Low Response Research Articles

P-564 Decoding ovarian response: the predictive power of FSH receptor gene expression in controlled ovarian stimulation

Abstract Study question Can profiling of variation in follicle-stimulating hormone receptor (FSHR) gene expression forecast response to Controlled Ovarian Stimulation (COS) in Assisted Reproductive Techniques? Summary answer Full-length FSHR transcript was the most common mRNA species. Nine distinct transcripts were characterised, but only one (deletion Exon 6) was associated with altered response. What is known already AMH levels and age are considered useful predictors of ovarian response to COS (high AMH and young age typically associated with high yields of oocytes; older ages and low AMH associated with fewer oocytes). However, it is not uncommon to see patients who do not fit this pattern, highlighting the limitations of these parameters in predicting response. Age-independent biomarkers capable of revealing patients at elevated risk of hyperstimulation, or those who might produce fewer than the optimal number of oocytes, are desirable. Alternative transcripts of the FSHR gene have been proposed as an explanation for variation in response to COS. Study design, size, duration FSHR splice variants in mRNA in granulosa cells from 126 patients were examined utilising long-read nanopore sequencing. This strategy permitted the sequencing of mRNA variants without fragmentation, allowing the detection of all splicing events in each mRNA strand. In addition to being categorised based on age and AMH levels, patients were also classified by the expression of FSHR transcript variants and their response to stimulation (high, low, or normal response). Participants/materials, setting, methods Patterns of FSHR mRNA splice variants were analysed in each of 126 patients. This involved extraction of RNA from the granulosa cells, followed by long-read nanopore sequencing, permitting analysis of whole transcripts in a single, contiguous sequence ‘read’. Patients were classified based upon their level of response to COS (low, normal, high), taking into account their age, AMH level and the number of oocytes retrieved. Patterns of FSHR transcript variation were compared to COS response. Main results and the role of chance Full-length FSHR transcript was detected in 97.6% of patients and skipping of Exon 6 was observed in 68%. Five novel transcripts were discovered, including partial insertion of ∼100bp segments of introns 1 or 2, seen in 6.55% of samples. In total, nine distinct FSHR mRNA variants were detected. As expected, increasing age was associated with higher FSH requirement per oocyte collected (p = 0.018), and AMH levels declined with age (2.8± 1.42 in women <38 versus 1.58 ±1.29 in women ≥38; p = 0.011). Consistent with previous analyses, AMH levels and amount of FSH per oocyte retrieved were negatively correlated (p < 0.001). One-third of the patients (33%) in this cohort displayed responses to COS that were not considered to be consistent with expectations based upon age and AMH levels. Expression of the novel FSHR transcript variants was not associated with FSH needed per oocyte retrieved (p = 0.78), nor the proportion of mature oocytes (p = 0.95).The only transcript potentially linked to an altered response to COS was the previously reported mRNA species, lacking exon 6, associated with significantly greater numbers of oocytes produced (p = 0.0087). Interestingly, women ≥38 expressed novel variants more frequently than their younger counterparts (p = 0.018), potentially indicative of an age-related decline in transcriptional fidelity. Limitations, reasons for caution It is possible that the use of controlled ovarian stimulation might alter the dynamics of transcription in cumulus cells. Therefore, it is possible that the spectrum of transcripts seen in this study might differ from those present in unstimulated cycles. Wider implications of the findings Expected associations between age, AMH levels and response to COS were observed. Skipping exon 6 may be associated with a superior response to COS, suggesting FSHR mRNA profiling might have a role in tailoring controlled ovarian stimulation protocols. Novel transcript variants were detected and seen most often in older women. Trial registration number not applicable

P-356 Fertility preservation for patients with breast cancer: altered response to ovarian stimulation and loss of cholesterol homeostasis in ovarian follicles

Abstract Study question Does the presence of breast cancer alter the ovarian response to hormonal stimulation and the cholesterol homeostasis in ovarian follicles? Summary answer The deleterious impact of breast cancer on the ovarian response might be link to an alteration of the cholesterol biosynthesis in cumulus cells. What is known already Breast cancer is the most frequent cancer in reproductive-aged women. The cancer itself seems to exert a deleterious impact on the ovarian functions. Indeed, cancer patients who undergo fertility preservation before cancer therapy initiation show a poorer response to ovarian stimulation than healthy women. Nevertheless, this impact remains controversial, and the mechanisms by which the cancer impairs the ovarian functions are poorly understood. To our knowledge, no study has yet evaluated the impact of breast cancer on the cholesterol biosynthesis pathway in human cumulus cells, a pathway essential for oocyte competence to maturation and fertilization. Study design, size, duration 30 patients with breast cancer (10 triple negative (TNBC), 10 hormone-receptor positive (HR+) and 10 HER2 positive (HER2+)) and 30 women oocytes donors undergoing oocyte cryopreservation will be included from January 2019. We assess ovarian response to stimulation (number, quality of retrieved oocytes; total FSH dose). We quantify the level of enzymes and regulators of the cholesterol biosynthesis pathway in cumulus cells (CC) by RT-qPCR. We plan to quantify cholesterol levels in follicular fluids (FF). Participants/materials, setting, methods Since January 2019, 25 breast cancer patients (9 TNBC, 8 HR+ and 8 HER2+) and 30 oocytes donors (control group) under 37 years old have been included. Ovarian stimulation was performed with antagonist protocol. Following ovarian pick up and denudation, CC and FF were collected. After total RNAs extraction from CC, the expression levels of enzymes and regulators of the cholesterol biosynthesis pathway were quantified by RT-qPCR. Cholesterol levels will be quantified in FF. Main results and the role of chance The clinico-biological characteristics (age, BMI) are comparable between cancer patients and the control group (p > 0.05). Serum AMH levels are lower in the TNBC subgroup (2.3±1.6 ng/mL) than in the control group (4.7±2.8 ng/mL, p = 0.04). A poorer ovarian response to ovarian stimulation is observed in the breast cancer group compared with the control group (number of mature oocytes: 9.4±5.2 vs. 14.5±7.7, p = 0.007). Among the cancer patients group, the TNBC subgroup shows the poorest ovarian response to stimulation (number of mature oocytes: 7.6±4.3 vs. 14.5±7.7 in control group, p = 0.006) despite the highest total administered FSH dose (2480±880 IU vs. 1831±460 IU in control group, p = 0.02). Dysregulation of the cholesterol biosynthesis pathway is observed in the breast cancer group. For TNBC and HR+ cancer patients, we observed an increase in the transcripts levels of CYP51 enzyme (respectively 3.28±1.69 vs. 1.84±2.33, p = 0.0098 and 1.77±1.78 vs. 1.84±2.33, p = 0.03) and SREBP2 activator (respectively 2.04±0.95 vs. 1.27±1.13, p = 0.003 and 1.12±0.47 vs. 1.27±1.13, p = 0.02) of the cholesterol biosynthesis pathway compared to the control group. In HER2+ cancer patients, a significant decrease in the expression levels of SQLE (0.39±0.34 vs 1.81±3.99, p = 0.001) and DHRC7 enzymes (0.33±0.32 vs 1.21±0.88, p = 0.0002) is observed compared to the control group. Limitations, reasons for caution Our preliminary results should be confirmed with the analysis of a larger number of participants. We should confirm that the observed modulations in the expression levels of enzymes and regulators of the cholesterol biosynthesis pathway led to a loss of cholesterol homeostasis by quantifying cholesterol in FF. Wider implications of the findings Our findings strengthen the hypothesis that cancer exerts a deleterious impact on the ovarian functions, as we observed a lower ovarian response in patients with breast cancer. This project will have clinical implications, such as to adapt the fertility preservation approach according to the breast cancer subtype. Trial registration number Not applicable

P-339 Identifying essential information for a valid informed consent (IC) of egg donors: An international Delphi study

Abstract Study question What information does an international group of professionals and egg donors consider relevant and morally necessary for prospective egg donors to provide valid IC? Summary answer In the first round, participants considered 56% of the information items relevant (e.g. all legal aspects) and 50% of the items as morally necessary information. What is known already Disclosure of relevant and adequate information is essential for IC in medical procedures like egg donation (ED). However, studies reveal inadequate risk awareness among donors. This raises questions about the adequacy of the provided information. The “Egg Donor Informed Consent Tool” aims to assess donors’ understanding of the ED process and its risks. However, Skillner et al. developed the tool exclusively with American endocrinologists and donors and do not touch upon all legal aspects or alternative hormone stimulation. No international study to date has determined what information professionals and egg donors consider relevant and morally necessary for prospective donors. Study design, size, duration This modified Delphi study used a survey in an iterative process of three rounds to reach a consensus on what information items are relevant and morally necessary for a valid informed consent of candidate egg donors. Invitations to participate were sent out in November 2023 and the first round lasted six weeks. Reminders and additional invitations were sent out every two weeks. Currently (January 2024), we are preparing the second round with 35 professional participants Participants/materials, setting, methods The 35 participants were experts in ED across diverse fields (social and medical sciences, bioethics, psychology, fertility medicine and law) from 14 countries. The egg donor part of round one is ongoing. The survey consisted of 13 categories and 118 information items, which participants score for relevance via a 4-point Likert scale and moral necessity on a dichotomous scale (yes/no). Content Validity Index (CVI) will be calculated for measuring relevance. A comment section was available. Main results and the role of chance Research shows that high content validity (“consensus”) is reached when there is an I-CVI (CVI per item) of .78 or higher. The same cut-off was selected to reach consensus for Moral Necessity. The following results are based on the first round, results from all three rounds will be presented at the congress. For 58 out of 131 information items, the I-CVI was lower than 0.78. The percentage of moral necessity was below 0.78 for 65 items. The relevancy for the total survey (S-CVI/Ave) for the first round was 0.80. Four information items reached a CVI of 1: all experts thought it was relevant for a candidate donor to know that 1) the need to undergo ovarian stimulation and 2) a pick-up procedure, as well as 3) her legal rights over the donated eggs after the pick-up procedure and 4) her legal right to withdraw consent. The latter is the only information item that scored a 100% of Moral Necessity. All 16 information items in the categories “issues concerning multiple donations”, “legal aspects” and “financial aspects” reached a consensus in relevance, but two of these items’ did not reach the cut-off of 0.78 for moral necessity. Limitations, reasons for caution There was a relatively low response rate of 24 percent, which can be attributed to the demographics of our population. These professionals typically have limited availability for participation and for some professionals the email addresses we found were outdated. Wider implications of the findings The final results can give professionals a standard of essential information to provide to make sure the women are adequately informed and know what to expect when they decide to donate. It also gives researchers a potential standard to evaluate the quality of the informed consent in fertility clinics. Trial registration number Not applicable

Early progression during or after cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy indicates poor outcome with rescue protocols in dogs with multicentric lymphoma.

Dogs with lymphoma that fail cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (CHOP) before completion of their protocol are commonly thought to have poor long-term outcome, but no previous studies have evaluated the effect of early relapse on progression-free interval (PFI) or overall survival time (OST) for patients undergoing rescue chemotherapy. Correlate rescue treatment outcomes in dogs with multicentric lymphoma with outcomes after 1st-line CHOP chemotherapy. Data were collected from 6 previous retrospective or prospective studies in 187 dogs with multicentric lymphoma that received 1st-line CHOP chemotherapy and then received either lomustine (CCNU), L-asparaginase and prednisone (LAP), or rabacfosadine (RAB, Tanovea), with or without prednisone or L-asparaginase. The PFI after initiation of CHOP chemotherapy was significantly associated with response rate postprogression, PFI, and postrescue survival time (ST) for both rescue protocols. Immunophenotype (B- vs T-cell) was not significantly associated with response, PFI or OST for LAP but was significantly associated with response and PFI for RAB. Dogs that experience short PFI during or after 1st-line CHOP chemotherapy had lower response rates to rescue treatment, with shorter PFI and ST. Immunophenotype did not significantly affect outcome with LAP but was associated with PFI for RAB.

P-578 A combined analysis to establish the equipotency of corifollitropin alfa in comparison to daily recombinant FSH including individual data of 3292 IVF/ICSI patients

Abstract Study question What daily dose of follitropin beta provides a similar ovarian response as single dose of corifollitropin alfa (CFA) in women with different ovarian reserve? Summary answer Regardless of ovarian reserve, a single dose of CFA provides a similar ovarian response as 300 IU/day follitropin beta in IVF/ICSI patients. What is known already A single dose of CFA replaces the first week of stimulation with daily recFSH and provides robust ovarian stimulation due to its unique pharmacokinetic profile. Previous controlled trials in IVF/ICSI patients have demonstrated that CFA yields more oocytes than daily recFSH. In women up to 36 years, on average +2.5 oocytes were obtained in comparison to daily 150 IU recFSH and +1.2 oocytes in comparison to daily 200 IU recFSH, whereas this difference was only +0.5 oocytes in comparison to daily 300 IU recFSH in women aging 35 to 42 years. Study design, size, duration This was a retrospective analysis using individual patient data from 3 large, randomized trials, including 1715 IVF patients receiving a single injection of 100 or 150 mg CFA, followed by daily follitropin beta injections from day 8, and 1577 IVF patients treated with daily follitropin beta with a fixed starting dose of 150 IU, 200 IU or 300 IU for the first week of stimulation. Participants/materials, setting, methods The mean number of oocytes retrieved were estimated for each treatment and predicted response group (Low: AFC≤7 (n = 595), Normal: 8≥AFC≤14 (n = 1899), High: AFC≥15 (n = 808)). Pooling of the three trials was enabled by adjusting for AFC, age, body weight, and the interaction between AFC and age, all as continuous covariates. The dose of follitropin beta corresponding to CFA was estimated by including log(dose) as a covariate in the model. Main results and the role of chance There were similar positive associations between AFC and oocytes and negative associations between age and oocytes following CFA and daily recFSH treatment. There was no clear association between body weight and oocytes following either treatment. A clear increase in number of oocytes was observed with increasing daily doses of recFSH in predicted normal and predicted high responders, but not in predicted low responders. Accordingly, regardless the dose, CFA was providing an ovarian response higher than daily 150 IU or 200 IU recFSH in normal and high responders. The number of oocytes following 100 mg and 150 mg CFA was comparable in all three subsets of predicted responders and similar to the number of oocytes following daily treatment with 300 IU recFSH. The analysis estimated a single dose of 150 mg CFA to be equipotent to daily 300 IU recFSH (95% CI 251-359 IU) and a single dose of 100 mg CFA to be equipotent to 297 IU recFSH daily (95% CI 217-405 IU). Limitations, reasons for caution This retrospective analysis excludes patients with an irregular cycle, suffering from PCOS or having an AFC >20. Thus, the data cannot be extrapolated to these patients Wider implications of the findings Daily doses of recFSH provide dose-related increases of ovarian response in normal and high responders. With CFA treatment, the potential of a single IVF cycle is maximised with an ovarian response comparable to daily 300 IU recFSH, which can be safely managed by GnRH agonist triggering and a freeze-all strategy. Trial registration number NCT00696800, NCT00702845, NCT01144416

In Situ Growth of COF/PVA-Carrageenan Hydrogel Using the Impregnation Method for the Purpose of Highly Sensitive Ammonia Detection.

Flexible ammonia (NH3) gas sensors have gained increasing attention for their potential in medical diagnostics and health monitoring, as they serve as a biomarker for kidney disease. Utilizing the pre-designable and porous properties of covalent organic frameworks (COFs) is an innovative way to address the demand for high-performance NH3 sensing. However, COF particles frequently encounter aggregation, low conductivity, and mechanical rigidity, reducing the effectiveness of portable NH3 detection. To overcome these challenges, we propose a practical approach using polyvinyl alcohol-carrageenan (κPVA) as a template for in the situ growth of two-dimensional COF film and particles to produce a flexible hydrogel gas sensor (COF/κPVA). The synergistic effect of COF and κPVA enhances the gas sensing, water retention, and mechanical properties. The COF/κPVA hydrogel shows a 54.4% response to 1 ppm NH3 with a root mean square error of less than 5% and full recovery compared to the low response and no recovery of bare κPVA. Owing to the dual effects of the COF film and the particles anchoring the water molecules, the COF/κPVA hydrogel remained stable after 70 h in atmospheric conditions, in contrast, the bare κPVA hydrogel was completely dehydrated. Our work might pave the way for highly sensitive hydrogel gas sensors, which have intriguing applications in flexible electronic devices for gas sensing.

P-259 Luteal phase in dual stimulation. Do we have the same outcomes in morphokinetics, laboratory, clinical and genetic parameters?

Abstract Study question Do luteal phase (LF) embryos have the same outcomes in laboratory and morphokinetics parameters and clinical and genetic rates that follicular phase (FF) embryos? Summary answer Laboratory outcomes, ploidy and clinical rates result similar between two phases. In morphokinetic analysis we obtained significant differences in the duration of visible pronuclei. What is known already Dual stimulation (DS) protocols are being proposed as a useful strategy in patients with poor prognosis, particularly in cases of low response or low ovarian reserve. Nevertheless, there is still a lack of solid evidence for their use. In this context, it is interesting to analyse if the embryos from the LF achieve the same results as those from the FF. Our previous studies have shown comparable data, although they included vitrified oocytes. To avoid the impact of vitrification, we only review those cycles with fresh oocytes. A morphokinetic analysis is also added to compare their development. Study design, size, duration This multicentre retrospective evaluated 81 cycles of DS and PGT-A in patients with some poor prognostic feature (Antimüllerian hormone <1ng/ml, antral follicle count <6, poor response, >39 years) with 161 pick-ups between January 2022-August 2023 (81 in FF and 80 in LF). A total of 398 embryos were biopsied (195 from FF and 203 from LF) and 59 frozen embryo transfers were performed (33 in FF and 26 in FL) between January 2022-December 2023. Participants/materials, setting, methods We compared several parameters between the two groups including gamete age, oocyte number, MII number, fertilization rate, blastocyst quality, biopsy rates, and genetic results. Additionally, clinical outcomes after embryo cryotransfer were also studied. We compared classical morphokinetic parameters as well. We performed this preliminary analysis on 226 embryos (99 FF, 127 LF) in two ways: comparing FF and LF embryos as two groups and comparing by patient within the same cycle in a paired analysis. Main results and the role of chance The average age of the patients was 40.5 (±2.3). No significant differences were found in terms of oocytes retrieved per patient (8.7 ±4.9 vs 9.2±5.9), maturity (7.2 ±4 vs 7.7±4.3) or number of embryo biopsied (6.54 ±3.9 vs 6.9±4.4). After genetic analysis, euploidy rate was found to be lower in LF compared to FF although not statistically significant (23.6% and 28.6%). Aneuploidy (67.4% vs 71.4%) and mosaicism rates (22.3% vs 19.1%) were also comparable between the two groups. In the same way, we did not find any statistically significant differences in the day of transfer, quality of the embryo transfer, neither pregnancy rates (54.5% vs 50%) nor life birth rate (54.5% vs 38.5%). In the preliminary morphokinetic analysis we only obtained significant differences in the time in which pronuclei were visible, being greater in the FF (16±3h vs 15±3h, p = 0.005/p=0.004 after adjusting for confounding variables). In addition, it appears that the pronuclei of the FF embryos tend to take longer to disappear. Also, these FF embryos complete the third cell cycle in a slower way than LF embryos, although none of these comparisons are statistically significant (p = 0.065 and p = 0.068). In the paired analysis we didn’t find any statistically significant difference. Limitations, reasons for caution This study is limited by its retrospective nature. Validation by a prospective study is recommended. Regarding morphokinetics, it is necessary to increase the number of embryos analysed to increase the statistical power of the study. Wider implications of the findings It is interesting to analyse LF embryos’ morphokinetics since there are few studies in this regard. Moreover, it is still unclear whether the oocytes obtained from the LF cycles are the result of the second stimulation or a persist effect of the first one, which could somehow affect embryo development. Trial registration number Not applicable

Machine Learning Prediction of Treatment Response to Biological Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis.

Background: Disease-modifying antirheumatic drugs (bDMARDs) have shown efficacy in treating Rheumatoid Arthritis (RA). Predicting treatment outcomes for RA is crucial as approximately 30% of patients do not respond to bDMARDs and only half achieve a sustained response. This study aims to leverage machine learning to predict both initial response at 6 months and sustained response at 12 months using baseline clinical data. Methods: Baseline clinical data were collected from 154 RA patients treated at the University Hospital in Erlangen, Germany. Five machine learning models were compared: Extreme Gradient Boosting (XGBoost), Adaptive Boosting (AdaBoost), K-nearest neighbors (KNN), Support Vector Machines (SVM), and Random Forest. Nested cross-validation was employed to ensure robustness and avoid overfitting, integrating hyperparameter tuning within its process. Results: XGBoost achieved the highest accuracy for predicting initial response (AUC-ROC of 0.91), while AdaBoost was the most effective for sustained response (AUC-ROC of 0.84). Key predictors included the Disease Activity Score-28 using erythrocyte sedimentation rate (DAS28-ESR), with higher scores at baseline associated with lower response chances at 6 and 12 months. Shapley additive explanations (SHAP) identified the most important baseline features and visualized their directional effects on treatment response and sustained response. Conclusions: These findings can enhance RA treatment plans and support clinical decision-making, ultimately improving patient outcomes by predicting response before starting medication.

An Intelligent Task Scheduling Approach for the Enhancement of Collaborative Learning in Cloud Computing

Cloud computing is the foremost technology that reliably connects end-to-end users. Task scheduling is a critical process affecting the performance enhancement of cloud computing. The scheduling of the enormous data results in increased response time, makespan time, and makes the system less efficient. Therefore, a unique Squirrel Search-based AlexNet Scheduler (SSbANS) is created for adequate scheduling and performance enhancement in cloud computing suitable for collaborative learning. The system processes the tasks that the cloud users request. Initially, the priority of each task is checked and arranged. Moreover, the optimal resource is selected using the fitness function of the squirrel search, considering the data rate and the job schedule. Further, during the scheduled task-sharing process, the system continuously checks for overloaded resources and balances based on the squirrel distribution function. The efficacy of the model is reviewed in terms of response time, resource usage, makespan time, and throughput. The model achieved a higher throughput and resource usage rate with a lower response and makespan time.

Autoimmune hepatitis with confluent necrosis indicates severe liver injury but responds well to standard immunosuppressive therapy.

We aimed to study the effects of different extensive confluent necrosis on complete biochemical remission, side effects of immunosuppressants, and outcomes in patients with autoimmune hepatitis (AIH). Patients with liver biopsy, receiving standard immunosuppressive therapy (IST), and regular follow-up were retrospectively recruited. Demographic and clinicopathological characteristics between Ishak confluent necrosis scores ≤4 (the non-severe AIH group) and ≥5 (the severe AIH group) were compared. The Kaplan-Meier Survival analysis, Cox regression analysis, and log-rank test were performed. Bilateral p<0.05 was considered statistical significance. One hundred and forty-two patients were enrolled, the median age was 56.0, and 83.8% were female. There were no significant differences in aminotransferases and immunological markers between the two groups. Patients in the severe AIH group had significantly worse liver synthetic function, a higher proportion of cirrhosis, and histologically a higher degree of portal inflammation, interface hepatitis, fibrosis stage, and a higher histological activity index score (all p<0.05). Patients in the severe AIH group had a lower response than the other group after four weeks (57.1% vs. 86.3%, p=0.002). However, differences in complete biochemical remission (CBR) were insignificant. Eight patients experienced end-point events. Kaplan-Meier survival analysis showed no significant difference between the two groups (p=0.343). For adverse effects of IST, patients in the severe group tended toward a higher incidence of corticosteroid adverse effects without statistical significance. Our study indicated that patients with histologically severe confluent necrosis (Ishak score≥5) had significantly worse liver synthetic function and a higher degree of liver fibrosis before IST. Compared with their counterparts, this subgroup of patients showed delayed biochemical response but eventually comparable CBRs, side effects, and long-term outcomes.

Evaluating Safety and Clinical Activity of Front-line Treatment with Cadonilimab plus Chemotherapy in Advanced/Metastatic Nonsmall Cell Lung Cancer Harboring STK11 Genetic Aberration: A Protocol of Phase II Study

BackgroundCadonilimab is a first-in-class bispecific PD-1/CTLA-4 antibody. Serine/threonine kinase (STK11) mutation was shown to be related to low PD-L1 expression and objective response rate (ORR) in nonsmall cell lung cancer (NSCLC), resulting in poor progression-free survival (PFS) and overall survival (OS). Herein, we hypothesized that combining cadonilimab with chemotherapy could enhance antitumor immunity and extend survival in these patients. Consequently, we designed this study to explore the clinical activity and safety of cadonilimab combined with chemotherapy in patients with advanced/metastatic NSCLC harboring STK11 alteration. Trial designThis single-center, open-label, single-arm phase II trial is conducted at the first affiliated hospital of Guangzhou Medical University. Treatment-naïve advanced/metastatic NSCLC patients harboring STK11 mutation will be enrolled in this study. Eligible patients will receive either cadonilimab (10mg/kg on Day 1) plus pemetrexed (500 mg/m2) and carboplatin (AUC = 5) for nonsquamous NSCLC or abraxane (100 mg/m2) and carboplatin (AUC = 5) for squamous NSCLC for 4 cycles, followed by maintenance therapy (cadonilimab plus pemetrexed or abraxane). The treatment will be discontinued when disease progression, intolerability to cadonilimab, and/or chemotherapy occurs. Measurable lesions were assessed according to the Response Evaluation Criteria in Solid Tumors (1.1). The main endpoint is ORR and safety. Subordinate endpoints include PFS, disease control rate, and duration of response. ResultsThe study commenced enrolment in September 2023, with preliminary findings regarding the primary endpoint anticipated by January 2025.

Mismatch repair deficiency and abnormal p53 expression has significant predictive value for progesterone resistance and endometrial tumorigenesis in patients with endometrial atypical hyperplasia receiving fertility-preserving treatment

ObjectiveThis study aimed to evaluate the prognostic ability of mismatch repair deficiency (MMR-d) and abnormal p53 expression (p53abn) in patients with endometrial atypical hyperplasia (EAH) who underwent fertility-preserving treatment. MethodsThis retrospective study evaluated 51 patients with EAH who underwent fertility-sparing treatment. Endometrial biopsy specimens obtained before hormone therapy were collected and used for immunohistochemical staining for MMR and p53 proteins. Response, relapse, and progression rates were assessed based on age, body mass index, diabetes, polycystic ovary syndrome, reproductive history, MMR status, and p53 status. ResultsOverall, 11/51 (21.6%) patients had loss of MMR proteins and 6/51 (11.8%) had p53abn. Patients with MMR-d had lower complete response (CR) rates than those with normal staining patients at 12 months after initial treatment (p = 0.049). Patients with MMR-d had significantly higher relapse rates than those with MMR-p at the 1-year follow-ups after achieving CR (p = 0.035). Moreover, patients with MMR-d had a higher incidence of disease progression at 2, 3, and 4 years after fertility-sparing treatment (p = 0.001, p = 0.01 and p = 0.035, respectively). Patients with p53abn had higher relapse rates than those with p53wt at the 1- and 2-year follow-ups after achieving CR (p = 0.047 and p = 0.036, respectively). Moreover, patients with p53abn had a higher incidence of disease progression at 3 and 4 years after fertility-sparing treatment (p = 0.02 and p = 0.049, respectively). ConclusionsEAH patients with MMR-d and p53abn have a significantly higher risk of disease relapse and progression. Thus, MMR-d and p53abn may be used as predictive biomarkers of progestin resistance and endometrial tumorigenesis in EAH.

A Blockchain-Based Model for Traceability and Quality Management of Raw Materials in Clothing Products

In this study, we employ blockchain-based traceability technology to construct a comprehensive model for raw material traceability and quality management in clothing products. Additionally, we investigate engineered water nanostructures (EWNS) for their antibacterial, hydrophilic, and anti-pilling effects on textiles. The EWNS can serve as an effective tool for monitoring quality, enabling precise tracking and verification of nanomaterials during clothing production. The research validated the traceability performance of the blockchain-based model for raw material traceability and quality management in clothing products, achieving a remarkable traceability accuracy of 99.92% and an exceptionally low traceability response time of merely 1.83 seconds. Moreover, after being treated with EWNS, antibacterial rates against E. coli and S. aureus in clothing antibacterial quality management reached 99.9% and 99.0%, respectively. In the hydrophilicity test, EWNS was applied to clothing for a duration of 1 to 7 hours, resulting in a significant reduction in the wetting time of clothing from 10.8 seconds to 1.2 seconds. In the anti-pilling tests, there was a notable enhancement in the effectiveness of anti-pilling properties after EWNS treatment. In summary, our model has achieved remarkable outcomes in material traceability and quality management, offering consumers and the clothing industry a reliable method to ensure product quality and traceability, while simultaneously improving performance aspects such as antibacterial efficacy, hydrophilicity, and resistance against pilling.

Atomistic modulating of structural, elastic, and optoelectronic behavior of pure TiO2 and Fe/TiO2 for photoelectrochemical water splitting application

Titanium dioxide (TiO2) has attracted much attention because of their desirable physicochemical properties especially in the water splitting process. In this work pure and Fe-doped TiO2 compounds are studies theoretically with the help of Generalized Gradient Approximation with the revised Pardew–Burke–Ernzerh (RPBE) exchange–correlation scheme. Total Density of States (TDOS) and Partial Density of States (DOS) were analyzed in detail which show that iron (Fe) and oxygen (O) orbitals hybridize, especially in the region of the doping system conduction band minima for both modes. Additionally, this interaction produces an energy level that effectively reduces the bandgap of the adsorbed system. Optical properties were elucidated which shows that Fe-doped TiO2 system results in high absorption and photoconductivity. Moreover, the results demonstrate low bandgap energy which is suitable for the reduction in water splitting without the need for external energy. Magnetic properties demonstrated that Fe-doped TiO2 systems show very low diamagnetic responses. The calculated elastic properties of Fe-doped TiO2 indicate ductile nature of the material with a strong average bond strength. Fe-doped TiO2 exhibited less microcracks with a mechanically stable composition.

Bifunctional black phosphorus quantum dots platform: Delivery and remarkable immunotherapy enhancement of STING agonist

Cancer immunotherapy has been developed to improve therapeutic effects for patients by activating the innate immune stimulator of interferon gene (STING) pathway. However, most patients cannot benefit from this therapy, mainly due to the problems of excessively low immune responses and lack of tumor specificity. Herein, we report a solution to these two problems by developing a bifunctional platform of black phosphorus quantum dots (BPQDs) for STING agonists. Specifically, BPQDs could connect targeted functional groups and regulate surface zeta potential by coordinating metal ions to increase loading (over 5 times) while maintaining high universality (7 STING agonists). The controlled release of STING agonists enabled specific interactions with their proteins, activating the STING pathway and stimulating the secretion release of immunosuppressive factors by phosphorylating TBK1 and IFN-IRF3 and secreting high levels of immunostimulatory cytokines, including IL-6, IFN-α, and IFN-β. Moreover, the immunotherapy was enhanced was enhanced mild photothermal therapy (PTT) of BPQDs platform, producing enough T cells to eliminate tumors and prevent tumor recurrence. This work facilitates further research on targeted delivery of small-molecule immune drugs to enhance the development of clinical immunotherapy.

All-organic nanocomposite with strong photo-pyroelectric response and its application in retinal prosthesis

In patients with retinal degenerative diseases, vision restoration is feasible through implanted artificial retinal prostheses to stimulate surviving neurons. Photoelectric composites based on ferroelectric polymers have been attempted to construct retinal prostheses. However, these materials normally have a low photoelectric response and a narrow response wavelength range. Here, we synthesize conjugated poly-Schiff base nanoparticles with ultra-small size, and the nanocomposites of the nanoparticles and poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) ferroelectric polymer generate a high photoelectric response (maximum peak-to-peak voltage > 90V) under visible and near-infrared light. This flexible all-organic nanocomposite has good biocompatibility and can establish effective signal transduction with neuron cells. We explored the use of composites to construct ferroelectric retinal prostheses. Electrophysiological tests and animal behavior analysis have preliminary shown that implanted retinal prostheses can restore the visible light sensitivity of blind rats and further endow them with the ability to perceive infrared light, demonstrating their potential application in bioelectronics. This work presents a novel all-organic ferroelectric polymer composite with flexibility, biocompatibility, and excellent photoelectric response that can be used for artificial retinal prostheses.The nanocomposite composed of ultra-small conjugated nanoparticles and ferroelectric P(VDF-TrFE) exhibits excellent photo-pyroelectric response under visible and infrared light, with a peak-to-peak voltage exceeding 90V. The ultra-thin retinal prostheses (~ 20µm) constructed from this nanocomposite can directly stimulate nerve cells, effectively restore the visual function of blind rats, and endow them with infrared light sensitivity.

Piezo sensor-based operational strain modal analysis of structures: Transition from lab to field application

This study evaluates the piezo sensors for modal identification of a scaled-down prototype of a pedestrian foot-over bridge under pedestrian motions and further extends the application in real-life structures. The piezo sensors-based results were compared with the accelerometers-based displacement modal parameters. Pedestrian motions are adopted to simulate the operational conditions of a pedestrian footover bridge with different patterns of pedestrian motions. Piezo sensors effectively capture the low amplitude dynamic strain response under pedestrian motions. Strain modal testing captures the modal parameters positively correlated with conventional acceleration modal testing. Staggered pedestrian motions are best suited for actuating the structure uniformly at all instrumented nodes. Piezo sensor-based modal testing is extended to modal testing of real-life footover bridges under low amplitude ambient pedestrian traffic. Piezo sensors successfully capture the bending and torsion modes with good correlation with accelerometers-based modes. The strain-based modal parameters are obtained with excellent repeatability and negligible deviation.

Impact of antibiotics, corticosteroids, and microbiota on immunotherapy efficacy in patients with non-small cell lung cancer

Lung cancer is a leading cause of morbidity and mortality globally, with its high mortality rate attributed mainly to non-small cell lung cancer (NSCLC). Although immunotherapy with immune checkpoint inhibitors (ICI) has revolutionized its treatment, patient response is highly variable and lacking predictive markers. We conducted a prospective study on 55 patients with NSCLC undergoing ICI therapy to identify predictive markers of both response and immune-related adverse events (IrAEs) in the airway microbiota. We also analyzed the clinical evolution and overall survival (OS) with respect to treatments that affect the integrity of the microbiota, such as antibiotics and corticosteroids. Our results demonstrated that respiratory microbiota differ significantly in ICI responders: they have higher alpha diversity values and lower abundance of the Firmicutes phylum and the Streptococcus genus. Employing a logistic regression model, the abundance of Gemella was the major predictor of non-ICI response, whereas Lachnoanaerobaculum was the best predictor of a positive response to ICI. The most relevant results were that antibiotic consumption is linked to a lower ICI response, and the use of corticosteroids correlated with poorer overall survival. Whereas previous studies have focused on gut microbiota, our findings highlight the importance of the respiratory microbiota in predicting the treatment response. Future research should explore microbiota modulation strategies to enhance immunotherapy outcomes. Understanding the impact of antibiotics, corticosteroids, and microbiota on NSCLC immunotherapy will help personalize treatment and improve patient outcomes.

Fracturing Construction Curves and Fracture Geometries of Coals in the Southern Qinshui Basin, China: Implication for Coalbed Methane Productivity.

Hydraulic fracturing technology has become a common practice to enhance the permeability of coal seams, and its effectiveness significantly impacts the productivity of coalbed methane (CBM) wells. In this study, multiple data sets, including fracturing reports, productivity data, and microseismic monitoring, were utilized to analyze the factors influencing fracturing effectiveness and gas well production at the southern margin of the Qinshui Basin, China, especially the Zhengzhuang and Fanzhuang blocks. Statistics revealed that the fracturing displacement, liquid consumption, and sand consumption were 8 m3/min, 17.69-1386.52 m3 (averaging 728.42 m3), and 28.5-46.1 m3 (averaging 40 m3), respectively. There were differences in the types of fracturing curves among blocks or well groups, and the natural fracture system was identified as the key factor affecting their characteristics. The coal seams with high density of microfractures in Zhengzhuang reduce the fracture threshold of reservoirs during hydraulic fracturing, resulting in a lower fracture response ratio than that of Fanzhuang (71.0 vs 80.3%). Well groups with higher microfracture width in coal seams (Group-ZC and DS) experienced a further reduction in fracture response (averaging 67.2 vs 80.3%), and the connection of hydraulic fractures (HFs) with these high-permeability microfractures lead to an increase in the proportion of fluctuating fracturing curves (averaging 52.2 vs 33.6%). Regional structural features and fracturing effectiveness jointly affected the production of CBM wells. The productivity in Zhengzhuang was lower than that in Fanzhuang due to the highly developed faults and deeply buried coal seams. Shallow coal seams with a high width of microfractures and a low-stress environment were easily supported by a proppant, forming a complex HF network and yielding a high productivity (Group-ZC and DS). For other deeper well groups, proppant migration became unfavorable once high-angle and complex branch HF clusters formed in coal seams, leading to local low-efficiency wells and fluctuating fracturing curves.

Circulating Lipid Profiles Associated With Resistance to Androgen Deprivation Therapy in Localized Prostate Cancer.

Intense androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs) before radical prostatectomy (RP) produced favorable pathologic responses in approximately 20% of patients. The molecular reason for the low rate of response remains unclear. Lipid metabolism is known to influence androgen receptor signaling and ARPI efficacy. The aim of the study was to identify circulating lipid profiles associated with ADT/ARPI resistance in localized prostate cancer. Two independent experimental approaches were used. Experiment 1: Post hoc analysis of the association between plasma lipidomic profiles and ADT/ARPI response was performed on patients (n = 104) from two phase II trials of neoadjuvant ADT/ARPI. Response to ADT/ARPI was defined by pathologic response. Experiment 2: Patient-derived tumor explants from RP (n = 105) were cultured in enzalutamide for 48 hours. Explant response to enzalutamide was evaluated against pre-RP plasma lipidomic profiles (n = 105) and prostate tissue lipidomic profiles (n = 36). Response was defined by Ki67 (cell proliferation marker) fold difference between enzalutamide and vehicle-treated explants. In both experiments, associations between lipid profiles and ADT/ARPI response were analyzed by latent class analysis. Pretreatment plasma lipid profiles classified each experimental cohort into two groups with differences in ADT/ARPI response rates. The response rates of the groups were 9.6% versus 29% in experiment 1 (chi-squared test P = .012) and 49% versus 70% in experiment 2 (chi-squared test P = .037). In both experiments, the group with a higher incidence of ADT/ARPI resistance had higher plasma levels of sphingomyelin, glycosylceramides, free fatty acids, acylcarnitines, cholesterol esters, and alkyl/alkenyl-phosphatidylcholine and lower plasma levels of triacylglycerols, diacylglycerols, and phosphoethanolamine (t-test P < .05). Pretreatment circulating lipid profiles are associated with ADT/ARPI resistance in localized cancer in both human cohorts and explant models.