Predicting viral exposure response from modeling the changes of co-expression networks using time series gene expression data.

BACKGROUND: Deciphering the relationship between clinical responses and gene expression profiles may shed light on the mechanisms underlying diseases. Most existing literature has focused on exploring such relationship from cross-sectional gene expression data. It is likely that the dynamic nature of time-series gene expression data is more informative in predicting clinical response and revealing the physiological process of disease development. However, it remains challenging to extract useful dynamic information from time-series gene expression data. RESULTS: We propose a statistical framework built on considering co-expression network changes across time from time series gene expression data. It first detects change point for co-expression networks and then employs a Bayesian multiple kernel learning method to predict exposure response. There are two main novelties in our method: the use of change point detection to characterize the co-expression network dynamics, and the use of kernel function to measure the similarity between subjects. Our algorithm allows exposure response prediction using dynamic network information across a collection of informative gene sets. Through parameter estimations, our model has clear biological interpretations. The performance of our method on the simulated data under different scenarios demonstrates that the proposed algorithm has better explanatory power and classification accuracy than commonly used machine learning algorithms. The application of our method to time series gene expression profiles measured in peripheral blood from a group of subjects with respiratory viral exposure shows that our method can predict exposure response at early stage (within 24 h) and the informative gene sets are enriched for pathways related to respiratory and influenza virus infection. CONCLUSIONS: The biological hypothesis in this paper is that the dynamic changes of the biological system are related to the clinical response. Our results suggest that when the relationship between the clinical response and a single gene or a gene set is not significant, we may benefit from studying the relationships among genes in gene sets that may lead to novel biological insights.

Mapping allele with resolved carrier status of Robertsonian and reciprocal translocation in human preimplantation embryos.

Reciprocal translocations (RecT) and Robertsonian translocations (RobT) are among the most common chromosomal abnormalities that cause infertility and birth defects. Preimplantation genetic testing for aneuploidy using comprehensive chromosome screening for in vitro fertilization enables embryo selection with balanced chromosomal ploidy; however, it is normally unable to determine whether an embryo is a translocation carrier. Here we report a method named "Mapping Allele with Resolved Carrier Status" (MaReCs), which enables chromosomal ploidy screening and resolution of the translocation carrier status of the same embryo. We performed MaReCs on 108 embryos, of which 96 were from 13 RecT carriers and 12 were from three RobT carriers. Thirteen of the sixteen patients had at least one diploid embryo. We have confirmed the accuracy of our carrier status determination in amniotic fluid karyotyping of seven cases as well as in the live birth we have thus far. Therefore, MaReCs accurately enables the selection of translocation-free embryos from patients carrying chromosomal translocations. We expect MaReCs will help reduce the propagation of RecT/RobT in the human population.

Transcriptional profiling of long noncoding RNAs and their target transcripts in ovarian cortical tissues from women with normal menstrual cycles and primary ovarian insufficiency.

Previous studies have shown that long noncoding RNAs (lncRNAs) show a highly tissue- and disease-specific expression pattern and that they regulate the expression of neighboring genes. Because lncRNAs have been shown to be secreted into the general circulation, they may be used as diagnostic tools for some diseases. Primary ovarian insufficiency (POI) is a disease in which women have menstrual cessation before the age of 40, accompanied by elevated follicle stimulating hormone and decreased estrogen levels. In this study, ovarian cortical tissues from five women with normal menstrual cycles and from five POI patients were used for next-generation RNA sequencing. We found 20 differentially expressed lncRNAs with 12 upregulated and eight downregulated lncRNAs in cortical tissues of POI ovaries, compared with normal controls (fold change ≥ 2 and false discovery rate[FDR] ≤ 0.05). We also found 52 differentially expressed messenger RNA transcripts, with 33 upregulated and 19 downregulated ones (foldchange ≥ 2 and FDR ≤ 0.05). Functional annotation showed that these differentially expressed transcripts were associated with follicular development and granulosa cell function. Thirteen differentially expressed lncRNAs and their targeted neighboring transcripts were coregulated in ovarian cortical tissues, including lnc-ADAMTS1-1:1/ADAMTS1, lnc-PHLDA3-3:2/CSRP1, lnc-COL1A1-5:1/COL1A1, lnc-SAMD14-5:3/COL1A1, and lnc-GULP1-2:1/COL3A1. Furthermore, serum levels of these lncRNAs in POI patients were significantly different from those in normal patients ( p < 0.05), and expression differences were consistent with those in ovarian cortical tissues. This study showed that key lncRNAs were differentially expressed in both ovarian cortical tissues and serum samples between women with normal menstrual cycles and POI patients. Further studies on the regulation of ovarian lncRNAs during follicular development are critical in understanding the etiologies of POI. Analyses of lncRNA expression in serum samples might provide a basis for early diagnosis and treatment of POI.

Accumulation and localization of cadmium in potato (Solanum tuberosum) under different soil Cd levels.

Phytoavailability and uptake mechanism of Cd in edible plant tissues grown on metal polluted agricultural soils has become a growing concern worldwide. Uptake, transport, accumulation and localization of cadmium in potato organs under different soil Cd levels were investigated using inductively-coupled plasma mass spectrometry and energy dispersive X-ray microanalysis. Results indicated that Cd contents in potato organs increased with increasing soil Cd concentrations, and the order of Cd contents in different organs was leaves > stems/roots > tubers. Root-to-stem Cd translocation coefficients ranged from 0.89 to 1.81. Cd localization in potato tissues suggested that leaves and stems should be the main compartment of Cd storage and uptake. Although low concentrations of Cd migrated from the root to tuber, Cd accumulation in the tuber exceeded the standard for food security. Therefore, the planting of potato plants in farmland containing Cd should be closely evaluated due to its potential to present health risks.

Relationship of environmental exposure temperature and temperature extremes on sperm DNA fragmentation index in men with different BMI values and the indirect effect of DNA fragmentation index on semen parameters.

Prior studies have established a significant correlation between the DNA fragmentation index (DFI) and infertility. Additionally, certain investigations suggest that environmental exposure may serve as an etiological factor impacting semen quality. This study aimed to explore the impact of season, ambient temperature, and weather extremes on the DFI of sperm, along with other relevant parameters. Furthermore, it sought to assess how ambient temperature affects the DFI of sperm and other semen parameters in populations with varying BMI values. Additionally, the study analyzed the transient indirect effect of DFI on sperm parameters. This retrospective study analyzed semen samples from 11,877 men, selected based on female factor considerations, spanning from January 2016 to December 2021. Participants were grouped according to the season of semen collection. The results showed that samples collected in summer had a lower semen volume and sperm motility, while those collected in autumn had a lower DFI. We analyzed the exposure-response ratio between environmental exposure temperature and semen parameters using a generalized additive model. Results showed that the curve of the exposure-response relationship was U-shaped or inverted U-shaped; when the air temperature exposure was below the threshold, for each degree of temperature increase, the total sperm motility, sperm concentration, and progressive motility increased by 0.16 %, 0.29 × 10 (Levine, 1999)/ml and 0.14 %, respectively, while the DFI and inactivity rate decreased by 0.078 % and 0.15 %, respectively. When the air temperature exposure exceeded the threshold, for each degree of temperature increase, the sperm concentration, total sperm motility, semen volume and progressive motility decreased by 0.42 × 10 (Levine, 1999)/ml, 0.11 %, 0.0078 ml and 0.15 %, respectively, while the DFI and inactivity rate increased by 0.13 % and 0.12 %, respectively. Extremely cold weather during spermatogenesis was positively correlated with DFI, and extremely hot weather was negatively correlated with sperm motility. Subgroup analysis revealed that individuals classified as overweight / obese exhibited more pronounced changes in sperm parameters and the DFI in response to variations in environmental exposure temperature compared to those with a normal BMI. In the analysis of the relationship between DFI and sperm parameters, the results showed an inverted U-shape relationship between DFI and semen volume, and a negative correlation between DFI and sperm concentration and sperm motility. And we found that ambient temperature affects sperm parameters through DFI at low as well as average temperatures, whereas at high temperatures this indirect effect is no longer present.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR-1707 in healthy adult subjects: two randomized, double-blind, single-ascending-dose, phase 1 studies.

BACKGROUND: SHR-1707 is a novel humanized anti-Aß IgG1 monoclonal antibody that binds to Aß fibrils and monomers to block the formation of Aß plaques or to promote the microglial phagocytosis of Aß. Preclinical studies showed that SHR-1707 reduced brain Aß deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects. METHODS: Two randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18-45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55-80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg). RESULTS: Sixty-two (part 1/2, n = 50/12; age range, 18-42/55-63 years) and 30 subjects (age range, 18-42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2-60 mg/kg in young adults; there was a dose-dependent increase in plasma Aß42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed. CONCLUSIONS: A single intravenous dose of SHR-1707 at 2-60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development. TRIAL REGISTRATION: NCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov.

Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial.

OBJECTIVE: To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel for untreated HER2 positive metastatic breast cancer. DESIGN: Randomised, double blind, placebo controlled, multicentre, phase 3 trial. SETTING: 40 centres in China between 6 May 2019 and 17 January 2022. PARTICIPANTS: 590 female patients (median age 52 (interquartile range 46-58) years) with untreated HER2 positive metastatic breast cancer. INTERVENTIONS: Eligible patients were randomised 1:1 to receive either oral pyrotinib (400 mg once daily) or placebo, both combined with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m2) on day 1 of each 21 day cycle. Randomisation was stratified by treatment history of trastuzumab in the (neo)adjuvant setting and hormone receptor status. Patients, investigators, and the sponsor's study team were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival as assessed by the investigator. RESULTS: Of the 590 randomised patients, 297 received pyrotinib, trastuzumab, and docetaxel treatment (pyrotinib group), and 293 received placebo, trastuzumab, and docetaxel treatment (placebo group). At data cut-off on 25 May 2022, the median follow-up was 15.5 months. The median progression-free survival according to the investigator was significantly longer in the pyrotinib group than in the placebo group (24.3 (95% confidence interval 19.1 to 33.0) months versus 10.4 (9.3 to 12.3) months; hazard ratio 0.41 (95% confidence interval 0.32 to 0.53); one sided P<0.001). Treatment related adverse events of grade 3 or higher were reported in 267 (90%) of the 297 patients in the pyrotinib group and 224 (76%) of the 293 patients in the placebo group. No treatment related deaths occurred in the pyrotinib group, and one (<1%; diabetic hyperosmolar coma) treatment related death occurred in the placebo group. Survival and toxicities are still under assessment with longer follow-up. CONCLUSIONS: Pyrotinib, trastuzumab, and docetaxel showed superiority by significantly improving progression-free survival compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2 positive metastatic breast cancer. The toxicity was manageable. The findings support this dual anti-HER2 regimen as an alternative first line treatment option in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03863223.

In Vitro Activation of Follicles and Fresh Tissue Auto-transplantation in Primary Ovarian Insufficiency Patients.

CONTEXT: Recently, two patients with primary ovarian insufficiency (POI) delivered healthy babies after in vitro activation (IVA) treatment followed by auto-transplantation of frozen-thawed ovarian tissues. OBJECTIVE: This study sought to report the first case of live birth after IVA treatment following fresh ovarian tissue grafting in patients with POI, together with monitoring of follicle development and serum hormonal changes. DESIGN: This was a prospective observational cohort study. SETTING: We performed IVA treatment in 14 patients with POI with mean age of 29 years, mean duration since last menses of 3.8 years, and average basal FSH level of 94.5 mIU/mL. INTERVENTIONS: Prior to IVA treatment, all patients received routine hormonal treatments with no follicle development. We removed one ovary from patients with POI and treated them with Akt stimulators. We improved upon early procedures by grafting back fresh tissues using a simplified protocol. MAIN OUTCOME MEASURES: In six of the 14 patients (43%), a total of 15 follicle development waves were detected, and four patients had successful oocyte retrieval to yield six oocytes. For two patients showing no spontaneous follicle growth, human menopausal gonadotropin treatment induced follicle growth at 6-8 months after grafting. After vitro fertilization of oocyte retrieved, four early embryos were derived. Following embryo transfer, one patient became pregnant and delivered a healthy baby boy, with three other embryos under cryopreservation. CONCLUSION: IVA technology can effectively activate residual follicles in some patients with POI and allow them to conceive their own genetic offspring. IVA may also be useful for treating patients with ovarian dysfunction including aging women and cancer survivors.

An research on the isolation methods of frozen-thawed human ovarian preantral follicles.

OBJECTIVE: To explore the effective isolation method for preantral follicles from human frozen-thawed ovarian tissue. METHODS: The ovarian cortical tissue was frozen by direct cover vitrification (DCV). The frozen-thawed ovarian tissue was used for isolation of preantral follicles with collagenase combined with mechanical method and mechanical method alone, respectively. RESULTS: 1. There was no statistical difference in the survival rates of follicles in various stages between before and after freezing (P > 0.05). 2. The survival rate of secondary follicles was higher, but the survival rate of primordial follicles was lower in mechanical method alone than in collagenase combined with mechanical method (all P < 0.05). 3. The diameters of follicles were larger and E2 levels were higher in mecha-nical method alone than that in collagenase combined with mechanical method (all P < 0.05). CONCLUSION: After the frozen-thawed ovarian tissue was cultured for 6 days, compared with collagenase combined with mechanical method, mechanical method alone can obtain higher survival rate of secondary follicles, greater follicular diameter and higher E2 level, which are conducive to follicular subsequent development.

Molecular karyotype single nucleotide polymorphism analysis of early fetal demise.

We explored the application of single nucleotide polymorphism microarray (SNP array) in molecular karyotype analysis for early spontaneous abortion detection in assisted reproductive technology (ART). SNP array was performed in 81 cases. Of the 81 cases, 16 experienced natural conception (NC) and 65 were pregnant by ART. Of the 65 cases, 4 underwent artificial insemination (AI), 32 fresh in vitro fertilization-embryo transfer (IVF-ET), 9 fresh intracytoplasmic sperm injection (ICSI), and 20 thawed embryo transfer. In the 81 cases examined 69.1% displayed an abnormal molecular karyotype. In the subjects greater than 35 years of age, the abnormal molecular karyotype rate was 87.5% higher compared to 61.4% in younger individuals (P < 0.05). There was no significant difference in the abnormal molecular karyotype rate or type between ART (64.6%) and NC (87.5%). Compared with traditional cytogenetic diagnosis, the SNP array can identify a greater number of abnormal karyotypes.