A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

AIM: The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. MATERIALS AND METHODS: This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. RESULTS: Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. CONCLUSIONS: At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

Identification of a pathogenic variant and pre-implantation genetic testing for a Chinese family affected with split-hand/foot malformation.

Split-hand/foot malformation is a serious congenital limb malformation characterized by syndactyly and underdevelopment of the phalanges and metatarsals. In this study, we reported a case of a fetus with hand-foot cleft deformity. Whole exome and Sanger sequencing were used to filter out candidate gene mutation sites and provide pre-implantation genetic testing(PGT) for family members. Genetic testing results showed that there was a homozygous mutation c.786G>A (p.Trp262*) in the fetal WNT10B, and both parents were carriers of heterozygous mutations. PGT results showed that out of the two blastocysts, one was a heterozygous mutant and the other was a homozygous mutant. All the embryos had diploid chromosomes. The heterozygous embryo was transferred, and a singleton pregnancy was successfully achieved. This study suggests that homozygous mutations in WNT10B are the likely cause of hand-foot clefts in this family. For families with monogenic diseases, preimplantation genetic testing can effectively prevent the birth of an affected child only after identifying the pathogenic mutation.

Research progress in spike mutations of SARS-CoV-2 variants and vaccine development.

The coronavirus disease 2019 (COVID-19) pandemic can hardly end with the emergence of different variants over time. In the past 2 years, several variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), such as the Delta and Omicron variants, have emerged with higher transmissibility, immune evasion and drug resistance, leading to higher morbidity and mortality in the population. The prevalent variants of concern (VOCs) share several mutations on the spike that can affect virus characteristics, including transmissibility, antigenicity, and immune evasion. Increasing evidence has demonstrated that the neutralization capacity of sera from COVID-19 convalescent or vaccinated individuals is decreased against SARS-CoV-2 variants. Moreover, the vaccine effectiveness of current COVID-19 vaccines against SARS-CoV-2 VOCs is not as high as that against wild-type SARS-CoV-2. Therefore, more attention might be paid to how the mutations impact vaccine effectiveness. In this review, we summarized the current studies on the mutations of the SARS-CoV-2 spike, particularly of the receptor binding domain, to elaborate on how the mutations impact the infectivity, transmissibility and immune evasion of the virus. The effects of mutations in the SARS-CoV-2 spike on the current therapeutics were highlighted, and potential strategies for future vaccine development were suggested.

Aggressive intraoperative warming versus routine thermal management during non-cardiac surgery (PROTECT): a multicentre, parallel group, superiority trial.

BACKGROUND: Moderate intraoperative hypothermia promotes myocardial injury, surgical site infections, and blood loss. Whether aggressive warming to a truly normothermic temperature near 37°C improves outcomes remains unknown. We aimed to test the hypothesis that aggressive intraoperative warming reduces major perioperative complications. METHODS: In this multicentre, parallel group, superiority trial, patients at 12 sites in China and at the Cleveland Clinic in the USA were randomly assigned (1:1) to receive either aggressive warming to a target core temperature of 37°C (aggressively warmed group) or routine thermal management to a target of 35·5°C (routine thermal management group) during non-cardiac surgery. Randomisation was stratified by site, with computer-generated, randomly sized blocks. Eligible patients (aged ≥45 years) had at least one cardiovascular risk factor, were scheduled for inpatient non-cardiac surgery expected to last 2-6 h with general anaesthesia, and were expected to have at least half of the anterior skin surface available for warming. Patients requiring dialysis and those with a body-mass index exceeding 30 kg/m2 were excluded. The primary outcome was a composite of myocardial injury (troponin elevation, apparently of ischaemic origin), non-fatal cardiac arrest, and all-cause mortality within 30 days of surgery, as assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03111875. FINDINGS: Between March 27, 2017, and March 16, 2021, 5056 participants were enrolled, of whom 5013 were included in the intention-to-treat population (2507 in the aggressively warmed group and 2506 in the routine thermal management group). Patients assigned to aggressive warming had a mean final intraoperative core temperature of 37·1°C (SD 0·3) whereas the routine thermal management group averaged 35·6°C (SD 0·3). At least one of the primary outcome components (myocardial injury after non-cardiac surgery, cardiac arrest, or mortality) occurred in 246 (9·9%) of 2497 patients in the aggressively warmed group and in 239 (9·6%) of 2490 patients in the routine thermal management group. The common effect relative risk of aggressive versus routine thermal management was an estimated 1·04 (95% CI 0·87-1·24, p=0·69). There were 39 adverse events in patients assigned to aggressive warming (17 of which were serious) and 54 in those assigned to routine thermal management (30 of which were serious). One serious adverse event, in an aggressively warmed patient, was deemed to be possibly related to thermal management. INTERPRETATION: The incidence of a 30-day composite of major cardiovascular outcomes did not differ significantly in patients randomised to 35·5°C and to 37°C. At least over a 1·5°C range from very mild hypothermia to full normothermia, there was no evidence that any substantive outcome varied. Keeping core temperature at least 35·5°C in surgical patients appears sufficient. FUNDING: 3M and the Health and Medical Research Fund, Food and Health Bureau, Hong Kong. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Can AMH levels predict the need to step up FSH dose for controlled ovarian stimulation following a long GnRH agonist protocol in PCOS women?

BACKGROUND: To explore the role of anti-Mullerian hormone (AMH) in predicting the need to step up recombinant FSH (rFSH) dose following long GnRH agonist protocol in IVF/ICSI cycles of polycystic ovarian syndrome (PCOS) women. METHODS: This is a retrospective cohort study of 825 PCOS women undergoing long GnRH agonist protocol enrolled from Jan 2019 to Dec 2021. The daily rFSH dose at which the first response to rFSH were recorded. The dose at which the first response to rFSH was based on folliculometry during follow up in which two or more follicles reached ≥ 11 mm. A receiver operating characteristic (ROC) curve analysis was done to investigate the ability of AMH to predict the need to step up initial rFSH dose. RESULTS: PCOS women who needed to step up initial rFSH dose had a significantly higher AMH compared with those didn't step up initial rFSH dose (11.37 ± 3.25ng/ml vs. 8.69 ± 3.16ng/ml, p < 0.001). In multivariate logistic regression analysis, increased AMH level was an independent factor for the need to step up initial rFSH dose in PCOS patients after adjusted for confounding factors. ROC curve analysis showed AMH could predict the need to step up initial rFSH dose (AUC = 0.738, 95%CI: 0.704-0.773), having 75.4% specificity and 63% sensitivity when the threshold AMH concentration was 9.30ng/ml. 58.8% PCOS women with AMH > 9.30 ng/ml required increased rFSH dose compared to 18.8% of women with AMH ≤ 9.30ng/ml (p < 0.001). Although the clinical pregnancy rate and live birth rate were not significantly different, there was a higher incidence of OHSS among women with AMH > 9.30 ng/ml vs. AMH ≤ 9.30ng/ml (20.8% vs. 15.3%, p = 0.043). CONCLUSION: PCOS women with AMH > 9.30 ng/ml were resistant to rFSH stimulation and require increased dose for the cycle recruitment of ovarian follicles.

Changes in Urinary Iodine Levels Following Bariatric Surgery.

OBJECTIVE: Obesity has become an epidemic in the United States. Although bariatric surgery can effectively achieve weight loss by altering the gastrointestinal tract, it commonly results in micronutrient deficiency, requiring supplementation. Iodine is an essential micronutrient for the synthesis of thyroid hormones. We aimed to investigate changes in urinary iodine concentrations (UIC) in patients following bariatric surgery. METHODS: 85 adults who underwent either laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass surgery were enrolled. At baseline and 3 months after surgery, we evaluated spot UIC and serum thyroid stimulating hormone (TSH), vitamin D, vitamin B12, ferritin, and folate levels. Participants provided a 24-hour diet recall for iodine-rich foods and information about multivitamin use at each time point. RESULTS: There was a significant increase in median UIC (201 [120.0 - 288.5] vs 334.5 [236.3 - 740.3] µg/L; P < .001), a significant decrease in mean body mass index (44.0 ± 6.2 vs 35.8 ± 5.9; P < .001) and a significant decrease in TSH levels (1.5 [1.2 - 2.0] vs 1.1 [0.7 - 1.6] uIU/mL; P < .001) at 3 months postoperatively compared to baseline. Body mass index, UIC, and TSH levels before and after surgery did not differ based on the type of weight loss surgery. CONCLUSION: In an iodine-sufficient area, bariatric surgery does not cause iodine deficiency nor clinically significant changes in thyroid function. Different surgical procedures with different anatomical alterations in the gastrointestinal tract do not significantly affect iodine status.

Discovery of pyrazole-carbohydrazide with indole moiety as tubulin polymerization inhibitors and anti-tumor candidates.

In this work, a series of indole-containing pyrazole-carbohydrazide derivatives A1-A25 were synthesized, and their biological activity on tubulin polymerization inhibition and mitotic catastrophe was evaluated. For introducing indole group to CA-4 pattern, the carbohydrazide linker was used for the first time. As the top hit, A18 suggested notable antiproliferation efficacy and tubulin polymerization inhibitory activity. Inferring comparable antitubulin effect with the positive control Colchicine, A18 indicated obviously lower cyto-toxicity. The cell scratch test showed that A18 could block the cell migration, while the confocal imaging depicted that A18 could induce the mitotic catastrophe via a Colchicine-like approach. The docking simulation visualized the probable binding pattern of A18. With the information in this work, some new hints on modification might be involved in further tubulin-related investigations.

Ultrafast Two-Dimensional Infrared Spectroscopy Resolved a Structured Lysine 159 on the Cytoplasmic Surface of the Microbial Photoreceptor Bacteriorhodopsin.

Bacteriorhodopsin (bR) is a light-driven microbial receptor, and lysine 159 (K159) is a charged residue on the cytoplasmic (CP) side of its E-F loop. However, its conformation and function remain unknown due to fast surface dynamics. By utilizing a 13C, 15N-labeled lysine (K) as an isotope probe, we created a network of site-specific amide-I vibrational signatures (backbone carbonyl stretch) to identify the frequency contribution of the labeled residues to the amide-I excitonic band structure. Thus, the red-shifted amide-I frequency in the 13C, 15N-lysine-labeled bR (uK-bR) to the unlabeled bR (WT-bR) could be differentiated and examined by ultrafast two-dimensional vibrational echo infrared (2D IR) spectroscopy. Our results showed that the backbone carbonyl of K159 is located at a high frequency of ca. 1693 cm-1 and has a vibrational excited-state relaxation time shorter than the bulk helical amide-I mode at the same frequency, suggesting that K159 may possess a hydrogen-bonded γ-turn structure with E161, one of the carboxylate residues on the CP surface of bR. The 2D solid-state NMR study of uK-bR also revealed conformational dependent lysine residues, from which K159 was found to involve the turn motif. This γ-turn structure maintained by K159 may help to stabilize the E-F loop and support E161 in attracting protons from the bulk during the late stage of the bR photocycle. The combined spectroscopic approach illustrated in this work may be applied to map residue-specific local structures and dynamics of other receptors and large proteins.

Vascular anatomy-based localization of intervertebral discs assisting needle puncture for constructing a mouse model of mechanical injury-induced lumbar intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) may be the primary cause of low back pain. Potential therapeutics for IDD must be validated in animal models, and their effectiveness quantified using functional metrics. Needle puncture of intervertebral discs (IVDs) has been used to induce IDD in mice and rats. Due to operational challenges, most animal IDD models are constructed using needle puncture of the caudal IVDs in mice, or by using larger animals, such as rats and rabbits. However, mouse IDD models involving lumbar IVD puncture are preferable because mice are genetically similar to humans and are the most commonly used transgenic animals, and because human IDD commonly affects the lumbar spine. We constructed a needle puncture-based mouse IDD model that relies on vascular anatomy to pinpoint lumbar IVDs. We evaluated the morphological and molecular changes in this model by using radiological, pathological, and immunostaining examinations. In our mechanical injury-induced IDD model, lumbar IVDs were accurately localized by injecting colored perfusates into the common iliac artery and vein, and right iliolumbar vein, which helped to visualize puncture positions, avoid neuromuscular injury, shorten the operation time, and decrease bleeding. Nucleus pulposus cells, defined by Krt19, and the disc height index gradually decreased after the surgery, and the degenerative effects peaked at 1 week. In conclusion, we established a mouse IDD model by performing precise puncture of lumbar IVDs via the ventral anterior approach assisted by vessel position. Our model effectively simulated the effects of IDD, and may serve as an efficient research tool.

Phytochemical Composition, Antioxidant Activity, α-Glucosidase and Acetylcholinesterase Inhibitory Activity of Quinoa Extract and Its Fractions.

This study is aimed to evaluate the chemical compositions and biological activities of quinoa, a novel and excellent food crop. Quinoa extract and its fractions were prepared by ethanol extraction and liquid-liquid extraction, including ethanol crude extract, and petroleum ether, chloroform, ethyl acetate (EAF), and n-butanol and water fractions. The total phenolic and flavonoid contents, antioxidant activities, α-glucosidase and acetylcholinesterase inhibitory abilities of the extract and fractions were further determined. Based on these foundations, the chemical composition of the EAF fraction exhibiting the strongest functional activity was analyzed by ultra-performance liquid chromatography-mass spectrometry. The results showed the EAF fraction had the highest phenolic and flavonoid contents, and the highest antioxidant activities, as well as the strongest α-glucosidase and acetylcholinesterase inhibitory abilities, which is even better than the positive control. The phytochemical composition of the EAF fraction indicated that 661 and 243 metabolites were identified in positive and negative ion modes, which were classified into superclass, class and subclass levels, respectively. Phenolic acids and flavonoids were the major bioactive compounds in the EAF fraction. This study found that quinoa, especially its ethyl acetate fraction, had the potential for the development of natural antioxidants, acetylcholinesterase inhibitors, and hypoglycemic agents.

Suppression of miR-4463 promotes phenotypic switching in VSMCs treated with Ox-LDL.

Vascular smooth muscle cell (VSMC) phenotypic switching is a hallmark of vascular remodeling that contributes to atherosclerotic diseases. MicroRNA 4463 (miR-4463) has been implicated in the development of arteriosclerosis obliterans, whereas the underlying mechanisms in VSMCs have not been fully addressed. In this study, we assessed whether miR-4463 is involved in the phenotypic switching process in VSMCs. Oxidized low-density lipoprotein (Ox-LDL, 50 mg/L) was used to simulate the oxidative stress condition, and miR-4463 expression in VSMCs was detected by a quantitative polymerase chain reaction. To determine the effect of Ox-LDL-mediated regulation of miR-4463 on the phenotypic switching of VSMCs, cell counting kit-8, cell migration assays, and cytoskeleton test were performed. After using specific antagonists of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), the relationship between miR-4463 and its downstream signaling proteins was explored. Ox-LDL induced oxidative stress to promote VSMC transformation from contraction to secretion, which clearly decreased the level of miR-4463. Then, downregulated miR-4463 enhanced the migration and phenotypic transformation of VSMCs and activated the phosphorylation of JNK and ERK; these effects were increased after Ox-LDL induction. As expected, inhibiting the two signaling proteins blocked the effect of the miR-4463 inhibitor combined with Ox-LDL. In addition, inhibition of miR-4463 led to the upregulation of basic fibroblast growth factor (bFGF) expression. The results of this study demonstrate that miR-4463 is a novel regulator of VSMC function in hypoxic conditions and modulates VSMC phenotypic switching via the JNK and ERK signaling pathways; bFGF may be the target gene of miR-4463.

KDM6B promotes ESCC cell proliferation and metastasis by facilitating C/EBPß transcription.

BACKGROUND: As an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression, KDM6B has been implicated in the development and malignant progression in various types of cancers. However, its potential roles in esophageal squamous cell carcinoma (ESCC) have not been explored. METHODS: The expression of KDM6B in human ESCC tissues and cell lines was examined using RT-qPCR, immunohistochemical staining and immunoblotting. The effects of KDM6B on the proliferation and metastasis of ESCC were examined using in vitro and in vivo functional tests. RNA-seq and ChIP-seq assay were used to demonstrate the molecular biological mechanism of KDM6B in ESCC. RESULTS: We show that the expression level of KDM6B increased significantly in patients with lymph node metastasis. Furthermore, we confirmed that KDM6B knockdown reduces proliferation and metastasis of ESCC cells, while KDM6B overexpression has the opposite effects. Mechanistically, KDM6B regulates TNFA_SIGNALING_VIA_NFκB signalling pathways, and H3K27me3 binds to the promoter region of C/EBPß, leading to the promotion of C/EBPß transcription. Besides, we show that GSK-J4, a chemical inhibitor of KDM6B, markedly inhibits proliferation and metastasis of ESCC cells. CONCLUSIONS: The present study demonstrated that KDM6B promotes ESCC progression by increasing the transcriptional activity of C/EBPß depending on its H3K27 demethylase activity.

Iodine Content in Meal Replacements in the United States.

OBJECTIVE: Iodine is essential for thyroid hormone production. The recommended dietary allowance for iodine in nonpregnant adults is 150 µg/d. However, most product labels do not list the iodine content. Meal replacements are not required to contain specific vitamins and minerals. Nevertheless, they are often marketed as good and convenient sources of a balanced nutrition. In this study, we aimed to assess the iodine content in meal replacements to determine how they may contribute to iodine deficiency or excess. METHODS: Twenty seven meal replacements from supermarkets in the Boston area were collected. The iodine concentration of each meal replacement was measured spectrophotometrically. Iodine content in meal replacements were compared according to form (liquid, bar, and powder) and type (vegan and nonvegan). RESULTS: The overall mean ± SD iodine content was 49.7 ± 125.4 µg/serving. However, 1 meal replacement was an outlier and had 671.9 µg iodine per serving. Mean iodine content differed between forms and was highest for liquids (mean ± SD: 37.4 ± 6.5 µg/serving). Nonvegan meal replacements had a higher mean iodine content than vegan meal replacements (mean ± SD: 31.6 ± 15.78 µg/serving). CONCLUSION: All of the meal replacements contained detectible amounts of iodine regardless of whether it was listed on their labels (41% did not list iodine). Overall, the meal replacements in this study were found to be good sources of iodine. However, consumers should be aware that packaging labels may not accurately reflect the amount of iodine present.

Iodine Status in Pregnant Women of Puerto Rico.

OBJECTIVE: Iodine deficiency is a worldwide public health problem and a preventable cause of neurodevelopmental delay in children. There are no data regarding iodine sufficiency and knowledge on iodine nutrition among pregnant women in Puerto Rico. The objective of this study was to assess iodine status, potential factors influencing iodine status, and knowledge regarding iodine nutrition among Puerto Rican pregnant women. METHODS: This was a cross-sectional study of 125 pregnant women recruited from an ambulatory high-risk obstetric clinic in San Juan, Puerto Rico. The participants completed a survey and provided spot urine samples. We excluded women on thyroid medications or those who had undergone iodinated contrast studies in the last 6 months. Spot urine iodine concentrations (UICs) were measured spectrophotometrically. RESULTS: The median UIC was 182 µg/L. Only 3 (2%) of the participants were aware that pregnant women need increased iodine intake, and 78% reported taking prenatal vitamins, 77% of which were prescription products. The participants who reported taking prescription prenatal vitamins had a median (range) UIC of 148.6 (15.3-1188.6) µg/L compared to those who were not taking prescription prenatal vitamins, who had a median UIC of 249.7 (47.8-2179.0) µg/L (P = .05). The iodine content of the prenatal vitamins was unknown. CONCLUSIONS: The World Health Organization has defined iodine deficiency as a median UIC of <150 µg/L in populations of pregnant women. Our sample of pregnant Puerto Rican women had an adequate iodine status. Most women used prescribed prenatal vitamins with unknown iodine content. The majority of participants reported not receiving any education by health care providers regarding dietary iodine needs.

Intrathecal morphine versus transversus abdominis plane block for caesarean delivery: a systematic review and meta-analysis.

BACKGROUND: The number of caesarean deliveries has been increasing. Although intrathecal morphine (ITM) can relieve pain and is widely applied in caesarean deliveries, it is associated with many side effects. Transversus abdominis plane block (TAPB), a new analgesic technology, has also began playing a certain role after caesarean delivery, with fewer adverse effects. This study mainly compares the analgesic and adverse effects of ITM and TAPB in caesarean delivery. METHODS: We systematically searched PubMed, Cochrane Library, EMBASE, and Web of Science, for randomised controlled trials (RCTs) published before 9 October, 2020 to compare the effects of ITM and TAPB. Primary outcome of the study was the pain score at rest 24 h after caesarean delivery, whereas the secondary outcomes were the pain score at movement 24 h after operation, postoperative nausea and vomiting (PONV), itching, and morphine consumption. For the outcome assessment, we conducted a sensitivity analysis. RESULT: Six RCTs involving 563 patients and meeting the study inclusion criteria were included in this study. Results indicated no significant difference in the pain score between ITM and TAPB at 24 h of rest or movement. The sensitivity analysis results indicated that the resting pain score (95% CI = - 1.27 to - 0.28; P = 0.002) and 24-h moving pain score (95% CI = - 1.8 to - 0.07; P = 0.03) of the ITM group were lower than those of the TAPB group. The consumption of morphine in the ITM group was lower than in the TAPB group (95% CI = 1.92 to 4.87; P < 0.00001); however, in terms of adverse reactions, the incidence of pruritus (95% CI = 1.17 to 8.26; P = 0.02) and PONV (95% CI = 1.92 to 4.87, P < 0.00001) in the ITM group was higher than in the TAPB group. CONCLUSION: Parturients in the ITM and TAPB groups exhibited similar analgesic effects. However, in the sensitivity analysis performed by eliminating the studies causing heterogeneity, the ITM group was found to have superior analgesic effects compared with the TAPB group, with less morphine consumption. Differently, the TAPB group displayed less side effects such as PONV. Therefore, TAPB is still a valuable analgesia option for patients who cannot use ITM for analgesia after caesarean delivery or those having a high risk of PONV. TRIAL REGISTRATION: Registration number: Registered on Prospero with the registration number of CRD42020210135 .

Aberrant expression of five miRNAs in papillary thyroid carcinomas.

BACKGROUND: The miRNAs play critical roles in the progression of various tumors. Our study aimed to screen and identify miRNAs to investigate their diagnostic and prognostic value for papillary thyroid carcinoma (PTC). METHODS: miRNAs were evaluated in PTC (n = 30) tissues, A-PTC (n = 30), benign nodules (n = 35) and A-benign nodules (n = 35). The expression levels of five miRNAs were quantified using real-time, quantitative PCR. ROC analysis was used to evaluate the miRNA diagnostic value. RESULTS: The expression of miR-1296-5p, miR-1301-3p, and miR-532-5p was significantly downregulated (p = 0.0001, p = 0.0006, p = 0.0024, respectively), while miR-551b-3p and miR-455-3p were significantly upregulated in PTC tissues compared to A-PTC tissues (p = 0.0005, p = 0.0046, respectively). Interestingly, the expression of miR-1296-5p was downregulated, while miR-551b-3p and miR-455-3p were upregulated in the A-PTC group compared to the A-benign group. Moreover, the miR-1296-5p expression level was associated with tumor size, the number of foci and the TNM stage; the miR-455-3p expression level was correlated with patient age, tumor size, and TNM stage; and the miR-532-5p expression level was correlated with patient age, lymph node metastasis and TNM stage correspondingly. ROC analysis revealed that the AUCs for miR-1301-3p, miR-1296-5p, miR-455-3p, miR-532-5p, and miR-551b-3p were 0.773, 0.790, 0.783, 0.744, and 0.650, respectively. CONCLUSIONS: Our results indicated that miR-1296-5p, miR-1301-3p, miR-532-5p, miR-551b-3p, and miR-455-3p are aberrantly expressed in papillary thyroid carcinomas and correlated with clinicopathological features. ROC curve analysis indicated that these five miRNAs have a potential diagnostic value. Consequently, we speculate that the five altered miRNAs may serve as potential diagnostic and prognostic biomarkers for PTC.

miR-1301-3p suppresses tumor growth by downregulating PCNA in thyroid papillary cancer.

OBJECTIVE: Thyroid carcinoma is the most common endocrine tumor, and thyroid papillary carcinoma is the most common form. Although thyroid papillary carcinoma presents a good prognosis, some patients still exhibit recurrence or distant metastasis. miR-1301-3p has been found involved in the occurrence and development of some special tumors. Our study aims to investigate the miR-1301-3p expression in thyroid papillary carcinoma, to explore its biological function, and to provide a potential marker for diagnosis and treatment of thyroid papillary carcinoma. MATERIALS AND METHODS: The tissue samples from 70 patients with PTC (n = 35) and benign tumors (n = 35) were collected respectively. miR-1301-3p expression were detected by qPCR. Diagnostic value of miR-1301-3p was analyzed by ROC curve. CCK-8 assays and flow cytometry were performed to detect the effect of miR-1301-3p on TPC-1 function. PCNA expression of protein was detected by WB. RESULTS: Compared with the normal group, the expression of miR-1301-3p was obviously decreased in both benign group and PTC group. With the higher T and N grades, the lower expression of miR-1301-3p. ROC curve analysis showed that the diagnostic values of miR-1301-3p for benign tumor and PTC were 0.766 and 0.881, respectively. Vitro experiments showed that miR-1301-3p was decreased in TPC-1 cells, then, upregulated miR-1301-3p blocked the TPC-1 cell cycle in G1/S phase, and inhibited the proliferation. PCNA expression was significantly increased in TPC-1 cells and significantly decreased after upregulation of miR-1301-3p. CONCLUSION: The present study showed that the expression of miR-1301-3p in PTC was significantly decreased, which was related to T and N grade. Upregulation of miR-1301-3p could inhibit cell proliferation and cell migration. miR-1301-3p may serve as a potential biomarker for the early diagnosis and treatment of PTC.

[Genetic analysis of a Chinese pedigree affected with congenital split-hand/foot malformation].

OBJECTIVE: To analyze the molecular genetics of a Chinese pedigree with congenital hand foot cleft. METHODS: Single nucleotide polymorphism microarray (SNP array) was used to analyze the whole genome copy number variation. RESULTS: SNP array analysis showed that there was a 433 kb repeat in 10q24.31-10q24.32 region, which contained LBX1, BTRC, POLL, OPCD and FBXW4 genes. CONCLUSION: Microduplication of chromosome 10q24.31-10q24.32 may be the cause of congenital hand foot cleft in this pedigree.

CLDN1 induces autophagy to promote proliferation and metastasis of esophageal squamous carcinoma through AMPK/STAT1/ULK1 signaling.

Tight junction is a structural constitution in cell-cell adhesion and play an important role in the maintenance of permeability and integrity of normal epithelial cell barrier. The protein encoded by Claudin 1 (CLDN1), a member of the claudin family, is an integral membrane protein and a component of tight junction strands. CLDN1 has been proved to regulate the proliferation and metastasis of multiple tumors, but little is known about its role in esophageal squamous cell carcinoma (ESCC). Here, we found that CLDN1 was aberrantly increased in ESCC tissues and cell lines, and mainly distributed in the nucleus of tumor cells. Furthermore, we confirmed that CLDN1 promoted the proliferation and metastasis of ESCC by triggering autophagy both in vitro and in vivo. Mechanically, we validated that CLDN1-induced autophagy via increasing Unc-51 like autophagy activating kinase 1 (ULK1) expression through AMP-activated protein kinase (AMPK)/signal transducer and activator of transcription 1 (STAT1) signaling pathway in ESCC cells. Taken together, our findings demonstrated that aberrant expression and distribution of CLDN1 promoted the proliferation and metastasis of esophageal squamous carcinoma by triggering autophagy through AMPK/STAT1/ULK1 signaling pathway.

ROS-induced NLRP3 inflammasome priming and activation mediate PCB 118- induced pyroptosis in endothelial cells.

Growing epidemiological evidence has shown that exposure to polychlorinated biphenyls (PCBs) is harmful to the cardiovascular system. However, how PCB 118-induced oxidative stress mediates endothelial dysfunction is not fully understood. Here, we explored whether and how PCB 118 exposure-induced oxidative stress leads to NLRP3 inflammasome-dependent pyroptosis in endothelial cells. As expected, PCB 118 was cytotoxic to HUVECs and induced caspase-1 activation and cell membrane disruption, which are characteristics of pyroptosis. Moreover, PCB 118-induced pyroptosis may have been due to the activation of the NLRP3 infammasomes. PCB 118 also induced excessive reactive oxygen species (ROS) in HUVECs. The ROS scavenger (±)-α-tocopherol and the NFκB inhibitor BAY11-7082 reversed the upregulation of NLRP3 expression and the increase in NLRP3 inflammasome activation induced by PCB 118 exposure in HUVECs. Additionally, PCB 118-induced oxidative stress and pyroptosis were dependent on Aryl hydrocarbon receptor (AhR) activation and subsequent cytochrome P450 1A1 upregulation, which we confirmed by using the AhR selective antagonist CH 223191. These data suggest that PCB 118 exposure induces NLRP3 inflammasome activation and subsequently leads to pyroptosis in endothelial cells in vitro and in vivo. AhR-mediated ROS production play a central role in PCB 118-induced pyroptosis by priming NFκB-dependent NLRP3 expression and promoting inflammasome activation.