Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial.

Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.

The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology.

We investigated the influence of DNA fragmentation index (DFI) on in vitro fertilization (IVF), embryo transfer (ET), and intracytoplasmic sperm injection (ICSI). We analyzed the semen parameters of 61 cycles in infertile couples undergoing IVF-ET and ICSI and determined DFI by sperm chromatin dispersion testing. Based on DFI, the patients were differentiated into a control group (DFI < 25%, n = 35) and a test group (DFI ≥ 25%, n = 26). Flow cytometry and immunofluorescence were used to investigate the extent of sperm reactive oxygen species (ROS) and apoptosis. We also investigated the effect of DFI on pregnancy outcomes of IVF-ET/ICSI. DFI was negatively related to sperm motility and positively correlated with ROS and apoptosis (P < 0.05). Abnormally elevated DFI reduced the rate of transplantable, high-quality embryos, implantation, clinical pregnancy, delivery, and live birth after IVF-ET, and increased the chance of early abortion per transfer cycle (P < 0.05). However, there was no significant correlation between DFI and fertilization rate, cleavage rate, transplantable rate, high-quality embryo rate, implantation rate, clinical pregnancy rate, early abortion rate, delivery rate and live birth rate when assisted by ICSI (P > 0.05). Sperm DNA integrity is crucial for fertilization and the development of healthy offspring. ROS may increase the level of DFI by inducing apoptosis in sperm.

Recombinant human thrombopoietin (rhTPO) of different dosing regimens for refractory/relapsed primary immune thrombocytopenia: a multicenter, randomized controlled trial and pharmacokinetics study.

Recombinant human TPO (rhTPO) is effective for refractory/relapsed primary immune thrombocytopenia (ITP), but optimal dosing regimen remains elusive. In this multicenter, randomized, controlled trial, a total of 282 adult ITP patients (mean age 47.3 years; 82 men) with a platelet count ≤30 × 109/L or >30 × 109/L with active bleeding randomly received a once daily (QD) subcutaneous injection of 7500 U (n = 64) or 15000 U rhTPO for 14 injections, or 15000 U or 30000 U rhTPO once every other day (QOD) for 7 injections. The primary outcomes included change from baseline in platelet count and total response rate (TRR) on day 14. On day 14, the median increase of platelet count from baseline was the highest in the 15000-U QD group (167.5 × 109/L, interquartile range [IQR] 23.0-295.0 × 109/L), followed by the 30000-U QOD group (57.5 × 109/L, IQR 9.0-190.0 × 109/L) (ANCOVA P < .001; P = .266 with baseline count as a covariate). The TRR on day 14 was also the highest in the 15000-U QD group (63.2%), followed by the 30000-U QOD group (59.7%). The rate of grade 3 and above adverse events did not differ among the four groups. There were no new safety concerns. All 4 regimens are safe and well-tolerated. The 30000-U QOD regimen is practically indistinguishable in efficacy to the 15000-U QD regimen.

What is the context? Relative thrombopoietin deficiency is implicated in primary immune thrombocytopenia (ITP), which is characterized by increased platelet destruction and impaired megakaryopoiesis.Patients who are innately unresponsive to or have relapsed after glucocorticoid treatment have limited treatment options.Recombinant human thrombopoietin (rhTPO) improves treatment response of primary ITP patients when added to high-dose dexamethasone.What is new? This trial sought to identify an optimal dosing regimen of rhTPO for patients who had failed or relapsed after glucocorticoid therapy.Of the 4 regimens, once daily 15000 U rhTPO for 14 injections yielded the greatest median increase in platelet count (167.5 × 10⁹/L) from baseline and attained the highest total response rate on day 14 (63.2%).30000 U rhTPO once every other day for 7 injections was effective in rapidly increasing platelet counts in the first 7 days.All 4 regimens were safe and well-tolerated.What is the impact? The 30000 U rhTPO once every other day regimen may offer an effective and safe regimen with less frequent injections, but future trials with longer follow-up are needed.

EIF3B Associates with Exacerbated Clinical Features, Poor Treatment Response and Survival in Adult Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia Patients.

Objective: This study was undertaken to investigate eukaryotic translation initiation factor 3 subunit B (EIF3B) expression and its clinical value for indicating disease progression and prognosis in adult Philadelphia chromosome negative acute lymphoblastic leukemia (Ph- ALL) patients. Methods: Totally, 76 adult Ph- ALL patients and 30 healthy donors (HDs) were included. Bone marrow (BM) samples before therapy (baseline), after 4-week therapy of Ph- ALL patients and the BM samples of HDs were collected. Then, EIF3B expression in BM was detected by reverse transcription quantitative polymerase chain reaction. Results: EIF3B expression was increased in Ph- ALL patients compared with HDs, which distinguished Ph- ALL patients from HDs (area under the curve [AUC]: 0.928; 95% confidence interval [CI]: 0.882-0.974) by receiver operating characteristic curve. Furthermore, higher baseline EIF3B expression was associated with elevated white blood cell and bone marrow blasts, while it was associated with lower complete remission (CR) within 4 weeks and less allogeneic hematopoietic stem cell transplant achievements in Ph- ALL patients. Additionally, higher baseline EIF3B expression was associated with decreased disease-free survival but not overall survival. However, it was associated with raised 1-year mortality and 3-year mortality in Ph- ALL patients. After 4-week therapy, EIF3B expression was reduced in total Ph- ALL patients. Notably, the reduction of EIF3B expression was more obvious in Ph- ALL patients who achieved CR within 4 weeks compared with Ph- ALL patients who did not achieve CR within 4 weeks. Conclusion: EIF3B overexpression is related to worsened clinical features, poor treatment response and survival in adult Ph- ALL patients.

A multicentre double-blind, double-dummy, randomised study of recombinant human thrombopoietin versus eltrombopag in the treatment of immune thrombocytopenia in Chinese adult patients.

We performed a double-blind, double-dummy controlled study to compare the efficacy between recombinant human thrombopoietin (rhTPO) and eltrombopag in rapidly increasing the platelet counts in Chinese patients with immune thrombocytopenia (ITP). A total of 96 patients diagnosed with ITP for ≥6 months who had baseline platelet counts of <30 × 109 /l were randomly assigned (1:1 ratio) to receive eltrombopag 25 mg/day or rhTPO 300 u/kg for 2 weeks. Compared with the eltrombopag group, a significantly higher proportion of patients in the rhTPO group achieved platelet counts of ≥50 × 109 /l [75·00% (36/48) vs. 43·75% (21/48), P = 0·003] or complete response (64·58% vs. 25·00%) on day 15. Moreover, a higher proportion of patients in the rhTPO group either had platelet counts that rapidly increased to twice that of baseline and with platelet counts of ≥30 × 109 /l, or reached ≥50 × 109 /l at least once when analysed on day 9, 12, and 15. However, upon discontinuation of the treatment, the platelet counts reduced to the baseline within 1 week in the rhTPO group, but on the fourth week in the eltrombopag group. Adverse events were similar in patients given rhTPO and eltrombopag. To conclude, rhTPO is superior to eltrombopag at 25 mg/day in rapidly increasing platelet counts in patients with ITP (ClinicalTrials.gov Identifier: NCT03771378).

Identification and Validation of STAT6 as a Prognostic and Predictive Biomarker in Acute Myeloid Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is one of the most common hematological diseases in adults. The overall survival rate remains unsatisfactory. It is urgent to identify potential prognostic biomarkers and develop new molecular therapeutic strategies for AML. Signal transducer and activator of transcription (STAT) is a family of genes that encode intracellular transcription factors. STATs are associated with leukemogenesis, cellular transformation, and cell cycle in AML. METHODS: We used sequencing data and clinical data from The Cancer Genome Atlas (TCGA) and ONCOMINE to identify expression difference, gene variability and correlation as well as prognostic effects of STAT genes in AML patients. Then, we verified the expression difference of STAT6 between healthy control and AML patients and its prognostic impact in Gene Expression Omnibus (GEO) database and our own recruited cohort. RESULTS: The mRNA level of STAT6 was increased in AML patients among TCGA, GEO and ONCOMINE public datasets and was found to be an independent risk factor of overall survival in all AML patients and patients who only received chemotherapy by multivariate analysis. In our study, STAT6 mRNA level was markedly up-regulated in AML patients (n=105) compared to healthy donor (n=39) (P=0.0435) as a validated cohort. Patients that only received chemotherapy in high STAT6 group showed significantly lower overall survival (OS) (P=0.0055). CONCLUSION: STAT6 expression was increased in AML patients. STAT6 was found to be an adverse prognosis factor in AML patients, especially those who only received chemotherapy treatments.

Effect of puerarin on the expression of extracellular matrix in rats with streptozotocin-induced diabetic nephropathy.

BACKGROUND: Inhibition of the formation of advanced glycation end-products delays the development of diabetic nephropathy. Puerarin decreases the formation of these products. We studied the effect of puerarin in a rat model of diabetic nephropathy. METHODS: Three groups of rats were studied: a control group, a diabetic group in whom diabetic nephropathy was induced by intraperitoneal injection of streptozotocin, and a puerarin group in which diabetic rats were treated with puerarin. During and after treatment, measurements were made on the rats' general status, blood glucose level, blood urea nitrogen, serum creatinine, creatinine clearance rate and urinary albumin excretion over 24 hours. The expression of collagen I and heparan sulphate proteoglycan in the extracellular matrix of the glomerulus was assessed by immunohistochemistry. RESULTS: Rats in the puerarin group had a better general condition than those with diabetes. They also had lower blood urea nitrogen, serum creatinine and urinary albumin excretion rate over 24 hours compared with those in the diabetic group. The creatinine clearance and expression of heparan sulphate proteoglycan in the kidney also increased significantly in the puerarin group compared with that in the diabetic group. CONCLUSION: Puerarin seems to have certain protective effects on diabetic nephropathy induced by streptozotocin. This is caused possibly by regulating the expression of glomerular extracellular matrix.

[Effect of compound Puerarin on the collage IV in streptozotocin-induced diabetic nephropathy rats].

OBJECTIVE: To observe the effect of compound Puerarin on collagen IV of streptozotocin-induced diabetic rats. METHODS: Diabetic nephropathy rats were induced by intraperitoneal injection of streptozotocin (STZ). Rats were allocated randomly to control group (10), diabetes model group (10), Vitamin C group (10), Puerarin group (10), vitamin C plus Puerarin group (10). The study period lasted for 12 weeks. During and after the treatment, the general state, blood glucose levels, glycosylated hemoglobin, blood urea nitrogen, serum collagen IV, blood urea nitrogen, serum creatinine, urinary albumin excretion rate of the 24-hour, and clearance rate of creatinine collagen IV protein were determined by immunohistochemistoche analysis as well as type the gene expression of collagen IV alpha 1 mRNA were determined by in situ hybridization analysis in the kidney tissue of different groups. RESULTS: (1) Diabetes mellitus and renal function lesion occurred in the four groups. (2) Vitamin C and Puerarin could improve the general conditions of diabetic Rats, decrease blood urea nitrogen [(8.68 +/- 0.43), (7.98 +/- 0.47) and (5.76 +/- 0.82) micromol/L, serum creatinine [(74.68 +/- 8.20), (75.52 +/- 7.98) and (58.66 +/- 6.65) mmol/L], and urinary albumin excretion rate of the 24-hour [(18.40 +/- 0.37), (17.24 +/- 0.30) and (9.97 +/- 1.27) mg/24 h x 10(-3)]; increase clearance rate of creatinine [(0.59 +/- 0.21), (0.61 +/- 0.14) and (0.69 +/- 0.32) ml/min], the expression of collage IV absorbance [(111.56 +/- 14.61), (110.78 +/- 9.69) and (95.44 +/- 9.97) ] in the diabetic Rats were significantly inhibited at the same time. CONCLUSION: The compound Puerarin might have some functions on preventing ren by inhibiting expression of type IV collagen.

[Study of regulation of Puerarin on blood P-selectin and the expression of aorta VCAM mRNA in diabetes].

OBJECTIVE: To observe the regulation of Puerarin on blood P-selectin and expression of aorta vascular cell adhesion molecule (VCAM) in diabetic rats induced by Streptozotocin. METHODS: Diabetic rats were induced by intraperitoneal injection of STZ. Rats were divided into normal control group, model group, and three Puerarin groups (20, 40 and 80 mg/kg, ip) for 16 weeks. After the treatment, its cholesterol, low density lipoprotein, high density lipoprotein, P-selectin, oxidative low density lipoprotein and glycosylated low density lipoprotein. Alteration of tissue morphology via H. E staining was observed after the aorta was taken out from the rats executed by narcosis. VCAM mRNA were determined by in situ hybridization analysis. RESULTS: (1) Diabetes mellitus and aorta lesion occurred in the four model groups. (2) Puerarin could decrease the levels of cholesterol (P < 0.05), low density lipoprotein (P < 0.05), P-selectin (P < 0.05), oxidative low density lipoprotein, and glycosylated low density (P < 0.05), lipoprotein increase high density lipoprotein (P < 0.05). The gene expression of VCAM in the aorta were significantly inhibited, and the action of Puerarin showed some dose reaction relationship at the same time (P < 0.05). CONCLUSION: Puerarin have a certain in preventing aorta by inhibiting expression of adhesion molecule.