Oral squamous cell carcinoma (OSCC) is a malignant tumor that seriously threatens human health. Its typical biological characteristics include strong local invasiveness, high lymph node metastasis rate, and high recurrence rate after treatment. Hepatocyte growth factor (HGF), cellular-mesenchymal to epithelial transition factor (c-Met), and the HGF/c-Met signaling pathway are involved in the regulation of the occurrence and development of OSCC. HGF and c-Met proteins are overexpressed in OSCC, and multiple studies have suggested that they are significantly associated with the malignant characteristics of tumors and poor prognosis. Furthermore, the abnormal activation of the HGF/c-Met signaling pathway (driven by HGF-dependent autocrine/paracrine or non-dependent mechanisms such as MET gene mutations, amplification, fusion, and protein overexpression) can synergistically promote tumor cell invasion, metastasis, and angiogenesis by activating downstream signaling pathways. However, HGF/c-Met can also mediate immune escape by promoting lactate secretion increase, inducing programmed death ligand 1 (PD-L1) expression upregulation, activating and expanding myeloid-derived suppressor cells, and promoting the proliferation of regulatory T cells (Tregs). In addition, the crosstalk between the HGF/c-Met signaling pathway and key pathways such as phosphatidylinositide 3-kinases (PI3K)/protein kinase B (AKT), epidermal growth factor receptor (EGFR), Janus kinase (JAK)/signal transducer and activator of transcription (STAT3), and non-coding RNAs can also promote tumor progression. Currently, three types of targeted drugs have been developed targeting the HGF/c-Met pathway: HGF monoclonal antibody, c-Met monoclonal antibody, and tyrosine kinase inhibitors. Some of these drugs have entered clinical trials. However, the emergence of drug resistance during treatment, especially the bidirectional compensatory activation of alternative signaling pathways such as EGFR, has become a major challenge in clinical practice. This article aims to provide an in-depth analysis of the mechanism of action of the HGF/c-Met pathway in OSCC and its interaction with other pathways, and to review the current research status of existing therapeutic drugs. The aim is to provide an important theoretical basis for developing more effective combined treatment strategies and achieving individualized precise treatment, ultimately improving the clinical prognosis and quality of life of patients.

Objective This study aimed to develop an automated method for syndrome element differenti-ation in Traditional Chinese Medicine(TCM).Methods We first constructed and trained an Instruction-tuned Multi-Task TCM text embedding model(Instr-MT-TCM)using four distinct TCM task datasets,including domain knowledge,synonymous terminology,syndrome differentiation and treatment,and TCM case labels.Subsequently,five TCM diagnostics experts holding master's degrees or higher were organized to screen a real-world TCM case dataset and annotate symptoms and signs.The purpose was to evaluate the F1-score of the proposed method—the combination of Instr-MT-TCM and a Large Language Model(LLM)—by comparing its performance against the manual annotation result on the syndrome element differentiation task.Finally,to validate its feasibility in real-world clinical settings,the method was applied to 48 prostate cancer cases to calculate the syndrome element scores.Results The Instr-MT-TCM model showed rapid performance improvement in its early training phase,achieving a Recall@1(R@1)of 0.848.Experts curated a dataset of 1,793 real-world clinical cases,covering 34 common diseases and 66 syndrome patterns.In the syndrome element differentiation task,the collaborative framework of LLM and Instr-MT-TCM achieved a mean F1-score of 0.927,outperforming the 0.512 from manual annota-tion.The syndrome element analysis revealed that the predominant elements of disease nature were fire(heat)and yin deficiency,while the main elements of disease location were bladder and kidney.Conclusion This study proposes and validates a novel method for automated TCM syndrome element dif-ferentiation based on the synergy between LLM and our custom Instr-MT-TCM model.Achieving a high F1-score(0.927)on real-world data,the method demonstrates excellent accuracy and generalization ability.Its application in prostate cancer analysis highlights its significant clinical potential,offering effective technical support,and a new research direction for intelligent TCM syndrome element differentiation.

Objective This study aimed to develop an automated method for syndrome element differenti-ation in Traditional Chinese Medicine(TCM).Methods We first constructed and trained an Instruction-tuned Multi-Task TCM text embedding model(Instr-MT-TCM)using four distinct TCM task datasets,including domain knowledge,synonymous terminology,syndrome differentiation and treatment,and TCM case labels.Subsequently,five TCM diagnostics experts holding master's degrees or higher were organized to screen a real-world TCM case dataset and annotate symptoms and signs.The purpose was to evaluate the F1-score of the proposed method—the combination of Instr-MT-TCM and a Large Language Model(LLM)—by comparing its performance against the manual annotation result on the syndrome element differentiation task.Finally,to validate its feasibility in real-world clinical settings,the method was applied to 48 prostate cancer cases to calculate the syndrome element scores.Results The Instr-MT-TCM model showed rapid performance improvement in its early training phase,achieving a Recall@1(R@1)of 0.848.Experts curated a dataset of 1,793 real-world clinical cases,covering 34 common diseases and 66 syndrome patterns.In the syndrome element differentiation task,the collaborative framework of LLM and Instr-MT-TCM achieved a mean F1-score of 0.927,outperforming the 0.512 from manual annota-tion.The syndrome element analysis revealed that the predominant elements of disease nature were fire(heat)and yin deficiency,while the main elements of disease location were bladder and kidney.Conclusion This study proposes and validates a novel method for automated TCM syndrome element dif-ferentiation based on the synergy between LLM and our custom Instr-MT-TCM model.Achieving a high F1-score(0.927)on real-world data,the method demonstrates excellent accuracy and generalization ability.Its application in prostate cancer analysis highlights its significant clinical potential,offering effective technical support,and a new research direction for intelligent TCM syndrome element differentiation.

Objective:To explore whether the duration of oral estrogen treatment before progesterone application affects neonatal outcome in single frozen-thawed embryo transfer (FET) with artificial cycles.Methods:It was a retrospective cohort study. Patients who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), receiving single frozen blastocyst transfer with artificial cycle and delivering a single live birth in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University between January 2015 and December 2019 were included. All FET cycles were divided into four groups according to the estrogen treatment duration before progesterone application, ≤12 d ( n=306), 13-15 d ( n=620), 16-18 d ( n=471), and ≥19 d ( n=275). Primary outcome was the incidence of small for gestational age (SGA). Secondary outcomes were the incidence of preterm birth, low birth weight, macrosomia and large for gestational age (LGA). Results:A total of 1 672 single blastocyst transfer cycles were included. The incidence of SGA among the four groups was 7.8% (24/306), 4.8% (30/620), 5.7% (27/471), and 7.6% (21/275), respectively, with no statistically significant difference ( P=0.204). The results of multiple logistic regression analysis showed that the duration of estrogen used before progesterone application did not affect the incidence of SGA in singleton offspring (with ≤12 d as the reference, 13-15 d: a OR=1.37, 95% CI: 0.70-2.70, P=0.361; 16-18 d: a OR=0.74, 95% CI: 0.40-1.36, P=0.336; ≥19 d: a OR=0.81, 95% CI: 0.44-1.49, P=0.501). There were no significant differences in neonatal preterm birth rate ( P=0.204), low birth weight ( P=0.582), incidences of macrosomia ( P=0.201) and LGA infants ( P=0.335) among the four groups. Conclusion:In artificial FET cycle, the duration of oral estrogen treatment before progesterone application does not affect the outcome of singleton offspring after single blastocyst transfer.

Objective:To explore whether the duration of oral estrogen treatment before progesterone application affects neonatal outcome in single frozen-thawed embryo transfer (FET) with artificial cycles.Methods:It was a retrospective cohort study. Patients who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), receiving single frozen blastocyst transfer with artificial cycle and delivering a single live birth in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University between January 2015 and December 2019 were included. All FET cycles were divided into four groups according to the estrogen treatment duration before progesterone application, ≤12 d ( n=306), 13-15 d ( n=620), 16-18 d ( n=471), and ≥19 d ( n=275). Primary outcome was the incidence of small for gestational age (SGA). Secondary outcomes were the incidence of preterm birth, low birth weight, macrosomia and large for gestational age (LGA). Results:A total of 1 672 single blastocyst transfer cycles were included. The incidence of SGA among the four groups was 7.8% (24/306), 4.8% (30/620), 5.7% (27/471), and 7.6% (21/275), respectively, with no statistically significant difference ( P=0.204). The results of multiple logistic regression analysis showed that the duration of estrogen used before progesterone application did not affect the incidence of SGA in singleton offspring (with ≤12 d as the reference, 13-15 d: a OR=1.37, 95% CI: 0.70-2.70, P=0.361; 16-18 d: a OR=0.74, 95% CI: 0.40-1.36, P=0.336; ≥19 d: a OR=0.81, 95% CI: 0.44-1.49, P=0.501). There were no significant differences in neonatal preterm birth rate ( P=0.204), low birth weight ( P=0.582), incidences of macrosomia ( P=0.201) and LGA infants ( P=0.335) among the four groups. Conclusion:In artificial FET cycle, the duration of oral estrogen treatment before progesterone application does not affect the outcome of singleton offspring after single blastocyst transfer.

Objective:To explore the effect of thin endometrial thickness (EMT) on the low birth weight (LBW) of singleton in fresh embryo transfer cycle.Methods:It was a retrospective cohort study. The data of singleton deliveries achieved after fresh cleavage embryo transfer in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University from January 2015 to February 2019 were included. A total of 2247 cycles were included and were divided into three groups depending on the EMT: group A≤7.5 mm, group B 7.6-12.0 mm and group C>12.0 mm. The major outcome measure was LBW. Binary logistic regression was performed to correct for confounding factors.Results:Singleton birthweight was lower in group A [3000(2525, 3350) g] compared with group B and group C [3350(3050, 3650) g, 3400(3100, 3690) g, all P<0.001]. The incidence of LBW in group A [24.7% (20/81)] was significantly higher than that in groups B and C [4.0% (57/1414), 5.3% (40/752), all P<0.001], while there was no statistical difference between groups B and C ( P>0.05). Body mass index ( P=0.029), estrogen level on the human chorionic gonadotropin (hCG) trigger day ( P=0.027), EMT ( P<0.001), gestational age ( P<0.001) and the gender of the newborn ( P<0.001) were independent factors of LBW. The incidence of LBW increased when the body mass index and gestational age were smaller and estrogen level on the hCG trigger day was ≥4000 ng/L. Taking group B as control group, the incidence of LBW in group A increased significantly and was an independent risk factor for LBW (a OR=4.39, 95% CI=1.85-10.46, P<0.001), while the incidence of LBW in group C had no significant difference (a OR=0.90, 95% CI=0.51-1.59, P=0.723). Conclusion:In the fresh cleavage stage embryo transfer cycle, singleton birth weight was lower in thin EMT group. And thin EMT was an independent risk factor for LBW of singleton delivery.

Objective:To compare the cumulative live birth rate (CLBR) of gonadotropin-releasing hormone (GnRH) antagonist protocol, medroxyprogesterone (MPA) protocol and clomiphene citrate (CC) protocol in low prognosis population with decreased ovarian reserve.Methods:It was a retrospective cohort study. Patients who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University from January 2015 to May 2018 were recruited. Including POSEIDON group 3 and group 4, GnRH-antagonist protocol, MPA, and CC protocol were used for ovulation stimulation. The basic data and clinical outcomes of the three protocols were analyzed. The main outcome measure was CLBR. With the GnRH-antagonist group as the reference, the adjusted odds ratio ( aOR) and 95% confidence interval ( CI) of the MPA group and the CC group were calculated. Results:In the POSEIDON group 3, the CLBR of the three protocols was not statistically different. After logistic regression analysis, the ovulation stimulation protocols did not affect the CLBR of POSEIDON 3 group ( P=0.226, P=0.468). In the POSEIDON group 4, the CLBR of the MPA group was higher than that of the CC group (10.7% vs. 5.4%, P=0.002). Using binary logistic regression and GnRH-antagonist group as the control, the CLBR of the MPA protocol was higher (a OR=2.22, 95% CI=1.17-4.24, P=0.021), the CLBR of the CC protocol was not significantly different from the GnRH-antagonist group (a OR=0.95, 95% CI=0.48-1.85, P=0.868). Conclusion:For patients under 35 years old with low ovarian reserve, the clinical outcomes of the three ovulation stimulation protocols were similar. For patients who are 35 years or older with low ovarian reserve, the CLBR of the MPA protocol was higher.

Objective:To explore the effect of thin endometrial thickness (EMT) on the low birth weight (LBW) of singleton in fresh embryo transfer cycle.Methods:It was a retrospective cohort study. The data of singleton deliveries achieved after fresh cleavage embryo transfer in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University from January 2015 to February 2019 were included. A total of 2247 cycles were included and were divided into three groups depending on the EMT: group A≤7.5 mm, group B 7.6-12.0 mm and group C>12.0 mm. The major outcome measure was LBW. Binary logistic regression was performed to correct for confounding factors.Results:Singleton birthweight was lower in group A [3000(2525, 3350) g] compared with group B and group C [3350(3050, 3650) g, 3400(3100, 3690) g, all P<0.001]. The incidence of LBW in group A [24.7% (20/81)] was significantly higher than that in groups B and C [4.0% (57/1414), 5.3% (40/752), all P<0.001], while there was no statistical difference between groups B and C ( P>0.05). Body mass index ( P=0.029), estrogen level on the human chorionic gonadotropin (hCG) trigger day ( P=0.027), EMT ( P<0.001), gestational age ( P<0.001) and the gender of the newborn ( P<0.001) were independent factors of LBW. The incidence of LBW increased when the body mass index and gestational age were smaller and estrogen level on the hCG trigger day was ≥4000 ng/L. Taking group B as control group, the incidence of LBW in group A increased significantly and was an independent risk factor for LBW (a OR=4.39, 95% CI=1.85-10.46, P<0.001), while the incidence of LBW in group C had no significant difference (a OR=0.90, 95% CI=0.51-1.59, P=0.723). Conclusion:In the fresh cleavage stage embryo transfer cycle, singleton birth weight was lower in thin EMT group. And thin EMT was an independent risk factor for LBW of singleton delivery.

Objective:To compare the cumulative live birth rate (CLBR) of gonadotropin-releasing hormone (GnRH) antagonist protocol, medroxyprogesterone (MPA) protocol and clomiphene citrate (CC) protocol in low prognosis population with decreased ovarian reserve.Methods:It was a retrospective cohort study. Patients who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University from January 2015 to May 2018 were recruited. Including POSEIDON group 3 and group 4, GnRH-antagonist protocol, MPA, and CC protocol were used for ovulation stimulation. The basic data and clinical outcomes of the three protocols were analyzed. The main outcome measure was CLBR. With the GnRH-antagonist group as the reference, the adjusted odds ratio ( aOR) and 95% confidence interval ( CI) of the MPA group and the CC group were calculated. Results:In the POSEIDON group 3, the CLBR of the three protocols was not statistically different. After logistic regression analysis, the ovulation stimulation protocols did not affect the CLBR of POSEIDON 3 group ( P=0.226, P=0.468). In the POSEIDON group 4, the CLBR of the MPA group was higher than that of the CC group (10.7% vs. 5.4%, P=0.002). Using binary logistic regression and GnRH-antagonist group as the control, the CLBR of the MPA protocol was higher (a OR=2.22, 95% CI=1.17-4.24, P=0.021), the CLBR of the CC protocol was not significantly different from the GnRH-antagonist group (a OR=0.95, 95% CI=0.48-1.85, P=0.868). Conclusion:For patients under 35 years old with low ovarian reserve, the clinical outcomes of the three ovulation stimulation protocols were similar. For patients who are 35 years or older with low ovarian reserve, the CLBR of the MPA protocol was higher.

Objective:To investigate the optimal number of oocytes retrieved of early follicular phase prolonged protocol and to reduce the risk of ovarian hyperstimulation syndrome (OHSS) while achieving a high cumulative live birth rate (CLBR).Methods:It was a retrospective cohort study. Patients who underwent the first in vitro fertilization or intracytoplasmic sperm injection in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University from January 2014 to December 2017 were included. According to the number of oocytes retrieved, we divided all patients into 5 groups, group A: 1-5 oocytes, group B: 6-10 oocytes, group C: 11-15 oocytes, group D: 15-20 oocytes, group E: >20 oocytes. The basic and clinical data of 5 groups were analyzed. The main outcome measures were CLBR and the incidence of OHSS. Binary logistic regression was used to correct confounding factors to analyze the factors affecting the CLBR and the incidence of OHSS. We calculated the CLBR and the incidence of OHSS in each group. Results:The maternal age (a OR=0.93, 95% CI=0.90-0.97, P<0.001) and body mass index (a OR=0.95, 95% CI=0.92-0.99, P=0.02) were risk factors for CLBR. The number of oocytes retrieved was the protection factor for CLBR (a OR=1.27, 95% CI=1.20-1.35, P<0.001). The maternal age (a OR=0.94, 95% CI=0.91-0.97, P<0.001), body mass index (a OR=0.96, 95% CI=0.93-0.99, P=0.04), and increase in the number of oocytes retrieved (a OR=1.84, 95% CI=1.64-2.06, P<0.001) were the independent risk factors of the incidence of OHSS. With the increase of the number of oocytes retrieved (group A to group C), CLBR increased significantly [51.6% (157/304), 64.8% (869/1314), 75.2% (1334/1774), P<0.001], while the differences among groups C, D and E were not statistically significant ( P>0.05). With the increase in the number of oocytes retrieved (group A to group E), the incidence of OHSS increased significantly [0.3% (1/304), 3.3% (44/1314), 5.0% (88/1774), 9.8% (104/1065), 15.4% (77/499), P<0.001], especially when the number of oocytes retrieved was >15. Conclusion:For the early follicular phase prolonged protocol, the optimal number of oocytes retrieved is 11-15, which can obtain higher CLBR, and reduce the incidence of OHSS.