Use of Chinese Herbal Medicine Therapies in Comprehensive Hospitals in Central China: A Parallel Survey in Cancer Patients and Clinicians

Summary： Chinese herbal medicine （CHM）, as the largest application category of traditional Chinese medicine （TCM）, is widely accepted among cancer patients in China. Herbal slice （HS） and Chinese patent drug （CPD） are commonly used CHM in China. This study aimed to investigate the utilization of CHM among clinicians and cancer patients in central China. Five hundred and twenty-five patients and 165 clinicians in 35 comprehensive hospitals in central China were asked to complete an anonymous questionnaire that was designed to evaluate the use of CHM. The results showed that 90.74% clinicians and 72.24% cancer patients used CHM during cancer treatment. The educational backgrounds of the clinicians and the age, education level, annual income, and cancer stage of the cancer patients were re- lated to use of CHM. More than 90% clinicians and cancer patients had used CPD. Comparatively, the percentage of HS use was 10% lower than that of CPD use among clinicians and cancer patients. More clinicians preferred to use CHM after surgery than cancer patients did （20.41% vs. 5.37%）. Enhancing physical fitness and improving performance status were regarded as the most potential effect of CHM on cancer treatment （85.71% among clinicians and 94.07% among cancer patients）, in comparison with directly killing tumor cells （24.49% among clinicians and 31.36% among patients）. As for refusal rea- sons, imprecise efficacy was the unanimous （100%） reason for clinicians＇ rejection of CHM, and 95.58% patients objected to using CHM also for this reason. Furthermore, the side effects of CHM were more concerned by clinicians than by patients （33.33% vs. 15.81%）. In conclusion, our survey revealed that CHM was popularly accepted by clinicians and cancer patients in central China. The reasons of use and rejection of CHM were different between clinicians and cancer patients.

Effect of Integrated Chinese and Western Medicine Therapy on Severe Hand, Foot and Mouth Disease: A Prospective, Randomized, Controlled Trial

Objective: To evaluate the efficacy and safety of Chinese medicine(CM) plus Western medicine(WM) in the treatment of pediatric patients with severe hand, foot and mouth disease(HFMD) by conducting a prospective, controlled, and randomized trial. Methods: A total of 451 pediatric patients with severe HFMD were randomly assigned to receive WM therapy alone(224 cases, WM therapy group) or CM [Reduning Injection(热毒宁注射液) or Xiyanping Injection(喜炎平注射液)] plus WM therapy(227 cases, CM plus WM therapy group) for 7–10 days, according to a web-based randomization system. The primary outcome was fever clearance time, which was presented as temperature decreased half-life time. The secondary outcomes included the rate of rash/herpes disappearance within 120 h, as well as the rate for cough, runny nose, lethargy and weakness, agitation or irritability, and vomiting clearance within 120 h. The drug-related adverse events were also recorded. Results: The temperature decreased half-life time was 40.4 h in the WM therapy group, significantly longer than 27.2 h in the CM plus WM therapy group(P<0.01). Moreover, the rate for rash/herpes disappearance within 120 h was 43.6%(99/227) in the CM plus WM therapy group, significantly higher than 29.5%(66/224) in the WM therapy group(P<0.01). In addition, the rate for cough, lethargy and weakness, agitation or irritability disappearance within 120 h was 32.6%(74/227) in the CM plus WM therapy group, significantly higher than 19.2%(43/224) in the WM therapy group(P<0.01). No drug-related adverse events were observed during the course of the study. Conclusions: The combined CM and WM therapy achieved a better therapeutic efficacy in treating severe HFMD than the WM therapy alone. Reduning or Xiyanping Injections may become an important complementary therapy to WM for relieving the symptoms of severe HFMD.

The mutational pattern of homologous recombination(HR)-associated genes and its relevance to the immunotherapeutic response in gastric cancer

Objective:Currently,there is an urgent need to identify immunotherapeutic biomarkers to increase the benefit of immune checkpoint inhibitors(ICIs)for patients with gastric cancer(GC).Homologous recombination deficiency(HRD)can modify the tumor immune microenvironment by increasing the presence of tumor-infiltrating lymphocytes and therefore might serve as a biomarker of immunotherapeutic response.We aimed to analyze the mutational pattern of HR-associated genes in Chinese patients with GC and its relevance to the tumor immune profile and clinical immunotherapeutic response.Methods:A panel of 543 cancer-associated genes was used to analyze genomic profiles in a cohort comprising 484 Chinese patients with GC.Correlations between HR gene mutations and tumor immunity or clinical outcomes were identified via bioinformatic analysis using 2 GC genomic datasets(TCGA and MSK-IMPACT).Results:Fifty-one of the 484(10.54%)patients carried at least one somatic mutation in an HR gene;ATM(16/484,3.31%)was among the most frequently mutated HR genes in the Chinese cohort.Mutations in HR genes were associated with elevated tumor mutational burden,enhanced immune activity,and microsatellite instability status.In the MSK-IMPACT cohort comprising 49 patients with stomach adenocarcinoma or gastroesophageal junction adenocarcinoma treated with ICIs,patients with HR-mut GC(n=12)had significantly better overall survival than those with HR-wt GC(n=37)(log-rank test,P<0.05).Conclusions:Our data suggest that detection of somatic mutations in HR genes might aid in identifying patients who might benefit from immune checkpoint blockade therapy.

Study of Candida Albicans Vaginitis Model in Kunming Mice

The model of vaginal candidiasis in Kunming mice was constructed in order to search for the optima construction conditions and provide an economic animal model of Candida albicans (C. albicans) vaginitis. Estrogen benzoate (E2) was given to mice at different concentrations ranging from 0.0 to 0.05 mg/mouse (4 levels) beginning 72 h prior to vaginal inoculation, then mice were in- oculated intravaginally with various concentrations of stationary-phase C. albicans blastoconidia (ATCC90028) (5 levels) in 20 μL of phosphate-buffered saline (PBS) in each E2 level. General state, scores of genital pathology, the hyphae and vaginal fungal burden (CFU) in vaginal lavage fluid, the hydrops rate of uterus and vaginal tissues for pathological section in mice were observed and ob- tained at day 2, 4, 7, 14 and 21 after inoculation. The results showed the infection rate in mice was related to the dosage of E2 and concentration of C. albicans blastoconidia. Additionally there was better cross-effect between the two treated factors. The infection rate was about 80% on the day 4, and could reach 100% on the day 7 until the end of experiment after inoculated intravaginally in groups of E2I3, E2 0.025 mg/mouse injected hypodermically and inoculated intravaginally with 5×104 C. albicans blastoconidia, and large amount of hyphae and blastoconidia could be observe in superfi- cial layer tissue and canal of vaginal by PAS. From the results in our experiment it was concluded that E2I3 was the optima construction condition in kunming mice.

Meta-analysis of subtotal stomach-preserving pancreaticoduodenectomy vs pylorus preserving pancreaticoduodenectomy

AIM: To investigate the differences in outcome following pylorus preserving pancreaticoduodenectomy(PPPD) and subtotal stomach-preserving pancreaticoduodenectomy(SSPPD).METHODS: Major databases including Pub Med(Medline), EMBASE and Science Citation Index Expanded and the Cochrane Central Register of Controlled Trials(CENTRAL) in The Cochrane Library were searched for comparative studies between patients with PPPD and SSPPD published between January 1978 and July 2014. Studies were selected based on specific inclusion and exclusion criteria. The primary outcome was delayed gastric emptying(DGE). Secondary outcomes included operation time, intraoperative blood loss, pancreatic fistula, postoperative hemorrhage, intraabdominal abscess, wound infection, time to starting liquid diet, time to starting solid diet, period of nasogastric intubation, reinsertion of nasogastric tube, mortality and hospital stay. The pooled odds ratios(OR) or weighted mean difference(WMD) with 95% confidence intervals(95%CI) were calculated using either a fixed-effects or random-effects model. RESULTS: Eight comparative studies recruiting 650 patients were analyzed, which include two RCTs, one non-randomized prospective and 5 retrospective trial designs. Patients undergoing SSPPD experienced significantly lower rates of DGE(OR = 2.75; 95%CI: 1.75-4.30, P < 0.00001) and a shorter period of nasogastric intubation(OR = 2.68; 95%CI: 0.77-4.58,P < 0.00001), with a tendency towards shorter time to liquid(WMD = 2.97, 95%CI:-0.46-7.83; P = 0.09) and solid diets(WMD = 3.69, 95%CI:-0.46-7.83; P = 0.08) as well as shorter inpatient stay(WMD = 3.92, 95%CI:-0.37-8.22; P = 0.07), although these latter three did not reach statistical significance. PPPD, however, was associated with less intraoperative blood loss than SSPPD [WMD =-217.70, 95%CI:-429.77-(-5.63); P = 0.04]. There were no differences in other parameters between the two approaches, including operative time(WMD =-5.30, 95%CI:-43.44-32.84; P = 0.79), pancreatic fistula(OR = 0.91; 95%CI: 0.56-1.49; P = 0.70), postoperative hemorrhage(OR = 0.51; 95%CI: 0.15-1.74; P = 0.29), intraabdominal abscess(OR = 1.05; 95%CI: 0.54-2.05; P = 0.89), wound infection(OR = 0.88; 95%CI: 0.39-1.97; P = 0.75), reinsertion of nasogastric tube(OR = 1.90; 95%CI: 0.91-3.97; P = 0.09) and mortality(OR = 0.31; 95%CI: 0.05-2.01; P = 0.22).CONCLUSION: SSPPD may improve intraoperative and short-term postoperative outcomes compared to PPPD, especially DGE. However, these findings need to be further ascertained by well-designed randomized controlled trials.

Inhibition of Xanthine Oxidase Activity by Gnaphalium Affine Extract

Objective To evaluate the inhibitory effect of Gnaphalium affine extracts on xanthine oxidase(XO) activity in vitro and to analyze the mechanism of this effect. Methods In this in vitro study, Kinetic measurements were performed in 4 different inhibitor concentrations and 5 different xanthine concentrations(60, 100, 200, 300, 400 μmol/L). Dixon and Lineweaver-Burk plot analysis were used to determine Ki values and the inhibition mode for the compounds isolated from Gnaphalium affine extract. Results Four potent xanthine oxidase inhibitors were found in 95% ethanolic(v/v) Gnaphalium affine extract. Among them, the f lavone Eupatilin exhibited the strongest inhibitory effect on XO with a inhibition constant(Ki) of 0.37 μmol/L, lower than the Ki of allopurinol(4.56 mol/L), a known synthetic XO inhibitor. Apigenin(Ki of 0.56 μmol/L, a proportion of 0.0053‰ in Gnaphalium affine), luteolin(Ki of 2.63 μmol/L, 0.0032‰ in Gnaphalium affine) and 5-hydroxy-6,7,3',4'-tetramethoxyflavone(Ki of 3.15 μmol/L, 0.0043‰ in Gnaphalium affine) also contributed to the inhibitory effect of Gnaphalium affine extract on XO activity. Conclusions These results suggest that the use of Gnaphalium affine in the treatment of gout could be attributed to its inhibitory effect on XO. This study provides a rational basis for the traditional use of Gnaphalium affine against gout.

Adefovir Dipivoxil plus Chinese Medicine in HBeAg-Positive Chronic Hepatitis B Patients:A Randomized Controlled 48-Week Trial

Objective:To evaluate the effects of a 48-week course of adefovir dipivoxil(ADV)plus Chinese medicine(CM)therapy,namely Tiaogan Jianpi Hexue(调肝健脾和血)and Tiaogan Jiedu Huashi(调肝解毒化湿)fomulae,in hepatitis B e antigen(HBeAg)-positive Chinese patients.Methods:A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group(EG,received ADV plus CM)and control group(CG,received ADV plus CM-placebo)for 48 weeks.The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12,24,36,48,respectively.Secondary endpoints including liver functions(enzymes and bilirubin readings)were evaluated every 4 weeks at the beginning of week 24,36,and 48.Routine blood,urine,and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations.Adverse events(AEs)were documented.Results:The combination therapy demonstrated superior HBeAg loss at 48 weeks,without additional AEs.The full analysis population was 560 and 280 in each group.In the EG,population achieved HBeAg loss on week 12,24,36,and 48 were 25(8.90%),34(12.14%),52(18.57%),and 83(29.64%),respectively;the equivalent numbers in the CG were 20(7.14%),41(14.64%),54(19.29%),and 50(17.86%),respectively.There was a statistically significant difference between two groups on week 48(P<0.01).No additional AEs were found in EG.Subgroup analysis suggested different outcomes among treatment patterns.Conclusion:Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy.The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile(ChiCTR-TRC-11001263).

Surgical Treatment of Poor Grade Middle Cerebral Artery Aneurysms Associated with Large Sylvian Hematomas Following Prophylactic Hinged Craniectomy

The clinical characteristics of patients who presented in poor clinical grade due to ruptured middle cerebral artery aneurysms （MCAAs） associated with large sylvian hematomas （SylH） were ana- lyzed and an ingenious designed prophylactic hinged craniectomy was introduced. Twenty-eight pa- tients were graded into Hunt-Hess grades IV-V and emergency standard micro-neurosurgeries （aneu- rysm clipping, hematoma evacuation and prophylactic hinged craniectomy） were performed, and their clinical data were retrospectively analyzed. 46.43% of the patients reached encouraged favorable out- comes on discharge. The favorable outcome group and the poor outcome group significantly differed in terms of patients＇ anisocoria, Hunt-Hess grade before surgery, extent of the midline shift and time to the surgery after bleeding （P〈0.05）. There were no significant differences in age, sex, volume and location of the hematoma, size of aneurysm between the favorable and poor groups （P〉0.05）. However, ingen- ious designed prophylactic hinged craniectomy efficiently reduced the patients＇ intracranial pressure （ICP） after surgery. It was suggested that preoperative conditions such as Hunt-Hess grading, extent of the midline shift and the occurrence of cerebral hernia affect the prognosis of patients, but time to the surgery after bleeding and prophylactic hinged craniectomy are of significant importance for optimizing the prognosis ofMCAA oatients 19resenting with large SylH.

Association of Serum Dkk-1 Levels with β-catenin in Patients with Postmenopausal Osteoporosis

Wnt signaling plays an important role in the bone development and remodeling. The Wnt antagonist Dkk-1 is a potent inhibitor of bone formation. The aims of this study were firstly to compare the serum Dkk-1 levels in postmenopausal osteoporosis patients with age-matched healthy controls, and secondly, to assess the possible relationship between Dkk-1 and β-catenin, sclerostin, or bone turnover markers [CTX, PINP, N-MID-OT and 25（OH）D] in the setting of postmenopausal osteoporosis. A total of 350 patients with postmenopausal osteoporosis and 150 age-matched healthy controls were enrolled, and the serum levels of Dkk-1, β-catenin, sclerostin, OPG, and RANKL were detected by ELISA, and bone turnover markers [CTX, PINP, N-MID-OT and 25（OH）D] were measured by Roche electrochemiluminescence system in two groups. Serum Dkk-1 levels were significantly higher in postmenopausal osteoporosis group than in control group（P〈0.001）. Univariate analyses revealed that serum Dkk-1 levels were weakly negatively correlated to β-catenin（r=–0.161, P=0.003） and OPG（r=–0.106, P=0.047）, while multiple regression analysis showed a negative correlation between serum Dkk-1 levels with β-catenin（β=–0.165, P=0.009） and BMD（β=–0.139, P=0.027）, and a positive correlation between serum Dkk-1 levels and CTX（β=0.122, P=0.040） in postmenopausal osteoporosis group. No similar correlations ware observed in control group. The results provided evidence for the role of Dkk-1 in bone metabolism and demonstrated the link of Dkk-1 and Wnt/β-catenin in some ways.

Herb-partitioned moxibustion alleviates colon injuries in ulcerative colitis rats

AIM To observe the effect of herb-partitioned moxibustion(HPM) on expression of colonic cytokines in ulcerative colitis(UC) rats.METHODS A UC rat model was established by protein immunization in combination with topical chemical stimulation.Rats in the HPM group(n = 8) received HPM at bilateral Tianshu(ST25) points.The gross injury and pathological scores of the colon were recorded.The expression profile of colonic cytokines was assayed using the protein microarray technique.Specific differential cytokines were selected and verified by ELISA.The corresponding Uni Prot Accessions of the differentially expressed cytokines were retrieved in the Uni Prot database.The pathways involved were analyzed with the help of the KEGG PATHWAY database.The DAVID database was used for functional cluster and pathway analysis.RESULTS HPM improved colon injuries in UC rats,manifested by accelerated repair of ulcers and alleviation of inflammation,and the gross injury and pathological scores both significantly decreased(P < 0.01).Fold change > 1.3 or < 0.77 was taken as the screening standard.There were 77 down-regulated and 9 up-regulated differentially expressed colonic cytokines in the HPM group compared with the model group,and expression of 20 differed significantly(P < 0.05).Twelve of the 20 significantly differentially expressed cytokines [β-catenin,interleukin-1 receptor 6(IL-1 R6),IL-1β,B7-1,nerve growth factor receptor,AMP-activated protein kinase-α1,neuropilin-2,orexin A,adipocyte differentiation-related protein,IL-2,Fas and Fas L] were up-regulated in the model group(n = 3,compared with the normal group) but downregulated in the HPM group(n = 3,compared with the model group).Functional cluster analysis showed that the differentially expressed colonic cytokines in the HPM group regulated apoptosis and protein phosphorylation.KEGG pathway analysis showed that 52 down-regulated and 7 up-regulated differentially expressed colonic cytokines in the HPM group had pathways.The pathways that interacted between the cytokines and their receptors accounted for the largest proportion(28 of the downregulated and 5 of the up-regulated cytokines).CONCLUSION HPM promotes the repair of colon injuries in UC rats,which is related to the regulation of several abnormally expressed cytokines.

Effects of Modified Qing'e Pill(加味青娥丸) on Expression of Adiponectin,Bone Morphogenetic Protein 2 and Coagulation-Related Factors in Patients with Nontraumatic Osteonecrosis of Femoral Head

Objective： To observe the regulation of Chinese herbal medicine, Modified Qing＇e Pill（加味青娥丸, MQEP）, on the expression of adiponectin, bone morphogenetic protein 2（BMP2）, osteoprotegerin（OPG） and other potentially relevant risk factors in patients with nontraumatic osteonecrosis of the femoral head（ONFH）. Methods： A total of 96 patients with nontraumatic ONFH were unequal randomly divided into treatment group（60 cases） and control group（36 cases）. The treatment group were treated with MQEP while the control group were treated with simulated pills. Both groups were given caltrate D. Six months were taken as a treatment course. Patients were followed up every 2 months. The levels of plasma adiponectin, BMP2, OPG, von Willebrand factor（vWF）, von Willebrand factor cleaving protease（vWF-cp）, plasminogen activator inhibitor 1（PAI-1）, tissue plasminogen activator（tPA）, C-reactive protein（CRP）, blood rheology, bone mineral density（BMD） of the femoral head and Harris Hip Score were measured before and after treatment. Results： After 6 months of treatment, compared with the control group, patients in the treatment group had significantly higher adiponectin and BMP2 levels（P〈0.01 and P=0.013, respectively）, lower vWF, PAI-1 and CRP levels（P=0.019, P〈0.01 and P〈0.01, respectively）, and lower blood rheology parameters. BMD of the femoral neck, triangle area and Harris Hip Score in the treatment group were significantly higher than those in the control group. Moreover, plasma adiponectin showed a positive association with BMP2（r=0.231, P=0.003） and a negative association with PAI-1（r=–0.159, P〈0.05）. Conclusions： MQEP may play a protective role against nontraumatic ONFH by increasing the expression of adiponectin, regulating bone metabolism and improving the hypercoagulation state, which may provide an experimental base for its clinical effects.

Influence ofβ-elemene on the secretion of angiotensin II and expression of AT1R in hepatic stellate cells

This study aims to investigate the influence ofβ-elemene on the secretion of angiotensin II(ANG II)and the expression of angiotensin receptor type 1(AT1R)in hepatic stellate cells(HSCs).In vitro,HSC-T6 were cultured for 24 hours and then treated with different doses ofβ-elemene(2.5,5 and 10 mg/L).A control group was also set up.The secretion of ANG II in the supernatant was detected by radioimmunoassay.The mRNA expression of AT1R at 4,12 and 24 h after treatment was detected by reverse transcription-polymerase chain reaction(RT-PCR),respectively.The protein expression of AT1R was detected by western blot.At the 4th h,the ANG II secretion in the supernatant was significantly inhibited by 10 mg/Lβ-elemene compared with the control group(P<0.05),while 5.0 mg/L and 2.5 mg/Lβ-elemene had no inhibitory effect on the secretion of ANG II(P>0.05).At the time point of the 12th h,the secretion of ANG II in the supernatant treated with 10 mg/L and 5.0 mg/Lβ-elemene was significantly lower than the control(P<0.01,P<0.05).Following the treatment with 5.0 mg/L and 2.5 mg/Lβ-elemene for 24 h,significant inhibition of ANG II secretion was observed(P<0.05),but 10 mg/Lβ-elemene had no such effect.β-elemene significantly reduced the amount of AT1R mRNA in HSCs after the treatment for 4,12,and 24 h in a dose-dependent manner.The expression of AT1R protein also decreased after the treatment withβ-elemene for 24 h.β-elemene can inhibit the secretion of ANG II and the gene and protein expression of AT1R,which may be the mechanism by whichβ-elemene prevents the progress of hepaticfibrosis.

Serum sclerostin levels associated with lumbar spine bone mineral density and bone turnover markers in patients with postmenopausal osteoporosis

Background Sclerostin, expressed exclusively by osteocytes, is a negative regulator of bone formation. To gain insights into the action of sclerostin in postmenopausal osteoporosis, we evaluated serum sclerostin levels in postmenopausal women and investigated its possible associations with bone turnover markers in patients with postmenopausal osteoporosis. Methods We detected serum sclerostin, and measured lumbar spine bone mineral density in 650 Chinese postmenopausal women. We also assessed serum levels of 13-isomerized C-terminal crosslinking of type I collagen, intact N-terminal propeptide of type I collagen, N-mid fragment of osteocalcin, 25-hydroxyvitamin D, and estradiol. Results Serum sclerostin levels were lower in postmenopausal osteoporotic women compared with non-osteoporotic postmenopausal women （（38.79＋7.43） vs. （52.86＋6.69） pmol/L, P 〈0.001）. Serum sclerostin was positively correlated with lumbar spine bone mineral density （r=0.391, P 〈0.001） and weakly negatively correlated with [3-isomerized C-terminal crosslinking of type I collagen, intact N-terminal propeptide of type I collagen, N-mid fragment of osteocalcin （t= -0.225, P 〈0.001; r= -0.091, P=0.046; r= -0.108, P=0.018; respectively） in postmenopausal osteoporosis. There was no significant association of serum sclerostin with age, body mass index, 25-hydroxyvitamin D, and estradiol （r= -0.004, P=0.926; r=0.067, P=0.143; r=0.063, P=0.165; r= -0.045, P=0.324; respectively）.Conclusion Sclerostin may be involved in the pathogenesis of postmenopausal osteoporosis and may play a role in bone turnover.