Haplotype-specific MAPK3 expression in 16p11.2 deletion contributes to variable neurodevelopment.

Recurrent proximal 16p11.2 deletion (16p11.2del) is a risk factor for diverse neurodevelopmental disorders with incomplete penetrance and variable expressivity. Although investigation with human induced pluripotent stem cell models has confirmed disruption of neuronal development in 16p11.2del neuronal cells, which genes are responsible for abnormal cellular phenotypes and what determines the penetrance of neurodevelopmental abnormalities are unknown. We performed haplotype phasing of the 16p11.2 region in a 16p11.2del neurodevelopmental disorders cohort and generated human induced pluripotent stem cells for two 16p11.2del families with distinct residual haplotypes and variable neurodevelopmental disorder phenotypes. Using transcriptomic profiles and cellular phenotypes of the human induced pluripotent stem cell-differentiated cortex neuronal cells, we revealed MAPK3 to be a contributor to dysfunction in multiple pathways related to early neuronal development, with altered soma and electrophysiological properties in mature neuronal cells. Notably, MAPK3 expression in 16p11.2del neuronal cells varied on the basis of a 132 kb 58 single nucleotide polymorphism (SNP) residual haplotype, with the version composed entirely of minor alleles associated with reduced MAPK3 expression. Ten SNPs on the residual haplotype were mapped to enhancers of MAPK3. We functionally validated six of these SNPs by luciferase assay, implicating them in the residual haplotype-specific differences in MAPK3 expression via cis-regulation. Finally, the analysis of three different cohorts of 16p11.2del subjects showed that this minor residual haplotype is associated with neurodevelopmental disorder phenotypes in 16p11.2del carriers.

L-Arginine Supplementation Improves Vascular Endothelial Dysfunction Induced by High-Fat Diet in Rats Exposed to Hypoxia.

INTRODUCTION: Our previous study showed that high-fat diet inhibited the increase in nitric oxide and endothelial nitric oxide synthase expression in the aortic endothelium of rats exposed to hypoxia, and hypoxia plus a high-fat diet led to earlier and more severe vascular endothelial dysfunction (VED) than hypoxia alone. The purpose of the present study was to investigate the effects of L-arginine on high-fat diet-induced VED of rats in hypoxia. METHODS: Forty male Sprague-Dawley rats were randomly divided into 4 groups and treated with hypoxia (H group), hypoxia plus high-fat diet (H+HFD group), hypoxia plus L-arginine (H+L-Arg group), and hypoxia plus high-fat diet and L-arginine (H+HFD+L-Arg group) for 1 wk. Hypoxia was simulated in a hypobaric chamber with an altitude of 5000 m. Aortic morphology and endothelium-dependent vasorelaxation were used to assess VED. RESULTS: High-fat diet impaired vascular remodeling and reduced endothelium-dependent vasodilator response to acetylcholine in rats exposed to hypoxia, secondary to dysregulation of the nitric oxide pathway. L-arginine supplementation significantly increased plasma nitrates and nitrites and endothelial nitric oxide synthase mRNA levels and improved ultrastructural changes in aortic endothelium and endothelium-dependent vasodilator response. CONCLUSIONS: L-arginine prevents aortic ultrastructural changes and reverses VED induced by high-fat diet in rats exposed to hypoxia, which may have implications for VED induced by high-fat diet in high altitude dwellers.

Efficient gene correction of an aberrant splice site in ß-thalassaemia iPSCs by CRISPR/Cas9 and single-strand oligodeoxynucleotides.

ß-thalassaemia is a prevalent hereditary haematological disease caused by mutations in the human haemoglobin ß (HBB) gene. Among them, the HBB IVS2-654 (C > T) mutation, which is in the intron, creates an aberrant splicing site. Bone marrow transplantation for curing ß-thalassaemia is limited due to the lack of matched donors. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), as a widely used tool for gene editing, is able to target specific sequence and create double-strand break (DSB), which can be combined with the single-stranded oligodeoxynucleotide (ssODN) to correct mutations. In this study, according to two different strategies, the HBB IVS2-654 mutation was seamlessly corrected in iPSCs by CRISPR/Cas9 system and ssODN. To reduce the occurrence of secondary cleavage, a more efficient strategy was adopted. The corrected iPSCs kept pluripotency and genome stability. Moreover, they could differentiate normally. Through CRISPR/Cas9 system and ssODN, our study provides improved strategies for gene correction of ß-Thalassaemia, and the expression of the HBB gene can be restored, which can be used for gene therapy in the future.

The value of oral contrast ultrasonography in the diagnosis of gastric cancer in elderly patients.

BACKGROUND: This study aims to investigate the value of oral contrast ultrasonography (OCUS) in the diagnosis of gastric cancer in elderly patients. METHODS: OCUS data obtained from patients ≥ 60 years old were retrospectively analyzed and compared with gastroscopy results. RESULTS: Among the 12,716 subjects examined by OCUS, 5021 subjects were ≥ 60 years old, which accounted for 39.48% (5021/12,716). Gastritis, gastric polyp, benign ulcer, and gastric cancer were detected by OCUS in 1099 patients. Among them, 196 patients underwent gastroscopy. Furthermore, ulcerative lesions were detected in 32 patients by OCUS and in 51 patients by gastroscopy, and the coincidence rate was 62.74%. Among these patients, gastric cancer was diagnosed in 18 patients by OCUS with a detection rate of 1.64% (18/1099) and detected in 19 patients by gastroscopy with a diagnostic coincidence rate of 94.73% (18/19). Furthermore, benign ulcer was detected in 14 patients by OCUS and in 32 patients by gastroscopy, and the diagnostic coincidence rate was 43.75% (14/32). CONCLUSION: OCUS helps to timely detect senile gastric cancer and can be used as a suitable technique for the detection of gastric diseases.

Same-admission versus delayed cholecystectomy for mild acute biliary pancreatitis: a systematic review and meta-analysis.

BACKGROUND: The timing of laparoscopic cholecystectomy (LC) performed after the mild acute biliary pancreatitis (MABP) is still controversial. We conducted a review to compare same-admission laparoscopic cholecystectomy (SA-LC) and delayed laparoscopic cholecystectomy (DLC) after mild acute biliary pancreatitis (MABP). METHODS: We systematically searched several databases (PubMed, EMBASE, Web of Science, and the Cochrane Library) for relevant trials published from 1 January 1992 to 1 June 2018. Human prospective or retrospective studies that compared SA-LC and DLC after MABP were included. The measured outcomes were the rate of conversion to open cholecystectomy (COC), rate of postoperative complications, rate of biliary-related complications, operative time (OT), and length of stay (LOS). The meta-analysis was performed using Review Manager 5.3 software (The Cochrane Collaboration, Oxford, United Kingdom). RESULTS: This meta-analysis involved 1833 patients from 4 randomized controlled trials and 7 retrospective studies. No significant differences were found in the rate of COC (risk ratio [RR] = 1.24; 95% confidence interval [CI], 0.78-1.97; p = 0.36), rate of postoperative complications (RR = 1.06; 95% CI, 0.67-1.69; p = 0.80), rate of biliary-related complications (RR = 1.28; 95% CI, 0.42-3.86; p = 0.66), or OT (RR = 1.57; 95% CI, - 1.58-4.72; p = 0.33) between the SA-LC and DLC groups. The LOS was significantly longer in the DLC group (RR = - 2.08; 95% CI, - 3.17 to - 0.99; p = 0.0002). Unexpectedly, the subgroup analysis showed no significant difference in LOS according to the Atlanta classification (RR = - 0.40; 95% CI, - 0.80-0.01; p = 0.05). The gallstone-related complications during the waiting time in the DLC group included gall colic, recurrent pancreatitis, acute cholecystitis, jaundice, and acute cholangitis (total, 25.39%). CONCLUSION: This study confirms the safety of SA-LC, which could shorten the LOS. However, the study findings have a number of important implications for future practice.

[Clinical value of contrast-enhanced ultrasonography in the diagnosis of prostate cancer in patients with different PSA concentrations].

OBJECTIVE: To investigate the clinical value of contrast-enhanced ultrasonography (CEUS) in the diagnosis of prostate cancer in patients with different concentrations of prostate-specific antigen (PSA). METHODS: Based on the PSA concentration, 186 patients were divided into three groups (PSA 4－10 µg/L, 11－20 µg/L, and >20 µg/L) and underwent transrectal CEUS and biopsy. We compared the pathological results with the CEUS features in different groups of patients and performed a statistical analysis on the characteristics of the CEUS manifestations of prostate cancer and benign prostatic lesions. RESULTS: Of the 186 patients, 118 (63.4%) were diagnosed by biopsy with prostate cancer and the other 68 (36.6%) with benign prostatic lesions. The positive rate of CEUS in the diagnosis of prostate cancer was above 95% in all the three groups, significantly higher than that of conventional ultrasound in the PSA 4－10 and >10－20 µg/L groups (P <0.01). CONCLUSIONS: Contrast-enhanced ultrasonography can achieve a high detection rate in the diagnosis of prostate cancer, especially for the patients with a low PSA concentration, and therefore can be used as one of the most valuable diagnostic techniques for this purpose.

Effects of Yishengukang decoction on expression of bone-specific alkaline phosphatase, carboxyterminal propeptide of type â procollagen, and carboxyterminal cross-linked telepeptide of type â collagen in malignant tumor patients with bone metastasis.

OBJECTIVE: To investigate the effect of Yishengukang decoction on the expression of the metabolic bone markers, bone-specific alkaline phosphatase (BAP), carboxyterminal propeptide of type Ⅰ procollagen (PICP), and arboxyterminal cross-linked telepeptide of type Ⅰ collagen (ICTP), in cancer patients with bone metastasis. METHODS: Patients (n = 180) were divided into three groups: (a) bone metastasis patients treated with Yishengukang and pamidronate disodium injection (treatment group, n = 60); (b) bone metastasis patients treated with pamidronate disodium injection alone (control group, n = 60); (c) cancer patients without metastatic bone lesion (non-bone metastasis group, n = 60). Serum levels of the metabolic markers BAP, PICP, and ICTP were detected by enzyme-linked immunosorbent assay pre- and post-therapy. RESULTS: A significant decrease in serum BAP level was observed in the treatment group compared with the control group. However there were no significant differences in serum levels of PICP and ICTP before or after treatment compared with the control group. CONCLUSION: Yishengukang decoction combined with pamidronate disodium injection reduced serum BAP level to a greater extent that pamidronate disodium injection alone. Furthermore, the combined therapy was more beneficial in regulating imbalanced bone metabolism after bone metastasis, and may represent the molecular mechanism underpinning the effects of Yishengukang decoction.

Effects of the aqueous extract of a Tibetan herb, Rhodiola algida var. tangutica on proliferation and HIF-1α, HIF-2α expression in MCF-7 cells under hypoxic condition in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhodiola algida var. tangutica is a traditional Tibetan herb. Its root and rhizome have been successfully used as an effective clinical remedy for the prevention and treatment of cancer and high-altitude sickness. This study aimed to investigate the effect of Rhodiola algida var. tangutica on hypoxic MCF-7 breast cancer cells and the underlying mechanisms. MATERIALS AND METHODS: The antiproliferative effects of R. algida on MCF-7 breast cancer cells were compared in vitro under hypoxic and normal conditions by using MTT analysis. The influence of R. algida on cancer cell apoptosis was determined by flow cytometry. The expression levels of hypoxia-inducible factor (HIF)-1α and HIF-2α were evaluated by western blot analysis. RESULTS: R. algida inhibited the proliferation of MCF-7 breast cancer cells in a dose- and time-dependent manner. The results of flow cytometry indicated that the antiproliferative effect of R. algida was mediated by apoptosis induction. Pretreatment with R. algida significantly suppressed the hypoxia-induced proliferation and expression of HIF-1α and HIF-2α in MCF-7 breast cancer cells. CONCLUSIONS: R. algida might exert an anti-carcinogenic effect on MCF-7 breast cancer cells by decreasing the protein levels of HIF-1α and HIF-2α, which are overexpressed under hypoxic conditions. This effect might be elicited by inhibiting the hypoxia-induced proliferation of MCF-7 breast cancer cells.

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels.

AIM: Sustained pulmonary vasoconstriction as experienced at high altitude can lead to pulmonary hypertension (PH). The main purpose of this study is to investigate the vasorelaxant effect of echinacoside (ECH), a phenylethanoid glycoside from the Tibetan herb Lagotis brevituba Maxim and Cistanche tubulosa, on the pulmonary artery and its potential mechanism. METHODS: Pulmonary arterial rings obtained from male Wistar rats were suspended in organ chambers filled with Krebs-Henseleit solution, and isometric tension was measured using a force transducer. Intracellular Ca(2+) levels were measured in cultured rat pulmonary arterial smooth muscle cells (PASMCs) using Fluo 4-AM. RESULTS: ECH (30-300 µmol/L) relaxed rat pulmonary arteries precontracted by noradrenaline (NE) in a concentration-dependent manner, and this effect could be observed in both intact endothelium and endothelium-denuded rings, but with a significantly lower maximum response and a higher EC50 in endothelium-denuded rings. This effect was significantly blocked by L-NAME, TEA, and BaCl2. However, IMT, 4-AP, and Gli did not inhibit ECH-induced relaxation. Under extracellular Ca(2+)-free conditions, the maximum contraction was reduced to 24.54%±2.97% and 10.60%±2.07% in rings treated with 100 and 300 µmol/L of ECH, respectively. Under extracellular calcium influx conditions, the maximum contraction was reduced to 112.42%±7.30%, 100.29%±8.66%, and 74.74%±4.95% in rings treated with 30, 100, and 300 µmol/L of ECH, respectively. After cells were loaded with Fluo 4-AM, the mean fluorescence intensity was lower in cells treated with ECH (100 µmol/L) than with NE. CONCLUSION: ECH suppresses NE-induced contraction of rat pulmonary artery via reducing intracellular Ca(2+) levels, and induces its relaxation through the NO-cGMP pathway and opening of K(+) channels (BKCa and KIR).

Antiproliferative effect of echinacoside on rat pulmonary artery smooth muscle cells under hypoxia.

The main purpose of this study is to evaluate the effect of echinacoside (ECH) on hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells (PASMCs) and the underlying mechanism. PASMCs were incubated under normoxia (nor), hypoxia (hyp), hypoxia + 0.35 mM ECH (hyp + ECH0.35), or hypoxia + 0.4 mM ECH (hyp + ECH0.4) for 24 h. Cell viability was assessed by MTS assays. The morphology of apoptosis was observed by DAPI staining, and apoptosis was quantified by flow cytometric analysis. Caspase-3 activity was determined by immunohistochemistry and real-time PCR, and the expressions of HIF-1α, Bax, Bcl-2, and Fas were determined by real-time PCR. Hypoxia induced significant proliferation of PASMCs, which could be inhibited by ECH in a concentration-dependent manner. This was associated with apoptosis of PASMCs. Z-DEVD-FMK could partly reduce the suppression effect of ECH; protein and gene expression of caspase-3 were significantly higher in the hyp + ECH0.4 and hyp + ECH0.35 groups. ECH significantly increased the expressions of Bax and Fas, but decreased the expressions of Bcl-2 and HIF-1α. ECH could inhibit hypoxia-induced proliferation of rat PASMCs, which is associated with apoptosis of PASMCs and improvement of hypoxia. ECH might be a potential agent for prevention and treatment of hypoxia-induced PAH.

Chemotherapy combined with bevacizumab for small cell lung cancer with brain metastases: A case report.

BACKGROUND: Small cell lung cancer (SCLC) is a common and aggressive subtype of lung cancer. It is characterized by rapid growth and a high mortality rate. Approximately 10% of patients with SCLC present with brain metastases at the time of diagnosis, which is associated with a median survival of 5 mo. This study aimed to summarize the effect of bevacizumab on the progression-free survival (PFS) and overall survival of patients with brain metastasis of SCLC. CASE SUMMARY: A 62-year-old man was referred to our hospital in February 2023 because of dizziness and numbness of the right lower extremity without headache or fever for more than four weeks. The patient was diagnosed with limited-stage SCLC. He received 8 cycles of chemotherapy combined with maintenance bevacizumab therapy and achieved a PFS of over 7 mo. CONCLUSION: The combination of bevacizumab and irinotecan effectively alleviated brain metastasis in SCLC and prolonged PFS.

Tissue-specific populations from amniotic fluid-derived mesenchymal stem cells manifest variant in vitro and in vivo properties.

Amniotic fluid derived mesenchymal stem cells (AFMSCs), shed along the fetal development, exhibit superior multipotency and immunomodulatory properties compared to MSCs derived from other somatic tissues (e.g., bone marrow and fat). However, AFMSCs display heterogeneity due to source ambiguity, making them an underutilized stem cells source for translational clinical trials. Consequently, there is an urgent need to identify a method to purify the AFMSCs for clinical use. We found that the AFMSCs can be categorized into three distinct groups: kidney-specific AFMSCs (AFMSCs-K), lung-specific AFMSCs (AFMSCs-L), and AFMSCs with an undefined tissue source (AFMSCs-X). This classification was based on tissue-specific gene expression pattern of single cell colony. Additionally, we observed that AFMSCs-X, a minority population within the AFMSCs, exhibited the highest multipotency, proliferation, resistance to senescence and immuno-modulation. Our results showed that AFMSCs-X significantly improved survival rates and reduced bacterial colony forming units (CFU) in cecal ligation and puncture (CLP)-induced septic mice. Therefore, our study introduces a novel classification method to enhance the consistency and efficacy of AFMSCs. These subpopulations, originating from different tissue source, may offer a valuable and innovative resource of cells for regenerative medicine purposes.

FOXO3a-dependent up-regulation of HSP90 alleviates cisplatin-induced apoptosis by activating FUNDC1-mediated mitophagy in hypoxic osteosarcoma cells.

Hypoxia-induced decrease in cisplatin (CDDP) sensitivity in human osteosarcoma (OS) is a significant obstacle to effective chemotherapy. Recently, mitophagy has been shown to be associated with CDDP sensitivity. However, whether it regulates hypoxia-induced decreases in CDDP sensitivity in OS and the underlying mechanisms remain unknown. In this study, we found that hypoxia activated mitophagy and suppressed mitophagy with specific inhibitors, mitochondrial division inhibitor-1 (Mdivi-1) or lysosome inhibitor chloroquine (CQ), which inhibited CDDP-induced apoptosis in hypoxic U-2OS and MG-63 cells. In addition, hypoxia upregulated the phosphorylation level of FUN14 domain-containing protein 1 (FUNDC1), whereas the activation of mitophagy and decreased CDDP sensitivity were inhibited by transfection with FUNDC1 small interfering RNA (siRNA). Hypoxia treatment also led to the up-regulation of heat shock protein 90 (HSP90), whereas HSP90 siRNA inhibited FUNDC1-mediated activation of mitophagy and decreased CDDP sensitivity. Furthermore, activation of Unc-51 like autophagy activating kinase 1 (Ulk1) was found in U-2OS and MG-63 cells after induction of hypoxia. Overexpression of Ulk1 prevented the inhibitory effect of HSP90 siRNA on the activation of FUNDC1 and mitophagy and decreased CDDP sensitivity in hypoxic U-2OS and MG-63 cells. Finally, hypoxia induced the activation of forkhead box transcription factor 3a (FOXO3a), whereas FOXO3a siRNA inhibited hypoxia-induced HSP90 up-regulation, Ulk1 activation, and FUNDC1-mediated activation of mitophagy, and decreased CDDP sensitivity in U-2OS and MG-63 cells. Using a chromatin immunoprecipitation (ChIP) assay, we confirmed that FOXO3a binds to the HSP90 promoter region. In conclusion, our findings suggest that hypoxia alleviates CDDP-induced apoptosis by activating mitophagy through the FOXO3a/HSP90/Ulk1/FUNDC1 signaling pathway in OS cells.

Hyperprogression after anti-programmed death-1 therapy in a patient with urothelial bladder carcinoma: A case report.

BACKGROUND: Immune checkpoint inhibitors, including programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) have recently been approved to treat locally advanced and metastatic urothelial carcinoma (UC). However, some patients experience rapid tumor progression rather than any clinical benefit from anti-PD-L1/PD-1 therapy. CASE SUMMARY: A 73-year-old woman with bladder UC showed the progression of multiple metastases after surgery and chemotherapy for over 12 mo. The patient could not tolerate further chemotherapy. Next-generation sequencing was performed, and the results indicated that the tumor mutational burden was 6.4 mutations/Mb. The patient received the anti-PD-L1 agent toripalimab combined with albumin-bound paclitaxel. Compared with the baseline staging before immunotherapy, the patient had a treatment failure time of < 2 mo, an increase in tumor burden of > 50%, and a > 2-fold increase in progression, indicating hyperprogression. CONCLUSION: Selecting patients most likely to respond to treatment with immunotherapeutic agents remains challenging. For older patients with advanced UC who have already exhausted multi-line chemotherapy options, immunotherapy should be used prudently if no effective biomarker is available. Further studies are required to clarify the causes and mechanisms of hyperprogression.

PAK2 is essential for chromosome alignment in metaphase I oocytes.

As a highly conserved and ubiquitously expressed serine/threonine kinase, p21-activated kinase 2 (PAK2) participates in diverse biologic events. However, its roles in mouse oocyte meiotic maturation remain unclear. The present study revealed that mouse oocytes depleted of Pak2 were unable to completely progress through meiosis and that a majority were arrested at metaphase I. Pak2 depletion thus prompted MI arrest and induced meiotic chromosome alignment defects in mouse oocytes, in part due to a reduction in polo-like kinase (PLK1). We demonstrated that PAK2's interaction with PLK1 protected it from degradation by APC/CCdh1, and that it promoted meiotic progression and bipolar spindle formation. Our data collectively display critical functions for PAK2 in meiotic progression and chromosome alignment in mouse oocytes.

[The value of high-frequency ultrasound in the diagnosis of duchenne muscular dystrophy in children].

OBJECTIVE: To study the value of high-frequency ultrasound in the diagnosis of duchenne muscular dystrophy diseases (DMD) in children. METHODS: Eight children with DMD were enrolled as DMD group and 10 healthy children as the control group. The echogenicity of the rectus femoris muscle and the gap between the gastrocnemius and soleus muscles in the two groups were detected by high-frequency ultrasound. RESULTS: Compared with the control group, rectus femoris and gastrocnemius muscles in the DMD group showed increased echogenicity and their muscle fibers were arranged irregularly, and the gap between the gastrocnemius and soleus muscles became wilder (P<0.01). CONCLUSIONS: High-frequency ultrasound is valuable in the diagnosis of DMD.

A metabolomic-based biomarker discovery study for predicting phototherapy duration for neonatal hyperbilirubinemia.

Background: Phototherapy is a recommended method for the treatment of neonatal hyperbilirubinemia. However, biomarkers for predicting the more effective duration of phototherapy prior to treatment are lacking. Therefore, we aimed to determine novel predictors for the timing of phototherapy from the perspective of metabolomics. Methods: A total of 12 newborns with neonatal hyperbilirubinemia were recruited on the day of admission. The infants were divided into a short-duration (<30 hours) phototherapy group and a long-duration (≥30 hours) phototherapy group based on the length of phototherapy treatment. Metabolites in serum samples were then explored using an untargeted metabolomics strategy. Results: In total, 59 of 1,073 significantly different metabolites were identified between the short-duration and long-duration phototherapy groups, including 18 upregulated and 41 downregulated metabolites. The results of metabolomic analysis showed that the differentially expressed metabolites were enriched in glycerophospholipid metabolism, which is closely associated with the excretion of bilirubin. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the metabolites were also enriched in alpha-Linolenic acid metabolism and fatty acid elongation. Spearman correlation hierarchical clustering analysis demonstrated that 9 metabolites were negatively correlated with the duration of phototherapy. Metabolites, especially phosphatidylethanolamine (PE) (22:1(13Z)/15:0), phosphatidylcholine (PC) (18:1(9Z)/18:1(9Z)), phosphatidylserine (PS) (22:0/15:0), 5,6-dihydrouridine, and PE (MonoMe(11,3)/MonoMe(13,5)), had better predictability for the duration of phototherapy [area under curve (AUC): 1; 95% confidence interval (CI): 1-1] than total serum total bilirubin and direct bilirubin (AUC: 0.806; 95% CI: 0.55-1), as revealed by receiver operating characteristic analysis. Conclusions: Our research found that the differential metabolites were associated with the duration of neonatal jaundice and that glycerophospholipid metabolism might have played a role in this biological process. Moreover, metabolites such as PE (22:1(13Z)/15:0), PC (18:1(9Z)/18:1(9Z)), PS (22:0/15:0), 5,6-dihydrouridine, and PE (MonoMe(11,3)/MonoMe(13,5)) could be used as predictors for phototherapy duration in neonatal hyperbilirubinemia and assist with decision-making.

Induction of Fetal Hemoglobin by Introducing Natural Hereditary Persistence of Fetal Hemoglobin Mutations in the γ-Globin Gene Promoters for Genome Editing Therapies for ß-Thalassemia.

Reactivation of γ-globin expression is a promising therapeutic approach for ß-hemoglobinopathies. Here, we propose a novel Cas9/AAV6-mediated genome editing strategy for the treatment of ß-thalassemia: Natural HPFH mutations -113A > G, -114C > T, -117G>A, -175T > C, -195C > G, and -198T > C were introduced by homologous recombination following disruption of BCL11A binding sites in HBG1/HBG2 promoters. Precise on-target editing and significantly increased γ-globin expression during erythroid differentiation were observed in both HUDEP-2 cells and primary HSPCs from ß-thalassemia major patients. Moreover, edited HSPCs maintained the capacity for long-term hematopoietic reconstitution in B-NDG hTHPO mice. This study provides evidence of the effectiveness of introducing naturally occurring HPFH mutations as a genetic therapy for ß-thalassemia.

Comparison of contrast-enhanced ultrasound targeted biopsies versus standard systematic biopsies for prostate cancer correction in different PSA value groups in rural China.

OBJECTIVE: To investigate prostate cancer detection rate of different biopsy protocols in different PSA value groups in rural China. METHODS: A total of 186 patients underwent contrast-enhanced ultrasound (CEUS) in order to determine the puncture target prior to biopsy were enrolled in this retrospective study. All patients underwent 12-core SB combined with CEUS-TB. The biopsy results of different biopsy protocols were compared in patients with stratification by PSA value. RESULTS: Among the 186 patients underwent prostate biopsy, the histopathologic results revealed prostate cancer (PCa) in 117 cases (62.9%) and benign lesions in 69 cases (37.1%). The PCa detection rate between 8-core SB and 12-core SB showed no significant difference in PSA 4-10 ng/ml group, while the 12-core SB was significantly higher than CEUS-TB (44.9% versus 32.7%, P = 0.01). In PSA 10-20 ng/ml group, the significant difference was not seen between SB and CEUS-TB (50.0% versus 45.7%, P = 0.15). As for PSA greater than 20 ng/ml group, the PCa detection rate by SB was higher than CEUS-TB, but showed no statistically significance (79.1% versus 76.9%, P = 0.15). In the overall patients, the biopsy core positive rate of CEUS-TB was significantly higher than SB (97% versus 55.5% and 28.5%, P = 0.0001). CONCLUSION: The flexible use of SB combined with CEUS-TB can reduce the number of biopsy cores in higher PSA groups. It has clinical importance in the detection of PCa in different PSA value groups in rural China.

Effects of aerobic exercise and resistance exercise on physical indexes and cardiovascular risk factors in obese and overweight school-age children: A systematic review and meta-analysis.

BACKGROUND: Obesity is a serious social and public health problem in the world, especially in children and adolescents. For school-age children with obesity, this stage is in the transition from childhood to adolescence, and both physical, psychological, and external environments will be full of challenges. Studies have showed that school-age children are the largest proportion of people who continue to be obese in adulthood. Physical exercise is considered as an effective way to control weight. Therefore, we focus on this point to study which factors will be improved to reduce childhood obesity. OBJECTIVE: To assess the effects of aerobic and resistance exercise on physical indexes, such as body mass index (BMI) and body fat percentage, and cardiovascular risk factors such as VO2peak, triglycerides (TG) and low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), insulin and insulin resistance in school-age children who are overweight or obese. METHOD: PubMed, SPORTDiscus, Medline, Cochrane-Library, Scopus, Ovid and Web of Science were searched to locate studies published between 2000 and 2021 in obese and overweight school-age children between 6-12 years old. The articles are all randomized controlled trials (RCTs) and in English. Data were synthesized using a random-effect or a fixed-effect model to analyze the effects of aerobic and resistance exercise on six elements in in school-age children with overweight or obese. The primary outcome measures were set for BMI. RESULTS: A total of 13 RCTs (504 participants) were identified. Analysis of the between-group showed that aerobic and resistance exercise were effective in improving BMI (MD = -0.66; p < 0.00001), body fat percentage (MD = -1.29; p = 0.02), TG (std.MD = -1.14; p = 0.005), LDL (std.MD = -1.38; p = 0.003), TC (std.MD = -0.77; p = 0.002), VO2peak (std.MD = 1.25; p = 0.001). However, aerobic and resistance exercise were not significant in improving HDL (std.MD = 0.13; p = 0.27). CONCLUSIONS: Aerobic exercise and resistance exercise are associated with improvement in BMI, body fat percentage, VO2peak, TG, LDL, TC, while not in HDL in school-age children with obesity or overweight. Insulin and insulin resistance were not able to be analyzed in our review. However, there are only two articles related to resistance exercise in children with obesity and overweight at school age, which is far less than the number of 12 articles about aerobic exercise, so we cannot compare the effects of the two types of exercises.