR) with the exposure as a time-varying variable. Results: Among the 55 818 participants who experienced sibling death in childhood (51.5% male and 48.5% female; median age at loss, 7.0 [interquartile range, 3.3-12.1] years), all-cause mortality risk was increased by 71% (MRR, 1.71; 95% CI, 1.57-1.87) during the follow-up of 37 years. The excess mortality risk was observed for groups with specific causes of death, and the higher MRRs were found when the sibling pairs died of the same cause (death due to disease [MRR, 2.16; 95% CI, 1.87-2.49]; death due to external cause [MRR, 1.91; 95% CI, 1.54-2.37]). The increased mortality risk after sibling death was seen across the follow-up period, regardless of the age at bereavement and the type of death among bereaved siblings, but the magnitude of association was stronger during the first year after sibling death (MRR, 2.51; 95% CI, 1.79-3.54). Higher MRRs were found among sibling pairs with the same sex (MRR, 1.92; 95% CI, 1.70-2.18) and close age (MRR, 1.94; 95% CI, 1.58-2.37). Conclusions and Relevance: Bereavement in childhood because of the death of a sibling was associated with an increased risk for mortality in the short and long term. Health care professionals should be aware of individuals' vulnerability due to sibling death, especially for sibling pairs of close age or the same sex. Social and health care support may help to minimize the potential adverse effects on the bereaved sibling.