A 6-Year Follow-up of a Chinese Child with Homozygous ß0-Thalaasemia and a Heterozygous KLF1 Mutation.

Patients with the genotype of ß0/ß0 for ß-thalassemia (ß-thal) usually behave as ß-thal major (ß-TM) phenotype which is transfusion-dependent. The pathophysiology of ß-thal is the imbalance between α/ß-globin chains. The degree of α/ß-globin imbalance can be reduced by the more effective synthesis of γ-globin chains, and increased Hb F levels, modifying clinical severity of ß-TM. We report a Chinese child who had homozygous ß0-thal and a heterozygous KLF1 mutation. The patient had a moderate anemia since 6 months old, keeping a baseline Hb value of 8.0-9.0 g/dL. She had normal development except for a short stature (3rd percentile) until 6 years old, when splenomegaly and facial bone deformities occurred. Although genetic alteration of KLF1 expression in ß0/ß0 patients can result in some degree of disease alleviation, our case shows that it is insufficient to ameliorate satisfactorily the presentation. This point should be borne in mind for physicians who provide the genetic counseling and prenatal diagnosis to at-risk families.

Oxfendazole Induces Apoptosis in Ovarian Cancer Cells by Activating JNK/MAPK Pathway and Inducing Reactive Oxygen Species Generation.

Ovarian cancer (OC) is one of the most common and high mortality type of cancer among women worldwide. The majority of patients with OC respond to chemotherapy initially; however, most of them become resistant to chemotherapy and results in a high level of treatment failure in OC. Therefore, novel agents for the treatment of OC are urgently required. Benzimidazole anthelmintics might have the promising efficacy for cancer therapy as their selectively binding activity to ß-tubulin. Recent study has shown that one of the benzimidazole anthelmintics oxfendazole inhibited cell growth of non-small cell lung cancer cells, revealing its anti-cancer activity; however, the pharmacological action and detailed mechanism underlying the effects of oxfendazole on OC cells remain unclear. Therefore, the present study investigated the cytotoxic effects of oxfendazole on OC cells. Our results demonstrated that oxfendazole significantly decreased the viability of OC cells. Oxfendazole inhibited the proliferation, induced G2/M phase arrest and apoptotic cell death in A2780 cells. The c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) pathway was activated and reactive oxygen species (ROS) generation was increased in OC cells treated with oxfendazole; oxfendazole-induced apoptosis was notably abrogated when co-treated with JNK inhibitor SP600125 and ROS scavenger N-acetyl-L-cysteine (NAC), indicating that JNK/MAPK pathway activation and ROS accumulation was associated with the oxfendazole-induced apoptosis of OC cells. Moreover, oxfendazole could also induce the proliferation inhibition and apoptosis of cisplatin resistant cells. Collectively, these results revealed that oxfendazole may serve as a potential therapeutic agent for the treatment of OC.

Application of QF-PCR Technology Combined With Early Pregnancy Ultrasound in Prenatal Screening for Fetal Chromosomal Aneuploidy.

Context: Abnormalities in the meiosis process after sperm-egg union can cause fetal chromosome aneuploidy. The rate of birth defects and the mortality of fetuses with chromosome aneuploidy is significantly higher than that of fetuses with normal chromosomes. Both ultrasound and quantitative fluorescence polymerase chain reaction (QF-PCR) have limitations when used singly, but their combined use may provide better diagnoses. Objective: The study intended to investigate the value of QF-PCR combined with ultrasound in early pregnancy for prenatal screening for fetal chromosomal aneuploidy, to contribute to the improvement of prenatal examinations, ultimately enhancing the early detection and management of the aneuploidies. Design: The research team performed a retrospective study. Setting: The study took place at the Affiliated Dongguan Hospital at Southern Medical University in Dongguan, China. Participants: Participants were 1082 pregnant women who underwent an ultrasound examination in early pregnancy, 11 weeks to 13 + 6 weeks, at the hospital between January 2019 and January 2022. Outcome Measures: Using the results of participants' ultrasounds and QF-PCR testing, the research team used the gold standard, a chromosomal karyotype analysis, to evaluate the efficacy in diagnosing fetal chromosomal aneuploidies, of ultrasound alone, QF-PCR testing alone, and their combination. Results: Early-pregnancy ultrasound detected 15 abnormalities, of which seven were an abnormal thickness of the transparent layer of the neck, 22 were abnormal nasal bone, four were a fish-scale appearance of bilateral soles of the feet, and three were other abnormalities, such as an incomplete quadrant of the heart, gastroceles, or dilatation of the pelvis. No cases of missed or failed karyotype cultures occurred. The QF-PCR detected 21 abnormal fetuses, including six with trisomy 21 syndrome, two with trisomy 18 syndrome, one with trisomy 13 syndrome, and 11 with sex-chromosome abnormalities. The sensitivity, specificity, and accuracy of QF-PCR in diagnosing fetal chromosomal aneuploidy were 85.7%, 99.81%, and 99.54%, respectively, and the Kappa value for its consistency with the gold standard was 0.88. The sensitivity, specificity, and accuracy of the ultrasound, combined with QF-PCR in diagnosing fetal chromosomal aneuploidy were 95.23%,99.71%, and 99.63%, respectively, and the Kappa value of combined tests' consistency with the gold standard was 0.91. Conclusion: QF-PCR combined with ultrasound in early pregnancy can effectively improve the accuracy of prenatal diagnosis of fetal chromosome aneuploidy, especially for high-risk pregnant women with a high, positive, predictive value, providing a feasible detection method for clinical practice.

Faecalibacterium prausnitzii Improves Lipid Metabolism Disorder and Insulin Resistance in Type 2 Diabetic Mice.

Purpose: Additional effective therapeutic strategies for Type 2 diabetes (T2D) patients are urgently needed. Gut microbiota plays an important role in T2D development and is a promising treatment strategy for T2D patients. Faecalibacterium prausnitzii (F. prausnitzii) is regarded as one of the most important bacterial indicators for a healthy gut, but the mechanisms of its anti-diabetic properties are still unclear. Methods and Results: The abundance of F. prausnitzii in feces of patients with T2D was detected by using qPCR. The effects of F. prausnitzii on glucose homeostasis, insulin resistance (IR), dyslipidemia, hepatic steatosis and inflammation were investigated in type 2 diabetic (T2D) db/db mice. We also investigated F. prausnitzii in people. Our results showed that the abundance of F. prausnitzii was significantly lower in T2D patients compared to healthy subjects. In T2D mice, we found that F. prausnitzii treatment significantly decreased fasting blood glucose and IR index, indicating improved glucose intolerance as well as IR. Furthermore, based on evaluation of lipid-regulating enzyme activities and proinflammatory cytokine levels, F. prausnitzii was not only able to improve inflammation in both adipose tissue and liver, but also ameliorate hepatic steatosis through inhibiting the activity of hepatic lipogenic enzymes. Conclusion: These results suggested that F. prausnitzii might serve as a therapeutic option for T2D by improved IR, lipid metabolism and inflammation.

Hb Wanjiang: A New ß-Globin Chain Variant with Two Amino Acid Substitutions (HBB: c.255_264delinsTTTTTCTCAG).

We report a new hemoglobin (Hb) variant that we have named Hb Wanjiang (HBB: c.255_264delinsTTTTTCTCAG). We identified this variant in a Chinese man by the next-generation sequencing (NGS) method. The father of the proband also carried the same variant. This variant results from a 10 bp deletion at codons 84-87 of the ß-globin chain, replaced with 10 nucleotides coming from the δ-globin gene at the same position, leading to the substitution of two amino acids in the peptide chain with no change in the ß-globin chain length. The heterozygotes had a normal hematological feature with no abnormal Hb variant detectable on capillary electrophoresis (CE) and high performance liquid chromatography (HPLC). The combination of Hb Wanjiang and ß-thalassemia (ß-thal) was not found to aggravate anemia.

Severe Hb H Disease Caused by Hb Zürich-Albisrieden (HBA1: c.178G>C): Another Case Report.

Hb Zürich-Albisrieden, [α59(E8)Gly→Arg, HBA1: c.178G>C] is a rare and highly unstable α-globin chain variant. The involved mutation has been reported in both HBA1 and HBA2 genes. A few compound heterozygotes of Hb Zürich-Albisrieden and α0-thalassemia have shown that this variant is associated with severe Hb H disease. We describe here another case of Hb Zürich-Albisrieden who presented with transfusion-dependent anemia beginning shortly after birth.

In Utero Exposure to Fine Particles Decreases Early Birth Weight of Rat Offspring and TLR4/NF-κB Expression in Lungs.

Particulate matter (PM2.5) exposure is reported to have deleterious effects on health. Maternal PM2.5 exposure has been confirmed to damage the growth of somatic cells and enhance the incidence of chronic respiratory diseases in children. Here we aim to investigate the impact of in utero PM2.5 exposure on early birth weight and postnatal lung development. Pregnant Sprague-Dawley rats were administered PM2.5 (0.1, 0.5, 2.5, or 7.5 mg/kg) intraperitoneally every 3 days until birth. Maternal and birth outcomes and somatic growth were monitored. Lungs were collected on PND1 (where PND = postnatal day) and PND28; the lung wet-to-dry weight ratio (W/D) was analyzed, and reactive oxygen species (ROS) levels were measured. Expression of Toll-like receptor 4 (TLR4) and NF-κB were evaluated by Western blotting and quantitative RT-PCR. There were no significant intergroup differences for maternal outcomes; however, offspring exposed in utero to 2.5 and 7.5 mg/kg PM2.5 were significantly smaller in litter weight than the controls. In utero exposure to 2.5 and 7.5 mg/kg PM2.5 led to lower body weight after birth and disrupted lung development during infancy. ROS levels were significantly increased in the 7.5 mg/kg PM2.5 group. PM2.5-treated rats showed upregulated pulmonary expression of TLR4 and NF-κB. Maternal PM2.5 exposure enhances the risk of low birth weight and affects lung alveolar development. The underlying molecular mechanisms may involve TLR4/NF-κB signaling.

KCNH3 Predicts Poor Prognosis and Promotes Progression in Ovarian Cancer.

BACKGROUND: Ovarian cancer (OC) is one of the most common causes of cancer-related death among women; accordingly, new biomarkers of OC are urgently needed. Potassium voltage-gated channel sub-family H member 3 (KCNH3) is a voltage-gated potassium channel member involved in cognitive function and diabetes. Here, we aimed to elucidate the role and potential molecular mechanisms of KCNH3 in OC. MATERIALS AND METHODS: KCNH3 expression levels in OC tissues were analyzed using TCGA data and confirmed by RT-qPCR and immunohistochemistry in OC tissues. The cell counting kit-8 was used to assess cell proliferation in OC cells in which KCNH3 was knocked-down with small interference RNA (siRNA). Wound-healing and transwell invasion assays were used to assess migratory and invasive abilities, respectively. Cell cycle distribution and apoptosis were determined using a flow cytometer. Gene set enrichment analysis and Western blot were used to investigate the potential pathways of KCNH3 in OC development. RESULTS: TCGA data and RT-qPCR results from patients with OC revealed high KCNH3 expression in OC tissues compared to normal ovarian tissues. Survival analysis in patients with OC suggested that high KCNH3 expression might be an independent predictor for poor overall survival and disease-free survival. In vitro studies showed that KCNH3 silencing in OC cells could inhibit cell proliferation and migration ability, and induce apoptosis and G2/M phase arrest. Furthermore, Western blot results showed that KCNH3 silencing might induce downregulation of RPA1 and RPA2 expression level in both SKOV3 and COC1 cells. CONCLUSION: KCNH3 plays an important role in cancer progression in patients with OC. Further investigation might reveal KCNH3 as a potential biomarker for prognosis or diagnosis in OC.

Claudin 10 acts as a novel biomarker for the prognosis of patients with ovarian cancer.

Ovarian cancer (OC) is one of the most fatal gynecological malignancies in the world and confers a poor 5-year survival rate. The present study was designed to discover novel prognostic markers for patients with OC in order to estimate disease metastasis or recurrence. Based on the large cohorts of transcriptome data from multicenter sources, a comprehensive analysis was performed to explore potential prognostic markers. A total of 269 differentially expressed genes were identified, of which 32 were upregulated and 237 downregulated in OC tissues compared with the corresponding expression in normal tissues. Kaplan-Meier analysis, log-rank test and nomogram analysis were employed to demonstrate that low expression levels of claudin 10 (CLDN10) were associated with a less favorable disease prognosis. The most promising prognostic marker for OC was subsequently selected. Additionally, the prognostic nomogram was constructed in order to assess the 5-year survival rate using CLDN10 expression as a prognostic marker for OC. Furthermore, gene set enrichment analysis and analysis of the tumor-associated competing endogenous RNA network were performed to elucidate the potential biological processes associated with CLDN10 expression. The current results indicated that CLDN10 may influence OC progression via transforming growth factor-ß (TGF-ß)- or WNT/ß-catenin-induced epithelial-to-mesenchymal transition (EMT). The associations among CLDN10, microRNA-486-5p, TGF-ß, WNT/ß-catenin and EMT should be further investigated in future studies.

Chaetocin induces caspase-dependent apoptosis in ovarian cancer cells via the generation of reactive oxygen species.

Ovarian cancer (OC) is one of the most common types of cancer among women worldwide. The majority of patients with OC respond to current chemotherapy approaches initially; however, patients are likely to experience cancer recurrence and become resistant to the chemotherapy. Therefore, novel agents for the treatment of OC are urgently required. Chaetocin, a natural product isolated from Chaetomium fungi, has been reported to exhibit anticancer activity against various types of cancer; however, the pharmacological action and detailed mechanism underlying the effects of chaetocin on OC cells remain unclear. Therefore, the present study investigated the cytotoxic effects of chaetocin on OC cells. A Cell Counting kit-8 assay was used to study cell viability, a colony formation assay was used to assess cell proliferation, flow cytometry was used to detect apoptosis, cell cycle and reactive oxygen species (ROS) generation, and western blotting was used to determine the protein levels of poly (ADP-ribose) polymerase, caspase-3 and cleaved-caspase-3. The results demonstrated that chaetocin significantly decreased the viability of OC cells. Chaetocin inhibited the proliferation and induced G2/M phase arrest of the OVCAR-3 OC cell line. Additionally, chaetocin induced apoptotic cell death in OVCAR-3 cells via the caspase pathway. It was observed that chaetocin induced the accumulation of ROS in OVCAR-3 cells. Treatment with the ROS scavenger N-acetyl-L-cysteine reversed the apoptotic effects and activation of the caspase pathway induced by chaetocin. Collectively, these results revealed that chaetocin suppressed the proliferation and promoted the caspase-dependent apoptosis of OC cells by increasing the levels of ROS. Therefore, chaetocin may serve as a potential therapeutic agent for the treatment of OC.

Predicting the success of vaginal birth after caesarean delivery: a retrospective cohort study in China.

OBJECTIVES: To develop a nomogram to predict the likelihood of vaginal birth after caesarean section (VBAC) among women after a previous caesarean section (CS). DESIGN: A retrospective cohort study. SETTING: Two secondary hospitals in Guangdong Province, China. PARTICIPANTS: Inclusion criteria were as follows: pregnant women with singleton fetus, age ≥18 years, had a history of previous CS and scheduled for trial of labour after caesarean delivery (TOLAC). Patients with any of the following were excluded from the study: preterm labour (gestational age <37 weeks), two or more CSs, contradictions for vaginal birth, history of other uterine incision such as myomectomy, and incomplete medical records. PRIMARY OUTCOME MEASURE: The primary outcome was VBAC, which was retrospectively abstracted from computerised medical records by clinical staff. RESULTS: Of the women who planned for TOLAC, 84.0% (1686/2006) had VBAC. Gestational age, history of vaginal delivery, estimated birth weight, body mass index, spontaneous onset of labour, cervix Bishop score and rupture of membranes were independently associated with VBAC. An area under the receiver operating characteristic curve (AUC) in the prediction model was 0.77 (95% CI 0.73 to 0.81) in the training cohort. The validation set showed good discrimination with an AUC of 0.70 (95% CI 0.60 to 0.79). CONCLUSIONS: TOLAC may be a potential strategy for decreasing the CS rate in China. The validated nomogram to predict success of VBAC could be a potential tool for VBAC counselling.

Expression of HMGB1 in maternal exposure to fine particulate air pollution induces lung injury in rat offspring assessed with micro-CT.

OBJECTIVES: Maternal particulate matter with less than 2.5 µm in diameter (PM2.5) is associated with an increased risk for acute lower respiratory infections and allergic airway inflammation; however, its effect on the developing lung remains unclear. The aim of this study is to determine the effect of maternal PM2.5 during pregnancy on lung development in offspring. METHODS: Timed pregnant Sprague-Dawley rats were treated with PM2.5 (0.1, 0.5, 2.5, or 7.5 mg/kg) once every 3 days from day 0-18 of pregnancy and delivered at term. Lungs were obtained on postnatal day 0, the structure of the lung was analyzed by quantitative micro-computed tomography (CT) and the levels of proinflammatory cytokines were analyzed using enzyme-linked immunosorbent assay (ELISA). The expression of high mobility group box-1 (HMGB1) was also detected by immunohistochemistry, Western blotting, and quantitative RT-PCR. RESULTS: Ground-glass opacity and high-density volumes in CT slice images of maternal PM2.5-exposure rats were observed. The concentrations of IL-1, IL-6 and TNF-α were significantly increased by 2.36-, 3.91- and 4.36-fold, respectively, in the rats of the PM-7.5 group compared with the rats in the control group. The PM2.5-treated rats showed a significant upregulated expression of HMGB1 in lungs. CONCLUSIONS: PM2.5 exposure during pregnancy results in lung inflammation in offspring mediated by increased HMGB1 expression, followed by upregulated IL-1, IL-6 and TNF-α secretions, which may contribute to the development of inflammatory lung diseases in later life.

Concurrent Genetic and Standard Screening for Hearing Impairment in 9317 Southern Chinese Newborns.

OBJECTIVE: The goal of this study was to investigate the use of concurrent genetic screening together with standard newborn hearing screening (NHS) in an effort to provide a scientific basis for the beneficial use of concurrent genetic hearing screening in newborns. Our aim was to improve the neonatal detection rate of hearing impairment and the potential for hearing loss, allowing for increased early intervention and potentially allowing for prevention of later onset hearing loss. This information could also be used to increase the effectiveness of genetic counseling regarding hearing impairment. METHODS: A total of 9317 neonates from Children's Hospital of Dongguan and Dongguan People's Hospital were included in this study between January 2015 and October 2015. Twenty hotspot hearing-associated mutations of four common deafness- susceptibility genes (GJB2, GJB3, SLC26A4, and MTRNR1) were analyzed by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The results of genetic screening and NHS were concurrently analyzed. RESULTS: A total of 129 infants (1.38%) exhibited hearing loss as determined by otoacoustic emission (OAE) testing. The genetic screening revealed that 348 (3.74%) individuals had at least one mutant allele. In total, 34 (0.36%) of the neonates carried a causal complement of mutations. The overwhelming majority of the genetically referred newborns passed the OAE hearing screening, but could be at risk for later hearing loss. CONCLUSION: This study furthers the understanding of the etiology of hearing loss and proves that it is beneficial to use genetic screening along with OAE screening of neonates to improve detection rates of at-risk infants. Our results show that this concurrent testing allows for better early identification of infants at risk for hearing loss, which may occur before speech and language development. Prevention of hearing loss can be achieved by avoiding the use of antibiotics containing amino glycosides in infants whose mutations make them extremely sensitive to these antibiotics. This information is also useful in genetic counseling, providing region-specific mutation information.

Retrospective review on obstetric cases of critically ill and dead patients in Dongguan.

This retrospective analysis was set to understand the epidemiological status of the critically ill obstetric patients in Dongguan city, Guangdong, China. Understanding the risk factors for the death cases can provide scientific evidences for future preventive strategies to decrease the maternal mortality rate. This retrospective included the statistical data and clinical data on the cases of critically ill and dead obstetric patients admitted to Dongguan People's Hospital and Dongguan Maternal & Child Health Hospital from September 1st, 2009 to August 31st, 2013. Data included numbers of the critically ill maternal and obstetric women, common obstetric and maternal comorbidities and complications in the critically ill patients, the basic characteristics of maternal and obstetric deaths, records of regular prenatal examinations, the time intervals between onset of acute symptoms and ICU admission, blood purification, and the acute physiology and chronic health evaluation II (APACHE II) score. During the 5-year period, there were increasing trend of critically ill pregnant and obstetric patients, and the prevalence rate of critically ill obstetric patients was 8.99-9.28 %. The most common obstetric causes of admission were massive postpartum hemorrhage (63.54 %), followed by pregnancy-associated hypertension (15.85 %) and placenta previa (8.92 %). The most common non-obstetric causes of admission were acute heart failure (1.98 %). In the observed period, 20 critically ill obstetric patients died in these two hospitals (mortality rate 0.24 %, 20/8,129). The mean age of dead women was (30.3 ± 6.6) years old and mean gestational age was (30.1 ± 9.3) weeks. 75 % of the patient had more than two pregnancies. Over 90 % of the patients received education below junior high school level. 85 % of the patients were non-Dongguan natives and regular prenatal care rate was only 15 % on dead cases. The most common causes of death were pregnancy-associated hypertension, acute heart failure, and massive postpartum hemorrhage. The dead patients experienced longer interval between onset of acute symptoms and ICU admission (media = 62.5 h), higher APACHE II score (25.4 ± 5.4), and lower blood purification treatment rate (10 %). The incidence of critically ill pregnant and obstetric patients is high in Dongguan city. The group of dead obstetric patients, the majority of which were non-Dongguan natives, usually experienced above-average pregnancies, lower educational level, lower regular prenatal care rate, and longer interval between onset of acute symptoms and ICU admission. Critically ill obstetric patients may benefit from publicized informed relevant education, government-supported health care, preventative interventions of critical obstetric and medical complications, timely ICU admission after onset of acute symptoms, and the enhanced support of organ functions within the ICU.