Combined human growth hormone and lactulose for prevention and treatment of multiple organ dysfunction in patients with severe chronic hepatitis B

AIM: To evaluate the efficiency and safety of combined recombinant human growth hormone (rhGH) and lactulose for treatment and/or prevention of multiple organ dysfunction in patients with chronic severe hepatitis B. METHODS: Forty-eight inpatients with chronic severe hepatitis B were randomly divided into rhGH group (n = 28)and control group (n = 20). In rhGH group, 4-4.5 IU of rhGH was injected intramuscularly once daily for 2-4 wk,and 100 mL of enema containing 30 mL of lactulose, 2 g of metronidazole and 0.9% saline was administered every 2 d for 2-4 wk. Their symptoms and complications were noted. Liver and kidney functions were analyzed by an Olympus analyzer. Serum GH, IGF-1, IGFBP1 and IGFBP3 were measured by ELISA.RESULTS: Clinical symptoms of 90% of these patients in rhGH group were obviously improved. The total effectiveness in rhGH group was better than that in control group (75% vs40%, P＜0.05). After 2- and 4-wk treatment of rhGH respectively, serum albumin (26.1±4.1 vs 30.2±5.3,31.9±5.1 g/L), prealbumin (79.6±28.0 vs 106.6±54.4,108.4±55.0 g/L), cholesterol (76.3±16.7 vs 85.6±32.3,96.1±38.7 mg/dL), and IGFBP1 (56.8±47.2 vs 89.7±50.3ng/mL after 2 wk) were significantly increased compared to control group (P＜0.05). However, serum GH was decreased. The increase of serum IGF1 and IGFBP3 after rhGH treatment was also observed.CONCLUSION: rhGH in combination with lactulose may be beneficial to the prevention and treatment of multiple organ dysfunction in patients with chronic severe hepatitis.

Altered Nutrition State in the Severe Multiple Trauma Patients Undergoing Adjuvant Recombinant Human Growth Hormone Nutritional Support Therapy

In order to observe the nutrition state in the severe multiple trauma patients undergoing adjuvant recombinant human growth hormone (rhGH) nutritional support therapy, 45 patients with severe multiple traumas (ISS>25) were randomly divided into 3 groups. All the 3 groups had been supplied with nitrogen and caloricity according to the need of patients for 16 days. The rhGH therapy started 48 h after surgery and lasted for 14 days in two rhGH-treated groups in which rhGH was 0.2 and 0.4 U/(kg·d) respectively, and the resting group served as control one. The levels of nitrogen balance, prealbumin and safety variables (blood sugar, Na+, TT3 and TT4) were observed and com- pared among the three groups. The levels of nitrogen balance on the postoperative day (POD) 3 and 5 in the rhGH-treated groups were -1.28±3.19, 5.45±2.00 and -0.18±2.55, 6.11±1.60, respectively, which were significantly higher than those in the control group (-5.17±1.68 and -1.08±3.31, P<0.01). The values of prealbumin on the POD 3 and 5 in the rhGH-treated groups were 180.19±27.15, 194.44±50.82 and 194.94±29.65, 194.11±16.17, respectively, which were significantly higher than those in the control group (117.42±19.10 and 135.63±28.31, P<0.01). There was no sig- nificant difference between the rhGH 0.2 U/(kg·d) group and rhGH 0.4 U/(kg·d) group in both of the levels of nitrogen balance and prealbumin. It is concluded that the nutritional support therapy with adjuvant rhGH which starts 48 h after surgery improves the nutrition state of the patients with severe multiple trauma. It is safe for severe multiple trauma patients who accept rhGH at the dose of 0.2 and 0.4 U/(kg·d).

Effects of recombinant human growth hormone on enterocutaneous fistula patients

AIM： To explore the effects of recombinant human growth hormone （rhGH） on intestinal mucosal epithelial cell proliferation and nutritional status in patients with enterocutaneous fistula. METHODS： Eight patients with enterocutaneous fistulas received recombinant human growth hormone （10 ug/d） for 7 d. Image analysis and immunohistochemical techniques were used to analyse the expression of proliferating cell nuclear antigen （PCNA） in intestinal mucosal epithelial cells in biopsy samples from the patients who had undergone an endoscopic biopsy through the fistula at day 0, 4 and 7. Body weights, nitrogen excretion, serum levels of total proteins, albumin, prealbumin, transferrin and fibronectin were measured at day 0, 4 and 7. RESULTS： Significant improvements occurred in the expression of PCNA in the intestinal mucosal epithelial cells at day 4 and 7 compared to day 0 （24.93 ± 3.41%, 30.46 ± 5.24% vs 12.92 ± 4.20%, p 〈 0.01）. These changes were accompanied by the significant improvement of villus height （500.54 ± 53.79 um, 459.03 ± 88.98um vs 210.94 ± 49.16 um, P 〈 0.01）, serum levels of total proteins （70.52 ± 5.13 g/L, 74.89 ± 5.16 g/L vs 63.51 ± 2.47 g/L, P 〈 0.01）, albumin （39.44 ± 1.18 g/L, 42.39 ± 1.68 g/L vs 35.74 ± 1.75 g/L, P 〈 0.01） and fibronectin （236.3 4- 16.5 mg/L, 275.8± 16.9 mg/L vs 172.5 ± 21.4 mg/L, P 〈 0.01） at day 4 and 7, and prealbumin （286.38 ± 65.61 mg/L vs 180.88 ± 48.28 mg/L, P 〈 0.05）, transferrin （2.61 ± 0.12 g/L vs 2.41 ±0.14 g/L, P 〈 0.05） at day 7. Nitrogen excretion was significantly decreased at day 7 （3.40 ± 1.65 g/d vs 7.25 ± 3.92 g/d, P 〈 0.05）. No change was observed in the body weight. CONCLUSION： Recombinant human growth hormone could promote intestinal mucosal epithelial cell proliferation and protein synthesis in patients with enterocutaneous fistula.

Effects of recombinant human growth hormone on growth of human gastric carcinoma xenograft model in nude mice

AIM： To study effects of recombinant human growth hormone （rhGH） on growth of a human gastric carcinoma cell in vivo. METHODS： Experimental mice were divided into control group, rhGH group, oxaliplatin （L-OHP） group and rhGH＋L-OHP group. Cultured human gastric carcinoma cells BGC823 were inoculated into right axilla of nude mice and carcinoma xenograft model was established successfully. Inhibitory rate of xenograft tumor growth was estimated by measuring tumor volume; expression of proliferating cell nuclear antigen （PCNA）, Bax and Bcl-2 proteins of xenograft tumor was detected using immunohistochemical S-P method. RESULTS： Tumor growth inhibitory rate, the positive expression rate of PCNA, Bax and Bcl-2 were 49.3%, 58.2%, 65.2% and 59.2% in rhGH＋L-OHP group respectively; 46.6%, 62.5%, 59.7% and 64.7% in L-OHP group; 5.0%, 82.7%, 23.2% and 82.2% in rhGH group and 0, 77.8%, 23.5% and 80.3% in control group. There was significant difference between rhGH＋L-OHP group （or L-OHP group ） and control group or rhGH group （P 〈 0.05）, whereas there were no significant differences （P 〉 0.05） between L-OHP group and rhGH＋L-OHP group and between rhGH group and control group. CONCLUSION： rhGH does not accelerate the proliferation of human gastric cancer cell in vivo.

Experimental study on effect of recombinant human growth hormone combined with chemotherapy on stomach neoplasms implanted in nude mice

Objective: To investigate the effect of different doses of recombined growth hormone (rhGH) on stomach neo- plasms implanted in nude mice, and its efficacy in combining with chemotherapy (flurouracil, 5-FU). Methods: Human stom- ach neoplasms model was established in nude mice. The nude mice were divided into control group, moderate-dose of rhGH group, low-dose rhGH group, 5-FU group, moderate-dose rhGH/5-FU group, and low-dose rhGH/5-FU group. The results of each group were observed after ten days. Results: After therapy, the body mass of rhGH groups was significantly increased compared with control group (P<0.05), the body mass of rhGH/5-FU groups was significantly increased compared with 5-FU group (P<0.05), but it was no significant difference between rhGH/5-FU groups and control group (P>0.05). The average tumor mass and volume of rhGH groups were not significantly increased compared with control group (P>0.05), but they were significantly reduced in 5-FU group and rhGH/5-FU groups (P<0.05). They were no significant difference between rhGH/5- FU groups and 5-FU group (P>0.05). After treatment, the percentages of S, G0/G1 and G2/M phases and proliferation index (PI) were not significantly changed in rhGH groups compared with control group (P>0.05), and the same with rhGH/5-FU groups compared with 5-FU group (P>0.05). The difference caused by dose of rhGH was not significant. Conclusion: rhGH enhances body mass, does not stimulate tumor growth, and has no adverse effects on tumor bearing nude mice. Combined with flurouracil, rhGH does not influence the efficacy of chemotherapy, and has no effect on tumor cell cycle kinetics.

Effect of cyclovirobuxine D on human growth-associated protein 43 and neurocan expression in ischemic brain tissue of stroke-prone renovascular hypertensive rats

BACKGROUND： Experimental data indicate that human growth-associated protein 43 mRNA expression coincides with axonal growth during nerve ganglion development; while neurocan, secreted from astrocytes, can inhibit sprouting and elongation of the axonal growth cone. OBJECTIVE： To verify regulatory effects of cyclovirobuxine D （CVB-D） extracted from Chinese box branchlet on human growth-associated protein 43 （GAP-43）, and neurocan expression in brain tissue of stroke-prone renovascular hypertensive （RHRSP） rats, at different time points after cerebral ischemia/reperfusion. DESIGN： Randomized grouping design and controlled animal study. SETTING： This study was performed at the Center of Guangdong Hospital of Traditional Chinese Medicine （a national key laboratory） from March 2003 to September 2006. MATERIALS： 100 healthy male Sprague-Dawley rats, aged 2 3 months and weighing 90-120 g, were selected for this study. CVB-D was provided by Nanjing Xiaoying Pharmaceutical Factory （Batch number： 307701）. METHODS： The initial tip of renal arteries was clamped bilaterally for 10 weeks to establish the RHRSP model. 100 RHRSP rats were randomly divided into 4 groups： naive group （n = 10）, sham surgery group （n = 10）, CVB-D group （n = 40）, and lesion group （n = 40）. Rats in the naive group did not undergo any treatment, and cervical vessels of rats in the sham surgery group were exposed, but not blocked. The right middle cerebral artery of rats in the CVB-D group and lesion group were occluded to establish cerebral ischemia. Rats in the CVB-D group were intraperitoneally injected with CVB-D （6.48 mg/kg） every day and with saline （1.5 mL/injection） twice a day. Rats in the lesion group were intraperitoneally injected with saline （2 mL/injection）. MAIN OUTCOME MEASURES： Immunohistochemistry was applied to detect GAP-43 and neurocan expression in the ischemic penumbra region of CVB-D and lesion brains at 2 hours post-cerebral ischemia and at 1, 7, 14, and 30 days post-perfusion （n = 10 at each time point）. Similarly, GAP-43 and neurocan expression was detected in the right hemisphere of naive and sham-operated animals. The results were expressed as positive cells. RESULTS： A total of 100 rats were included in the final analysis. The number of GAP-43 positive cells increased in the CVB-D group 1, 7, 14, and 30 days post-cerebral ischemia/perfusion compared to the lesion group, as indicated by a significant difference between the CVB-D and lesion group （P 〈 0.054）.01）. The number of neurocan-positive cells decreased in the CVB-D group on the first day compared to the model group; however, there was no significant difference between the two groups （P 〉 0.05）. On post-ischemia days 7, 14, and 30, the number of neurocan-positive cells in the CVB-D group was significantly less than in the lesion group （P 〈 0.05）. Both, GAP-43 and neurocan expression was not detectable in brains of naive and sham-operated animals. CONCLUSION： CVB-D treatment up-regulated GAP-43 expression and down-regulated neurocan expression in the ischemic region of RHRSP rats.

MEASUREMENTS OF URINARY HUMAN GROWTH HORMONE IN SUBJECTS WITH NORMAL AND ABNORMAL GROWTH:A CRITICAL OF ITS POTENTIAL CLINICAL UTILITY

Ovrmight urinary human growth hormone (HGH) levels in 53 normal growthprepuberty children,38 primary short stature chjildren ahildren them 11 cases with GH defi-ciency (GHD), 27 cases with normal GH reset to the conveatnd pharmacutical provocative tests diagnosed as idiopathic growth failure or non-GHD short children and 3adults with acromegaly were measured by the LAB-ELISA technique,The levelsdemonstrated stable in normal growth prepubertal children,but significantly rasised inacromegaly,and decreased in GHD,and in non=GHD short children,Thus,the resultsshow that measurement of urinary HGH being useful for Jiagnosis of GHD and forscreening the non-GHD growth failure.

Application of human growth hormone to patients with polycystic ovary syndrome during in vitro fertilization

Objective:To observe the effect of applying human growth hormone during in vitro fertilization to patients with polycystic ovary syndrome(PCOS) Methods:One hundred and twenty-one cycles of in vitro fertilization and embryo transfer in PCOS patients with anovulation from Dec.2008 to Nov.2010 were studied retrospectively.Of these 121 cycles,48 were with treatment of growth hormone(GH group),73 without GH treatment(control group).The dose of gonadotropin(Gn),the number of retrieved oocytes,good-quality embryo rate,implantation rate,frozen embryo rate,and pregnancy rate were compared. Results:The dosage of Gn was slightly higher in GH group than that in control group(29.18±8.33 vs.23.43±8.68 ampoullas,4U/ampoulla) and the number of retrieved oocytes in GH group were slightly less than that in control group(10.73±6.0 vs.14.0±8.57),but there were no significant differences(P>0.05).The good-quality embryo rate(59.1%vs.33.3%),frozen embryo rate(87.5%vs.58.9%),pregnancy rate(56.5%vs. 35.3%) and implantation rate(35.3%vs.20.4%) in GH group were all significantly higher than those in control group(P<0.05). Conclusion:Early usage of GH in the ovarian hyperstimulation in PCOS patients could significantly improve good-quality embryo rate,implantation rate and pregnancy rate.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer

BACKGROUND Patients with human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer have poor outcomes.Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer.Inetetamab is a novel anti-HER2 drug,and its efficacy and safety in gastric cancer have not yet been reported.AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin(SOX)regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer.METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroeso-phageal junction adenocarcinoma were randomly divided into two groups:One group received inetetamab combined with the SOX regimen,and the other group received trastuzumab combined with the SOX regimen.After 4-6 cycles,patients with stable disease received maintenance therapy.The primary endpoints were progression-free survival(PFS)and overall survival(OS),and the secondary endpoints were the objective response rate,disease control rate,and adverse events(AEs).RESULTS Thirty-seven patients completed the trial,with 18 patients in the inetetamab group and 19 patients in the trastuzumab group.In the inetetamab group,the median PFS was 8.5 months,whereas it was 7.3 months in the trastuzumab group(P=0.046);this difference was significant.The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months(P=0.33),and the objective response rate was 50%vs 42%(P=0.63),respectively;these differences were not significant.Common AEs included leukopenia,thrombocytopenia,nausea,and vomiting.The incidence rates of grade≥3 AEs were 56%in the inetetamab group and 47%in the trastuzumab group(P=0.63),with no significant difference.CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer,inetetamab and trastuzumab showed comparable efficacy.The inetetamab group showed superior PFS,and both groups had good safety.

BIRC3 induces the phosphoinositide 3-kinase-Akt pathway activation to promote trastuzumab resistance in human epidermal growth factor receptor 2-positive gastric cancer

BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses significant challenges.AIM To identify the key genes associated with trastuzumab resistance.These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes.METHODS High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation.Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance.We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3,followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms.RESULTS In patients with HER2-positive gastric cancer,there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage,tumor node metastasis stage,as well as poor overall survival and progressionfree survival.BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines,where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt(PI3K-AKT)pathway in HER2-positive gastric cancer cells,both in vivo and in vitro.CONCLUSION This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer.Thus,the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation,stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis,ultimately leading to trastuzumab resistance.

Inetetamab combined with tegafur as second-line treatment for human epidermal growth factor receptor-2-positive gastric cancer: A case report

BACKGROUND Human epidermal growth factor receptor-2(HER-2)plays a vital role in tumor cell proliferation and metastasis.However,the prognosis of HER2-positive gastric cancer is poor.Inetetamab,a novel anti-HER2 targeting drug independently developed in China,exhibits more potent antibody-dependent cell-mediated cytotoxicity than trastuzumab,which is administered as the first-line treatment for HER2-positive gastric cancer in combination with chemotherapy.In this case,the efficacy and safety of inetetamab combined with tegafur was investigated as a second-line treatment for HER2-positive gastric cancer.CASE SUMMARY A 52-year-old male patient with HER2-positive gastric cancer presented with abdominal distension,poor appetite,and fatigue two years after receiving six cycles of oxaliplatin combined with tegafur as first-line treatment after surgery,followed by tegafur monotherapy for six months.The patient was diagnosed with postoperative recurrence of gastric adenocarcinoma.He received 17 cycles of a combination of inetetamab,an innovative domestically developed anti-HER2 monoclonal antibody,and tegafur chemotherapy as the second-line treatment(inetetamab 200 mg on day 1,every 3 wk combined with tegafur twice daily on days 1–14,every 3 wk).Evaluation of the efficacy of the second-line treatment revealed that the patient achieved a stable condition and progression-free survival of 17 months.He tolerated the treatment well without exhibiting any grade 3-4 adverse events.CONCLUSION Inetetamab combined with chemotherapy for the treatment of metastatic HER2-positive gastric cancer demonstrates significant survival benefits and acceptable safety.

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Efficacy of recombinant human epidermal growth factor plus sodium hyaluronate eye drops in diabetic dry eye post-cataract surgery

BACKGROUND Dry eye syndrome(DES)after diabetic cataract surgery can seriously affect the patient’s quality of life.Therefore,effective alleviation of symptoms in patients with this disease has important clinical significance.AIM To explore the clinical effect of recombinant human epidermal growth factor(rhEGF)plus sodium hyaluronate(SH)eye drops on DES after cataract surgery in patients with diabetes.METHODS We retrospectively evaluated 82 patients with diabetes who experienced DES after cataract surgery at Tianjin Beichen Hospital,Affiliated Hospital of Nankai University between April 2021 and April 2023.They were classified into an observation group(42 cases,rhEGF+SH eye drops)and a control group(40 cases,SH eye drops alone),depending on the different treatment schemes.The therapeutic efficacy,dry eye symptom score,tear film breakup time(TFBUT),basic tear secretion score[assessed using Schirmer I test(SIt)],corneal fluorescein staining(FL)score,tear inflammatory markers,adverse reactions during treat-ment,and treatment satisfaction were compared between the two groups.RESULTS Therapeutic efficacy was higher in the observation group compared with the control group.Both groups showed improved TFBUT and dry eye,as well as improved SIt and FL scores after treatment,with a more pronounced improvement in the observation group.Although no marked differences in adverse reactions were observed between the two groups,treatment satisfaction was higher in the observation group.CONCLUSION rhEGF+SH eye drops rendered clinical benefits to patients by effectively ameliorating dry eye and visual impairment with favorable efficacy,fewer adverse reactions,and high safety levels.Thus,this treatment should be promoted in clinical practice.

Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer

BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.

Effects of recombinant human growth hormone (r-hGH) on experimental osteoporotic fracture healing

Objective:: To observe the effect of recombinant human growth hormone (r-hGH) on osteoporotic fracture healing in rats, and to provide an effective therapy for osteoporotic fracture. Methods: Thirty-six female 8-month-old SD rats were randomized into two groups: therapy group and control group. After the experimental model of osteoporotic fracture was established, the therapy group was treated with r-hGH of 2.7 mg/kg body weigh/day (1 mg=3 IU) for 10 days continuously by daily subcutaneous injection; whereas the control group was treated with equivalent saline. Plasma insulin-like growth factor I concentration was detected and bone mineral density (BMD) as well as biomechanical strength of callus were measured at 2, 4, 8 weeks. Results: Plasma insulin-like growth factor I concentration in the therapy group was higher than that in the control group (P< 0.005 ) at 2nd week and began to decline at 4th week. At 8th week, there was no significant difference between the two groups. At 4th week, callus area and BMD in therapy group were higher than those in the control group, but at 8th week, they were lower and BMD had a significant difference between the two groups (P< 0.001 ). Biomechanical testing of callus showed that torsional strength of the therapy group was higher than that of the control group at 4th or 8th week, meanwhile maximum torsional angle had a significant difference between the two groups (P< 0.005 ).Conclusions: The results show that exogenous r-hGH can stimulate osteoporotic fracture healing in rats.

Site-specific PEGylation of Human Growth Hormone by Mutated Sortase A

Human growth hormone（hGH）, a classic therapeutic protein, which promotes growth and wound healing, is released from the pituitary gland. As a protein drug, its short half-life is its main barrier to therapeutic efficacy. Various strategies have been designed to prolong its serum half-life, the most conunon of which is the conjugation with polyethylene glycol（PEG）, as this has been shown to significantly extend protein＇s serum half-life. However, PEGylation often results in random conjugation, which can lead to impaired protein function and hinder purification, characterization and evaluation of the PEGylated protein. Therefore, site specific PEGylation is a promising direction for PEG-protein conjugation. Here we took advantages of the mutated sortase A（7M） enzyme, which can enzymati- cally ligate the universal a-amino acids to a C-terminal tagged protein. This then allows specific modification of the C-terminal of hGH with PEG. This site-specific bound PEG-hGH has similar efficacy, receptor binding and cell proliferation as wild-type hGH; however, pharmacokinetic analysis demonstrates that its serum half-life is almost 24 times that of wild-type hGH. Herein, we provided a promising advancement in the development of site specific PEGylated therapeutic proteins.

Concentration and Preservation of Very Low Abundance Biomarkers in Urine, such as Human Growth Hormone (hGH), by Cibacron Blue F3G-A Loaded Hydrogel Particles

Urine is a potential source of diagnostic biomarkers for detection of diseases,and is a very attractive means of non-invasive biospecimen collection.Nonetheless,proteomic measurement in urine is very challenging because diagnostic biomarkers exist in very low concentration(usually below the sensitivity of common immunoassays)and may be subject to rapid degradation.Hydrogel nanoparticles functionalized with Cibacron Blue F3G-A(CB)have been applied to address these challenges for urine biomarker measurement.We chose one of the most difficult low abundance,but medically relevant,hormones in the urine:human growth hormone(hGH).The normal range of hGH in serum is 1 to 10 ng/mL but the urine concentration is suspected to be a thousand times less,well below the detection limit(50 pg/mL)of sensitive clinical hGH immunoassays.We demonstrate that CB particles can capture,preserve and concentrate hGH in urine at physiological salt and urea concentrations,so that hGH can be measured in the linear range of a clinical immunometric assay.Recombinant and cadaveric hGH were captured from synthetic and human urine,concentrated and measured with an Immulite chemiluminescent immunoassay.Values of hGH less than 0.05 ng/mL(the Immulite detection limit)were concentrated to 2 ng/mL,with a urine volume of 1 mL.Dose response studies using 10 mL of urine demonstrated that the concentration of hGH in the particle eluate was linearly dependent on the concentration of hGH in the starting solution,and that all hGH was removed from solution.Thus if the starting urine volume is 100 mL,the detection limit will be 0.1 pg/mL.Urine from a healthy donor whose serum hGH concentration was 1.34 ng/mL was studied in order detect endogenous hGH.Starting from a volume of 33 mL,the particle eluate had an hGH concentration of 58 pg/mL,giving an estimated initial concentration of hGH in urine of 0.175 pg/mL.The nanotechnology described here appears to have the desired precision,accuracy and sensitivity to support large scale clinical studies of urine hGH levels.

Growth-Promoting Effect of Recombinant Human Growth Hormone and Stanozolol in Girls with Turner Syndrome

Summary: Ten girls with Turner syndrome were treated with a combination therapy of recombinant human growth hormone (R hGH) and low dose stanozolol for a period of 8 to 36 months. The results showed that when compared with the growth rate before the treatment, the growth rates after treatment with R hGH and stanozolol showed a sustained increase, reaching 9.0±1.9 cm/year during the first year of treatment; the height age increase by 2.5±0.8 years while the bone age increase were 1.0±0.7 years; and the predicted final adult height at the end of the first year of the treatment increased to 149.4±6.1 cm compared to their original mean of 142.8±4.2 cm. We are led to conclude that therapy with R hGH in combination with stanozolol can increase the growth velocity and significantly increase the predicted adult height of children with Turner syndrome.

Clinical evaluation of recombinant human growth hormone injection in children with growth hormone deficiency

Recombinant human growth hormone(rhGH)has been widely used in the clinical treatment of growth hormone deficiency.To simplify the injection process and increase drug compliance,application of the GH injection has become a new treatment plan in recent years.The purpose of the current study was to evaluate the efficacy and safety of rhGH injection for the treatment of growth hormone deficiency(GHD)in children in China.In a nationwide,noncomparative,prospective,randomized,open trial,31 children with confirmed complete GHD received subcutaneous injection of rhGH at 0.25 mg/kg$wk(0.107 IU/kg$d).The injection was given daily and the total weekly amount was separated into 6–7 injections.The patients were followed up at 3-month intervals and the treatment duration was 12 months.The height(HT),annual growth velocity(GV),mean height standard deviation score(HT SDS),blood serum insulin-like growth factor I(IGF-I),insulin-like growth factor binding protein 3(IGFBP-3),and bone maturity before and after treatment were compared,and the safety of the treatment was analyzed.The mean HT,GV,and HT SDS were increased from 109.0�14 cm,2.7�0.9 cm/yr,and–4.62�1.46 at baseline to 121.8�13.4 cm,12.9�3.3 cm/yr,and–2.47�1.86 after 12 months of treatment,respectively(P<0.001).At the same time,blood IGF-I and IGFBP-3 were increased significantly[41.27�64.43μg/L vs 159.21�167.92μg/L and 1540.00�1325.11 mg/L vs 3533.93�1413.82 mg/L,respectively(P<0.001)].The bone age assessments performed 6 and 12 months after the treatment showed that no advanced bone maturation was noted.No serious adverse events occurred during the treatment,and the drug-related adverse events were mainly decreased thyroid function.We conclude that rhGH injection is a safe and effective drug for treatment of growth hormone deficiency in children.