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Selective activation of Pt(IV) prodrugs within tumors has emerged as a promising strategy in tumor treatment. Although progress has been made with photo- and ultrasound-activated Pt(IV) prodrugs, concerns remain over the non-specific activation of photosensitizers (PS) and the potential for phototoxicity and chemical toxicity. In this study, a sequential dual-locked Pt(IV) nano-prodrug that can be activated by both the acidic tumor microenvironment and light was developed. The Pt(IV) prodrug was prepared by conjugating PS-locked Pt(IV) to a polymeric core, which was then chelated with metallo iron to lock its photoactivity and form a metallo-nano prodrug. Under acidic tumor microenvironment conditions, the metallo-nano prodrug undergoes dissociation of iron, triggering a reduction process in oxaliplatin under light irradiation, resulting in the activation of both chemotherapy and photodynamic therapy (PDT). Additionally, the prodrug could induce metallo-triggered ferroptosis and polarization of tumor-associated macrophages (TAM), thereby enhancing tumor inhibition. The dual-lock strategy employed in a nanoparticle delivery system represents an expansion in the application of platinum-based anticancer drugs, making it a promising new direction in cancer treatment.

Abstract Background Previous studies on whole grain consumption had inconsistent findings and lacked quantitative assessments of evidence quality. Therefore, we aimed to summarize updated findings using the Burden of Proof analysis (BPRF) to investigate the relationship of whole grain consumption on type 2 diabetes (T2D), colorectal cancer (CRC), stroke, and ischemic heart disease (IHD). Methods We conducted a literature search in the Medline and Web of Science up to June 12, 2023, to identify related cohort studies and systematic reviews. The mean RR (relative risk) curve and uncertainty intervals (UIs), BPRF function, risk-outcome score (ROS), and the theoretical minimum risk exposure level (TMREL) were estimated to evaluate the level of four risk-outcome pairs. Results In total, 27 prospective cohorts were included in our analysis. Consuming whole grain at the range of TMREL (118.5–148.1 g per day) was associated with lower risks: T2D (declined by 37.3%, 95% UI: 5.8 to 59.5), CRC (declined by 17.3%, 6.5 to 27.7), stroke (declined by 21.8%, 7.3 to 35.1), and IHD (declined by 36.9%, 7.1 to 58.0). For all outcomes except stroke, we observed a non-linear, monotonic decrease as whole grain consumption increased; For stroke, it followed a J-shaped curve (the greatest decline in the risk of stroke at consuming 100 g whole grain for a day). The relationships between whole grain consumption and four diseases are all two-star pairs (ROS: 0.087, 0.068, 0.062, 0.095 for T2D, CRC, stroke, and IHD, respectively). Conclusion Consuming 100 g of whole grains per day offers broad protective benefits. However, exceeding this threshold may diminish the protective effects against stroke. Our findings endorse replacing refined grains with whole grains as the main source of daily carbohydrates. Registry and registry number for systematic reviews or meta-analyses We have registered our research in PROSPERO, and the identifier of our meta-analyses is CRD42023447345.

Sorafenib (SF), a multi-targeted tyrosine kinase inhibitor, serves as a primary therapeutic modality for advanced liver cancer. Nonetheless, its clinical efficacy is hindered by various obstacles, such as limited bioavailability and inadequate accumulation. This study introduces a novel biomimetic mineralization enzyme, known as BSA@Pt/Ce6/SF@M (PCFM). The PCFM incorporates platinum (Pt) as a catalytic agent, SF as a molecular-targeted therapeutic agent, and Ce6 as a photosensitizer within liver cancer cell membranes. This strategy enables the combination of various anti-tumor treatments, such as photodynamic therapy (PDT) and autophagy induction, leading to increased bioavailability of SF and achieving a multidimensional synergistic anticancer effect. The PDT effect produced by Ce6 in PCFM greatly enhances SF-induced autophagy, effectively promoting autophagic cell death. Furthermore, Pt dissociates from the biomineralization process, acquiring peroxidase properties through chemokinetic reactions. This facilitates the catalysis of significant oxygen generation, addressing the challenge of hypoxia in the tumor microenvironment and improving the efficacy of PDT. Moreover, the SF further enhances therapeutic efficacy by inducing autophagy in response to energy deprivation, as indicated by the reduced levels of HIF-1α, p62, along with increased levels of ROS and LC3-Ⅱ/Ι. This biomineralization-based nanoenzyme exhibits strong anti-tumor characteristics, offering a novel strategy for overcoming challenges in liver cancer treatment.

In the post-COVID-19 pandemic era, influenza virus infections continuously lead to a global disease burden. Evaluating vaccine effectiveness against influenza infection is crucial to inform vaccine design and vaccination strategy. In this study, we recruited 1120 patients with influenza-like illness (ILI) who attended fever clinics of 4 sentinel hospitals in the Ili Kazakh Autonomous Prefecture, Xinjiang Uygur Autonomous Region, China, from January 1 to April 7, 2024. Using a test-negative design, we estimated influenza vaccine effectiveness (VE) of 54.7% (95% CrI: 23.7, 73.1) against medical-attended influenza infection, with 62.3% (95% CrI: 29.3, 79.8) against influenza A, and 51.2% (95% CrI: 28.7, 83.0) against influenza B. Despite the moderate VE estimated in this study, influenza vaccination remains the most important approach to prevent influenza at the community level.

Background: The relationship between fruit, whole grain, and total energy consumption and the gut microbiome in the Chinese population remains unclear. Objective: We investigated the relationship between intakes of fruits, whole grains, and energy, and the diversity and composition of gut microbiota. Design: This cross-sectional study included 167 subjects aged 40-75 years who underwent colonoscopy at Nankai Hospital in Tianjin, China. Each of the participants completed a personal history questionnaire, a 7-day dietary record, and donated a fecal sample. The V3-V4 hypervariable region of the bacterial 16S rRNAgene was amplified and sequenced using Illumina Novaseq. The relationship between diet and gut microbiota was evaluated in terms of both the overall composition and the abundance of specific taxon. Results: Fruits intake was positively related to the abundance of Bacilli, Porphyromonadaceae, Streptococcaceae, Parabacteroides, Streptococcus, and Bilophila in fecal samples. Higher whole grains intake was associated with higher microbial diversity, as measured by Shannon, Simpson, and Chao1 indices. Specifically, there was a significant increase inthe relative abundance of Lachnospiraceae and a decrease in Actinobacteria with increased whole grains intake. Moreover, higher intake of total energy was associated with a lower abundance of Anaerostipes and a higher abundance of Lactobacillales and Acidaminococcus. Conclusion: Whole grains intake was positively associated with gut microbial diversity. Fruits and total energy intake were related to the abundance of specifictaxon (e.g., Bacilli and Acidaminococcus). These findings highlight the potential importance of dietary interventions for modulating gut microbiota composition and promoting overall health.

Objective To evaluate the willingness of healthcare providers to perform population-based screening in primary healthcare institutions in China.Methods Healthcare providers of 262 primary healthcare institutions in Tianjin were invited to fill out a questionnaire consisting of demographic characteristics, workload, and knowledge of, attitude towards and willingness to perform breast, cervical and colorectal cancer screening. Willingness to screen was the primary outcome. Multilevel logistic regression models were conducted to analyse the determinants of healthcare providers’ willingness to screen. ORs and 95% CIs were estimated.Results A total of 554 healthcare providers from 244 institutions answered the questionnaire. 67.2%, 72.1% and 74.3% were willing to perform breast, cervical and colorectal cancer screening, respectively. A negative attitude towards screening was associated with a low willingness for cervical (OR=0.27; 95% CI 0.08, 0.94) and colorectal (OR=0.08; 95% CI 0.02, 0.30) cancer screening, while this was not statistically significant for breast cancer screening (OR=0.30; 95% CI 0.08, 1.12). For breast, cervical and colorectal cancer screening, 70.1%, 63.8% and 59.0% of healthcare providers reported a shortage of staff dedicated to screening. A perceived reasonable manpower allocation was a determinant of increased willingness to perform breast (OR=2.86; 95% CI 1.03, 7.88) and colorectal (OR=2.70; 95% CI 1.22, 5.99) cancer screening. However, this was not significant for cervical cancer screening (OR=1.76; 95% CI 0.74, 4.18).Conclusions In China, healthcare providers with a positive attitude towards screening have a stronger willingness to contribute to cancer screening, and therefore healthcare providers’ attitude, recognition of the importance of screening and acceptable workload should be optimised to improve the uptake of cancer screening.

Abstract Accurate assessment of infection presence risk level, timely diagnosis, and effective control are critical for decreasing mortality of Acute‑on‑chronic liver failure (ACLF). We aimed to develop and validate a novel diagnostic model to accurately assess infection presence risk level in ACLF patients. 185 ACLF patients with/without infection were enrolled, and their demographic, physical findings, immune-inflammatory, hepatic function, metabolism, and coagulation-fibrinolysis indicators were analyzed. Regression analysis was performed to identify the independent diagnostic parameters, which were further used to establish diagnostic models with a nomogram for visual. An area under receiver operating characteristic curve (AUROC), calibration plots, clinical impact curves, decision curve analysis, and net reclassification index were used to evaluate and identify the best model. An external validating cohort was introduced to verify the diagnostic accuracy. We screened out white blood cell (WBC) count, LYM%, blood urea nitrogen (BUN), and D-dimer for assessing infection presence risk levels in ACLF patients. WBD (WBC + BUN + D-dimer) was established and proposed as a novel diagnostic model for infection presence risk levels assessment in ACLF patients with an AUROC of 0.803 (95%CI 0.723–0.883), 0.885 (95%CI 0.786–0.984) in training and external cohorts, respectively. In stratification analysis by ACLF etiology and stages, WBD achieved an AUROC of 0.791 (95%CI 0.691–0.891) and 0.873 (95%CI 0.78–0.966) in HBV-related and early-stage patients, respectively. Whereas a higher AUROC of 0.905 (95%CI 0.807–1.00) in the early-stage of HBV-related ACLF patients indicated its optimum application scope. WBD, a novel laboratory-based nomogram, can serve as a decision-making support tool for clinicians to assess infection presence risk levels in ACLF patients.

Abstract Introduction Geriatric assessment (GA) is widely used to detect vulnerability in older patients. As this process is time-consuming, prescreening tools have been developed to identify patients at risk for frailty. We aimed to assess whether the Geriatric 8 (G8) or the Korean Cancer Study Group Geriatric Score (KG-7) shows better performance in identifying patients who are in need of full GA. Materials and methods A consecutive series of patients aged ≥ 60 years with colorectal cancer were included. The sensitivity, specificity, predictive value, and 95% confidence intervals (95% CI) were calculated for the G8 and the KG-7 using the results of GA as the reference standard. ROC(Receiver Operating Characteristic) was used to evaluate the accuracy of the G8 and the KG-7. Results One hundred four patients were enrolled. A total of 40.4% of patients were frail according to GA, and 42.3% and 50.0% of patients were frail based on the G8 and the KG-7, respectively. The sensitivity and specificity of the G8 were 90.5% (95% CI: 77.4–97.3%) and 90.3% (95% CI: 80.1–96.4%), respectively. For the KG-7, the sensitivity and specificity were 83.3% (95% CI: 68.6–93.0%) and 72.6% (95% CI: 59.8–83.1%), respectively. Compared to the KG-7, the G8 had a higher predictive accuracy (AUC: (95% CI): 0.90 (0.83–0.95) vs. 0.78 (0.69–0.85); p

Abstract Background Little is known on the association of types of grains with mortality and the moderating effect of lifestyle on this association. This study aims to evaluate the single or joint associations of types of grains and lifestyle with all-cause mortality among Chinese older adults. Methods Data were derived from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) from 1998 to 2018. Subjects aged ≥ 65 years were eligible. The types of grains included wheat, total rice, and coarse cereals. Lifestyle was derived using smoking, alcohol consumption, physical activity, and dietary pattern. All-cause mortality was the primary outcome. Results This study included 30275 participants with a mean age 87 ± 11 years and documented 19261 deaths during a mean follow-up of 4.8 years. Compared to wheat, in those with healthy and intermediate lifestyle, total rice was associated with a 13% (HR: 0.87, 95% CI 0.80, 0.93) and 6% (HR: 0.94, 95% CI 0.90, 1.00) lower risk of mortality, respectively, and coarse cereals were associated with a 14% (HR: 0.86, 95% CI 0.74, 1.00) and 12% (HR: 0.88, 95% CI 0.79, 0.97) lower risk of mortality, respectively. Meanwhile, an increase per SD in intakes of wheat and coarse cereals was associated with a 10% (HR: 1.10, 95% CI 1.03, 1.18) and 25% (HR: 1.25, 95% CI 1.08, 1.44) higher mortality rate in those with healthy lifestyle, and a 13% (HR: 1.13, 95% CI 1.08, 1.19) and 29% (HR: 1.29, 95% CI 1.17, 1.44) higher mortality in females but not males. In addition, a U-shaped association of intake of total grains with all- cause mortality was observed (P for non-linearity = 0.002), and a J-shaped association of intake of total rice with all- cause mortality was observed (P for non-linearity = 0.003). Conclusions Specific types of grains and lifestyle were separately or jointly associated with all-cause mortality. Compared to wheat, total rice and coarse cereals were advanced grains for participants with a relatively healthy lifestyle. Intake of total rice was related to all-cause mortality in a dose–response manner. Therefore, a combination of intermediate intake of total rice and healthy lifestyle should be encouraged in older adults.

Abstract Background Resistance to conventional dose schemes and radiotoxicity of healthy tissue is a clinical challenge in the radiation therapy of large locally advanced drug-resistant gastrointestinal stromal tumor (LADR-GIST). This study aimed to assess the feasibility of using multi-shell Simultaneous Integrated Boost Intensity-Modulated modality (SIB-IMRT) strategy to provide a safe and effective escalation dose regimen for LADR-GIST. Methods 7 patients with LADR-GIST were selected in this study. The modified SIB-IMRT plans for all patients were generated by delivering different escalation-dose gradients to four ring shaped regions (shells) within the gross tumor volume (GTV). The doses of the central volume of the tumor (GTVcenter) were escalated up to 70–92.5 Gy (25 fractions), while the doses of planning target volume (PTV) and shell-1 were kept at 50.0 Gy. Based on different escalation-dose gradients, the modified SIB-IMRT plans were divided into four groups (SIB-IMRT groups). For comparison purposes, plans obtained by conventional IMRT technique (Con-IMRT) with 50 Gy (25 fractions) were also generated for all patients (Con-IMRT group). All plans were normalized to cover 95% of the PTV with the prescribed dose of 50.0 Gy. The equivalent uniform dose (EUD), relative equivalent uniform dose (rEUD), dose volume histogram (DVH), dose profile, conformity index (CI) and monitor unit (MU) were evaluated in five groups. The Friedman Test was performed to determine whether there were significant differences (P

Background To decrease the burden of breast cancer (BC), the Chinese government recently introduced biennial mammography screening for women aged 45-70 years. In this study, we assess the effectiveness and cost-effectiveness of implementing this programme in urban China using a micro-simulation model.Methods The ‘Simulation Model on radiation Risk and breast cancer Screening’ (SiMRiSc) was applied, with parameters updated based on available data for the Chinese population. The base scenario was biennial mammography screening for women aged 45-70 years, and this was compared to a reference population with no screening. Seven alternative scenarios were then simulated by varying the screening intervals and participant ages. This analysis was conducted from a societal perspective. The discounted incremental cost- effectiveness ratio (ICER) was compared to a threshold of triple the gross domestic product (GDP) per life years gained (LYG), which was 30 785 USD/LYG. Univariate sensitivity analyses were conducted to evaluate model robustness. In addition, a budget impact analysis was performed by comparing biennial screening with no screening at a time horizon of 10 years.Results Compared with no screening, the base scenario was cost-effective in urban China, giving a discounted average cost-effectiveness ratio (ACER) of 17 309 USD/LYG. The model was most sensitive to the cost of mammography per screen, followed by mean size of self- detected tumours, mammographic breast density and the cumulative lifetime risk of BC. The efficient frontier showed that at a threshold of 30 785 USD/LYG, the base scenario was the optimal scenario with a discounted ICER of 25 261 USD/LYG. Over 10 years, screening would incur a net cost of almost 38.1 million USD for a city with 1 million citizens. Conclusion Compared to no screening, biennial mammography screening for women aged from 45-70 is cost-effective in urban China.

The associations of dynapenic abdominal obesity and transitions with frailty progression remain unclear among middle-aged and older adults. We included 6937 participants from the China Health and Retirement Longitudinal Study (CHARLS) and 3735 from the English Longitudinal Study of Aging (ELSA). Participants were divided into non-dynapenia and non-abdominal obesity (ND/NAO), abdominal obesity alone (AO), dynapenia alone (D), and dynapenic abdominal obesity (D/AO). Frailty status was assessed by the frailty index (FI), and a linear mixed-effect model was employed to analyze the associations of D, AO, D/AO, and transitions with frailty progression. Participants with AO, D, and D/AO had increased FI progression compared with ND/NAO in both cohorts. D/AO possessed the greatest additional annual FI increase of 0.383 (95% CI: 0.152 to 0.614), followed by D and AO in the CHARLS. Participants with D in the ELSA had the greatest magnitude of accelerated FI progression. Participants who transitioned from ND/NAO to D and from AO to D/AO presented accelerated FI progression in the CHARLS and ELSA. In conclusion, dynapenic abdominal obesity, especially for D/AO and D, presented accelerated frailty progression. Our findings highlighted the essential intervention targets of dynapenia and abdominal obesity for the prevention of frailty progression.

Background and purposeUnderstanding the temporal trends of stroke burden and its attributable risk factors are essential for targeted prevention strategies. We aimed to describe the temporal trends and attributable risk factors of stroke in China.MethodsData on the stroke burden [incidence, prevalence, mortality, and disability-adjusted life years (DALYs)] and the population-attributable fraction for stroke risk factors from 1990 to 2019 were obtained from the Global Burden of Disease Study 2019 (GBD 2019). We analyzed trends in the burden of stroke and its attributable risk factors from 1990 to 2019, and the characteristics of stroke-attributable risk factors by sex, age group, and stroke subtype.ResultsFrom 1990 to 2019, the age-standardized incidence, mortality, and DALY rates for total stroke decreased by 9.3% (3.3, 15.5), 39.8% (28.6, 50.7), and 41.6% (30.7, 50.9) respectively. The corresponding indicators all decreased for intracerebral hemorrhage and subarachnoid hemorrhage. The age-standardized incidence rate of ischemic stroke increased by 39.5% (33.5 to 46.2) for male patients and by 31.4% (24.7 to 37.7) for female patients, and the age-standardized mortality and DALY rates remained almost unchanged. The three leading stroke risk factors were high systolic blood pressure, ambient particulate matter pollution, and smoking. High systolic blood pressure has remained the leading risk factor since 1990. The attributable risk of ambient particulate matter pollution shows a clear upward trend. Smoking and alcohol consumption were important risk factors for men.ConclusionThis study reinforced the findings of an increased stroke burden in China. Precise stroke prevention strategies are needed to reduce the disease burden of stroke.

Objective: Glucokinase-maturity-onset diabetes of the young (GCK-MODY; MODY2) is a rare genetic disorder caused by mutations in the glucokinase (GCK) gene. It is often under- or misdiagnosed in clinical practice, but correct diagnosis can be facilitated by genetic testing. In this study, we examined the genes of three patients diagnosed with GCK-MODY and tested their biochemical properties, such as protein stability and half-life, to explore the function of the mutant proteins and identify the pathogenic mechanism of GCK-MODY.Methods: Three patients with increased blood glucose levels were diagnosed with MODY2 according to the diagnostic guidelines of GCK-MODY proposed by the International Society for Pediatric and Adolescent Diabetes (ISPAD) in 2018. Next-generation sequencing (whole exome detection) was performed to detect gene mutations. The GCK gene and its mutations were introduced into the pCDNA3.0 and pGEX-4T-1 vectors. Following protein purification, enzyme activity assay, and protein immunoblotting, the enzyme activity of GCK was determined, along with the ubiquitination level of the mutant GCK protein.Results: Genetic testing revealed three mutations in the GCK gene of the three patients, including c.574C>T (p.R192W), c.758G>A (p.C253Y), and c.794G>A (p.G265D). The biochemical characteristics of the protein encoded by wild-type GCK and mutant GCK were different, compared to wild-type GCK, the enzyme activity encoded by the mutant GCK was reduced, suggesting thermal instability of the mutant GST-GCK. The protein stability and expression levels of the mutant GCK were reduced, and the enzyme activity of GCK was negatively correlated with the levels of fasting blood glucose and HbA1c. In addition, ubiquitination of the mutant GCK protein was higher than that of the wild-type, suggesting a higher degradation rate of mutant GCK than WT-GCK.Conclusion:GCK mutations lead to changes in the biochemical characteristics of its encoded proteins. The enzyme activities, protein expression, and protein stability of GCK may be reduced in patients with GCK gene mutations, which further causes glucose metabolism disorders and induces MODY2.

ObjectiveThe clinical characteristics of Ulnar-mammary syndrome (UMS) caused by mutations in TBX3 (T-Box transcription factor 3) were studied and the correlation between genotype and clinical phenotype were analyzed to improve awareness and early diagnosis of the disease.MethodsThe clinical data of a boy aged 13 years and 5 months with left forearm deformity and growth retardation as the main features were analyzed. Genomic exon detection was performed, and the results were verified by Sanger sequencing. Simultaneously, we performed literature review to analyze the correlation between clinical phenotypes and genotypes.ResultsThe clinical manifestations in the child were short stature, ulnar hypoplasia of the forearm, hypohidrosis, retracted nipple, micropenis, and cryptorchidism. Laboratory examination revealed hyperthyroidism, growth hormone deficiency, and hypogonadotropic hypogonadism. Imaging results displayed delayed bone age, small pituitary gland, and persistence of Rathke's cleft cyst. The results of the exome sequencing revealed the deletion of AGA at positions 1121–1,124 of TBX3, which resulted in a frameshift mutation (c.1121–1124del AGAG; pGlu374fs). According to the American College of Medical Genetics (ACMG) assessment, the mutation is a pathogenic variant. A definitive diagnosis of UMS was made on the basis of the clinical phenotype of the patient. The Chinese and English literature were reviewed to analyze the correlation between TBX3 genotype and clinical phenotype.ConclusionUMS is a rare hereditary disease caused by mutations in TBX3. There is significant clinical heterogeneity associated with the variants of this gene. To our knowledge, this mutation site in TBX3 has been reported for the first time, thereby expanding the mutation spectrum of this gene.

Introduction: Magnetic resonance imaging (MRI) has shown the potential to improve the screening effectiveness among women with dense breasts. The introduction of fast abbreviated protocols (AP) makes MRI more feasible to be used in a general population. We aimed to investigate the cost-effectiveness of AP-MRI in women with dense breasts (heterogeneously/extremely dense) in a population-based screening program. Methods: A previously validated model (SiMRiSc) was applied, with parameters updated for women with dense breasts. Breast density was assumed to decrease with increased age. The base scenarios included six biennial AP-MRI strategies, with biennial mammography from age 50–74 as reference. Fourteen alternative scenarios were performed by varying screening interval (triennial and quadrennial) and by applying a combined strategy of mammography and AP-MRI. A 3% discount rate for both costs and life years gained (LYG) was applied. Model robustness was evaluated using univariate and probabilistic sensitivity analyses. Results: The six biennial AP-MRI strategies ranged from 132 to 562 LYG per 10,000 women, where more frequent application of AP-MRI was related to higher LYG. The optimal strategy was biennial AP-MRI screening from age 50–65 for only women with extremely dense breasts, producing an incremental cost-effectiveness ratio of € 18,201/LYG. At a threshold of € 20,000/LYG, the probability that the optimal strategy was cost-effective was 79%. Conclusion: Population-based biennial breast cancer screening with AP-MRI from age 50–65 for women with extremely dense breasts might be a cost-effective alternative to mammography, but is not an option for women with heterogeneously dense breasts.

Background Glucocorticoids (GCs) are commonly used to treat autoimmune diseases and malignancies in children and adolescents. Growth retardation is a common adverse effect of GC treatment in pediatric patients. Accumulating evidence indicates that non-coding RNAs (ncRNAs) are involved in the pathogenesis of glucocorticoid-induced growth retardation (GIGR), but the roles of specific ncRNAs in growth remain largely unknown. Methods In this study, 2-week-old male Sprague-Dawley rats had been treated with 2 mg/kg/d of dexamethasone for 7 or 14 days, after which the growth plate tissues were collected for high-throughput RNA sequencing to identify differentially expressed mRNAs, lncRNAs, circRNAs, and miRNAs in GIGR rats. Results Transcriptomic analysis identified 1,718 mRNAs, 896 lncRNAs, 60 circRNAs, and 72 miRNAs with different expression levels in the 7d group. In the 14d group, 1,515 mRNAs, 880 lncRNAs, 46 circRNAs, and 55 miRNAs with differential expression were identified. Four mRNAs and four miRNAs that may be closely associated with the development of GIGR were further validated by real-time quantitative fluorescence PCR. Function enrichment analysis indicated that the PI3K-Akt signaling pathway, NF-kappa B signaling pathway, and TGF-β signaling pathway participated in the development of the GIGR. Moreover, the constructed ceRNA networks suggested that several miRNAs (including miR-140-3p and miR-127-3p) might play an important role in the pathogenesis of GIGR. Conclusions These results provide new insights and important clues for exploring the molecular mechanisms underlying GIGR.

BackgroundLipoid congenital adrenal hyperplasia (LCAH) is a rare and severe disorder that is caused by mutations in the steroidogenic acute regulatory protein (StAR). Non-classic LCAH is defined as late-onset glucocorticoid deficiency and even complete male external genitalia in 46,XY individuals. However, to date, few cases of non-classic LCAH have been reported.MethodsIt was attempted to describe the clinical characteristics of a male child with complete male external genitalia in terms of age of onset, adrenal function, and biochemical indicators. Previously reported cases were also reviewed to investigate the relationship of age of onset with enzymatic activity in non-classic LCAH.ResultsThe patient with complete male external genitalia was diagnosed with non-classic LCAH, in which the reason for his referral to a local hospital at the of age 1.25 years was progressive skin hyperpigmentation, and plasma adrenocorticotropic hormone (ACTH) level was elevated to higher than 1,250 pg/ml. The compound heterozygous mutations c.772C>T/c.562C>T in STAR gene were identified via genetic testing. The literature review resulted in identification of 47 patients with non-classic LCAH from 36 families. The mutational analysis showed that c.562C>T mutation was prevalent in patients with non-classic LCAH, accounting for 37.2% of the total mutant alleles, which could reflect the founder effect on the non-classic LCAH population. In total, 28 46,XY patients were reported, including 22 (78.5%) cases with complete male external genitalia and six (21.5%) cases with different degrees of hypospadias.ConclusionThe clinical phenotypes of non-classic LCAH are highly variable. Routine physical examination, laboratory measurement, genetic testing, and, importantly, enzymatic activity assay may facilitate the early diagnosis of non-classic LCAH. The age of primary adrenal insufficiency (PAI) onset may not be a diagnostic basis for non-classic LCAH, and enzymatic activity assay determination may be more effective.

Background: Whether the World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR) dietary recommendations affect the gut microbiota and inflammatory status remains unclear. We examined the association of dietary adherence scores to the WCRF/AICR with gut microbiota and inflammation in a cross-sectional setting. Methods: The WCRF/AICR diet adherence scores were calculated for 151 participants (adenoma 97, non-adenoma 54) from 7-day dietary records. The gut microbiota was analyzed by 16S rRNA gene sequencing of fecal samples. The levels of inflammatory biomarkers in both blood (i.e., IL-6, IL-8, IgA, IgM, and IgG) and fecal samples (i.e., FCP) were evaluated in 97 colorectal adenoma patients who had blood samples available. Multivariable linear regression analyses were conducted to examine the association of individual and total dietary adherence scores with gut microbiota and inflammatory biomarker levels. Results: Participants with higher adherence had lower relative abundance of Proteobacteria (β = −0.041, 95%CI: −0.073, −0.009), Enterobacteriaceae (β = −0.035, 95%CI: −0.067, −0.003), and unidentified Enterobacteriaceae at the genus level (β = −0.029, 95%CI: −0.055, −0.003) compared to those with lower adherence. Plant-based food intake was positively correlated with increased abundance of Phascolarctobacterium (β = 0.013, 95%CI: 0.001, 0.026). Restricting fast food was linked to high abundance of Bacteroidaceae (β = 0.149, 95%CI: 0.040, 0.257) and Bacteroides (β = 0.149, 95%CI: 0.040, 0.257). Limiting sugary drinks was associated with reduced abundance of Lachnospiraceae (β = −0.155, 95%CI: −0.292, −0.018). Plant-based food intake (β = −0.251, 95%CI: −0.450, −0.052) and restriction of fast food (β = −0.226, 95%CI: −0.443, −0.008) were associated with reduced IGG levels in men. Alcohol restriction was linked to lower IL-6 (β = −7.095, 95%CI: −11.286, −2.903) and IL-8 (β = −7.965, 95%CI: −14.700, −1.230) levels in women, but with higher IL-6 (β = 0.918, 95%CI: 0.161, 1.675) levels in men. Conclusions: Our findings support the association of adherence to the WCRF/AICR diet with gut microbiota and inflammation. These results need to be validated in additional prospective or interventional studies.

BackgroundThe gut microbiome is important for host nutrition and metabolism. Whether the gut microbiome under normal diet regulate human height remains to be addressed. Our study explored the possible relationship between gut microbiota, its metabolic products and the pathogenesis of idiopathic short stature disease (ISS) by comparing the gut microbiota between children with ISS and of normal height, and also the short-chain fatty acids (SCFAs) produced by the gut microbiota.MethodsThe subjects of this study were 32 prepubescent children aged 4-8 years. The fecal microbial structure of the subjects was analyzed by 16S rRNA high-throughput sequencing technology. The concentrations of SCFAs in feces were determined by gas chromatography-mass spectrometry.ResultsThe richness of gut microbiota in ISS group was decreased, and the composition of gut microbiota was significantly different between ISS group and control group. The relative abundance of nine species including family Ruminococcaceae and genera Faecalibacterium and Eubacterium, in ISS group was significantly lower than that in control group (P

BackgroundThe global gamma passing rate is the most commonly used metric for patient-specific pretreatment quality assurance in radiation therapy. However, the optimal region for evaluation and specific action limits (ALs) need to be explored. Therefore, this study was carried out to explore the optimal region for evaluation of the global gamma passing rate and define ALs by using the COMPASS software.MethodsA total of 93 intensity-modulated radiation therapy (IMRT) plans for nasopharyngeal cancer (NPC) patients, including 61 original plans and 32 multileaf collimator (MLC) error-introduced test plans, were selected for retrospective analysis. Firstly, the dose distribution was divided into six isodose regions (“≥10%”, “≥20%”, “≥30%”, “≥40%”, “≥50%”, and “≥60%”) based on the prescribed dose and one clinically oriented region for evaluation (“whole”) to perform the three-dimensional (3D) global gamma reanalysis. Meanwhile, the percentage gamma passing rate (%GP), mean gamma index (μGI) based on 3%/2 mm criteria, and percentage dose error (%DE) of the dose–volume histogram (DVH) metrics were recorded by COMPASS application. Secondly, the Pearson’s correlation coefficient was used to analyze the correlation between %GP and %DE and between μGI and %DE in different regions. Additionally, receiver operating characteristic (ROC) methodology was applied to quantify the fraction of patient-specific plans evaluated as “fail” and “pass”. In order to improve the correlation between gamma analysis result and clinical criteria, ROC analysis was carried out in accordance with hybridization analysis criteria (%DE ≤3%, %GP ≥90% and %DE ≤3%, μGI ≤0.6). ROC was performed for two purposes: 1) to analyze the sensitivity and specificity of %GP and μGI in different regions for evaluation and 2) to define the ALs of %GP and μGI in the optimal region for evaluation. Finally, the plans introduced with MLC errors were prepared for validation. Moreover, we also compared the positive rate of ALs of both %GP and μGI in detecting MLC error-introduced plans in different regions.Results1) In our study, a number of DVH-based metrics were found to be correlated with the evaluation parameters. The corresponding number was 4, 2, 1, 1, 1, 1, and 3 in γwhole, γ10%, γ20%, γ30%, γ40%, γ50%, and γ60%, respectively, and 5, 3, 0, 1, 1, 4, and 2 in μGIwhole, μGI10%, μGI20%, μGI30%, μGI40%, μGI50%, and μGI60%, respectively. The results by COMPASS have revealed that the %DE of specific structures has a slightly higher correlation with both %GP and μGI of the “whole” region compared with that of any other region. However, it is a moderate correlation (0.5 ≤ |r| < 0.8). 2) The areas under the curves (AUCs) of γwhole, μGIwhole, μGI40%, μGI50%, and μGI60% were >0.7 based on 3%/2 mm criteria. According to the Youden coefficient, we defined the ALs of γwhole ≥92%, μGIwhole ≤0.36, μGI40% ≤0.43, and μGI60% ≤0.40 based on 3%/2 mm criteria. 3) In the validation, for original plans, the accuracy of ALγwhole, ALγ10%, ALμGIwhole, ALμGI40%, ALμGI50%, and ALμGI60% was 23%, 9.8%, 90%, 80.3%, 9.8%, and 88.5%, respectively. For test plans with systematic MLC errors smaller than 0.8 mm, the positive rates of ALγwhole, ALγ10%, ALμGIwhole, ALμGI40%, ALμGI50%, and ALμGI60% were 25%, 58%, 92%, 92%, 42%, and 100%, respectively. For the plans with systematic MLC errors higher than 0.8 mm, the positive rates of all AL%GP and ALμGI were 100%. From the COMPASS validation results, the accuracy of γwhole, μGIwhole, μGI40%, and μGI60% was higher than that of the conventional γ10% and commonly used μGI50%.ConclusionsCompared with the traditional evaluation region (i.e., the criteria with a threshold of 10% or a threshold of 50%, it was the same with the isodose regions of “≥10%”, “≥50%” based on the prescribed dose in our study), the “whole” region is more meaningful to the clinic by COMPASS. The accuracy of μGIwhole is higher than that of the conventional γ10% and the commonly used μGI50%.

Abstract Background A colorectal cancer screening programme (CCSP) was implemented from 2012 to 2017 in Tianjin, China. Residents with a positive faecal immunochemical test (FIT) or positive self-reported symptom questionnaire (SRSQ) were recommended to undergo colonoscopy. The objective was to investigate the potential factors associated with nonadherence to colonoscopy among a risk-increased population. Methods Data were obtained from the CCSP database, and 199,522 residents with positive FIT or positive SRSQ during two screening rounds (2012–2017) were included in the analysis. Logistic regression analysis was performed to assess the association between nonadherence to colonoscopy and potential predictors. Results A total of 152,870 (76.6%) individuals did not undergo colonoscopy after positive FIT or positive SRSQ. Residents with positive SRSQ but without positive FIT were more likely not to undergo colonoscopy (negative FIT: OR, 2.35; 95% CI, 2.29–2.41, no FIT: OR, 1.27; 95% CI, 1.24–1.31). Patients without a cancer history were less likely to undergo colonoscopy even if they received risk-increased reports based on the SRSQ. Conclusion In the CCSP, seventy-seven percent of the risk-increased population did not undergo colonoscopy. FIT should be recommended since positive FIT results are related to improved adherence to colonoscopy. Residents with negative FIT but positive SRSQ should be informed of the potential cancer risk to ensure adherence to colonoscopy.

The toxicity and side effects of chemotherapeutic drugs remain a crucial obstacle to the clinical treatment of hepatocellular carcinoma (HCC). Identifying combination therapy from Chinese herbs to enhance the sensitivity of tumors to chemotherapeutic drugs is of particular interest. Astragalus polysaccharide (APS), one of the natural active components in Astragalus membranaceus, has been reported to exhibit anti-tumor properties in diverse cancer cell lines. The aim of this study was to determine the effect of APS on Doxorubicin (Dox)-induced apoptosis in HCC and the underlying mechanism. The results showed that APS dose-dependently promoted Dox-induced apoptosis and enhanced endoplasmic reticulum (ER) stress. Additionally, APS decreased the mRNA level and protein stability of O-GlcNAc transferase (OGT), and increased the O-GlcNAcase (OGA) expression. Furthermore, OGT lentiviral transfection or PugNAc (OGA inhibitor) treatment reversed the ER stress and apoptosis induced by the combination of Dox and APS. A xenograft tumor mouse model confirmed that the combination of APS and Dox showed an advantage in inhibiting tumor growth in vivo. These findings suggested that APS promoted Dox-induced apoptosis in HCC cells through reducing the O-GlcNAcylation, which led to the exacerbation of ER stress and activation of apoptotic pathways.

Background: Instead of a single value for mammographic sensitivity, a sensitivity function based on tumor size more realistically reflects mammography’s detection capability. Because previous models may have overestimated size-specific sensitivity, we aimed to provide a novel approach to improve sensitivity estimation as a function of tumor size. Methods: Using aggregated data on interval and screen-detected cancers, observed tumor sizes were back-calculated to the time of screening using an exponential tumor growth model and a follow-up time of 4 years. From the observed number of detected cancers and an estimation of the number of false-negative cancers, a model for the sensitivity as a function of tumor size was determined. A univariate sensitivity analysis was conducted by varying follow-up time and tumor volume doubling time (TVDT). A systematic review was conducted for external validation of the sensitivity model. Results: Aggregated data of 22,915 screen-detected and 10,670 interval breast cancers from the Dutch screening program were used. The model showed that sensitivity increased from 0 to 85% for tumor sizes from 2 to 20 mm. When TVDT was set at the upper and lower limits of the confidence interval, sensitivity for a 20-mm tumor was 74% and 93%, respectively. The estimated sensitivity gave comparable estimates to those from two of three studies identified by our systematic review. Conclusion: Derived from aggregated breast screening outcomes data, our model’s estimation of sensitivity as a function of tumor size may provide a better representation of data observed in screening programs than other models.

BackgroundIn the patient-specific quality assurance (QA), DVH is a critical clinically relevant parameter that is finally used to determine the safety and effectiveness of radiotherapy. However, a consensus on DVH-based action levels has not been reached yet. The aim of this study is to explore reasonable DVH-based action levels and optimal DVH metrics in detecting systematic MLC errors for cervical cancer RapidArc plans.MethodsIn this study, a total of 148 cervical cancer RapidArc plans were selected and measured with COMPASS 3D dosimetry system. Firstly, the patient-specific QA results of 110 RapidArc plans were retrospectively reviewed. Then, DVH-based action limits (AL) and tolerance limits (TL) were obtained by statistical process control. Secondly, systematic MLC errors were introduced in 20 RapidArc plans, generating 380 modified plans. Then, the dose difference (%DE) in DVH metrics between modified plans and original plans was extracted from measurement results. After that, the linear regression model was used to investigate the detection limits of DVH-based action levels between %DE and systematic MLC errors. Finally, a total of 180 test plans (including 162 error-introduced plans and 18 original plans) were prepared for validation. The error detection rate of DVH-based action levels was compared in different DVH metrics of 180 test plans.ResultsA linear correlation was found between systematic MLC errors and %DE in all DVH metrics. Based on linear regression model, the systematic MLC errors between -0.94 mm and 0.88 mm could be caught by the TL of PTV95 ([-1.54%, 1.51%]), and the systematic MLC errors between -1.00 mm and 0.80 mm could also be caught by the TL of PTVmean ([-2.06%, 0.38%]). In the validation, for original plans, PTV95 showed the minimum error detection rate of 5.56%. For error-introduced plans with systematic MLC errors more than 1mm, PTVmean showed the maximum error detection rate of 88.89%, and then was followed by PTV95 (86.67%). All the TL of DVH metrics showed a poor error detection rate in identifying error-induced plans with systematic MLC errors less than 1mm.ConclusionIn 3D quality assurance of cervical cancer RapidArc plans, process-based tolerance limits showed greater advantages in distinguishing plans introduced with systematic MLC errors more than 1mm, and reasonable DVH-based action levels can be acquired through statistical process control. During DVH-based verification, main focus should be on the DVH metrics of target volume. OARs in low-dose regions were found to have a relatively higher dose sensitivity to smaller systematic MLC errors, but may be accompanied with higher false error detection rate.

Abstract Background Cucumber (Cucumis sativus L.) is an economically important vegetable crop species. However, it is susceptible to various abiotic and biotic stresses. WRKY transcription factors play important roles in plant growth and development, particularly in the plant response to biotic and abiotic stresses. However, little is known about the expression pattern of WRKY genes under different stresses in cucumber. Results In the present study, an analysis of the new assembly of the cucumber genome (v3.0) allowed the identification of 61 cucumber WRKY genes. Phylogenetic and synteny analyses were performed using related species to investigate the evolution of the cucumber WRKY genes. The 61 CsWRKYs were classified into three main groups, within which the gene structure and motif compositions were conserved. Tissue expression profiles of the WRKY genes demonstrated that 24 CsWRKY genes showed constitutive expression (FPKM > 1 in all samples), and some WRKY genes showed organ-specific expression, suggesting that these WRKYs might be important for plant growth and organ development in cucumber. Importantly, analysis of the CsWRKY gene expression patterns revealed that five CsWRKY genes strongly responded to both salt and heat stresses, 12 genes were observed to be expressed in response to infection from downy mildew and powdery mildew, and three CsWRKY genes simultaneously responded to all treatments analysed. Some CsWRKY genes were observed to be induced/repressed at different times after abiotic or biotic stress treatment, demonstrating that cucumber WRKY genes might play different roles during different stress responses and that their expression patterns vary in response to stresses. Conclusions Sixty-one WRKY genes were identified in cucumber, and insight into their classification, evolution, and expression patterns was gained in this study. Responses to different abiotic and biotic stresses in cucumber were also investigated. Our results provide a better understanding of the function of CsWRKY genes in improving abiotic and biotic stress resistance in cucumber.

Abstract Background The occurrence of multiple endocrine neoplasia type 2B (MEN2B) in Asians is very rare. In particular, patients with intractable constipation as the main clinical manifestation are even rarer. Atypical clinical manifestations are likely to lead to a diagnostic delay. In this report, we described a case of a delayed diagnosis of MEN2B, and the first clinical manifestation was intractable constipation. Case presentation A female teenager had suffered from intractable constipation since infancy. Because the colonoscopy and biopsy results from local hospitals did not confirm the presence of congenital megacolon, the girl had been followed up at a local clinic for a long time. The diagnosis was not confirmed until thyroid masses were found in the Pediatric Department of Shanghai Ruijin Hospital when she was 12 years old. According to our detailed evaluation, she suffered from Hirschsprung disease (HD), growth retardation, medullary thyroid carcinoma (MTC) and mucosal neuroma due to a mutation in the RET gene. Thus, the diagnosis of MEN2B was confirmed. Afterward, the girl underwent several surgeries and was still being followed up before the article was published. Conclusion MEN2B has atypical clinical symptoms in the early stage. Refractory constipation may be the only clinical manifestation that lasts for several years. Therefore, we recommend that early screening and gene sequencing should be performed for patients with severe constipation due to HD to determine the cause of the disease and to improve the survival outcome.

Terpene synthase (TPS) is related to the production of aromatic substances, but there are few studies on the impact of abiotic stress on TPS and its molecular mechanism, especially in peaches. This study found that salt resistance and abscisic acid (ABA) sensitivity of transgenic tomatoes were enhanced by overexpression of PpTPS1. Moreover, it was found that PpTPS1 interacted with and antagonized the expression of the bZIP transcription factor ABA INSENSITIVE 5 (PpABI5), which is thought to play an important role in salt suitability. In addition, PpTCP1, PpTCP13, and PpTCP15 were found to activate the expression of PpTPS1 by yeast one-hybrid (Y1H) and dual-luciferase assays, and they could also be induced by ABA. In summary, PpTPS1 may be involved in the ABA signaling regulatory pathway and play an important role in salt acclimation, providing a new reference gene for the improvement of salt resistance in peaches.

Purpose. To evaluate the association of near heterophoria with refraction and axial length (AL) in Chinese school children. Methods. This school-based cross-sectional study included 15,081 Chinese primary school children (grades 1–6) examined during 2017. Near heterophoria was measured at 33 cm using the Maddox rod and prism test. Noncycloplegic refraction and AL were also measured. A generalized additive model with a Gaussian link was used to determine the association of near heterophoria with refraction and AL. Analyses were adjusted for age to account for differences in the age distribution of the sample. Results. Overall, data were analyzed for 11,013 students ranging in age from 6 to 13 years. The most common type of near heterophoria was exophoria (64.96%), the proportion and value of which increased according to grade. Exophoria accounted for 62.53% (2,328/3,723), 65.03% (2,501/3,846), and 67.51% (2,325/3,444) of near heterophoria cases for grades 1-2, grades 3-4, and grades 5-6, respectively. Prism diopter (PD) values for near heterophoria in these grades were −6.30 ± 3.69, −6.81 ± 4.01, and −8.32 ± 5.12 PD, respectively. The average spherical equivalent (SE) in children with orthophoria was 0.23 D and 0.25 D lower than those in children with exophoria and esophoria, respectively (P

Background and Objective: Few studies have explored the relationship between malnutrition measured by the Geriatric Nutritional Risk Index (GNRI) and cognitive performance. This study aimed to investigate the association of malnutrition with cognitive function in the Chinese population.Methods: It was a prospective longitudinal study and used three waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) data in 2011–2012, 2014, and 2017–2018. Participants aged 60 years or older without mental illness and cerebrovascular diseases were eligible. The GNRI was used to assess nutritional status as follows: normal nutrition (a GNRI > 98), mild malnutrition (92 ≤ a GNRI ≤ 98), and moderate-to-severe malnutrition (a GNRI < 92). Cognitive performance was evaluated by the Mini-Mental State Examination (MMSE) scores. The relationship between the GNRI and cognitive function was analyzed using a linear mixed-effects model.Results: A total of 1,632 subjects were analyzed, including 741 males and 891 females. Of these, 65.0, 19.4, and 15.6% of subjects were at normal nutritional status, mild, and moderate-to-severe malnutrition, respectively. After adjusting for potential confounders, participants under mild and moderate-to-severe malnutrition status have a lower MMSE score [β (95% CI): –0.95 (–1.60, –0.25) and –1.39 (–2.21, –0.57), respectively], compared with those having normal nutrition. Also, there was a linear trend in the association of malnutrition risk with cognitive function in the total population [β (95% CI): –0.74 (–1.13, –0.35)]. However, a significant association of malnutrition with cognitive function was observed only among illiterate females aged above 90 years.Conclusion: This study suggested that there was a significant relationship between the GNRI and cognitive function in the Chinese elderly. Furthermore, subjects with more serious malnutrition have a worse cognitive function, especially in the oldest illiterate females. Clinicians should put more emphasis on assessing the nutritional and cognitive status of the elderly to timely intervene and prevent cognitive impairment.

The effect of lanthanum addition on the formation behaviors of inclusions in Q355B weathering steel was investigated by laboratory experiments and thermodynamic calculations. The results demonstrate that the main inclusions in weathering steel without La addition are large-sized irregular Al2O3 and MnS, with an average size of about 5.35 μm. As La content increases from 0.0075 to 0.0184 wt.%, the dominant inclusions transform from MnS, LaAlO3, and Al2O3-LaAlO3 into MnS, La2O3, and LaAlO3-La2O3. Meanwhile, the average size of inclusions significantly decreases from 3.4 to 2.48 μm and the distribution is more dispersive. When the La content increases to 0.0425 wt.%, the original MnS and Al2O3 inclusions are completely modified into La2O2S and La2O3 but the inclusions demonstrate serious agglomeration and growth. The thermodynamic calculations indicate that Al2O3 and various lanthanum-containing inclusions are formed in the liquid phase. As the La content in molten steel increases from 0 to 0.0425 wt.%, the Al2O3 inclusion is inclined to be modified into lanthanum oxide and lanthanum oxysulfide and the modification process is Al2O3 → LaAlO3 → La2O3 → La2O2S, which is very consistent with the experimental observations.

Background: Central precocious puberty (CPP) is one of the most common and complex problems in clinical pediatric endocrinology practice. Mutation of the MKRN3 gene can cause familial CPP.Methods and Results: Here we reported a Chinese patient bearing a novel MKRN3 mutation (c.G277A/p.Gly93Ser) and showing the CPP phenotype. Functional studies found that this mutation of MKRN3 attenuated its autoubiquitination, degradation, and inhibition on the transcriptional activity of GNRH1, KISS1, and TAC3 promoters.Conclusion: MKRN3 (Gly93Ser) is a loss-of-function mutation, which attenuates the inhibition on GnRH1-related signaling, suggesting that this mutant can lead to central precocious puberty.

It is estimated that around 10–20% of hypospadias are caused by genetic abnormalities worldwide although the spectrum of associated genes does vary across different ethnicities. The prevalence of hypospadias among the Chinese population has been increasing the last couple of decades. However, the pathogenesis underlying the disease and its associated genetic abnormality remains unclear. Here we performed a genetic analysis of 81 children with karyotype 46, XY and the hypospadias phenotype in order to characterize the genetic components that contribute to the development of hypospadias in Chinese patients. 15 candidate genes, including sex determination genes-SOX9, SRY, NR0B1 (DAX1), NR5A1 (SF1), DHH, sex differentiation genes-AR, SRD5A2, MAMLD1, INSL3, and hypospadias-associated genes-FGF8, FGF10, BMP4, BMP7, ATF3, and MID1 were screened by using next generation sequencing. A total of 18 patients were found to have mutations identified by PCR and sequencing, including 11 cases of SRD5A2 genes, 6 cases of AR genes, and 1 case of MID1 gene, respectively. One novel missense mutation p.I817N was discovered in AR gene. Further molecular analysis found that subcellular localization of the ARI817N was the same as that of wild type ARWT in the absence or presence of hormone. But it led to 50% reduction in AR-induced transcriptional activity in the presence of either the synthetic androgen R1881 or the natural ligand dihydrotestosterone. Our results indicate that SRD5A2 and AR genes are two top candidate genes associated with 46, XY hypospadias in Chinese patients. Further epidemiological and genetic analysis are still needed to further clarify the pathogenesis of hypospadias in Han Chinese patients.

Abstract Background The prevalence of general and abdominal obesity has increased rapidly in China. The aims of this study were to estimate the dynamic prevalence of overweight, general obesity, and abdominal obesity and the distribution of body mass index (BMI) and waist circumference (WC) among Chinese adults. Methods Data were obtained from the China Health and Nutrition Survey (CHNS). According to the suggestions of the WHO for Chinese populations, overweight was defined as a 23 kg/m2 ≤ BMI

Abstract Background Psoralen is a coumarin-like and coumarin-related benzofuran glycoside, which is a commonly used traditional Chinese medicine to treat patients with kidney and spleen-yang deficiency symptom. Psoralen has been reported to show estrogen-like activity, antioxidant activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. However, the antitumor mechanism of psoralen is not fully understood. This study aimed to investigate the therapeutic efficacy of psoralen in human hepatoma cell line SMMC7721 and the mechanism of antitumor effects. Results Psoralen inhibited proliferation of SMMC7721 in a dose- and time-dependent manner, and promoted apoptosis. Further, psoralen activated the ER stress signal pathway, including the expansion of endoplasmic reticulum, increasing the mRNA levels of GRP78, DDIT3, ATF4, XBP1, GADD34 and the protein levels of GDF15, GRP78, IRE1α, XBP-1s in a time-dependent manner. Psoralen induces cell cycle arrest at G1 phase by enhancing CyclinD1 and reducing CyclinE1 expression. Moreover, TUDC couldn’t inhibit the psoralen-induced ER stress in SMMC7721 cells. Conclusions Psoralen can inhibit the proliferation of SMMC7721 cells and induce ER stress response to induce cell apoptosis, suggesting that psoralen may represent a novel therapeutic option for the prevention and treatment hepatocellular carcinoma.

Non–small-cell lung cancer (NSCLC) is one of the most fatal malignant tumors harmful to human health. Previous studies report that Platycodin D (PD) exhibits anti-tumor effects in multiple human cancers, including NSCLC, but the underlying mechanisms are largely unknown. Accumulating evidence indicates that non-coding RNAs (ncRNAs) participate in NSCLC disease progression, but the link between PD and the ncRNAs in NSCLC is poorly elucidated. Here, we used whole transcriptome sequencing to systematically investigate the RNAs-associated regulatory network in the PD treating NSCLC cell lines. A total of 942 significantly dysregulated RNAs were obtained. Among those, five circRNAs and six IncRNAs were rigorously selected via database and in vitro validation. In addition, the functional enrichment study of differentially expressed mRNAs, single nucleotide polymorphisms (SNPs) within PD-related mRNA structures, and the interaction between PD and mRNA-related proteins were analyzed through gene set enrichment analysis (GSEA), structural variant analysis, and molecular docking, respectively. With further in vitro validation, the results show that PD inhibits cell proliferation, arrests the cell cycle, and induces cell apoptosis through targeting BCL2-related proteins. We hope these data can provide a full concept of PD-related molecular changes, leading to a new treatment for NSCLC.

In this paper, the purification of lanthanum was studied by using zone-refining technology. The equilibrium distribution coefficient of impurities was calculated using a liquidus slope method to reveal impurities’ distribution properties. Meanwhile, the analysis of impurities’ concentration distribution for Fe and Si has been investigated based on the SPIM model. The calculated findings based on SPIM were found to be in good agreement with the experimental results. In addition, the influence of the zone-refining rate and the number of passes on the purification of lanthanum were studied. It was found that after ten times of zone refining with a zone-refining rate of 5 mm/min, the contents of Fe and Si impurities in metal decreased to 4 and 2 ppm, respectively.

Abstract Background Dwarfism is a common severe growth disorder, but the etiology is unclear in the majority of cases. Recombinant human growth hormone may be a treatment option, but it has limited efficacy. The currently known laboratory assays do not meet the precision requirements for clinical diagnosis. Here, we have constructed a targeted next-generation sequencing (NGS) panel of selected genes that are suspected to be associated with dwarfism for genetic screening. Methods Genetic screening of 91 children with short stature of unknown etiology was performed with the help of the NGS panel. All the coding regions and exon-intron boundaries of 166 genes were included in the panel. To clarify the pathogenicity of these mutations, their clinical data were reviewed and analyzed. Results The assay identified p.A72G, p.I282V, and p.P491S variants of the PTPN11 gene and a p.I437T variant of the SOS1 gene in 4 cases with Noonan syndrome. A frameshift mutation (p.D2407fs) of the ACAN gene was identified in a case of idiopathic short stature with moderately advanced bone age. A p.R904C variant of the COL2A1 gene was found in a patient, who was accordingly diagnosed with Stickler syndrome. Severe short stature without limb deformity was associated with a p.G11A variant of HOXD13. In addition, we evaluated evidence that a p.D401N variant of the COMP gene may cause multiple epiphyseal dysplasia. Conclusions Our findings suggest that syndromes, particularly Noonan syndrome, may be overlooked due to atypical clinical features. This gene panel has been verified to be effective for the rapid screening of genetic etiologies associated with short stature and for guiding precision medicine-based clinical management.

Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by cafe’-au-lait spots, skinfold freckles, the formation of neurofibromas, skeletal dysplasia, vascular dysplasia, and an increased risk of malignant tumors. In this study, two Chinese NF1 children troubled with bone lesions or hypertension were reported. A de novo NF1 mutation (c.4925T > A/p.V1642E) and a maternally inherited NF1 mutation (c.4883T > A/p.L1628∗) were identified by molecular sequence. According to the ACMG/AMP guidelines, the c.4925T > A was classified as variants of uncertain significance (VOUS) while the c.4883T > A mutation was identified as likely Pathogenic. Further study found that these two NF1 mutants had lost their function to inhibit the Ras/Erk signaling and the proliferation of cells, which could interpretate some phenotypes of these two NF1 patients. We also observed these two NF1 mutants displayed decreased protein stability with increased ubiquitination levels compared with that of wild-type NF1.

Abstract Background Neurofibromatosis type 1 is an autosomal dominant inherited disease and caused by NF1 gene mutation. Its clinical manifestations include multiple cafe´‐au lait (CAL) spots, skinfold freckling, neurofibroma, bone dysplasia, learning disabilities, and an increased risk of malignancy. Methods and Results Here, we reported a Chinese patient bearing with a novel NF1 mutation (c.2064delGGATGCAGCGG/p.Gly672AsnfsTer24) and complaining mainly about bone phenotype. Functional studies found that this novel mutation caused the damage of NF1 mRNA and protein levels, and lost the inhibition on Ras/Erk signaling. Conclusion A novel mutation in NF1 gene was identified and in vitro functional studies were performed, which provided a potential molecular mechanism to explain the bone maldevelopment of patients with neurofibromatosis type 1.

ObjectiveCatch-up growth (CUG) in small for gestational age (SGA) leads to increased risk of metabolic syndrome and cardiovascular diseases in adults. It remains unclear if microbiota could play an important role in CUG-SGA independent of genetic or nutritional factors. The present study explored the role of gut microbiota in, and its association with, metabolic disorders during CUG-SGA.MethodsAn SGA rat model was established by restricting food intake during pregnancy, and the rats were divided into catch-up growth (CUG-SGA) and non-catch-up growth (NCUG-SGA) groups based on body weight and length at the fourth postnatal week. High-throughput sequencing of 16S rRNA was conducted to detect the diversity and composition of the gut microbiota. Fecal short-chain fatty acids (SCFAs) were detected by gas chromatography-mass spectrometry. Transcriptome sequencing of liver tissue was performed and verified using real-time PCR. Concentrations of insulin and total cholesterol were determined using enzyme-linked immunosorbent assay.ResultsThe composition of gut microbiota in CUG-SGA rats differed from that of NCUG-SGA rats, with reduced abundance of Lactobacillus in the CUG-SGA group. The decrease in Lactobacillus was significantly associated with increased body weight and upregulated insulin and total cholesterol levels. Five SCFAs and two branched chain fatty acids were significantly higher in the CUG-SGA group than in the NCUG-SGA group. Additionally, SCFAs were positively associated with clinical indices such as weight, body mass index, insulin, and total cholesterol. Transcriptomic data revealed that insulin-like growth factor-2 expression was significantly decreased in CUG-SGA rats and was associated with a decrease in Lactobacillus bacteria.ConclusionLactobacillus and SCFAs were associated with the metabolic disorders during CUG in SGA. Gut microbiome may play a certain role on metabolic disorders during catch-up growth in small-for-gestational-age.

The zone refining technology is considered to be one of the most effective means of purifying lanthanum. However, it is tough to obtain the temperature distribution of the molten region through experimental methods. In this study, finite element analysis was used to establish the zone refining simulation model, and the impurity distribution of lanthanum after purification was investigated experimentally. Good agreement between the simulated and experimental results was obtained. The effects of the current and the frequency on the temperature distribution and the width of the region were studied using the simulation model. Through the zone refining experiment, the impurity distributions under different widths of molten region were revealed. Finally, the influence of molten region width on the limiting distribution was calculated by solving the limiting distribution equation.

Erbium metal with purity ≥ 99% was cold rolled to 30%, 40%, 50%, and 60% deformations and the Er metal of 60% deformation was annealed at different temperatures for 1 h. The effect of cold rolling deformation and annealing on the microstructure and texture evolution of Er metal was investigated by XRD, EBSD, Microhardness tester, and OM. P is the orientation index, which is used to judge the preferred orientation. The research results showed that grains were broken and refined gradually with increasing deformation, the average grain size was 3.37 µm, and the orientation distribution was uniform for 60% deformation; deformation twins appeared in the grain when the deformation was less than 40%, which contributed to the generation of (0001) plane orientation. Comparing with the initial state, the (011−0) plane orientation gradually weakened and the (111−0) plane orientation had a trend of further strengthening with the increasing deformation; the (1−21−0) plane orientation remained unchanged, but there was a gradual weakening trend when the deformation was greater than 50%. For 60% deformation of Er metal, the deformed microstructure was replaced by fine equiaxed grains with the increasing annealing temperature, and the high-performance Er metal with fine and uniform equiaxed grains can be obtained under annealing at 740 °C for 1 h.

Abstract Background We aimed to clarify the feasibility of a community-based screening strategy for breast cancer in Tianjin, China; to identify the factors that most significantly influenced its feasibility; and to identify the reference range for quality control. Methods A state-transition Markov model simulated a hypothetical cohort of 100,000 healthy women, the start aged was set at 35 years and the time horizon was set to 50 years. The primary outcome for the model was the incremental cost-utility ratio (ICUR), defined as the program’s cost per quality-adjusted life year (QALY) gained. Three screening strategies providing by community health service for women aged 35 to 69 years was compared regarding to different intervals. Result The probability of the ICUR being below 20 272USD (i.e., triple the annual gross domestic product [3 GDPs]) per QALY saved was 100% for annual screening strategy and screening every three years. Only when the attendance rate was > 50%, the probability for annual screening would be cost effective > 95%. The probability for the annual screening strategy being cost effective could reach to 95% for a willingness-to-pay (WTP) of 2 GDPs when the compliance rate for transfer was > 80%. When 10% stage I tumors were detected by screening, the probability of the annual screening strategy being cost effective would be up to 95% for a WTP > 3 GDPs. Conclusion Annual community-based breast cancer screening was cost effective for a WTP of 3 GDP based on the incidence of breast cancer in Tianjin, China. Measures are needed to ensure performance indicators to a desirable level for the cost-effectiveness of breast cancer screening.

Abstract Background Hypospadias is a common congenital malformation of male external genitalia, which mainly manifests as an abnormal urethral opening on the ventral side of the penis. The etiology and clinical phenotype of hypospadias is highly heterogeneous, and its clinical diagnosis is challenging. Currently, over 70% of patients have an unknown etiology. Here, we performed a targeted analysis of gene mutations in 130 patients with hypospadias of unknown etiology to find the precise genetic cause. Methods We developed a targeted next‐generation sequencing (NGS) panel, encompassing the exon coding regions of 105 genes involved in external genitalia and urogenital tract development and performed sequencing analysis on 130 children with hypospadias of unknown etiology. Results In total, 25 patients with hypospadias (19.2%) were found to have 20 mutations among the nine genes involved in external genitalia and urogenital tract development, including 16 reported and four novel mutation sites. Twenty‐two patients (16.9%) had diagnostic variants. Multiple genetic mutations were identified in three of the 25 patients. Hypospadias combined with micropenis was the most common phenotype (68%) in 25 patients. Conclusions Higher frequency mutations were identified in SRD5A2 (52%) and AR (24%) in our patient cohort. Middle or posterior hypospadias with micropenis may be significant indicators of genetic variations. Polygenic inheritance may be a rare genetic cause of hypospadias.

In Asian countries, ultrasound has been proposed as a possible alternative for mammography in breast cancer screening because of its superiority in dense breasts, accessibility and low costs. This research aimed to meta-analyze the evidence for the diagnostic performance of ultrasound compared to mammography for breast cancer screening in Asian women. PubMed, Web of Science, and China National Knowledge Infrastructure databases were searched for studies that concurrently compared mammography and ultrasound in 2000–2019. Data extraction and risk of bias were performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) statement. The primary outcome was the sensitivity and specificity. Bivariate random models were used to generate pooled estimates of diagnostic parameters and 95% confidence intervals (95% CI). In total, 4424 studies were identified of which six studies met the inclusion criteria with a sample size of 124,425 women. The pooled mean prevalence of the included studies was 3.7‰ (range: 1.2–5.7‰). The pooled sensitivity of mammography was significantly higher than that of ultrasound (0.81 [95% CI 0.71–0.88] versus 0.65 [95% CI 0.58–0.72], p = 0.03), but no significant differences were found in specificity (0.98 [95% CI: 0.94–1.00] versus 0.99 [95% CI: 0.97–1.00], p = 0.65). In conclusion, based on the currently available data on sensitivity alone, there is no indication that ultrasound can replace mammography in breast cancer screening in Asian women.

Background In China, there is insufficient evidence to support that screening programs can detect breast cancer earlier and improve outcomes compared with patient self-reporting. Therefore, we compared the pathological characteristics at diagnosis between self-detected and screen-detected cases of invasive breast cancer at our institution and determined whether these characteristics were different after the program’s introduction (vs. prior to). Methods Three databases were selected (breast cancer diagnosed in 1995–2000, 2010, and 2015), which provided a total of 3,014 female patients with invasive breast cancer. The cases were divided into self-detected and screen-detected groups. The pathological characteristics were compared between the two groups and multiple imputation and complete randomized imputation were used to deal with missing data. Results Compared with patient self-reporting, screening was associated with the following factors: a higher percentage of stage T1 tumors (75.0% vs 17.1%, P = 0.109 in 1995–2000; 66.7% vs 40.4%, P < 0.001 in 2010; 67.8% vs 35.7%, P < 0.001 in 2015); a higher percentage of tumors with stage N0 lymph node status (67.3% vs. 48.4%, P = 0.007 in 2010); and a higher percentage of histologic grade I tumors (22.9% vs 13.9%, P = 0.017 in 2010). Conclusion Screen-detected breast cancer was associated with a greater number of favorable pathological characteristics. However, although screening had a beneficial role in early detection in China, we found fewer patients were detected by screening in this study compared with those in Western and Asian developed countries.

BackgroundThere have been few studies on the association between the incidence of hypertension and the presence and distribution of body fat. The aim of this article was to evaluate this association. Methods and ResultsData were obtained from the China Health Nutrition Survey, a 22‐year cohort study of 12 907 participants. Body mass index and triceps skinfold thickness were used as markers of body fat, whereas waist circumference (WC) was used as a marker of fat distribution. Cox regression was used to examine the association of body mass index, WC, and skinfold thickness with the incidence of hypertension. The interval between the baseline and hypertension diagnosis was the time variable, and hypertension was the end event. The mean age and proportion of men and women were 38.29 and 38.03 years and 45.63% and 54.37%, respectively. Compared with normal WC, abdominal obesity was associated with hypertension (P

Enterovirus 71 (EV71) is the major etiological agent of hand, foot, and mouth disease (HFMD). Early studies showed that EV71-infected patients with severe complications exhibited elevated plasma levels of IL-1β, indicating that EV71 may activate inflammasomes. Our current study demonstrates that the NLRP3 inflammasome plays a protective role against EV71 infection of mice in vivo. EV71 replication in myeloid cells results in the activation of the NLRP3 inflammasome and secretion of IL-1β. Conversely, EV71 counteracts inflammasome activation through cleavage of NLRP3 by viral proteases 2A and 3C, which cleave NLRP3 protein at the G493-L494 or Q225-G226 junction, respectively. Moreover, EV71 3C interacts with NLRP3 and inhibits IL-1β secretion when expressed in mammalian cells. These results thus reveal a set of reciprocal regulations between enterovirus 71 and the NLRP3 inflammasome.