Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field.

Acetaminophen (APAP), the most frequently used mild analgesic and antipyretic drug worldwide, is implicated in causing 46% of all acute liver failures in the USA and between 40% and 70% in Europe. The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine (NAC); however, its efficacy is limited in cases of advanced liver injury or when administered at a late stage. In the current study, we discovered that treatment with a moderate intensity static magnetic field (SMF) notably reduced the mortality rate in mice subjected to high-dose APAP from 40% to 0%, proving effective at both the initial liver injury stage and the subsequent recovery stage. During the early phase of liver injury, SMF markedly reduced APAP-induced oxidative stress, free radicals, and liver damage, resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione (GSH). During the later stage of liver recovery, application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery, even 24 h post overdose, when the effectiveness of NAC alone substantially declines. Overall, this study provides a non-invasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose. Of note, this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP, and potentially other toxic overdoses.

Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas.

Objective: There is an ongoing debate about whether the management of gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) should follow the guidelines of small-cell lung cancer (SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart. Methods: We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing (NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC (LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes. Results: We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas. Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC ( TERT amplification), colorectal NEC ( KRAS mutation), and bile tract NEC ( ARID1A mutation). The gene disparities between small-cell NEC (SCNEC) and large-cell NEC (LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/ RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in 22.2% of the patients, and they had longer progression-free survival (PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40 (0.21-0.75), P=0.006]. Conclusions: This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.

Real-world evaluation of first-line treatment of extensive-stage small-cell lung cancer with atezolizumab plus platinum/etoposide: a focus on patients with brain metastasis.

PURPOSE: A previous real-world study conducted in China confirmed that first-line atezolizumab, in combination with etoposide/platinum (EP), leads to significantly longer progression-free survival (PFS) compared to EP alone in patients with extensive-stage small-cell lung cancer (ES-SCLC). The present study aimed to provide updated survival outcome data and evaluate the clinical efficacy of atezolizumab plus chemotherapy in ES-SCLC patients with brain metastasis (BM). METHODS: This retrospective study included 225 patients with ES-SCLC who were treated with EP alone (EP group) or a combination of EP + atezolizumab (atezolizumab group). Survival outcomes for the total study sample and patients in the BM subgroup were estimated using the Kaplan-Meier method. RESULTS: The atezolizumab group continued to demonstrate significantly longer PFS than the EP group (hazard ratio [HR], 0.68). The median overall survival (OS) was 26.2 months in the atezolizumab group vs. 14.8 months in the EP group (HR, 0.63). Additionally, among the BM patients in our study, the median PFS was found to be longer in the atezolizumab group (7.0 months) than in the EP group (4.1 months) (HR, 0.46). The OS of the BM patients did not differ significantly between the two treatment groups. CONCLUSIONS: The addition of atezolizumab to EP as a first-line treatment for ES-SCLC was found to improve survival outcomes. This treatment combination may also prolong PFS in patients with BM, regardless of the administration of cranial irradiation. However, among the BM patients in our study, there was no significant difference in OS between the two treatment groups.

Cluster analysis reveals a homogeneous subgroup of PCOS women with metabolic disturbance associated with adverse reproductive outcomes.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a heterogeneous and complex reproductive endocrinological disease that could lead to infertility. There were many attempts to classify PCOS but it remains unclear whether there is a specific subgroup of PCOS that is associated with the best or worst reproductive outcomes of assisted reproductive techniques (ART). METHODS: Infertile PCOS patients who underwent their first cycle of in vitro fertilization (IVF) in West China Second University Hospital, Sichuan University from January 2019 to December 2021 were included. Basic clinical and laboratory information of each individual were extracted. Unsupervised cluster analysis was performed. Controlled ovarian stimulation parameters and reproductive outcomes were collected and compared between the different clusters of PCOS. RESULTS: Our analysis clustered women with PCOS into "reproductive", "metabolic", and "balanced" clusters based on nine traits. Reproductive group was characterized by high levels of testosterone (T), sex hormone-binding globulin (SHBG), follicular stimulation hormone (FSH), luteinizing hormone (LH), and anti-Müllerian hormone (AMH). Metabolic group was characterized by high levels of body mass index (BMI), fasting insulin, and fasting glucose. Balanced group was characterized by low levels of the aforementioned reproductive and metabolic parameters, except for SHBG. Compared with PCOS patients in reproductive and balanced clusters, those in metabolic cluster had lower rates of good quality day 3 embryo and blastocyst formation. Moreover, PCOS patients in the reproductive cluster had greater fresh embryo transfer (ET) cancelation rate and clinical pregnancy rate after fresh ET than metabolic cluster (odds ratio [OR] = 3.37, 95% confidence interval [CI]: 1.77-6.44, and OR = 6.19, 95% CI: 1.58-24.24, respectively). And compared with PCOS of metabolic cluster, PCOS of balanced cluster also had higher chance for fresh ET cancelation (OR = 2.83, 95% CI: 1.26-6.35). CONCLUSION: Our study suggested that PCOS patients in metabolic cluster may be associated with adverse reproductive outcomes and might need individualized treatment and careful monitoring before and during ART.

Thyroid transcription factor 1 (TTF-1) negativity as a predictor of unfavorable response to EGFR-TKI therapy in advanced lung adenocarcinoma patients with EGFR mutations.

BACKGROUND: The absence of thyroid transcription factor 1 (TTF-1) is associated with a lower frequency of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD). The aim of this study was to assess the impact of TTF-1 expression on the clinical response to EGFR-tyrosine kinase inhibitor (TKI) treatment in patients with advanced LUAD. METHODS: The data of patients with advanced LUAD who were admitted to the Beijing Tiantan Hospital and Peking University Cancer Hospital (China) between April 2009 and May 2023 was retrospectively analyzed. RESULTS: A total of 227 patients diagnosed with advanced LUAD were included, of which 28.2% (64/227) had TTF-1-negative adenocarcinoma, while 54.6% (124/227) harbored EGFR mutations. Negative TTF-1 expression significantly correlated with male sex (68.8% vs. 42.3%, p < 0.001), history of heavy smoking (57.8% vs. 36.2%, p = 0.003), poorly differentiated tumors (86.5% vs. 43.2%, p < 0.001), and lower frequency of EGFR mutations (26.6% vs. 65.6%, p < 0.001) compared with TTF-1 positivity. Multivariable logistic regression showed that low prevalence of EGFR mutations (p < 0.001) and male sex (p = 0.006) were independent predictive factors for the negative expression of TTF-1. Patients lacking TTF-1 also exhibited worse overall response rate (ORR; 23.5% vs. 54.2%, p = 0.019), disease control rate (DCR; 58.8% vs. 89.7%, p = 0.003), and median progression-free survival (PFS; 2.9 vs. 11.6 months, p < 0.001) following treatment with EGFR-TKIs compared to the TTF-1-positive patients with EGFR mutations. CONCLUSIONS: Patients with TTF-1-negative and EGFR-mutant LUAD show a diminished response to EGFR-TKIs.

Clinical outcomes of atezolizumab in combination with etoposide/platinum for treatment of extensive-stage small-cell lung cancer: A real-world, multicenter, retrospective, controlled study in China.

Objective: Atezolizumab along with chemotherapy has prolonged the survival of patients with extensive-stage small-cell lung cancer (ES-SCLC) worldwide, although real-world (RW) data are lacking in China. This study was designed to evaluate the efficacy and clinical outcomes of atezolizumab plus etoposide/platinum (EP). Methods: Data obtained in this retrospective study were captured from six oncology units of five medical facilities from January 2019 to April 2022. For first-line treatments, atezolizumab combined with EP vs. EP alone, we primarily evaluated progression-free survival (PFS); other efficacy indicators, including overall survival (OS), objective response rate (ORR), and patterns of SCLC progression and adverse events (AEs) were assessed. Results: The primary analysis included data from 225 patients, of whom 133 received EP along with atezolizumab (atezolizumab group) and 92 received EP alone (EP group). The PFS duration of the atezolizumab group [7.10 months; 95% confidence interval (95% CI), 6.53-9.00] exceeded that of the EP group (6.50 months; 95% CI, 4.83-7.53). Overall, the hazard ratio (HR) was 0.69 (95% CI, 0.49-0.97) (P=0.029); particularly, the HR was 0.54 (95% CI, 0.36-0.80) among patients undergoing ≥4 chemotherapy cycles and 0.33 (95% CI, 0.20-0.56) among individuals with atezolizumab maintenance. The ORR and disease-control rate (DCR) were similar between the two groups. Because of incomplete OS data, the median OS was not determined for either group. Bone marrow suppression was the most common AE detected (58.6%) in the atezolizumab group. Immune-related AEs occurred in 19 patients in the atezolizumab group (14.3%), with only one case of grade 3 encephalitis. Conclusions: This RW study in China demonstrated improved clinical outcomes of atezolizumab along with EP for ES-SCLC, particularly in the chemosensitive population. These results align with the results of the IMpower133 study, although the impact of this treatment modality on OS warrants additional follow-up studies.

The Essential Role of Body Weight in Adjusting Gn Dosage to Prevent High Ovarian Response for Women With PCOS During IVF: A Retrospective Study.

Polycystic ovarian syndrome (PCOS) is the major cause of anovulatory infertility. Since women with PCOS are often accompanied by increased body weight and hyper response to controlled ovarian stimulation, individualized gonadotropin (Gn) dose is required to achieve a therapeutic effect while minimizing the risk of ovarian hyperstimulation simultaneously. We aimed to investigate the essential role of body weight in optimizing initial Gn dosage for PCOS patients during in vitro fertilization (IVF). We retrospectively included 409 infertile PCOS patients who used gonadotropin-releasing hormone (GnRH)-antagonist fixed protocol and underwent their first cycle of IVF in West China Second University Hospital from January 2019 to June 2021. Baseline characteristics controlled ovarian stimulation parameters, and reproductive outcomes were compared between patients with different body weights and different ovarian responses. Multivariable linear regression analyses were adopted to investigate the relationship between body weight and initial Gn dosage. Receiver operating characteristic (ROC) curves were drawn to find the optimal cut-off value of body weight in predicting the starting Gn dosage so as to prevent high ovarian response (HOR). We found that luteinizing hormone (LH) level and Anti-Mullerian hormone (AMH) level were lowest in the group with body weight over 70 kg and was highest in the group with body weight less than 50 kg. Increased body weight was significantly correlated to the rise of initial Gn dosage (Beta = 0.399, t = 8.921, p < 0.001). Normal ovarian response (NOR) patients had significantly less fresh cycle cancel rate and ovarian hyperstimulation syndrome (OHSS) rate which outweighed the fewer embryos compared with HOR patients. Using ROC curves, 53.25 kg (sensitivity, 84.2%; specificity, 53.8%) and 70.5 kg (sensitivity, 58.8%; specificity, 93.0%) were identified as the optimal cut-off values to predict the initial Gn dosage of no more than 150 IU and 225 IU, respectively. In conclusion, adjusting the initial Gn dosage based on body weight is crucial to preventing ovarian hyperstimulation while not influencing reproductive outcomes for PCOS patients during IVF.

[Analysis of the Effcacy and Safety of Amivantamab in Non-small Cell Lung Cancer 
Patients with EGFR/MET Gene Abnormalities: A Single Center's Experience].

BACKGROUND: Epidermal growth factor receptor (EGFR) and cellular-mesenchymal to epithelial transition factor (c-Met) are widely expressed on cancer cells. There is a synergistic effect of EGFR and HGF/c-Met pathways on proliferation, downstream activation of signal transduction and an additive effect. Studies show that combination of both signaling pathways could potentially be targeted in a synergistic fashion. Amivantamab, a bispecific monoclonal antibody targeting EGFR and c-Met, yielded robust and durable responses in a variety of clinicals trials. However, few researches have reported its efficacy in Chinese non-small cell lung cancer (NSCLC) patients. This study was conducted to evaluate the effectiveness and tolerance of Amivantamab in NSCLC patients with EGFR/MET gene abnormalities at Peking University Cancer Hospital. METHODS: The study enrolled NSCLC patients who received Amivantamab in our hospital between August 2020 and December 2021, and analyzed the response, survival, and treatment-related adverse events. RESULTS: Fifteen patients were enrolled in this research, and six of them received Amivantamab treatment and the other nine patients received Amivantamab plus Lazertinib treatment. The rates of partial response (PR), stable disease (SD), and progressive disease (PD) were 46.7% (7/15), 46.7% (7/15) and 6.7% (1/15), respectively. The overall response rate (ORR) and disease control rate (DCR) were 28.6% (2/7) and 100.0% (7/7) in seven patients with EGFR exon 20 insertion, respectively. The ORR and DCR were 40.0% (2/5) and 100.0% (5/5) in five post-osimertinib EGFR-mutant patients, respectively. After a median follow-up of 8.7 months, the median progression-free survival and overall survival were not reached. The most common treatment-related adverse events were rash (86.7%), paronychia (80.0%), and infusion-related reactions (60.0%), and most of them were graded as 1 to 2. Grade 3 to 4 adverse events included rash (33.3%), alanine aminotransferase elevation (13.3%), gamma-glutamyl transpeptidase elevation (13.3%), peripheral edema (6.7%), thromboembolism (6.7%), interstitial lung disease (6.7%), and thrombocytopenia (6.7%). CONCLUSIONS: Amivantamab was effective in Chinese NSCLC patients with EGFR exon 20 insertion and post-Osimertinib EGFR-mutant patients, similar to the results of clinical trials conducted in western countries. Amivantamab was well tolerated and emphases should be put on adverse events such as rash, paronychia, and infusion-related reactions.

The Association Between Vitamin C and Cancer: A Two-Sample Mendelian Randomization Study.

In recent years, many studies have indicated that vitamin C might be negatively associated with the risk of cancer, but the actual relationship between vitamin C and cancer remains ambivalent. Therefore, we utilized a two-sample Mendelian randomization (MR) study to explore the causal associations of genetically predicted vitamin C with the risk of a variety of cancers. Single-nucleotide polymorphisms (SNPs) associated with vitamin C at a significance level of p < 5 × 10-8 and with a low level of linkage disequilibrium (LD) (r2 < 0.01) were selected from a genome-wide association study (GWAS) meta-analysis of plasmid concentration of vitamin C consisting of 52,018 individuals. The data of the GWAS outcomes were obtained from United Kingdom Biobank, FinnGen Biobank and the datasets of corresponding consortia. In the inverse-variance weight (IVW) method, our results did not support the causal association of genetically predicted vitamin C with the risk of overall cancer and 14 specific types of cancer. Similar results were observed in sensitivity analyses where the weighted median and MR-Egger methods were adopted, and heterogeneity and pleiotropy were not observed in statistical models. Therefore, our study suggested that vitamin C was not causally associated with the risk of cancer. Further studies are warranted to discover the potential protective and therapeutic effects of vitamin C on cancer, and its underlying mechanisms.

The involvement of Parkin-dependent mitophagy in the anti-cancer activity of Ginsenoside.

Colon cancer, the third most frequent occurred cancer, has high mortality and extremely poor prognosis. Ginsenoside, the active components of traditional Chinese herbal medicine Panax ginseng, exerts antitumor effect in various cancers, including colon cancer. However, the detailed molecular mechanism of Ginsenoside in the tumor suppression have not been fully elucidated. Here, we chose the representative ginsenoside Rg3 and reported for the first time that Rg3 induces mitophagy in human colon cancer cells, which is responsible for its anticancer effect. Rg3 treatment leads to mitochondria damage and the formation of mitophagosome; when autophagy is inhibited, the clearance of damaged mitochondria can be reversed. Next, our results showed that Rg3 treatment activates the PINK1-Parkin signaling pathway and recruits Parkin and ubiquitin proteins to mitochondria to induce mitophagy. GO analysis of Parkin targets showed that Parkin interacts with a large number of mitochondrial proteins and regulates the molecular function of mitochondria. The cellular energy metabolism enzyme GAPDH is validated as a novel substrate of Parkin, which is ubiquitinated by Parkin. Moreover, GAPDH participates in the Rg3-induced mitophagy and regulates the translocation of Parkin to mitochondria. Functionally, Rg3 exerts the inhibitory effect through regulating the nonglycolytic activity of GAPDH, which could be associated with the cellular oxidative stress. Thus, our results revealed GAPDH ubiquitination by Parkin as a crucial mechanism for mitophagy induction that contributes to the tumor-suppressive function of ginsenoside, which could be a novel treatment strategy for colon cancer.

The prevalence and real-world therapeutic analysis of Chinese patients with KRAS-Mutant Non-Small Cell lung cancer.

OBJECTIVE: Kirsten rat sarcoma viral oncogene homolog (KRAS) is an important driver gene of non-small cell lung cancer (NSCLC). Despite a rapid progress achieved in the targeted therapy, chemotherapy remains the standard treatment option for patients with KRAS-mutant NSCLC. This study aimed to assess real-world data of Chinese patients with KRAS-mutant NSCLC undergoing chemotherapy and/or immunotherapy. METHODS: KRAS mutational status was analyzed using next-generation sequencing of 150,327 NSCLC patients from the Lung Cancer Big Data Precise Treatment Collaboration Group (LANDSCAPE) project (Cohort I). Treatment data were collected and analyzed retrospectively from 4348 NSCLC patients who were admitted to the Peking University Cancer Hospital and Institute between January 2009 and October 2020 (Cohort II). RESULTS: In Cohort I, 18,224 patients were detected with KRAS mutations (12.1%) of whom G12C (29.6%) was the most frequent subtype, followed by G12D (18.1%) and G12V (17.5%). In case of concomitant mutations, TP53 had the highest incidence of 33.6%, followed by EGFR (11.6%), STK11 (10.4%), KEAP1(6.2%), and CDKN2A (6.0%). Cohort II included 497 patients (11.4%) with KRAS mutations. In the first-line chemotherapeutic analysis of Cohort II, patients benefited more from the pemetrexed/platinum (PP) regimen than the gemcitabine/platinum (GP) or taxanes/platinum (TP) regimen (median progression-free survival [PFS], 6.4 vs. 4.9 vs. 5.6 months, hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.48-0.88, p = 0.033 and HR = 0.69, 95% CI 0.47-1.00, p = 0.05, respectively), with no significant difference when combined with bevacizumab. Regarding patients who received immune checkpoint inhibitors (ICIs), the objective response rate was 26% for a median PFS of 9.6 months (95% CI 6.16-13.03). Patients who received ICIs combined with chemotherapy had a significantly longer survival than monotherapy (median PFS, 13.9 vs. 5.2 months, HR = 0.59, 95% CI 0.35-0.99, p = 0.049). CONCLUSION: KRAS is an important driver gene in NSCLC, compromising 12.1% in this study, and G12C was noted as the most common subtype. Patients with KRAS-mutant NSCLC could benefit from pemetrexed-based chemotherapy and ICIs.

Biomarker subset analysis of a phase IIIb, open-label study of afatinib in EGFR tyrosine kinase inhibitor-naive patients with EGFRm+ non-small-cell lung cancer.

Aim: To explore the relationship between mutations in cfDNA and response to afatinib. Patients & methods: In total, 64 patients from one Chinese site with locally advanced/metastatic EGFRm+ non-small-cell lung cancer, who received afatinib 40 mg once daily, were included. Results: Overall, 33 (82.5%) patients became EGFRm- by visit 3; median progression-free survival was longer in these patients vs those who did not (11.0 vs 5.5 months). Progression-free survival was shorter in 42 (45.2%) patients with non-EGFR co-mutations at baseline vs those without (8.1 vs 12.5 months). Neither difference was significant. Conclusion: Afatinib provided clinical benefit for patients with EGFRm+ non-small-cell lung cancer across all subgroups. EGFRm status assessment in plasma cfDNA is a useful method of monitoring treatment.

We conducted a study in 64 Chinese patients with non-small-cell lung cancer to investigate the relationship between cancer mutations detected in the blood and the response to treatment with afatinib, which is known to be effective against EGFR mutations. Technology is now available to detect these mutations in the blood, as an alternative to obtaining and testing lung tissue samples. All 64 patients had EGFR mutations (and some patients had additional types of mutations) when afatinib was started (visit 1 in the study). By visit 3, most patients (82.5%) no longer had EGFR mutations detected in their blood, and these patients responded better to afatinib than those who still had EGFR mutations in their blood. Patients with additional types of mutations generally did not respond as well as those who had only EGFR mutations. Although results showed clinical benefit with afatinib using assessment of mutation status in the blood, statistical significance could not be shown due to the small size of the study. Clinical Trial Registration: NCT01953913 (ClinicalTrials.gov).

Single Cell Proteomics Profiling Reveals That Embryo-Secreted TNF-α Plays a Critical Role During Embryo Implantation to the Endometrium.

It has been long-known that endometrium-secreted cytokines play a critical role during embryo implantation. However, whether cytokines secreted from the embryo are relevant to the process of embryo implantation remains unclear. The concentration of cytokines in embryo culture medium was tested using a newly developed, high-sensitivity single-cell proteomic platform and evaluated in comparison to embryo quality and clinical outcome. The effect of TNF-α on embryo and endometrium Ishikawa cells was investigated using immunofluorescence staining, CCK-8 assay, TUNEL staining, and RT-qPCR. Of the 10 cytokines measured, only TNF-α concentration was significantly higher in the group with embryo implantation failure. Immunofluorescence staining showed that the expression of TNF-α was unevenly distributed in blastocysts, and the expression level was significantly correlated with the blastocyst inner cell mass (ICM) quality score. Gene profiling showed that addition of TNF-α led to increased expression of tumor necrosis factor receptor 1 (TNFR1) and apoptosis-related genes and that this could be inhibited by the TNF-α receptor inhibitor etanercept (ETA). In addition, an increased expression of water and ion channels, including AQP3, CFTR, ENaCA, and CRISP2 was also observed which could also be inhibited by ETA. Our results show that higher embryo-secreted TNF-α levels are associated with implantation failure through activation of TNF-α receptor, and TNF-α may be an independent predictor for pre-transfer assessment of the embryo development potential in IVF patients.

The Genetic Association of Polycystic Ovary Syndrome and the Risk of Endometrial Cancer: A Mendelian Randomization Study.

The association between polycystic ovary syndrome (PCOS) and endometrial cancer remains unclear. We aimed to investigate the causal association between genetically predicted PCOS and endometrial cancer risk in two ethnic groups through a two-sample Mendelian randomization (MR) approach. Our study includes 13 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for PCOS in Europeans, and another 13 SNPs are used as IVs for PCOS in Asians. Outcome data were obtained from the largest published meta-GWAS of European ancestry to date, as well as from the BioBank Japan Project of Asian ancestry. Our study demonstrates that genetically predicted PCOS is not causally associated with the risk of overall endometrial cancer in either Europeans or Asians (odds ratio (OR) = 0.93, 95% confidence interval (CI) = 0.85-1.01, p = 0.09 and OR = 0.98, 95% CI 0.84-1.13, p = 0.75, respectively). Subgroup analyses according to histotype further illustrate that PCOS might not be associated with the risk of either endometrioid endometrial cancer or non-endometrioid endometrial cancer in European ancestry. No pleiotropy is found in our study, and a sensitivity analysis shows similar results. Our results indicate that genetically predicted PCOS might not be associated with the risk of endometrial cancer.

The Association Between Genetically Predicted Systemic Inflammatory Regulators and Polycystic Ovary Syndrome: A Mendelian Randomization Study.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic diseases among women of reproductive age. Inflammation may be involved in the pathogenesis of PCOS, but its exact relationship with PCOS remains unclear. Herein, we investigate the causal association between systemic inflammatory regulators and PCOS risk through a two-sample Mendelian randomization (MR) approach based on the latest and largest genome-wide association study (GWAS) of 41 systemic inflammatory regulators in 8293 Finnish participants and a GWAS meta-analysis consisting of 10,074 PCOS cases and 103,164 controls of European ancestry. Our results suggest that higher levels of IL-17 and SDF1a, as well as lower levels of SCGFb and IL-4, are associated with an increased risk of PCOS (OR = 1.794, 95% CI = 1.150 - 2.801, P = 0.010; OR = 1.563, 95% CI = 1.055 - 2.315, P = 0.026; OR = 0.838, 95% CI = 0.712 - 0.986, P = 0.034; and OR = 0.637, 95% CI = 0.413 - 0.983, P = 0.042, respectively). In addition, genetically predicted PCOS is related to increased levels of IL-2 and VEGF (OR = 1.257, 95% CI = 1.022 - 1.546, P = 0.030 and OR = 1.112, 95% CI = 1.006 - 1.229, P = 0.038, respectively). Our results indicate the essential role of cytokines in the pathogenesis of PCOS. Further studies are warranted to assess the possibility of these biomarkers as targets for PCOS prevention and treatment.

Differential immune responses in pregnant patients recovered from COVID-19.

Pregnant women are generally more susceptible to viral infection. Although the impact of SARS-CoV-2 in pregnancy remains to be determined, evidence indicates that the risk factors for severe COVID-19 are similar in pregnancy to the general population. Here we systemically analyzed the clinical characteristics of pregnant and non-pregnant female COVID-19 patients who were hospitalized during the same period and found that pregnant patients developed marked lymphopenia and higher inflammation evident by higher C-reactive protein and IL-6. To elucidate the pathways that might contribute to immunopathology or protective immunity against COVID-19 during pregnancy, we applied single-cell mRNA sequencing to profile peripheral blood mononuclear cells from four pregnant and six non-pregnant female patients after recovery along with four pregnant and three non-pregnant healthy donors. We found normal clonal expansion of T cells in the pregnant patients, heightened activation and chemotaxis in NK, NKT, and MAIT cells, and differential interferon responses in the monocyte compartment. Our data present a unique feature in both innate and adaptive immune responses in pregnant patients recovered from COVID-19.

Efficacy and Safety of Combination Treatment With Apatinib and Osimertinib After Osimertinib Resistance in Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Carcinoma-A Retrospective Analysis of a Multicenter Clinical Study.

Currently, there are limited treatment options for patients who developed resistance to osimertinib, a third-generation epidermal growth factor receptor (EGFR) inhibitor. Resistance to EGFR inhibitors is frequently associated with enhanced vascular endothelial growth factor (VEGF) levels. This multicenter, retrospective study aimed to evaluate the efficacy of the combination treatment with apatinib and osimertinib in 39 patients with EGFR-mutant non-small cell lung carcinoma (NSCLC) who developed osimertinib resistance. The patients received the combination of oral apatinib 250 mg qd and osimertinib 80 mg qd. The efficacy was evaluated after the first month then every 2 months thereafter. The primary endpoint was progression-free survival (PFS). The overall response rate (ORR) and the disease control rate (DCR) of the combination of apatinib and osimertinib was 12.8% (5/39) and 79.5% (31/39), respectively. The median PFS was 4 months [95% confidence interval (CI): 3.5-4.5 months]. Fourteen patients were administered with at least 6 months of combination therapy, and 11 of them remained on treatment programs. The 6-month PFS rate was 38%. Nine patients underwent biopsies after failing osimertinib treatment, and five of six patients with TP53 mutations had PFS of less than 3 months. The spectrum of resistance to osimertinib mechanisms included c-mesenchymal-epithelial transition factor (c-Met) amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gain-of-function mutation, phosphatase and tensin homolog (PTEN) loss-of-function mutation, Erb-B2 receptor tyrosine kinase 2 (ERBB2) amplification, and insulin-like growth factor 1 receptor (IGF1R) mutation. The most common adverse events were hypertension (30.7%, 12/39), diarrhea (15.4%, 6/39), and proteinuria (12.8%, 5/39). The combination of apatinib and osimertinib improved the ORR and the DCR of patients with osimertinib-refractory EGFR-positive NSCLC, thus making it a reasonable treatment choice after the development of osimertinib resistance.

Evaluation of different treatment strategies between right-sided and left-sided pneumonectomy for stage I-IIIA non-small cell lung cancer patients.

BACKGROUND: This study aimed to assess the different survival outcomes of stage I-IIIA non-small cell lung cancer (NSCLC) patients who received right-sided and left-sided pneumonectomy, and to further develop the most appropriate treatment strategies. METHODS: We accessed data from the Surveillance, Epidemiology, and End Results database from the United States for the present study. An innovative propensity score matching analysis was used to minimize the variance between groups. RESULTS: For 2,683 patients who received pneumonectomy, cancer-specific survival [hazard ratio (HR) =0.863, 95% confidence interval (CI): 0.771 to 0.965, P=0.010] and overall survival (OS; HR =0.875, 95% CI: 0.793 to 0.967, P=0.008) were significantly superior in left-sided pneumonectomy patients compared with right-sided pneumonectomy patients. Cancer-specific survival (HR =0.847, 95% CI: 0.745 to 0.963, P=0.011) and OS (HR =0.858, 95% CI: 0.768 to 0.959, P=0.007) were also significantly longer with left-sided compared to right-sided pneumonectomy after matching analysis of 2,050 patients. Adjuvant therapy could significantly prolong cancer-specific survival (67 versus 51 months, HR =1.314, 95% CI: 1.093 to 1.579, P=0.004) and OS (46 versus 30 months, HR =1.458, 95% CI: 1.239 to 1.715, P<0.001) among left-sided pneumonectomy patients after the matching procedure, while adjuvant therapy did not increase cancer-specific survival for right-sided pneumonectomy patients (46 versus 42 months, HR =1.112, 95% CI: 0.933 to 1.325, P=0.236). Subgroup analysis showed that adjuvant chemotherapy could significantly improve cancer-specific survival and OS for all pneumonectomy patients. However, radiotherapy was associated with worse survival for patients with right-sided pneumonectomy. CONCLUSIONS: Pneumonectomy side can be deemed as an important factor when physicians determine the most optimal treatment strategies.

Efficacy and safety of pemetrexed maintenance chemotherapy for advanced non-small cell lung cancer in a real-world setting.

BACKGROUND: Pemetrexed maintenance therapy offers a survival benefit in patients with nonprogressive advanced nonsquamous non-small cell lung cancer (NSCLC) with good tolerability. This study was designed to analyze the efficacy and safety of pemetrexed maintenance chemotherapy in advanced nonsquamous NSCLC patients in a real-world setting. METHODS: The response rate (RR) and adverse events in 71 nonsquamous NSCLC patients treated with pemetrexed-based chemotherapy were observed until disease progression or unacceptable toxicities. Measures of survival were analyzed during follow-up. RESULTS: Of 69 efficacy-evaluable patients, the objective response rate (ORR) was 46.4% and the disease control rate (DCR) was 98.6%. ORR showed no significant difference between patients who received pemetrexed as first-line therapy and those who received pemetrexed as second-line or higher treatment. The median treatment cycle for all patients was 8. The median progression-free survival (PFS) was 9.5 months (m) and median overall survival (OS) was 30.5 m. The univariate and multivariate analyses showed that the number of chemotherapy cycles was an independent factor for PFS. The most common adverse reactions were grade 1 to 2 hematologic toxicities, gastrointestinal reactions, and liver enzyme abnormalities. Only 1 patient experienced a grade 3 gastrointestinal event. CONCLUSIONS: Pemetrexed maintenance chemotherapy can improve PFS in patients with advanced nonsquamous NSCLC with good tolerability.

Identification of serum biomarkers to predict pemetrexed/platinum chemotherapy efficacy for advanced lung adenocarcinoma patients by data-independent acquisition (DIA) mass spectrometry analysis with parallel reaction monitoring (PRM) verification.

BACKGROUND: Pemetrexed/platinum chemotherapy has been the standard chemotherapy regimen for lung adenocarcinoma patients, but the efficacy varies considerably. METHODS: To discover new serum biomarkers to predict the efficacy of pemetrexed/platinum chemotherapy, we analyzed 20 serum samples from advanced lung adenocarcinoma patients who received pemetrexed/platinum chemotherapy with the data-independent acquisition (DIA) quantitative mass spectrometry (MS). RESULTS: The 20 patients were categorized as "good response" [12 patients achieving partial response (PR)] and "poor response" [8 patients with progressive disease (PD)] groups. Altogether 23 significantly different expressed proteins were identified, which had relative ratios higher than 1.2 or lower than -0.83, with 7 proteins having an area under the curve (AUC) above 0.8. To further validate the DIA results, we used the parallel reaction monitoring (PRM) method to examine 16 candidate serum biomarkers in the study cohort of 20 patients and another cohort of 22 advanced lung adenocarcinoma patients (16 PR and 6 PD). Quantitative validation using PRM correlated well with the DIA results, and 10 promising proteins exhibited a similar up- or downregulation. It is worth noting that glutathione peroxidase 3 (GPX3) exhibits significant upregulation in the poor response group compared with the good response group, which was validated by both DIA and PRM methods. CONCLUSIONS: Our study confirmed that combined DIA MS and PRM approaches were effective in identifying serum predictive biomarkers for advanced lung adenocarcinoma patients. Further studies are needed to explore the potential biological mechanism underlying these biomarkers.