The cost-effectiveness of iruplinalkib versus alectinib in anaplastic lymphoma kinase-positive crizotinib-resistant advanced non-small-cell lung cancer patients in China.

Background: Iruplinalkib is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC), which is independently developed by a Chinese pharmaceutical company. This study examined the cost-effectiveness of iruplinalkib versus alectinib in the Chinese healthcare setting. Methods: A partitioned survival model was developed to project the economic and health outcomes. Efficacy was derived using unanchored matching-adjusted indirect comparison (MAIC). Cost and utility values were obtained from the literature and experts' opinions. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to evaluate the model's robustness. Results: Treatment with iruplinalkib versus alectinib resulted in a gain of 0.843 quality-adjusted life years (QALYs) with incremental costs of $20,493.27, resulting in an incremental cost-effectiveness ratio (ICER) of $24,313.95/QALY. Parameters related to relative efficacy and drug costs were the main drivers of the model outcomes. From the PSA, iruplinalkib had a 90% probability of being cost-effective at a willingness-to-pay threshold of $37,863.56/QALY. Conclusion: Compared to alectinib, iruplinalkib is a cost-effective therapy for patients with ALK-positive crizotinib-resistant advanced NSCLC.

Secondary follicles enable efficient germline mtDNA base editing at hard-to-edit site.

Efficient germline mtDNA editing is required to construct disease-related animal models and future gene therapy. Recently, the DddA-derived cytosine base editors (DdCBEs) have made mitochondrial genome (mtDNA) precise editing possible. However, there still exist challenges for editing some mtDNA sites in germline via zygote injection, probably due to the suspended mtDNA replication during preimplantation development. Here, we introduce a germline mtDNA base editing strategy: injecting DdCBEs into oocytes of secondary follicles, at which stage mtDNA replicates actively. With this method, we successfully observed efficient G-to-A conversion at a hard-to-edit site and also obtained live animal models. In addition, for those editable sites, this strategy can greatly improve the base editing efficiency up to 3-fold, which is more than that in zygotes. More important, editing in secondary follicles did not increase more the risk of off-target effects than that in zygotes. This strategy provides an option to efficiently manipulate mtDNA sites in germline, especially for hard-to-edit sites.

Neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy for human epidermal growth factor receptor 2 positive breast cancer: a real-world retrospective single-institutional study in China.

INTRODUCTION: Real-world studies on neoadjuvant dual anti-HER2 therapy combined with chemotherapy for breast cancer (BC) are scarce in China. This study aimed to evaluate the efficacy and safety of neoadjuvant dual anti-HER2 therapy combined with chemotherapy in a real-world setting. Moreover, differences in estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation cell nuclear antigen (Ki-67) expression pre- and post-neoadjuvant therapy were analyzed. METHODS: Clinical and pathological data of patients with HER2-positive BC who received neoadjuvant dual anti-HER2 therapy combined with chemotherapy at Liaoning Cancer Hospital & Institute, China, between September 2021 and September 2023, were retrospectively reviewed. RESULTS: Among 179 included patients, a pathologic complete response (pCR) was achieved in 109 patients (60.9%). The univariate analysis results indicated that the hormone receptor (HR) status (P = 0.013), HER2 status (P = 0.003), and cycles of targeted treatment (P = 0.035) were significantly correlated with pCR. Subsequent multivariable analysis showed that HR negative and HER2 status 3 + were independent predictive factors of pCR. Anemia was the most common adverse event (62.0%), and the most common grade 3-4 adverse event was neutropenia (6.1%). The differences in HER2 (34.5%) and Ki-67 (92.7%) expression between core needle biopsy and the residual tumor after neoadjuvant therapy were statistically significant, whereas the differences were insignificant in terms of ER or PR status. CONCLUSIONS: The combination of neoadjuvant trastuzumab and pertuzumab with chemotherapy showed good efficiency, and the toxic side effects were tolerable in patients with BC. In cases where pCR was not achieved after neoadjuvant therapy, downregulation of HER2 and Ki-67 expressions was observed.

Harnessing accurate mitochondrial DNA base editing mediated by DdCBEs in a predictable manner.

Introduction: Mitochondrial diseases caused by mtDNA have no effective cures. Recently developed DddA-derived cytosine base editors (DdCBEs) have potential therapeutic implications in rescuing the mtDNA mutations. However, the performance of DdCBEs relies on designing different targets or improving combinations of split-DddA halves and orientations, lacking knowledge of predicting the results before its application. Methods: A series of DdCBE pairs for wide ranges of aC or tC targets was constructed, and transfected into Neuro-2a cells. The mutation rate of targets was compared to figure out the potential editing rules. Results: It is found that DdCBEs mediated mtDNA editing is predictable: 1) aC targets have a concentrated editing window for mtDNA editing in comparison with tC targets, which at 5'C8-11 (G1333) and 5'C10-13 (G1397) for aC target, while 5'C4-13 (G1333) and 5'C5-14 (G1397) for tC target with 16bp spacer. 2) G1333 mediated C>T conversion at aC targets in DddA-half-specific manner, while G1333 and G1397 mediated C>T conversion are DddA-half-prefer separately for tC and aC targets. 3) The nucleotide adjacent to the 3' end of aC motif affects mtDNA editing. Finally, by the guidance of these rules, a cell model harboring a pathogenic mtDNA mutation was constructed with high efficiency and no bystander effects. Discussion: In summary, this discovery helps us conceive the optimal strategy for accurate mtDNA editing, avoiding time- and effort-consuming optimized screening jobs.

Deep learning analysis for rapid detection and classification of household plastics based on Raman spectroscopy.

The overuse of plastics releases large amounts of microplastics. These tiny and complex pollutants may cause immeasurable damage to human social life. Raman spectroscopy detection technology is widely used in the detection, identification and analysis of microplastics due to its advantages of fast speed, high sensitivity and non-destructive. In this work, we first recorded the Raman spectra of eight common plastics in daily life. By adjusting parameters such as laser wavelength, laser power, and acquisition time, the Raman data under different acquisition conditions were diversified, and the corresponding Raman spectra were obtained, and a database of eight household plastics was established. Combined with deep learning algorithms, an accurate, fast and simple classification and identification method for 8 types of plastics is established. Firstly, the acquired spectral data were preprocessed for baseline correction and noise reduction, Then, four machine learning algorithms, linear discriminant analysis (LDA), decision tree, support vector machine (SVM) and one-dimensional convolutional neural network (1D-CNN), are used to classify and identify the preprocessed data. The results showed that the classification accuracy of the three machine learning models for the Raman spectra of standard plastic samples were 84%, 93% and 93% respectively. The 1D-CNN model has an accuracy rate of up to 97% for Raman spectroscopy. Our study shows that the combination of Raman spectroscopy detection techniques and deep learning algorithms is a very valuable approach for microplastic classification and identification.

Effect of small follicles on clinical pregnancy and multiple pregnancy rates in intrauterine insemination: a cohort study.

STUDY QUESTION: What is the effect of small follicles on clinical pregnancy and multiple pregnancy rates in women undergoing IUI with ovarian stimulation (IUI-OS)? SUMMARY ANSWER: The presence of ≥2 small follicles with a diameter of 10-12 or 12-14 mm was associated with an increased chance of clinical pregnancy and the presence of any 12-14 mm or larger follicles, but not smaller follicles, was statistically significantly associated with an increased risk for multiple pregnancy. WHAT IS KNOWN ALREADY: IUI-OS is widely used as the first-line treatment for unexplained or mild male factor infertility. However, IUI is associated with the risk of multiple pregnancy. While the positive association between the number of follicles ≥14 mm and the chance of pregnancy and the risk of multiple pregnancy is known, the impact of smaller follicles is uncertain. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study that included women undergoing IUI cycles from January 2007 to May 2021 in one assisted reproduction center. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied the impact of the number and size of follicles on trigger day on clinical pregnancy and multiple pregnancy rates. Generalized estimation equation regression models were used to compute unadjusted and adjusted odds ratios and 95% CI in all women and only women who achieved clinical pregnancy separately. The chance of clinical pregnancy and multiple pregnancy for different numbers of small follicles in cycles with one >18-mm follicle was calculated using marginal effects estimate. MAIN RESULTS AND THE ROLE OF CHANCE: This cohort included 12 933 IUI cycles in 7504 women. The overall clinical pregnancy rate was 16.1% (2081/12 933), with a multiple pregnancy rate of 10.5% (218/2081). In the adjusted analysis, the chance of clinical pregnancy increased significantly with the increase in the number of follicles with the diameter of 14-16, 16-18, and 18-20 mm. As for 10-12 mm [adjusted odds ratio (aOR) 1.22, 95% CI 1.02-1.46] and 12-14 mm (aOR 1.29, 95% CI 1.07-1.56) follicles, only groups with ≥2 follicles of those sizes showed significantly increased chance of clinical pregnancy. In cycles that led to pregnancy, follicles with the diameter of 12-14 mm were associated with an increased risk of multiple pregnancy (aOR 1.73, 95% CI 1.19-2.53 for one such follicle; aOR 2.27, 95% CI 1.44-3.56 for ≥2 such follicles), while 10- to 12-mm follicles were not significantly associated with multiple pregnancy (aOR 1.18, 95% CI 0.72-1.95 for ≥2 such follicles). The associations of multiple pregnancy were similar when including all cycles. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective observational study from a single center. The records of follicle diameter in our center were of a 2-mm interval which limited our ability to analyze the size of follicle as a continuous variable. Also, the number of cycles with a high number of small follicles was still limited which impeded more detailed analysis on the ≥2 follicles subgroup. Similarly, the value of some parts of the marginal probability estimation for multiple pregnancy versus pregnancy according to size and number of follicles was also limited by the low sample size of certain combinations. WIDER IMPLICATIONS OF THE FINDINGS: Follicles larger than 10 mm, especially those ≥12 mm, may need to be clearly recorded during transvaginal ultrasound surveillance and their potential effects on both pregnancy and multiple pregnancy can be discussed with couples undergoing IUI. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (Grant numbers 82201912, 82371651, and 82071615) and Shanghai Sailing Program (21YF1423200). B.W.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.M. reports consultancy for ObsEva and Merck and travel support from Merck. B.W.M. has received research funding from Ferring and Merck. The authors declare no other competing interests. TRIAL REGISTRATION NUMBER: N/A.

Factors affecting male-to-female ratio at birth in frozen-thawed embryo transfer cycles: a large retrospective cohort study.

Background: ICSI (intracytoplasmic sperm injection) leads to a reduced male-to-female ratio at birth, whereas blastocyst transfer results in an increased male-to-female ratio. However, limited knowledge exists regarding the impact of these factors on the live birth rate for each gender. This study aimed to investigate the influence of patient characteristics and treatment parameters on the live birth rate for each gender, as well as the ultimate male-to-female ratio at birth in frozen-thawed embryo transfer (FET) cycles. Method: This retrospective cohort study involved a total of 28,376 FET cycles and 9,217 subsequent deliveries, spanning from January 2003 to December 2015. The study consisted of two parts. First, logistic regression models were constructed to determine the factors influencing the male-to-female ratio among babies born after FET. Second, we aimed to investigate the mechanisms underlying this sex ratio imbalance by analyzing data from all transfer cycles. Generalized estimated equations were employed to assess the impact of risk factors on rates of male and female live births separately. Results: ICSI resulted in a lower proportion of male offspring compared to in vitro fertilization (IVF) (50.1% vs. 53.7%, aOR: 0.87, 95% CI: 0.80-0.96). Conversely, blastocyst transfer yielded a higher proportion of male offspring than cleavage-stage embryo transfer (58.7% vs. 51.6%, aOR: 1.32, 95% CI: 1.17-1.48). Analysis of all cycles indicated that ICSI resulted in a reduced likelihood of male live birth in comparison to IVF (19.8% vs. 21.6%, aOR: 0.90, 95% CI: 0.83-0.97). However, the transfer of blastocysts rather than cleavage-stage embryos not only increased the chance of male live birth (26.9% vs. 20.2%, aOR: 1.70, 95% CI:1.56-1.85) but also facilitated female live birth (20.3% vs. 19.3%, aOR: 1.26, 95% CI: 1.15-1.39). Conclusion: ICSI was associated with a reduction in the male-to-female sex ratio and a lower rate of male live births, while blastocyst transfer was associated with an increased male-to-female sex ratio at birth and a higher rate of male live births.

OsTOC1 plays dual roles in the regulation of plant circadian clock by functioning as a direct transcription activator or repressor.

Plant clock function relies on precise timing of gene expression through complex regulatory networks consisting of activators and repressors at the core of oscillators. Although TIMING OF CAB EXPRESSION 1 (TOC1) has been recognized as a repressor involved in shaping oscillations and regulating clock-driven processes, its potential to directly activate gene expression remains unclear. In this study, we find that OsTOC1 primarily acts as a transcriptional repressor for core clock components, including OsLHY and OsGI. Here, we show that OsTOC1 possesses the ability to directly activate the expression of circadian target genes. Through binding to the promoters of OsTGAL3a/b, transient activation of OsTOC1 induces the expression of OsTGAL3a/b, indicating its role as an activator contributing to pathogen resistance. Moreover, TOC1 participates in regulating multiple yield-related traits in rice. These findings suggest that TOC1's function as a transcriptional repressor is not inherent, providing flexibility to circadian regulations, particularly in outputs.

On singular values of large dimensional lag-τ sample auto-correlation matrices.

We study the limiting behavior of singular values of a lag-τ sample auto-correlation matrix Rτϵ of large dimensional vector white noise process, the error term ϵ in the high-dimensional factor model. We establish the limiting spectral distribution (LSD) that characterizes the global spectrum of Rτϵ, and derive the limit of its largest singular value. All the asymptotic results are derived under the high-dimensional asymptotic regime where the data dimension and sample size go to infinity proportionally. Under mild assumptions, we show that the LSD of Rτϵ is the same as that of the lag-τ sample auto-covariance matrix. Based on this asymptotic equivalence, we additionally show that the largest singular value of Rτϵ converges almost surely to the right end point of the support of its LSD. Based on these results, we further propose two estimators of total number of factors with lag-τ sample auto-correlation matrices in a factor model. Our theoretical results are fully supported by numerical experiments as well.

Does Day 3 embryo status matter to reproductive outcomes of single blastocyst transfer cycles? A cohort study.

OBJECTIVE: To investigate whether Day 3 (D3) embryo status matter to reproductive outcomes of blastocyst transfer cycles. DESIGN: Retrospective cohort study. SETTING: Assisted Reproduction Department of Shanghai Ninth People's Hospital, Shanghai, China. POPULATION: A total of 6906 vitrified-thawed single blastocyst transfer cycles in 6502 women were included. METHODS: Generalised estimated equation regression models were used to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the associations between embryo status and pregnancy outcomes. MAIN OUTCOME MEASURES: Biochemical pregnancy, miscarriage, live birth. RESULTS: High-quality blastocysts derived from poor-grade D3 embryos had comparable pregnancy outcomes to those derived from high-grade D3 embryos (40.0% versus 43.2%, aOR 1.00, 95% CI 0.85-1.17 for live birth rate; 8.3% versus 9.5%, aOR 0.82, 95% CI 0.63-1.07 for miscarriage rate). Cycles with low D3 cell number (five cells or fewer) had significantly higher miscarriage rate (9.2% versus 7.6%, aOR 1.33, 95% CI 1.02-1.75) compared with cycles with eight cells on D3. CONCLUSIONS: Poor-quality cleavage embryos should be cultivated to the blastocyst stage because high-quality blastocysts derived from poor-grade D3 embryos had acceptable pregnancy outcomes. When the blastocyst grade is identical, choosing embryos with higher D3 cell number (eight or more cells) for transfer could reduce the risk of early miscarriage.

Controllable preparation of mesoporous spike gold nanocrystals for surface-enhanced Raman spectroscopy detection of micro/nanoplastics in water.

Microplastics and nanoplastics are emerging classes of environmental contaminants that pose significant threats to human health. In particular, small nanoplastics (<1 µm) have drawn considerable attention owing to their adverse effects on human health; for example, nanoplastics have been found in the placenta and blood. However, reliable detection techniques are lacking. In this study, we developed a fast detection method that combines membrane filtration technology and surface-enhanced Raman spectroscopy (SERS), which can simultaneously enrich and detect nanoplastics with sizes as small as 20 nm. First, we synthesized spiked gold nanocrystals (Au NCs), achieving a controlled preparation of thorns ranging from 25 nm to 200 nm and regulating the number of thorns. Subsequently, mesoporous spiked Au NCs were homogeneously deposited on a glass fiber filter membrane to form an Au film as a SERS sensor. The Au-film SERS sensor achieved in-situ enrichment and sensitive SERS detection of micro/nanoplastics in water. Additionally, it eliminated sample transfer and prevented the loss of small nanoplastics. Using the Au-film SERS sensor, we detected 20 nm to 10 µm standard polystyrene (PS) microspheres with a detection limit of 0.1 mg/L. We also realized the detection of 100 nm PS nanoplastics at the 0.1 mg/L level in tap water and rainwater. This sensor provides a potential tool for rapid and susceptible on-site detection of micro/nanoplastics, especially small-sized nanoplastics.

Efficacy of Cellular Therapy for Azoospermia in Animal Models: A Systematic Review and Meta-Analysis.

This study investigated the efficacy of stem cell transplantation for azoospermia, a major cause of male infertility. We conducted a systematic meta- analysis to assess the therapeutic effectiveness of stem cell transplant, using different transplant methods, injection sites, and stem cell types, and the reliability of this approach in different animal species. PubMed, the Cochrane Library, and Embase were searched for studies published from January 2006 to February 2022 that evaluated the use of stem cell transplant to treat azoospermia. We included 18 studies and conducted the analyses using Review Manager 5.2 software. Expression of the meiosis-related genes Vasa, Scp3, and Dazl and the average hematoxylin and eosin- positive staining area were improved after stem cell transplant. Subgroup analyses by mode of transplant showed higher expression of Scp3 and Dazl in the xenotransplant group. Although subgroup analyses by injection site showed that the seminiferous tubule group showed the most significant effect on Scp3 expression, spermatogenesis and repair of damaged testis were induced in the tunica albuginea group. The testicular torsion group also induced high levels of Scp3. Another subgroup analysis by stem cell type showed that umbilical cord mesenchymal stem cells promoted the highest expression of meiosis-related genes and successfully induced spermatogenesis and the repair of damaged testis. Urine-derived stem cells, spermatogonial stem cells, and amniotic fluid-derived stem cells showed significantly therapeutic effects; however, more studies are needed for definitive conclusions. Subgroup analyses by type of azoospermia animal model indicated that the use of stem cell transplant in rat or mouse models had an obvious therapeutic effect, but no significant therapeutic effect was seen in azoospermia hamsters. The meta-analysis confirmed that stem cell transplant can effectively treat azoospermia in animal models. Xenotransplant is shown to enhance the therapeutic effects of stem cell transplant on azoospermia.

Impact of recurrent pregnancy loss history on reproductive outcomes in women undergoing fertility treatment.

BACKGROUND: Recurrent pregnancy loss negatively affects the reproductive outcomes of natural conception. Preimplantation genetic testing for aneuploidies has been the focus of interventions in women with recurrent pregnancy loss. However, the risk of no embryos being available, high costs, and uncertainties surrounding its effectiveness limit its use. Factors beyond euploidy, such as an appropriate intrauterine environment, are also important for improving the reproductive outcomes in women with recurrent pregnancy loss. It remains unknown whether a history of recurrent pregnancy loss can affect reproductive outcomes after fertility treatment. OBJECTIVE: This study aimed to investigate the impact of history of recurrent pregnancy loss on the reproductive outcomes of women undergoing fertility treatment. STUDY DESIGN: This was a retrospective cohort study of women who underwent their first frozen embryo transfer cycle or intrauterine insemination cycle between January 2014 and July 2020 in Shanghai, China. We excluded couples with known karyotypic abnormalities (eg, balanced translocation) or uterine malformation. We performed multivariate binary logistic regressions for biochemical pregnancy, miscarriage, and live birth rates to investigate the associations between recurrent pregnancy loss history and reproductive outcomes. RESULTS: A total of 29,825 women who underwent frozen embryo transfer cycles and 5476 women who underwent intrauterine insemination cycles were included in this study. In those who underwent frozen embryo transfer, history of recurrent pregnancy loss was not significantly associated with biochemical pregnancy (adjusted odds ratio, 1.19; 95% confidence interval, 0.87-1.63), miscarriage (adjusted odds ratio, 0.99; 95% confidence interval, 0.78-1.26), or live birth rates (adjusted odds ratio, 0.91; 95% confidence interval, 0.79-1.06). Similarly, in frozen embryo transfer cycles that led to clinical pregnancy, recurrent pregnancy loss history was not significantly associated with live birth (adjusted odds ratio, 0.99; 95% confidence interval, 0.76-1.28) or miscarriage rates (adjusted odds ratio, 1.04; 95% confidence interval, 0.81-1.35). In women with intrauterine insemination, history of recurrent pregnancy loss showed no significant associations with fertility outcomes in all cycles ([adjusted odds ratio, 1.36; 95% confidence interval, 0.88-2.10] for live birth rate and [adjusted odds ratio, 1.74; 95% confidence interval, 0.75-4.01], for miscarriage rate) and in cycles that led to clinical pregnancy ([adjusted odds ratio, 0.70; 95% confidence interval, 0.31-1.63] for live birth rate and [adjusted odds ratio, 1.45; 95% confidence interval, 0.58-3.63] for miscarriage rate). CONCLUSION: In women without obvious chromosome abnormality and uterine malformation who undergo fertility treatment, recurrent pregnancy loss history was not significantly associated with miscarriage and live birth rates, suggesting that it has little or no prognostic value in predicting the reproductive outcomes of frozen embryo transfer or intrauterine insemination cycles.

Impact of uterine malformations on pregnancy and neonatal outcomes of IVF/ICSI-frozen embryo transfer.

STUDY QUESTION: What is the impact of uterine malformations on reproductive and neonatal outcomes of IVF/ICSI-frozen embryo transfer? SUMMARY ANSWER: Unification defective uteri are associated with poorer neonatal outcomes including higher preterm delivery rate and lower birthweight, and septate uteri are associated with worse fertility outcomes including higher miscarriage and lower live birth rates (LBRs). WHAT IS KNOWN ALREADY: Several studies have investigated the negative effects of uterine malformations on pregnancy outcomes. However, an all-round and definitive conclusion has not been reached yet owing to the relatively low incidence of the disease and the heterogeneity of study populations, especially among women undergoing ART. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study including 411 women with congenital uterine anomalies and 14 936 women with a normal uterus who underwent first frozen-thawed embryo transfer cycles of IVF/ICSI from July 2008 to August 2019. We compared reproductive outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Reproductive outcomes of women with uterine malformations were studied through three propensity score-matched comparisons (patients with bicorporeal uterus, septate uterus and hemi-uterus [bicorporeal, septate and hemi-uterus groups, respectively] along with corresponding control groups without uterine malformations). We also compared pregnancy and neonatal outcomes, and performed subgroup analysis addressing didelphus, bicornuate uteri and septate uteri before and after surgery independently. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to the matched control group, women with a bicorporeal uterus had a significantly lower LBR (24.4% versus 34.8%, odds ratio (OR) 0.61 [95% CI: 0.37, 1.00], P = 0.048). The incidence of miscarriage and preterm delivery was higher but not statistically significant (29.0% versus 18.1%, OR 1.85 [95% CI: 0.82, 4.19], P = 0.135; 22.6% versus 9.9%, OR 2.64 [95% CI: 1.07, 6.52], P = 0.063, respectively). In addition, the bicorporeal group had a significantly lower gestational age, higher caesarean rate and lower birthweight than bicorporeal control. Women with a septate uterus had comparable clinical pregnancy rates to controls (43.3% versus 49.9%, OR 0.77 [95% CI: 0.57, 1.04], P = 0.091), increased miscarriage rates (23.5% versus 13.0%, OR 2.05 [95% CI: 1.18, 3.58], P = 0.010) and lower LBRs (29.4% versus 42.2%, OR 0.57 [95% CI: 0.41, 0.79], P = 0.001). In both singleton and twins pregnancies, pregnancy and neonatal outcomes were comparable between women with a septate uterus and control. Women with a hemi-uterus had a tendency for lower clinical pregnancy rate (36.8% versus 42.3%, OR 0.80 [95% CI: 0.52, 1.21], P = 0.287) and LBR (29.8% versus 33.1%, OR 0.86 [95% CI: 0.55, 1.34], P = 0.502), compared to women without malformations. The incidences of miscarriage and preterm delivery, respectively, were 16.7% versus 16.6% (OR 1.01 [95% CI: 0.41, 2.47], P = 0.989), and 9.5% versus 11.4% (OR 0.82 [95% CI: 0.27, 2.51], P = 1) in women with a hemi-uterus as compared to control. LIMITATIONS, REASONS FOR CAUTION: This was a single-centre, retrospective study in which neonatal data were extracted from parental questionnaires. The information on uteri septum type and surgery methods was poorly presented, with limited detail. In patients with uterine malformations, the number of babies with birth defects and twin pregnancies was relatively small, limiting the power of the study. WIDER IMPLICATIONS OF THE FINDINGS: Compared to patients with a normal uterus, women with uterine malformation have poorer reproductive outcomes. Pregnant women with a uterine anomaly need to be managed as high-risk pregnancies and followed with appropriate obstetric review. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Ministry of Technology (2018YFC1003000), the Elite Team Project of Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JY201801), Shanghai Sailing Program (21YF1423200) and the Fundamental Research Program Funding of Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JYZZ117). B.W.M. is supported by an NHMRC Investigatorgrant (GNT1176437). B.W.M. reports consultancy (with stock options) for ObsEva. B.W.M. has received research funding from Ferring and Merck. The authors declare no other competing interests. TRIAL REGISTRATION NUMBER: N/A.

[Effects of Chinese herbal recipe Weichang'an in inducing apoptosis and related gene expression in human gastric cancer grafted onto nude mice].

OBJECTIVE: To investigate the mechanism of Chinese herbal recipe Weichang'an (WCA) in inducing cell apoptosis of human gastric cancer grafted onto nude mice. METHODS: The high performance liquid chromatography was used for monitoring the stability of WCA. A human gastric cancer cell line SGC-7901 grafted in nude mouse was used as the animal model. The mice were divided into untreated group and two experimental groups. Animals in the two experimental groups received either WCA over a 34-day period or 5-fluorouracil (5-FU) over a 6-day period starting at the 8th day after grafting. Animals in the untreated group received normal saline on an identical schedule. Animals were killed 41 days after being grafted. To assess the effect of the treatment on tumor, the tumor weight was determined by the electron balance immediately after the animals were killed. SP immunohistochemical method was used to detect the expression of proliferating cell nuclear antigen (PCNA) in grafts. Apoptotic indices (AI) of the tumor cells were examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate fluorescence nick end labeling (TUNEL) method. SP method was also used to detect the expressions of cleaved caspase-3, caspase-8 and caspase-9. SYBR green dye I real-time quantitative polymerase chain reaction (real-time quantitative [corrected] PCR) was used to assess the related gene alterations in mRNA level. The expressions of phospho-Stat3 (Tyr705) and bcl-2 proteins were detected by using SP method. RESULTS: Compared with the untreated group, tumor growth was significantly inhibited by treatment of WCA or 5-FU (P<0.01, respectively). The tumor inhibition rate in the WCA-treated group was 48.70% and that in the 5-FU-treated group was 60.10%. The average labeling index (LI) for PCNA in the WCA-treated group and 5-FU-treated group was significantly decreased as compared with that in the untreated group, respectively. The AI of human gastric cancer grafted in the nude mice detected by using TUNEL method was significantly increased to (9.72+/-4.51)% in the WCA-treated group, while it was (2.45+/-1.37)% in the untreated group. 5-FU-treated group was also found a significantly increased AI compared with the untreated group. The expressions of cleaved caspase-3 and caspase-9 in the WCA-treated group and 5-FU-treated group were significantly increased as compared with those in the untreated group. But caspase-8 showed no significant alteration either in the WCA-treated group or in the 5-FU-treated group. The expression levels of Stat3 (2(-)delta delta C(T))=0.16) and bcl-2 (2(-)delta delta C(T))=0.10) detected by using real-time quantitative [corrected] PCR were lower in the WCA-treated group than those in the untreated group. The expressions of phospho-Stat3 (Tyr705) and bcl-2 in the WCA-treated group were significantly decreased as compared with those in the untreated group. CONCLUSIONS: Chinese herbal recipe WCA can inhibit gastric cancer cell SGC-7901 growth in vivo, induce gastric cancer cell apoptosis and suppress the cell proliferation. WCA induces apoptosis through the caspase-9 and caspase-3 pathway in vivo. Its mechanism might be involved in the down-regulation of Stat3 and bcl-2 genes.