Background:To compare the efficacy and safety of monthly administrations of gonadotropin releasing hormone (GnRH) agonists LY01005 and Zoladex ? in Chinese patients with premenopausal breast cancer. Methods:From October 2020 to November 2021, 188 premenopausal breast cancer patients were enrolled in 34 hospitals and randomized 1:1 to receive either LY01005 or Zoladex ? every 28 days for a total of three injections. All patients concomitantly received oral tamoxifen (TAM). The primary efficacy endpoint was cumulative probability of maintaining menopausal level [oestradiol (E2) ≤30 pg/ml] from day 29 to day 85. The second efficacy endpoint included changes in E2, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) compared with the baseline. Pharmacokinetics (PK), pharmacodynamics (PD), and safety were analyzed. The study also evaluated the pharmacokinetic and pharmacodynamic characteristics of LY01005. Results:A total of 188 patients were randomised and 187 patients received either LY01005 or Zoladex ?. Cumulative probabilities of maintaining menopausal level (E2≤30 pg/ml) from day 29 to day 85 were 93.1% for LY01005 and 86.3% for Zoladex ?. The between-group difference was 6.8% (95% CI: -2.3%, 15.9%) and primary efficacy in the LY01005 group was not inferior to that in the Zoladex ? group. Changes in E2, LH, and FSH levels compared with the baseline were equivalent between the two groups (E2: 89.34% to 90.23% vs. 82.11% to 85.02%; LH: 88.89% to 95.52% vs. 89.70% to 97.02%; FSH: 75.36% to 80.85% vs.73.07% to 80.24%, respectively). After three consecutive doses of LY01005, the LH and FSH levels of the subjects showed a transient increase after the first dose, reached a peak on the second day and then started to decrease. The LH and FSH reached a lower level and remained at or below that level until the 85th day. Both treatments were well-tolerated. Conclusion:LY01005 is as effective as Zoladex ? in suppressing E2 to menopausal levels in Chinese patients with premenopausal breast cancer, with a similar safety profile.

Background:To compare the efficacy and safety of monthly administrations of gonadotropin releasing hormone (GnRH) agonists LY01005 and Zoladex ? in Chinese patients with premenopausal breast cancer. Methods:From October 2020 to November 2021, 188 premenopausal breast cancer patients were enrolled in 34 hospitals and randomized 1:1 to receive either LY01005 or Zoladex ? every 28 days for a total of three injections. All patients concomitantly received oral tamoxifen (TAM). The primary efficacy endpoint was cumulative probability of maintaining menopausal level [oestradiol (E2) ≤30 pg/ml] from day 29 to day 85. The second efficacy endpoint included changes in E2, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) compared with the baseline. Pharmacokinetics (PK), pharmacodynamics (PD), and safety were analyzed. The study also evaluated the pharmacokinetic and pharmacodynamic characteristics of LY01005. Results:A total of 188 patients were randomised and 187 patients received either LY01005 or Zoladex ?. Cumulative probabilities of maintaining menopausal level (E2≤30 pg/ml) from day 29 to day 85 were 93.1% for LY01005 and 86.3% for Zoladex ?. The between-group difference was 6.8% (95% CI: -2.3%, 15.9%) and primary efficacy in the LY01005 group was not inferior to that in the Zoladex ? group. Changes in E2, LH, and FSH levels compared with the baseline were equivalent between the two groups (E2: 89.34% to 90.23% vs. 82.11% to 85.02%; LH: 88.89% to 95.52% vs. 89.70% to 97.02%; FSH: 75.36% to 80.85% vs.73.07% to 80.24%, respectively). After three consecutive doses of LY01005, the LH and FSH levels of the subjects showed a transient increase after the first dose, reached a peak on the second day and then started to decrease. The LH and FSH reached a lower level and remained at or below that level until the 85th day. Both treatments were well-tolerated. Conclusion:LY01005 is as effective as Zoladex ? in suppressing E2 to menopausal levels in Chinese patients with premenopausal breast cancer, with a similar safety profile.

Objective:To investigate the synergistic antitumor effect of pyrotinib in combination with 5-fluorouracil(5-Fu)on human epidermal growth factor receptor 2(HER2)positive breast cancer cells and its underlying molecular mechanism. Methods:HER2 positive breast cancer cells were screened by Western blotting.HER2 positive SKBR-3 and BT474 cells were treated with pyrotinib and 5-Fu individually or in combination for the following experiments.MTT assay was used to assess the effect of different drugs on the proliferation of the treated cells,and the combination index(CI)values were calculated using Combidrug software.Colony formation assay was used to evaluate the effect of different drugs on the colony-forming ability of the treated cells.FCM assay was used to analyze the effect of different drugs on the apoptosis rate and cell cycle of the treated cells.Western blotting was used to examine the effect of different drugs on the expression levels of proteins in the proliferation-and apoptosis-related signaling pathways.SKBR-3-cell-based tumor xenograft model was established using BALB/c nude mice.After treatment with pyrotinib and 5-Fu individually or in combination,the growth profiles of the xenograft tumors were recorded and the expression levels of proteins in the proliferation-and apoptosis-related signaling pathways were examined in the tumor tissues. Results:HER2 positive breast cancer cell lines SKBR-3 and BT474 were selected for further experiments after screening.The proliferation SKBR-3 and BT474 cells could be inhibited after treatment with pyrotinib and 5-Fu individually or in combination(all P＜0.05).Compared with pyrotinib or 5-Fu single drug treatment,pyrotinib in combination with 5-Fu had higher inhibition rate on the proliferation of SKBR-3 and BT474 cells with a Cl value of＜1,indicating the synergistic effect of pyrotinib and 5-Fu.In addition,in contrast to pyrotinib or 5-Fu single drug treatment,there was a further decrease in the number of colonies formed,increase in apoptosis rate,and increase in the percentage of G0/G,cells in SKBR-3 and BT474 cells after treatment with pyrotinib in combination with 5-Fu(all P＜0.01).Animal experiment results showed that the growth rate of xenograft tumors in mice treated with pyrotinib in combination with 5-Fu was significantly slower than that of the single-drug treated mice(P＜0.05).Western blotting analysis showed that the expression levels of HER2,HER4,AKT and phosphorylated ERK were significantly decreased after treatment with pyrotinib in combination with 5-Fu both in vitro and in vivo(all P＜0.01),indicative of the blockage of proliferation-related signaling pathways.Meanwhile,analysis of the apoptosis-related proteins revealed a decrease in the expression levels of caspase 3,poly ADP-ribose polymerase(PARP),and Bcl-2(all P＜0.01),while an increase in the expression levels of cleaved-caspase 3,cleaved-PARP,and p21(all P＜0.01). Conclusion:Pyrotinib and 5-Fu had synergistical antitumor effect on HER2 positive breast cancer cells,and the underlying mechanism may be related to the blockage of proliferation-associated signaling pathways and the induction of apoptosis and cell cycle arrest.

Objective:To observe the application effect of the multi-disciplinary team (MDT) process and program supported by WeChat group in the perioperative period of secondary hyperparathyroidism (SHPT) .Methods:A total of 80 SHPT patients who were hospitalized in Hunan Provincial People’s Hospital and Qidong County People’s Hospital from Jul. 2017 to Oct. 2019 were selected and divided into MDT group (40 cases) and control group (40 cases) according to the principle of complete randomization. In MDT group, there were 21 females and 19 males, aged (48.80±9.08) years old, ranging from 26 to 74 years; in the control group, there were 23 females and 17 males, aged (47.90±8.89) years old, ranging from 24 to 74 years. The control group were given a conventional treatment plan, and the MDT group were implemented with the WeChat MDT process on this basis. The perioperative preparation time, operation time, intraoperative blood loss, postoperative extubation time, and continuous full parathyroid were compared between the two groups. The levels of intact parathyroid hormone (iPTH) and blood calcium and phosphorus were compared with the postoperative complications and patient satisfaction in the two groups. The data in this study were analyzed using SPSS 23.0 statistical software.Results:The preoperative preparation time (4.35±1.12) d, operation time (130.00±32.58) min, intraoperative blood loss (15.75±7.89) ml, and postoperative extubation time (3.80±0.82) d in the MDT group were significantly lower than the preoperative preparation time of the control group (6.86±1.85) d, operation time (162.57±41.65) min, intraoperative blood loss (60.75±11.5) ml, postoperative extubation time (5.97±1.25) d ( P<0.05) 1 week after operation, the iPTH (20.86±1.52) pg/ml and blood calcium level (2.23±0.24) mmol/L of the MDT group were significantly lower than those of the control group (103.47±8.27) pg/ml and blood calcium level (2.87±0.21) mmol/L ( P<0.05) , meanwhile the blood phosphorus level of the MDT group (1.52±0.56) mmol/L was significantly higher than the blood phosphorus level of the control group (1.18±0.25) mmol/L ( P<0.05) . The number of complications in the MDT group (20 cases) was significantly lower than the number of complications in the control group (48 cases) ( P<0.05) ; and the satisfaction of treatment in the MDT group (100.00%) was significantly better than that of the control group (80.00%) ( P<0.05) . Conclusion:The WeChat MDT diagnosis and treatment process and treatment plan are safe and effective, which can effectively shorten the operation time, reduce the operation risk, reduce postoperative complications, and increase patient satisfaction. It can be further promoted in the clinic.

[摘 要] 目的：用组织代谢组学方法，探讨甲状腺乳头状癌（papillary thyroid carcinoma, PTC）组织及癌旁组织的代谢差异，寻找PTC的潜在生物标志物，探索PTC的发病机制与治疗策略。方法：收集2018年10月至2020年2月期间湖南省人民医院乳甲外科手术切除的40例PTC患者的癌组织及癌旁组织标本。利用HPLC-MS技术平台对PTC组织及癌旁组织样本的差异性代谢物进行多维统计分析，寻找与PTC相关的异常代谢通路。结果：经PCA、PLS-DA、OPLS-DA分析得知癌组织和癌旁组织的代谢轮廓具有显著性差异。经OPLS-Loading plot分析，结合VIP>1、FC>2，且P<0.05，筛选出76个潜在差异性代谢物。其中亮氨酸、2-褪黑素、香草酸等33种代谢物在PTC组织中表达上调；3-葡萄糖苷、甘油磷脂、磷脂酰胆碱、乳糖等43代谢物在PTC癌组织中表达下调。寻找到与差异性代谢物相关的13条异常代谢通路，如半胱氨酸与蛋氨酸代谢、与甘油磷脂代谢、嘧啶代谢、半乳糖代谢以及丙氨酸、天冬氨酸和谷氨酸代谢、柠檬酸循环等，这些代谢通路可能参与PTC代谢的病理生理过程。ROC曲线下面积大于0.9的差异性代谢物有5种，分别是庚二酸、糖醇、辛二酸、乳糖和L-丝氨酸。结论：PTC组织中半乳糖代谢和氨基酸代谢发生改变，PTC组织细胞中存在沃伯格效应(Warburg effect)。庚二酸、糖醇、辛二酸、乳糖、L-丝氨酸五种差异性代谢物可以用来区分PTC患者与正常人。

OBJECTIVE： To investigate the effects of total flavonoids of Jasminum nudiflorum （TFJN） on pancreatic islet function in type 2 diabetes mellitus （T2DM） model mice and its possible mechanism. METHODS： Totally 10 Kunming mice were included in blank group and given normal diet. Other 75 mice were included in model group and given high-lipid and high-glucose diet for 4 weeks combined with streptozotocin once via sublingual vein to induce T2DM model. After modeling， the mice were randomly divided into model group， metformin hydrochloride group （positive control， 350 mg/kg）， TFJN low-dose， medium-dose and high-dose groups （100， 200， 400 mg/kg， by crude drug）， with 10 mice in each group. Blank group and model group were given constant volume of normal saline intragastrically； administration groups were given relevant medicine intragastrically； once a day， for consecutive 6 weeks. The level of fasting dynamic blood glucose was measured after modeling （before medication） and 2， 4， 6 weeks after medication. The histomorphological characteristics of pancreatic tissue were observed by HE staining. The contents of serum insulin （INS）， insulin cell antibody （IAA）， TNF-α， IL-1β， IL-6， IL-18， CRP， leptin （LP） and adiponectin （ADPN） were measured by ELISA. RESULTS： Compared with blank group， islet atrophy， blurred boundary， insufficient cytoplasm and smaller volume of pancreatic tissue were observed in model group. The fasting dynamic blood glucose level （at different time points after medication）， the contents of IAA， TNF-α， IL-1β， IL-6， IL-18， CRP and LP were increased significantly， while the contents of INS and ADPN were decreased significantly （P＜0.01）. Compared with model group， above symptoms of pancreatic tissue in administration groups were relieved， and the fasting dynamic blood glucose level （2， 4， 6 weeks after administration in metform in hydrochloride group， 4， 6 weeks after administration in TFJN groups）， the contents of IAA， TNF-α， IL-1β， IL-6， IL-18， CRP and LP were decreased signifi- cantly， while the contents of INS and ADPN were increased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS： TFJN can repair the damaged pancreas of mice with T2DM， reduce the level of blood glucose， and improve the sensitivity of the body to insulin， the mechanism of which may be associated with reducing the secretion of inflammatory factors.

To study the clinical and pathological characteristics and prognostic factors of primary breast diffuse large B-cell lymphoma (PBDLBCL). Methods: Clinical and pathological data of 62 patients with PBDLBCL from January 2006 to December 2016 were retrospectively analyzed. The Kaplan-Meier method was used for univariate analysis and the Cox regression model for multivari-ate analysis. Results: The 62 patients analyzed included women aged 26-71 years, with a median age of 47 years. Patients were fol-lowed up from 6 to 105 months; the 3-year overall survival (OS) rate was 71.0%, and 5-year OS rate was 51.0%. The univariate analysis showed statistically significant differences in the clinical stage, lactic acid dehydrogenase level, International Prognostic Index score, Myc/Bcl-2 protein expression, and chemotherapy regimen at 3 and 5 years associated with OS rates. The multivariate analysis showed that Myc/Bcl-2 protein expression was an independent prognostic factor of OS. Conclusions: Comprehensive treatment with chemo-therapy and radiotherapy is appropriate for PBDLBCL. Myc/Bcl-2 protein expression is an independent adverse prognostic factor for PB-DLBCL.

Objective To explore relationship between the change of serum N terminal brain natriuretic peptide (NT-proBNP) , central venous oxygen saturation (SCVO2 ) and venous-arterial partial pressure of carbon dioxide [P(v-a)CO2 ] levels and prognosis in elderly patients with septic shock .Methods 94 cases of elderly patients with septic shock ,treated from March 2015 to July 2016 in Intensive Care Unit (ICU) of our hospital ,were chosen as the observation group A ,another 80 cases of nonsevere sepsis patients were chosen as the observation group B ,and a total of 56 patients healthy volunteers with the physical examination at the same peri-od of time in our hospital as normal control group .The serum NT-proBNP level was detected by electrochemiluminescence immuno-assay ,and PvCO2 ,PaCO2 and SCVO2 levels were detected by blood gas analyzer .records of patients with central venous blood car-bon dioxide .The NT-proBNP and P (v-a) CO2 levels in the serum of the three groups were compared between the groups of pa-tients in the observation group (SCVO2 ) .Logistic regression analysis was used to analyze the prognostic factors in elderly patients with septic shock ,and the receiver operating characteristic curve (ROC) was used to analyze the predictive value of NT-proBNP ,P (v-a)SCVO2 and SCVO2 levels .Results The serum NT-proBNP level of the observation group A was higher than that in the the observation group B and the control group (P<0 .05) .The SCVO2 level of the A group was lower than that in the B group ,and the P(v-a)CO2 level of the A group was higher than that in the B group ,the difference was statistically significant (P<0 .05) .The age , NT-proBNP ,P(v-a)CO2 ,lactic acid level and APACHE II score in the death group were higher than those in the survival group , and the difference was statistically significant (P< 0 .05) .SCVO2 level in the death group was lower than that in the survival group ,and the difference was statistically significant (P<0 .05) .Logistic multivariate regression analysis showed that NT-proBNP , P(v-a)CO2 and SCVO2 levels were the risk factors for the prognosis of elderly patients with septic shock .ROC curve showed AUC and the sensitivity of P(v-a)CO2 were higher than those of NT-proBNP ,SCVO2 .Conclusion The levels of serum NT-proBNP ,SC-VO2 and P(v-a)CO2 are related to the prognosis of elderly patients with septic shock ,and P(v-a)CO2 has a high value in the prog-nosis of the patients with septic shock ,and has a good clinical value .

Objective To investigate the mechanism by which heat shock protein 90 (HSP90) regulates 26S proteasome in hyperthermia. Methods Hyperthermic HepG2 cell models established by exposure of the cells to 42 ℃ for 3, 6, 12, and 24 h were examined for production of reactive oxygen species (ROS) and cell proliferation, and the changes in Hsp90α and 26S proteasome were analyzed. Results ROS production in the cells increased significantly after hyperthermia (F=28.958, P<0.001), and the cell proliferation was suppressed progressively as the heat exposure time extended (F=621.704, P<0.001). Hyperthermia up-regulated Hsp90α but decreased the expression level (F=164.174, P<0.001) and activity (F=133.043, P<0.001) of 26S proteasome. The cells transfected with a small interfering RNA targeting Hsp90α also showed significantly decreased expression of 26S proteasome (F=180.231, P<0.001). Conclusion The intracellular ROS production increases as the hyperthermia time extends. Heat stress and ROS together cause protein denature, leading to increased HSP90 consumption and further to HSP90 deficiency for maintaining 26S proteasome assembly and stability. The accumulation of denatured protein causes unfolded protein reaction in the cells to eventually result in cell death.

Objective To investigate the mechanism by which heat shock protein 90 (HSP90) regulates 26S proteasome in hyperthermia. Methods Hyperthermic HepG2 cell models established by exposure of the cells to 42 ℃ for 3, 6, 12, and 24 h were examined for production of reactive oxygen species (ROS) and cell proliferation, and the changes in Hsp90α and 26S proteasome were analyzed. Results ROS production in the cells increased significantly after hyperthermia (F=28.958, P<0.001), and the cell proliferation was suppressed progressively as the heat exposure time extended (F=621.704, P<0.001). Hyperthermia up-regulated Hsp90α but decreased the expression level (F=164.174, P<0.001) and activity (F=133.043, P<0.001) of 26S proteasome. The cells transfected with a small interfering RNA targeting Hsp90α also showed significantly decreased expression of 26S proteasome (F=180.231, P<0.001). Conclusion The intracellular ROS production increases as the hyperthermia time extends. Heat stress and ROS together cause protein denature, leading to increased HSP90 consumption and further to HSP90 deficiency for maintaining 26S proteasome assembly and stability. The accumulation of denatured protein causes unfolded protein reaction in the cells to eventually result in cell death.