The development of chimeric antigen receptor T-cells against CD70 for renal cell carcinoma treatment.

In this study, we investigated CD70 as a promising target for renal cell carcinoma (RCC) therapy and developed a potent chimeric antigen receptor T (CAR-T) cells for potential clinical testing. CD70, found to be highly expressed in RCC tumors, was associated with decreased survival. We generated CAR-T cells expressing VHH sequence of various novel nanobodies from immunized alpaca and a single-chain variable fragment (scFv) derived from human antibody (41D12). In our in vitro experiments, anti-CD70 CAR-T cells effectively eliminated CD70-positive tumor cells while sparing CD70-negative cells. The nanobody-based CAR-T cells demonstrated significantly higher production of cytokines such as IL-2, IFN-γ and TNF-ɑ during co-culture, indicating their potential for enhanced functionality. In xenograft mouse model, these CAR-T cells exhibited remarkable anti-tumor activity, leading to the eradication of RCC tumor cells. Importantly, human T cell expansion after infusion was significantly higher in the VHH groups compared to the scFv CAR-T group. Upon re-challenging mice with RCC tumor cells, the VHH CAR-T treated group remained tumor-free, suggesting a robust and long-lasting anti-tumor response. These findings provide strong support for the potential of nanobody-based CD70 CAR-T cells as a promising therapeutic option for RCC. This warrants further development and consideration for future clinical trials and applications.

The association between long noncoding RNA ABHD11-AS1 and malignancy prognosis: a meta-analysis.

BACKGROUND: Accumulating evidence has highlighted that lncRNA ABHD11-AS1 plays an essential role in tumorigenesis and is expected to become a new predictive biomarker and ideal target for cancer therapy, whereas some of their findings are conflicting due to the relatively small sample size of individual studies. Thus, this meta-analysis aimed to quantitatively ascertain the association of ABHD11-AS1 with diverse human malignancies. METHODS: Eight databases were comprehensively screened for relevant articles on January 1, 2024. The significance of ABHD11-AS1 in malignancies was determined by odds ratios (ORs) or hazard ratios (HRs) with corresponding 95% confidence interval (CI). Subgroup analyses and sensitivity analyses were applied to verify the reliability and robustness of the pooled results. Simultaneously, the GEPIA2021 and UCSC Xena databases were applied to further strengthen the results. RESULTS: Fourteen clinical studies comprising eight kinds of malignancies and 1215 malignancy cases were enrolled into this meta-analysis. The pooled results showed that increased ABHD11-AS1 expression was remarkably associated with lymph node metastasis (OR = 2.73, 95%CI [1.97, 3.77], I2 = 0%, p < 0.00001), advanced tumor stage ( OR = 3.14, 95%CI [2.34, 4.21], I2 = 39%, p < 0.00001), and unfavorable overall survival (OS) (HR = 1.81, 95%CI [1.58, 2.06], I2 = 0%, p < 0.00001). Subgroup analyses and sensitivity analyses indicated that the pooled results were reliable and robust. Additionally, ABHD11-AS1 was significantly increased in eight kinds of malignancies according to the validation of the GEPIA2021 database. Meanwhile, the UCSC Xena databases further revealed that elevated ABHD11-AS1 expression was significantly associated with poor prognosis as assessed by progression free interval (PFI), disease free interval (DFI), disease specific survival (DSS), and OS. CONCLUSIONS: Current evidence supports the association of elevated ABHD11-AS1 expression with poor prognosis. Thereby, ABHD11-AS1 may be considered as a promising biomarker to screen cancer and predict malignancy prognosis. Also, there is a necessity for larger-scale multicenter studies with uniform study protocols from different countries to further validate the conclusions.

Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators.

The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.

Structure of the full-length glucagon class B G-protein-coupled receptor.

The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a ß-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a ß-hairpin conformation and interacts with the stalk to form a compact ß-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.

Cognitive impairment and factors influencing depression in adolescents with suicidal and self-injury behaviors: a cross-sectional study.

BACKGROUND: Non-suicidal self-injury (NSSI) and suicide attempts (SAs) by adolescent patients with depression have become serious public health problems. There is still insufficient research evidence on the effects of NSSI and SAs on neurocognitive functioning in adolescents. Cognitive function alterations may be associated with SAs and self-injury. NSSI and SAs have different influencing factors. METHODS: Participants were recruited from outpatient clinics and included 142 adolescent patients with depression (12-18 years old). This cohort included the SAs group (n = 52), NSSI group (n = 65), and depression without SAs/NSSI control group (n = 25). All participants underwent a clinical interview and neuropsychological assessment for group comparisons, and post-hoc tests were performed. Finally, partial correlation analysis was used to explore factors related to changes in cognitive function. RESULTS: The SAs group performed significantly worse than the control group in executive function and working memory. The depression score was directly proportional to the executive function of the SAs group, whereas cognitive functioning in the NSSI group was associated with borderline traits and rumination. CONCLUSIONS: These findings suggest that impairment of executive function and working memory may be a common pattern in adolescent depressed patients with SAs. However, borderline traits and rumination may be indicative of NSSI but not SAs.

Gaussian optics optimization of an optical particle counter for measurement in high-pressure gas.

An optimization model for the parameters of the pressure-resistant lens of an optical particle counter, based on Gaussian optics theory, was established to increase the measurement accuracy of the counter for high-pressure natural gas. Comparing the experimental and calculated values of the calibrated model, when the pressure-resistant lens is displaced by 2 mm under atmospheric pressure, the relative error of the measured body deformation is 0.15%. When the air pressure varies in the range 0.10-5.09 MPa, the maximum relative error of optical measurement volume deformation with the change of refractive index is 0.13%, which shows that the model has high reliability and accuracy.

Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide.

Unimolecular dual agonists of the glucagon (GCG) receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) are a new class of drugs that are potentially superior to GLP-1R-specific agonists for the management of metabolic disease. The dual-agonist, peptide 15 (P15), is a glutamic acid 16 analog of GCG with GLP-1 peptide substitutions between amino acids 17 and 24 that has potency equivalent to those of the cognate peptide agonists at the GCGR and GLP-1R. Here, we have used cryo-EM to solve the structure of an active P15-GCGR-Gs complex and compared this structure to our recently published structure of the GCGR-Gs complex bound to GCG. This comparison revealed that P15 has a reduced interaction with the first extracellular loop (ECL1) and the top of transmembrane segment 1 (TM1) such that there is increased mobility of the GCGR extracellular domain and at the C terminus of the peptide compared with the GCG-bound receptor. We also observed a distinct conformation of ECL3 and could infer increased mobility of the far N-terminal His-1 residue in the P15-bound structure. These regions of conformational variance in the two peptide-bound GCGR structures were also regions that were distinct between GCGR structures and previously published peptide-bound structures of the GLP-1R, suggesting that greater conformational dynamics may contribute to the increased efficacy of P15 in activation of the GLP-1R compared with GCG. The variable domains in this receptor have previously been implicated in biased agonism at the GLP-1R and could result in altered signaling of P15 at the GCGR compared with GCG.

Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists.

Relaxin family peptide receptors (RXFPs) are the potential therapeutic targets for neurological, cardiovascular, and metabolic indications. Among them, RXFP3 and RXFP4 (formerly known as GPR100 or GPCR142) are homologous class A G protein-coupled receptors with short N-terminal domain. Ligands of RXFP3 or RXFP4 are only limited to endogenous peptides and their analogues, and no natural product or synthetic agonists have been reported to date except for a scaffold of indole-containing derivatives as dual agonists of RXFP3 and RXFP4. In this study, a new scaffold of tricyclic derivatives represented by compound 7a was disclosed as a selective RXFP4 agonist after a high-throughput screening campaign against a diverse library of 52,000 synthetic and natural compounds. Two rounds of structural modification around this scaffold were performed focusing on three parts: 2-chlorophenyl group, 4-hydroxylphenyl group and its skeleton including cyclohexane-1,3-dione and 1,2,4-triazole group. Compound 14b with a new skeleton of 7,9-dihydro-4H-thiopyrano[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-8(5H)-one was thus obtained. The enantiomers of 7a and 14b were also resolved with their 9-(S)-conformer favoring RXFP4 agonism. Compared with 7a, compound 9-(S)-14b exhibited 2.3-fold higher efficacy and better selectivity for RXFP4 (selective ratio of RXFP4 vs. RXFP3 for 9-(S)-14b and 7a were 26.9 and 13.9, respectively).

Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders.

Glucagon is a peptide hormone secreted by islet α cells. It plays crucial roles in glucose homeostasis and metabolism by activating its cognate glucagon receptor (GCGR). A naturally occurring deleterious mutation V368M in the human GCGR leads to reduced ligand binding and down-regulation of glucagon signaling. To examine the association between this mutation and metabolic disorders, a knock-in mouse model bearing homozygous V369M substitution (equivalent to human V368M) in GCGR was made using CRISPR-Cas9 technology. These GcgrV369M+/+ mice displayed lower fasting blood glucose levels with improved glucose tolerance compared with wild-type controls. They also exhibited hyperglucagonemia, pancreas enlargement and α cell hyperplasia with a lean phenotype. Additionally, V369M mutation resulted in a reduction in adiposity with normal body weight and food intake. Our findings suggest a key role of V369M/V368M mutation in GCGR-mediated glucose homeostasis and pancreatic functions, thereby pointing to a possible interplay between GCGR defect and metabolic disorders.

High-Throughput Screening Campaign Identified a Potential Small Molecule RXFP3/4 Agonist.

Relaxin/insulin-like family peptide receptor 3 (RXFP3) belongs to class A G protein-coupled receptor family. RXFP3 and its endogenous ligand relaxin-3 are mainly expressed in the brain with important roles in the regulation of appetite, energy metabolism, endocrine homeostasis and emotional processing. It is therefore implicated as a potential target for treatment of various central nervous system diseases. Since selective agonists of RXFP3 are restricted to relaxin-3 and its analogs, we conducted a high-throughput screening campaign against 32,021 synthetic and natural product-derived compounds using a cyclic adenosine monophosphate (cAMP) measurement-based method. Only one compound, WNN0109-C011, was identified following primary screening, secondary screening and dose-response studies. Although displayed agonistic effect in cells overexpressing the human RXFP3, it also showed cross-reactivity with the human RXFP4. This hit compound may provide not only a chemical probe to investigate the function of RXFP3/4, but also a novel scaffold for the development of RXFP3/4 agonists.

High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4.

Relaxin/insulin-like family peptide receptor 4 (RXFP4) is a class A G protein-coupled receptor (GPCR), and insulin-like peptide 5 (INSL5) is its endogenous ligand. Although the precise physiological role of INSL5/RXFP4 remains elusive, a number of studies have suggested it to be a potential therapeutic target for obesity and other metabolic disorders. Since selective agonists of RXFP4 are scarcely available and peptidic analogs of INSL5 are hard to make, we conducted a high-throughput screening campaign against 52,000 synthetic and natural compounds targeting RXFP4. Of the 109 initial hits discovered, only 3 compounds were confirmed in secondary screening, with JK0621-D008 displaying the best agonism at human RXFP4. Its S-configuration stereoisomer (JK1) was subsequently isolated and validated by a series of bioassays, demonstrating a consistent agonistic effect in cells overexpressing RXFP4. This scaffold may provide a valuable tool to further explore the biological functions of RXFP4.

W2476 ameliorates ß-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway.

Recent evidence shows that high glucose levels recruit carbohydrate response element-binding protein, which binds the promoter of thioredoxin-interacting protein (txnip), thereby regulating its expression in ß-cells. Overexpression of txnip not only induces ß-cell apoptosis but also reduces insulin production. Thus, the discovery of compounds that either inhibit TXNIP activity or suppress its expression was the focus of the present study. INS-1E cells stably transfected with either a txnip proximal glucose response element connected to a luciferase reporter plasmid (BG73) or full-length txnip promoter connected to a luciferase reporter plasmid (CL108) were used in primary and secondary high-throughput screening campaigns, respectively. From 256 000 synthetic compounds, a small molecule compound, W2476 [9-((1-(4-acetyl-phenyloxy)-ethyl)-2-)adenine], was identified as a modulator of the TXNIP-regulated signaling pathway following the screening and characterized using a battery of bioassays. The preventive and therapeutic properties of W2476 were further examined in streptozotocin-induced diabetic and diet-induced obese mice. Treatment with W2476 (1, 5, and 15 µmol/L) dose-dependently inhibited high glucose-induced TXNIP expression at the mRNA and protein levels in INS-1E cells and rat pancreatic islets. Furthermore, W2476 treatment prevented INS-1E cells from apoptosis induced by chronic exposure of high glucose and enhanced insulin production in vitro. Oral administration of W2476 (200 mg·kg-1·d-1) rescued streptozotocin-induced diabetic mice by promoting ß-cell survival and enhancing insulin secretion. This therapeutic property of W2476 was further demonstrated by its ability to improve glucose homeostasis and insulin sensitivity in diet-induced obese mice. Thus, chemical intervention of the TXNIP-regulated signaling pathway might present a viable approach to manage diabetes.

Clinical evidence of coenzyme Q10 pretreatment for women with diminished ovarian reserve undergoing IVF/ICSI: a systematic review and meta-analysis.

BACKGROUND: To quantitatively evaluate the effect of coenzyme Q10 (CoQ10) pretreatment on outcomes of IVF or ICSI in women with diminished ovarian reserve (DOR) based on the existing randomized controlled trials (RCTs). METHODS: Nine databases were comprehensively searched from database inception to November 01, 2023, to identify eligible RCTs. Reproductive outcomes of interest consisted of three primary outcomes and six secondary outcomes. The sensitivity analysis was adopted to verify the robustness of pooled results. RESULTS: There were six RCTs in total, which collectively involved 1529 participants with DOR receiving infertility treatment with IVF/ICSI. The review of available evidence suggested that CoQ10 pretreatment was significantly correlated with elevated clinical pregnancy rate (OR = 1.84, 95%CI [1.33, 2.53], p = 0.0002), number of optimal embryos (OR = 0.59, 95%CI [0.21, 0.96], p = 0.002), number of oocytes retrieved (MD = 1.30, 95%CI [1.21, 1.40], p < 0.00001), and E2 levels on the day of hCG (SMD = 0.37, 95%CI [0.07, 0.66], p = 0.01), along with a reduction in cycle cancellation rate (OR = 0.60, 95%CI [0.44, 0.83], p = 0.002), miscarriage rate (OR = 0.38, 95%CI [0.15, 0.98], p = 0.05), total days of Gn applied (MD = -0.89, 95%CI [-1.37, -0.41], p = 0.0003), and total dose of Gn used (MD = -330.44, 95%CI [-373.93, -286.96], p < 0.00001). The sensitivity analysis indicated that our pooled results were robust. CONCLUSIONS: These findings suggested that CoQ10 pretreatment is an effective intervention in improving IVF/ICSI outcomes for women with DOR. Still, this meta-analysis included relatively limited sample sizes with poor descriptions of their methodologies. Rigorously conducted trials are needed in the future.

Clinical evidence of hyperbaric oxygen therapy for Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials.

Objective: To evaluate the potential benefits of hyperbaric oxygen intervention on people with Alzheimer's disease (AD) based on the existing randomized controlled trials (RCTs). Methods: A systematic search was conducted in nine databases until November 17, 2023, for RCTs assessing the effect of hyperbaric oxygen intervention for AD. The primary outcomes included Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), activities of daily living (ADL), and adverse events. All results were shown in forest plots, and sensitivity analysis was adopted to further verify the robustness of the pooled results. Results: A total of 11 RCTs recruiting 847 participants were included in this meta-analysis. Based on the pooled evidence, hyperbaric oxygen could remarkably ameliorate MMSE [MD = 3.08, 95%CI (2.56, 3.61), p < 0.00001], ADAS-Cog [MD = -4.53, 95%CI (-5.05, -4.00), p < 0.00001], ADL [MD = 10.12, 95%CI (4.46, 15.79), p = 0.0005], MDA levels [SMD = -2.83, 95%CI (-5.27, -0.38), p = 0.02], SOD levels [SMD = 2.12, 95%CI (1.10, 3.15), p < 0.0001], IL-1-ß levels [SMD = -1.00, 95%CI (-1.48, -0.53), p < 0.0001], and TGF-ß1 levels [MD = 4.87, 95%CI (3.98, 5.76), p < 0.00001] without adverse events [OR = 1.17, 95%CI (0.68, 2.03), p = 0.58] for people with AD. The pooled results were robust after checking by sensitivity analysis. Conclusion: These evidences suggest that hyperbaric oxygen is an effective and safe intervention for the treatment of AD. Further studies with more rigorous design will help to fully evaluate the clinical value of hyperbaric oxygen on cognition function in people with AD. Systematic review registration: https://www.crd.york.ac.uk, identifier CRD42023483726.

The clinical value of acupuncture for women with premature ovarian insufficiency: a systematic review and meta-analysis of randomized controlled trials.

Objective: The aim of this study was to evaluate the therapeutic implications of acupuncture on improving ovarian function in women diagnosed with premature ovarian insufficiency (POI) through the implementation of randomized clinical trials (RCTs). Methods: A comprehensive search of eight databases was conducted to identify RCTs up until 5 October 2023. The outcomes included the levels of sex hormones, antral follicle count (AFC), Kupperman score, and total effective rate. The risk of bias (RoB) tool was utilized to evaluate the quality of the included studies. In order to guarantee the robustness and reliability of the findings, subgroup and sensitivity analyses were performed to investigate potential sources of heterogeneity. Results: A total of 13 RCTs comprising 775 patients were included in the study. Acupuncture demonstrated significant efficacy in reducing follicle-stimulating hormone (FSH) [SMD = 0.83, 95% CI (0.27, 1.39), I 2 = 92%, p = 0.004], enhancing estradiol levels (E2) [SMD = 0.50, 95% CI (0.07, 0.93), p = 0.02, I 2 = 87%], and increasing anti-Müllerian hormone (AMH) [SMD = 0.24, 95% CI (0.05, 0.44), p = 0.01, I 2 = 8%], as well as improving the overall effective rate [RR = 1.22, 95% CI (1.10, 1.35), p < 0.01, I 2 = 14%]. Subgroup analysis revealed that compared with non-acupuncture therapy, the acupuncture with Chinese herbal medicine (CHM) and hormone replacement therapy (HRT) group exhibited a substantial reduction in FSH levels [SMD = 1.02, 95% CI (0.52, 1.51), I 2 = 60%, p < 0.01]. Furthermore, the acupuncture with CHM group also exhibited a substantial reduction [SMD = 4.59, 95% CI (1.53, 7.65), I 2 = 98%, p < 0.01]. However, only the acupuncture with CHM and HRT group demonstrated a significant increase in E2 levels [SMD = 0.55, 95% CI (0.23, 0.87), I 2 = 12%, p < 0.01]. Conclusion: Acupuncture has demonstrated superiority over non-acupuncture in diminishing serum FSH levels and increasing serum E2, AMH, and the overall efficacy rate in women diagnosed with POI. These research findings suggest the necessity for broader-scale research with meticulous designs to fully demonstrate the efficacy and safety of acupuncture in the treatment of women with POI. Systematic review registration: https://www.crd.york.ac.uk, identifier CRD42023467751.

Prognostic effect of lncRNA BBOX1-AS1 in malignancies: a meta-analysis.

Background: With the increasing number of new cancer cases and mortality rates, cancer has become a serious global health problem, but there are no ideal cancer biomarkers for effective diagnosis. Currently, mounting evidence demonstrates that lncRNAs play a fundamental role in cancer progression. BBOX1 anti-sense RNA 1 (BBOX1-AS1) is a recently clarified lncRNA and has been identified as dysregulated in various carcinomas, and it contributes to poor survival in cancer patients. Methods: We thoroughly searched six databases for eligible articles published as of 27, April 2023. The association of BBOX1-AS1 expression levels with prognostic and clinicopathological parameters was assessed by odds ratios (OR) and hazard ratios with 95% CIs. Additionally, we further validated our results utilizing the GEPIA online database. Results: Eight studies comprising 602 patients were included in this analysis. High BBOX1-AS1 expression indicated poor overall survival (OS) (hazard ratios = 2.30, 95% Cl [1.99, 2.67], p < 0.00001) when compared with low BBOX1-AS1 expression. Furthermore, BBOX1-AS1 expression was positively correlated with lymph node metastasis (OR = 3.00, 95% CI [1.71-5.28], p = 0.0001) and advanced tumor stage (OR = 3.74, 95% CI [2.63-5.32], p < 0.00001) for cancer patients. Moreover, BBOX1-AS1 was remarkably upregulated in 12 malignancies, and the elevated BBOX1-AS1 expression predicted poorer OS and worse disease-free survival (DFS) confirmed through the GEPIA online gene analysis tool. Conclusion: The findings highlight that BBOX1-AS1 was significantly associated with detrimental overall survival, disease-free survival, lymph node metastasis and tumor stage; thus, it could act as a novel promising biomarker to predict the clinicopathological characteristics and prognosis for various cancers.

Clinical evidence of growth hormone for infertile women with diminished ovarian reserve undergoing IVF: a systematic review and meta-analysis.

Objective: To appraise the current randomized clinical trials (RCTs) for evidence of the association of growth hormone (GH) with improved outcomes in infertile women with diminished ovarian reserve (DOR) undergoing in vitro fertilization (IVF). Methods: Relevant RCTs published in Chinese or English were identified through a comprehensive search of nine databases from the period of database inception to April 20, 2023. We included trials investigating adjuvant GH during ovarian stimulation and reported the subsequent outcomes. The group with adjuvant GH treatment and the group without adjuvant GH treatment were set up as the trial and control groups, respectively. The quality of RCTs was measured according to the Cochrane Collaboration Handbook. Results: Of the 579 studies initially identified, 10 RCTs comprising 852 infertile women with DOR were included. The GH dose of individual trials ranged between 3 and 5 IU/day. Overall, we judged the trials to be at high risk of bias in the blinding domain. Pooled results showed that GH was associated with an increased clinical pregnancy rate (RR = 1.63, 95%CI [1.31, 2.03], p < 0.0001) and a greater number of oocytes retrieved (MD = 0.91, 95%CI [0.47, 1.35], p < 0.0001). Favorable associations were also observed when ovarian stimulation was combined with GH therapy for improving the optimal embryos rate (RR = 1.84, 95%CI [1.30, 2.59], p = 0.0005) and the number of optimal embryos (MD = 0.28, 95%CI [0.08, 0.48], p = 0.005) along with reducing the cycle cancellation rate (RR = 0.46, 95%CI [0.24, 0.89], p = 0.02). Moreover, GH resulted in an increase in the fertilization rate (RR = 1.33, 95%CI [1.18, 1.50], p < 0.00001) and the embryo implantation rate (RR = 1.56, 95%CI [1.21, 2.01], p = 0.0006). In addition, there was a significant enhancement in estradiol levels (SMD = 1.18, 95%CI [0.46, 1.91], p = 0.001) and endometrial thickness (MD = 0.75, 95%CI [0.41, 1.09], p < 0.0001) on the day of hCG. With regard to the total number of days and total dose of gonadotrophins used, GH treatment was correlated with shorter days (MD = -0.26, 95%CI [-0.46, -0.06], p = 0.01) and lower dose (MD = -460.97, 95%CI [-617.20, -304.73], p < 0.00001) of gonadotrophins applied during ovarian stimulation. Furthermore, GH in conjunction with the GnRH antagonist protocol was more conducive to improving the number of oocytes retrieved when compared with the GnRH agonist protocol (p < 0.0001). Moreover, a notable association was also seen in IVF combined with GH more than or equal to 4.5 IU/day to increase the number of optimal embryos and estradiol levels on the day of hCG (p < 0.05). Conclusion: For infertile women with DOR undergoing IVF, adjuvant treatment with GH during ovarian stimulation protocols showed better clinical outcomes, shorter days and lower dosages of gonadotrophin required. Furthermore, well-designed RCTs are needed to verify our results in the future. Systematic review registration: https://www.crd.york.ac.uk PROSPERO (CRD42023421739).

Prognostic significance of long noncoding RNA TTN-AS1 in various malignancies.

BACKGROUND: Increasing evidence has demonstrated that high TTN-AS1 expression is highly related to poor prognosis in diverse human cancers. However, the findings concerning the prognostic value of TTN-AS1 were inconsistent, as these conclusions were usually drawn with relatively small sample sizes. Hence, this meta-analysis proposes to investigate the prognostic significance of TTN-AS1 in multiple malignancies systematically. METHODS: Web of Science, Springer, Embase, PubMed, Cochrane Library, and Scopus databases were comprehensively searched to retrieve studies related to the TTN-AS1 expression with the prognosis of malignancies. The significance of the TTN-AS1 in cancers was estimated by hazard ratios (HRs) or odds ratios (ORs). Additionally, the Gene Expression Profiling Interactive Analysis (GEPIA) analysis tool was used to strengthen our results further. RESULTS: Twenty studies involving 17 different cancers and 1330 patients were recruited into this meta-analysis. The research revealed that high TTN-AS1 expression was remarkably associated with unfavorable overall survival (OS) (HR = 2.07, 95%CI [1.78, 2.41], p < .00001) when compared with low TTN-AS1 expression in malignancies. Additionally, elevated TTN-AS1 expression significantly contributed to lymph node metastasis (OR = 4.09, 95%CI [3.08, 5.44], p < .0001), larger tumor size (OR = 2.42, 95%CI [1.56, 3.77], p < .0001), worse tumor differentiation (OR = 0.36, 95%CI [0.22, 0.59], p < .0001) and more advanced tumor stage (OR = 0.29, 95%CI [0.22, 0.38], p < .0001) with low or no heterogeneity existing. Moreover, high TTN-AS1 expression  was connected with worse disease-free survival in five different cancers based on the GEPIA online database. CONCLUSIONS: The results of this meta-analysis support that high TTN-AS1 expression significantly correlates with worse prognosis in various cancers. Therefore, TTN-AS1 may be considered as a novel biomarker for malignancies.

The effect of ovarian injection of autologous platelet rich plasma in patients with poor ovarian responder: a systematic review and meta-analysis.

Objective: To evaluate the effects of ovarian injection of autologous platelet rich plasma (aPRP) on patients with poor ovarian responder (POR) based on the existing clinical evidence. Methods: According to systematic review and meta-analysis, we comprehensively searched nine databases established as of September 6, 2023, and evaluated the impact of ovarian PRP infusion on poor ovarian responder. The research results include serum follicle-stimulating hormone(FSH) and anti-Mullerian hormone(AMH) levels, antral Follicle Count(AFC), oocyte number, and embryo number. The Newcastle Ottawa Scale (NOS) was used to evaluate the quality of inclusion in trials. Results: Add up to 10 studies consisting of 793 participants were included in the meta-analysis. A review of existing evidence showed that intraovarian injection of PRP has significant therapeutic effects in increasing levels of anti-Müllerian hormone (AMH) (SMD=0.44,95% CI [0.07,0.81], p=0.02), antral follicle count (AFC) (MD=1.15,95% CI [0.4,1.90], p=0.003), oocyte count (MD=0.91, 95% CI [0.40, 1.41], p=0.0004), and embryo number (MD=0.78, 95% CI [0.5,1.07], p<0.0001). We compared the relevant data of patients before and after treatment after 2 months of intervention. It can be seen that ovarian injection of PRP treatment for 2 months has better effects in reducing FSH levels, increasing AMH levels, increasing antral follicle count, and increasing the number of oocytes and embryos (p<0.05). When the dose of PRP injected into each ovary was ≥ 4ml, there was also a significant correlation (p<0.05) with improving the number of AFC, oocytes and embryos. Significant heterogeneity existed among the studies. Conclusion: The pooled results suggest that intra-ovarian injection of PRP can promote ovarian regeneration and improve the reproductive outcomes of patients with ovarian dysfunction. This therapy may have significant clinical potential in improving sex hormone levels, increasing AFC, oocyte count, and embryo count. However, this findings still requires more rigorous and extensive trials worldwide to determine the value of intra-ovarian injection of PRP in POR patients. Systematic review registration: https://www.crd.york.ac.uk, Identifier CRD42023451232.

The clinical value of progestin-primed ovarian stimulation protocol for women with diminished ovarian reserve undergoing IVF/ICSI: a systematic review and meta-analysis.

Background: To determine whether progestin-primed ovarian stimulation (PPOS) is more effective for women with diminished ovarian reserve (DOR) than clomiphene citrate (CC)/letrozole (LE) plus gonadotropin in IVF or ICSI treatment. Methods: Nine databases were searched until May 24, 2023, to identify relevant studies. Forest plots were used to present the results of this meta-analysis. Begg's and Egger's tests were applied to estimate publication bias. Subgroup and sensitivity analysis were performed to check the potential sources of heterogeneity and verify the robustness of the pooled results, respectively. Results: A total of 14 studies with 4182 participants were included for meta-analysis. There was evidence of a statistically notable increase in clinical pregnancy rate (OR = 1.39, 95%CI [1.01, 1.91], p = 0.05), optimal embryos rate (OR = 1.50, 95%CI [1.20, 1.88], p = 0.0004), and cumulative pregnancy rate (OR = 1.73, 95%CI [1.14, 2.60], p = 0.009), the duration and the amount of gonadotropin required (MD = 1.56, 95%CI [0.47, 2.66], p = 0.005; SMD = 1.51, 95%CI [0.90, 2.12], p < 0.00001), along with decrease cycle cancellation rate (OR = 0.78, 95%CI [0.64, 0.95], p = 0.02), luteinizing hormone (LH) level on the day of hCG (SMD = -0.81, 95%CI [-1.10, -0.53], p < 0.00001), and premature LH surge rate (OR = 0.10, 95%CI [0.07, 0.15], p < 0.00001) when PPOS was used. No evidence for publication bias within results was revealed. Conclusions: Based on evidence-based results, PPOS protocol seems to improve IVF/ICSI outcomes for women with DOR. More research with larger sample sizes and rigorous designs are required to further explore the value of PPOS among women diagnosed with DOR. Systematic review registration: www.crd.york.ac.uk, identifier CRD42023430202.