Asymmetric Construction of Ethenyl-Substituted Acyclic Quaternary Stereocenters at the α-Position of Carbonyl Surrogates via Stereoselective Sulfonylvinylation-Reductive Desulfonylation.

N-Sulfinyl metalloenamines, derived from geometry-defined ß,ß-disubstituted enesulfinamides, undergo conjugate addition-elimination reaction with ß-tosyl nitroolefin to afford α-sulfonylvinylated ketimines with high stereocontrol. Further desulfonylation using sodium naphthalenide gives carbonyl surrogates bearing a less-accessible acyclic quaternary α-stereocenters substituted with an ethenyl group and two sterically and electronically similar groups (e.g., methyl and ethyl). Synthetic application of the described protocol was demonstrated by enantioselective synthesis of (S)-bakuchiol.

Stereoselective Electrophilic Sulfenylation of ß,ß-Disubstituted Enesulfinamides: Asymmetric Construction of Less Accessible Acyclic α,α-Disubstituted α-Sulfenylated Ketimines.

Current methods for the asymmetric α-sulfenylation of carbonyls cannot be applied to acyclic carbonyls that have two similar substituents at the α-position. This research demonstrated that the electrophilic sulfenylation of geometry-defined acyclic ß,ß-disubstituted enesulfinamides using S-aryl or S-alkyl benzenethiosulfonates can be highly stereoselective. This process results in enantioenriched α,α-disubstituted α-sulfenylated ketone surrogates with sulfur-containing acyclic tetrasubstituted carbon stereocenters bearing two electronically and sterically similar substituents (e.g., methyl and ethyl). Furthermore, by employing the corresponding stereoisomers of enensulfinamides, any of the four stereoisomers of α-sulfenylated ketimines can be selectively accessed.

An Unusual Cause of Intestinal Ulcers Masquerading as Inflammatory Bowel Disease: A Case Report of Allied Disorders of Hirschsprung's Disease.

Background: Allied disorders of Hirschsprung's disease (ADHD) exhibit symptoms akin to those of Hirschsprung's disease, primarily characterized by intestinal obstruction, bowel dilatation, and chronic constipation. The occurrence of amyloid complications in patients with ADHD is infrequent. In this report, we present a case of ADHD with intestinal ulcers as the initial gastrointestinal manifestation, and subsequent pathological examination revealed the presence of amyloid deposits in the colonic mucosa. Case Report: A male patient, aged 20, exhibited recurring abdominal distension and intestinal obstruction for a duration of three years. Multiple colonoscopies revealed the presence of recurrent colonic ulcers, with pathological examination indicating the existence of amyloid deposits within the mucosal layer of the colon. Abdominal CT scans suggested colonic dilatation. Following a multidisciplinary consultation, a subtotal resection of the colon was performed, and subsequent postoperative pathology confirmed a decrease and absence of myenteric plexus ganglion cells. Considering the patient's symptoms and the findings from the postoperative pathology, a diagnosis of ADHD was made. The patient's symptoms resolved postoperatively and he was discharged from the hospital and followed up for 1 year in stable condition. Conclusion: Our study highlights the potential association between ADHD and the initial presentation of recurrent colonic ulcers, accompanied by amyloid deposition in the intestinal mucosa. This finding suggests a possible pathogenic mechanism for ADHD and offers a novel perspective on its diagnosis.

Stereoselective Construction of Less-Accessible Acyclic α,α-Disubstituted ß-Ketiminonitriles via Electrophilic Cyanation of ß,ß-Disubstituted Enesulfinamides.

The metalloenamines, formed by NH-deprotonation of ß,ß-disubstituted enesulfinamides, can undergo reactions with commercially available electrophilic cyanating reagents such as tosyl cyanide (TsCN) or 3-oxo-1,2-benziodoxole-1(3H)-carbonitrile (CBX). Through the utilization of appropriate stereoisomers of enesulfinamides, this method enables the selective synthesis of any of the four stereoisomers of α,α-disubstituted ß-sulfinylimino nitriles, which feature acyclic quaternary stereocenters and are typically more challenging to synthesize. These compounds can then undergo stereoselective nucleophilic addition, leading to the creation of valuable enantioenriched multisubstituted ß-amino carbonyl surrogates with a high degree of structural diversity.

miRNA-27b-3p, let-7f-5p and miRNA-142-5p can be Used in a Novel Serum Diagnostic Panel for Clear Cell Renal Cell Carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a prevalent malignant tumor affecting the urinary system. Due to its unfavorable prognosis, there is a pressing need to discover effective approaches for early diagnosis and treatment of ccRCC. Extensive research has consistently demonstrated the presence of stable microRNAs (miRNAs) in human serum. Accordingly, the objective of this study was to identify a specific panel of miRNAs in serum that can serve as a reliable and non-invasive biomarker for the early detection of ccRCC. METHODS: The study comprised of training and validation phases to identify potential biomarkers. In the training phase, a total of 10 miRNAs exhibiting the most significant differential expression among 28 ccRCC patients and 28 healthy controls (HCs) were identified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). In the subsequent validation phase, these 10 miRNAs were assessed in serum samples obtained from an additional 80 ccRCC patients and 84 HCs using RT-qPCR. To construct a panel with optimal diagnostic capability, backward stepwise logistic regression analysis was conducted. Furthermore, bioinformatics analysis was performed on this selected miRNA panel. RESULTS: In ccRCC patients, the serum expression level of miRNA-142-5p was found to be significantly elevated compared to healthy controls (HCs), whereas the expression levels of let-7f-5p, miRNA-27b-3p, miRNA-212-3p, and miRNA-216-5p were significantly reduced. To assess their diagnostic potential for ccRCC, receiver operating characteristic (ROC) curve analysis was performed. The analysis revealed that miRNA-27b-3p, let-7f-5p, and miRNA-142-5p exhibited moderate diagnostic capabilities for ccRCC, with area under the curve (AUC) values of 0.826, 0.828, and 0.643, respectively. To further enhance diagnostic accuracy, a final diagnostic panel consisting of these three miRNAs was constructed, demonstrating good diagnostic value with an AUC of 0.952. CONCLUSIONS: The miRNA serum biomarker panel (miRNA-27b-3p, let-7f-5p, and miRNA-142-5p) identified in this study holds promise for early, non-invasive, and accurate diagnosis of ccRCC. This panel could potentially provide a valuable tool in clinical settings to aid in the timely detection and management of ccRCC.

Testing the accuracy of a four serum microRNA panel for the detection of primary bladder cancer: a discovery and validation study.

BACKGROUND: Bladder cancer (BC) is one of the ten most common cancers worldwide with late detection and early age of diagnosis. There is abundant evidence that early detection and timely intervention can lead to a better prognosis of BC. Substantial evidence has indicated that microRNAs (miRNAs) are specific to different tumour types and are remarkably stable, indicating that serum miRNAs may serve as potential cancer diagnostic markers. This study aimed to identify suitable serum miRNAs to create a panel that can be used to diagnose primary BC. METHODS: In this study, 18 miRNAs that were differentially expressed in BC were obtained from the PubMed or Gene Expression Omnibus database. Then, 18 BC-related-miRNAs were verified in screening and validation sets created using 56 (28 primary BC vs. 28 NCs) and 168 (84 primary BC vs. 84 NCs) serum samples, respectively. Quantitative reverse transcription-PCR (qRT-PCR) was performed to verify the identity of the differential miRNAs. A multi-miRNA panel with superior diagnostic performance was constructed. TCGA and KEGG databases were used to conduct the survival analysis and bioinformatics analysis, respectively. RESULTS: Six serum miRNAs (miR-221-5p, miR-181a-5p, miR-98-5p, miR-15a-5p, miR-222-3p, and miR-197-3p) were significantly aberrantly expressed in the BC patients, while four miRNAs from among them (miR-221-5p, miR-181a-5p, miR-15a-5p, miR-222-3p) were assembled into a panel that showed high diagnostic value (AUC = 0.875, 95% CI: 0.815 - 0.921; sensitivity: 82.14%; and specificity: 85.71%) based on the logistic regression analysis. The survival analysis showed that miR-181a-5p was closely associated with BC prognosis (Log-rank p-value < 0.05). CONCLUSION: The combination of the four miRNAs (miR-221-5p, miR-181a-5p, miR-15a-5p and miR-222-3p) may be a novel non-invasive serological biomarker for BC screening.

Early detection and timely intervention can lead to a better prognosis of bladder cancer.This study aimed to identify suitable serum miRNAs to create a panel that can be used to diagnose primary bladder cancer.

A panel based on three-miRNAs as diagnostic biomarker for prostate cancer.

Background: Prostate cancer (PCa) is one of the most prevalent malignancies affecting the male life cycle. The incidence and mortality of prostate cancer are also increasing every year. Detection of MicroRNA expression in serum to diagnose prostate cancer and determine prognosis is a very promising non-invasive modality. Materials and method: A total of 224 study participants were included in our study, including 112 prostate cancer patients and 112 healthy adults. The experiment consisted of three main phases, namely, the screening phase, the testing phase, and the validation phase. The expression levels of serum miRNAs in patients and healthy adults were detected using quantitative reverse transcription-polymerase chain reaction. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to evaluate the diagnostic ability, specificity, and sensitivity of the candidate miRNAs. Result: Eventually, three miRNAs most relevant to prostate cancer diagnosis were selected, namely, miR-106b-5p, miR-129-1-3p and miR-381-3p. We used these three miRNAs to construct a diagnostic panel with very high diagnostic potential for prostate cancer, which had an AUC of 0.912 [95% confidence interval (CI): 0.858 to 0.950; p < 0.001; sensitivity = 91.67%; specificity = 79.76%]. In addition, the three target genes (DTNA, GJB1, and TRPC4) we searched for are also expected to be used for prostate cancer diagnosis and treatment in the future.

Diastereoselective Synthesis of Less Accessible Fluorine-Containing Acyclic Tetrasubstituted Stereocenters via Electrophilic Fluorination of ß,ß-Disubstituted Metalloenamines.

A stereocontrolled protocol was developed to construct less accessible fluorine-containing acyclic tetrasubstituted stereocenters bearing two sterically and electronically similar alkyl groups at the α-position of carbonyls. In this process, tBuOK-promoted stereospecific α-deprotonation of α,α-disubstituted N-tert-butanesulfinyl ketimines or NH deprotonation of ß,ß-disubstituted enesulfinamides generates geometry-defined multisubstituted metalloenamines, followed by stereoselective electrophilic fluorination with the N-fluoro ammonium salt of quinine, affording the acyclic α-fluorinated ketimines with excellent diastereoselectivities.

Enantioselective Formal 1,2-Diamination of Ketenes with Iminosulfinamides: Asymmetric Synthesis of Unnatural α,α-Disubstituted α-Amino Acid Derivatives.

A method was developed for the enantioselective formal 1,2-diamination of disubstituted ketenes using iminosulfinamides as nitrogen sources. The protocol involves the addition of lithium iminosulfinamides to ketenes to form N-iminosulfinyl amide metalloenolates. These metalloenolates then undergo a [2,3]-sigmatropic rearrangement to yield unnatural α,α-disubstituted α-amino acid derivatives with high enantiopurity. The chirality present at the sulfur atom in the iminosulfinamides is effectively transferred to α carbon of the resulting products, facilitating the highly enantioselective amination of ketenes.

Sensitivity-Enhanced, Room-Temperature Detection of NH3 with Alkalized Ti3C2Tx MXene.

A layered Ti3C2Tx MXene structure was prepared by etching MAX-phase Ti3AlC2 with hydro-fluoric acid (HF), followed by alkalization in sodium hydroxide (NaOH) solutions of varying concentrations and for varying durations. Compared to sensors utilizing unalkalized Ti3C2Tx, those employing alkalized Ti3C2Tx MXene exhibited enhanced sensitivity for NH3 detection at room temperature and a relative humidity of 40%. Both the concentration of NaOH and duration of alkalization significantly influenced sensor performance. Among the tested conditions, Ti3C2Tx MXene alkalized with a 5 M NaOH solution for 12 h exhibited optimal performance, with high response values of 100.3% and a rapid response/recovery time of 73 s and 38 s, respectively. The improved sensitivity of NH3 detection can be attributed to the heightened NH3 adsorption capability of oxygen-rich terminals obtained through the alkalization treatment. This is consistent with the observed increase in the ratio of oxygen to fluorine atoms on the surface terminations of the alkalization-treated Ti3C2Tx. These findings suggest that the gas-sensing characteristics of Ti3C2Tx MXene can be finely tuned and optimized through a carefully tailored alkalization process, offering a viable approach to realizing high-performance Ti3C2Tx MXene gas sensors, particularly for NH3 sensing applications.

Boosting Hydrogen Storage Performance of MgH2 by Oxygen Vacancy-Rich H-V2O5 Nanosheet as an Excited H-Pump.

MgH2 is a promising high-capacity solid-state hydrogen storage material, while its application is greatly hindered by the high desorption temperature and sluggish kinetics. Herein, intertwined 2D oxygen vacancy-rich V2O5 nanosheets (H-V2O5) are specifically designed and used as catalysts to improve the hydrogen storage properties of MgH2. The as-prepared MgH2-H-V2O5 composites exhibit low desorption temperatures (Tonset = 185 °C) with a hydrogen capacity of 6.54 wt%, fast kinetics (Ea = 84.55 ± 1.37 kJ mol-1 H2 for desorption), and long cycling stability. Impressively, hydrogen absorption can be achieved at a temperature as low as 30 °C with a capacity of 2.38 wt% within 60 min. Moreover, the composites maintain a capacity retention rate of ~ 99% after 100 cycles at 275 °C. Experimental studies and theoretical calculations demonstrate that the in-situ formed VH2/V catalysts, unique 2D structure of H-V2O5 nanosheets, and abundant oxygen vacancies positively contribute to the improved hydrogen sorption properties. Notably, the existence of oxygen vacancies plays a double role, which could not only directly accelerate the hydrogen ab/de-sorption rate of MgH2, but also indirectly affect the activity of the catalytic phase VH2/V, thereby further boosting the hydrogen storage performance of MgH2. This work highlights an oxygen vacancy excited "hydrogen pump" effect of VH2/V on the hydrogen sorption of Mg/MgH2. The strategy developed here may pave a new way toward the development of oxygen vacancy-rich transition metal oxides catalyzed hydride systems.

Combining cisplatin with Pinellia pedatisecta Schott lipid-soluble extract induces tumor immunogenic cell death in cervical cancer.

BACKGROUND: Pinellia pedatisecta Schott extract (PE) is extracted from Pinellia pedatisecta Schott (PPS), a traditional Chinese medicinal plant with the potential for direct anticancer effects or eliciting an anti-tumor response by activating the immune system. PURPOSE: To explore PE's ability and mechanism to reconstruct cisplatin's immunogenicity. METHODS: Cervical cancer cells were treated with cisplatin (CDDP) and/or PE. The exposure of calreticulin (CRT) on cell membrane was investigated by flow cytometry. The extracellular of ATP and HMGB1 was investigated by Western blot analysis, immunofluorescence and ELISA assay. Changes in immune profiles were using flow cytometry in vaccination and anti-tumor assays in vivo. Lastly, the mechanism of PE influenced the ROS/ERS pathway was examined by ROS assay kit, flow cytometry and Western blotting. RESULTS: PE treatment induced translocation of CRT from the endoplasmic reticulum to the cell membrane of tumor cells, concomitantly triggering immunogenic cell death (ICD). In terms of mechanisms, endoplasmic reticulum (ER) stress relievers could impede the ability of PE to induce immunogenicity. This indicates that PE is activated by ER stress, leading to subsequent induction of ICD. Upon analyzing RNA-seq data, it was observed that PE primarily induces programmed cell death in tumors by impeding upstream antioxidant mechanisms. Additionally, it transforms dying tumor cells into vaccines, activating a series of immune responses. CONCLUSIONS: This study observed for the first time that PE-induced CRT exposure on the membrane of cervical cancer cells compensates for the defect of nonimmunogenic cell death inducer CDDP thereby stimulating potent ICD. This ability restores the immunogenicity of CDDP through ER stress induced by the ROS signal. ROS played a role in PE's ability to induce ICD, leading to increased expression of ER stress-related proteins, including ATF3 and IRE-1α. PE exerted anti-cancer effects by increasing the ROS levels, and ROS/ERS signaling may be a potential avenue for cervical cancer treatment. Hence, the synergistic use of PE and CDDP holds potential for enhancing immunochemotherapy in cancer treatment.

The value of a panel of circulating microRNAs in screening prostate cancer.

Background: Prostate cancer (PCa) remains a worldwide public health problem that poses a serious threat to the health of men worldwide. Many studies have found that microRNA (miRNA) in serum has the potential to be a biomarker for cancer screening. Our study was conducted to investigate the value of serum miRNAs in PCa screening. Methods: We selected 12 miRNAs from past studies for its association with PCa. We checked the expression levels of these miRNAs in the serum of 112 PCa patients and 112 healthy controls in a two-stage experiment. We plotted the receiver operating characteristic curve of miRNAs in the validation stage and constructed a four-miRNA panel with the highest diagnostic value using stepwise logistic regression. We also predicted the target genes with these four miRNAs through online databases and performed Gene Ontology functional annotation and pathway analysis. Results: The results showed that six miRNAs (miR-429, miR-10a-5p, miR-183-5p, miR-181a-5p, miR-1231, miR-129-5p) were abnormally expressed in the serum of PCa patients. We used four of these miRNAs including miR-1231, miR-10a-5p, miR-429 and miR-129-5p to construct a combination of miRNAs with high specificity and sensitivity in screening PCa (area under the curve =0.878). Bioinformatics analysis showed that the genes targeted by these miRNAs can be linked to the development of PCa. Conclusions: Our study detected and identified a set of miRNAs that serves as screening marker for PCa, which may assist in early diagnosis and treatment of PCa.

Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody.

BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

Serological investigation and isolation of Salmonella abortus equi in horses in Xinjiang.

BACKGROUND: Salmonella enterica subspecies enterica serovar abortus equi (S. abortus equi) is one of the main pathogens that causes abortion in pregnant horses and donkeys, which was highly infectious and greatly restricts the healthy development of the horse industry. OBJECTIVES: In order to investigate the prevalence and biological characteristics of S. abortus equi in different regions and breeds of horses in Xinjiang. METHODS: This study conducted ELISA detection of S. abortus equi antibodies on serum samples of 971 horses collected from three large-scale horse farms and five free-range horse farms in Yili Prefecture and Bayingol Mongolian Autonomous Prefecture of Xinjiang from 2020 to 2023. On this basis, bacterial isolation, culture, identification, and drug sensitivity tests were conducted on 42 samples of aborted foal tissues and 23 mare vaginal swabs. RESULTS: The results showed that the positive rate of S. abortus equi antibody was as high as 20.91% in 971 horse serum samples. Among them, the positive rate in the Ili region (29.09%) was significantly higher than that in the Bayingole region (11.24%), and the positive rate in mares (22.45%) was higher than that in stallions (14.05%). In terms of horse breeds, the positive rates of self-propagating thoroughbred horses, half-bred horses, Ili horses and Yanqi horses were 43.22%, 28.81%, 14.72% and 11.24% respectively. In addition, S. abortus equi was more susceptible to juvenile and elderly horses, with positive rates of 70.00%and 41.86%, respectively, both of which were significantly higher than young (10.97%) and adult (19.79%) horses. Further, 9 strains of S. abortus equi were obtained through bacterial isolation, culture and identification, which were resistant to five antibiotics (Clarithromycin, Clindamycin, penicillin, Sulfamethoxazole and Rifampicin), and sensitive to 13 antimicrobial agents (Amoxicillin, Ciprofloxacin and Gentamicin, et al.). CONCLUSION: There was a high infection rate of S. abortus equi in Ili Prefecture and self-propagating thoroughbred horses, and juvenile or old mares were more susceptible, which will provide scientific basis for the prevention of S. abortus equi infection in different regions and breeds of horses in Xinjiang.

Stereoselective Cyclopropanation of Multisubstituted Enesulfinamides: Asymmetric Construction of α-Tertiary Cyclopropylamine Derivatives Containing ß-Quaternary Stereocenters.

Enesulfinamides with α,ß,ß-trisubstitution undergo a Simmons-Smith reaction to yield multisubstituted cyclopropylamine derivatives with high stereocontrol. The resulting α-tertiary cyclopropylamine derivatives, which feature ß-quaternary stereocenters bearing two electronically and sterically similar substituents (e.g., methyl and ethyl), are seldom achieved by using conventional methods. By adjusting the stereochemistry of the carbon-carbon double bond and/or sulfinyl group within the enesulfinamides, it is feasible to selectively produce four stereoisomers of the cyclopropylamines, each with different absolute configurations at the α- and ß-carbons.

Stereoselective Electrophilic Chlorination of ß,ß-Disubstituted Enesulfinamides with Chloramine-T: Asymmetric Synthesis of Acyclic α,α-Disubstituted α-Chlorinated Carbonyl Surrogates.

Enamine and iminium ion-mediated asymmetric organocatalysis was not successful in achieving highly stereoselective α-chlorination of acyclic α,α-disubstituted carbonyls. To address this limitation, an alternative method was developed, which involved the use of geometry-defined persubstituted enesulfinamides to intercept the electrophilic chlorinating reagent. This approach enables the asymmetric construction of challenging acyclic α,α-disubstituted α-chlorinated ketimines with a high degree of stereoselectivity. The use of chloramine-T, a cost-effective and stable chlorine source rarely utilized in asymmetric electrophilic chlorination, plays a crucial role in achieving superior stereocontrol.

Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .

Human Fallopian Tube-Derived Organoids with TP53 and RAD51D Mutations Recapitulate an Early Stage High-Grade Serous Ovarian Cancer Phenotype In Vitro.

RAD51D mutations have been implicated in the transformation of normal fallopian tube epithelial (FTE) cells into high-grade serous ovarian cancer (HGSOC), one of the most prevalent and aggressive gynecologic malignancies. Currently, no suitable model exists to elucidate the role of RAD51D in disease initiation and progression. Here, we established organoids from primary human FTE and introduced TP53 as well as RAD51D knockdown to enable the exploration of their mutational impact on FTE lesion generation. We observed that TP53 deletion rescued the adverse effects of RAD51D deletion on the proliferation, stemness, senescence, and apoptosis of FTE organoids. RAD51D deletion impaired the homologous recombination (HR) function and induced G2/M phase arrest, whereas concurrent TP53 deletion mitigated G0/G1 phase arrest and boosted DNA replication when combined with RAD51D mutation. The co-deletion of TP53 and RAD51D downregulated cilia assembly, development, and motility, but upregulated multiple HGSOC-associated pathways, including the IL-17 signaling pathway. IL-17A treatment significantly improved cell viability. TP53 and RAD51D co-deleted organoids exhibited heightened sensitivity to platinum, poly-ADP ribose polymerase inhibitors (PARPi), and cell cycle-related medication. In summary, our research highlighted the use of FTE organoids with RAD51D mutations as an invaluable in vitro platform for the early detection of carcinogenesis, mechanistic exploration, and drug screening.