Effective Management of Polycythemia Vera With Ropeginterferon Alfa-2b Treatment.

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm. Ropeginterferon alfa-2b is a new-generation polyethylene glycol-conjugated proline-interferon. It is approved for the treatment of PV at a starting dose of 100 µg (50 µg for patients receiving hydroxyurea (HU)) and dose titrations up to 500 µg by 50 µg increments. The study was aimed at assessing its efficacy and safety at a higher starting dose and simpler intra-patient dose escalation. Methods: Forty-nine patients with PV having HU intolerance from major hospitals in China were treated biweekly with an initial dose of 250 µg, followed by 350 µg and 500 µg thereafter if tolerated. Complete hematological response (CHR) was assessed every 12 weeks based on the European LeukemiaNet criteria. The primary endpoint was the CHR rate at week 24. The secondary endpoints included CHR rates at weeks 12, 36 and 52, changes of JAK2V617F allelic burden, time to first CHR, and safety assessments. Results: The CHR rates were 61.2%, 69.4% and 71.4% at weeks 24, 36, and 52, respectively. Mean allele burden of the driver mutation JAK2V617F declined from 58.5% at baseline to 30.1% at 52 weeks. Both CHR and JAK2V617F allele burden reduction showed consistent increases over the 52 weeks of the treatment. Twenty-nine patients (63.0%) achieved partial molecular response (PMR) and two achieved complete molecular response (CMR). The time to CHR was rapid and median time was 5.6 months according to central lab results. The CHRs were durable and median CHR duration time was not reached at week 52. Mean spleen index reduced from 55.6 cm2 at baseline to 50.2 cm2 at week 52. Adverse events (AEs) were mostly mild or moderate. Most common AEs were reversible alanine aminotransferase and aspartate aminotransferase increases, which were not associated with significant elevations in bilirubin levels or jaundice. There were no grade 4 or 5 AEs. Grade 3 AEs were reversible and manageable. Only one AE led to discontinuation. No incidence of thromboembolic events was observed. Conclusion: The 250-350-500 µg dosing regimen was well tolerated and effectively induced CHR and MR and managed spleen size increase. Our findings demonstrate that ropeginterferon alfa-2b at this dosing regimen can provide an effective management of PV and support using this dosing regimen as a treatment option.

Tormentic acid, a triterpenoid isolated from the fruits of Chaenomeles speciose, protected indomethacin-induced gastric mucosal lesion via modulating miR-139 and the CXCR4/CXCL12/PLC/PKC/Rho a/MLC pathway.

CONTEXT: Tormentic acid (TA), an effective triterpenoid isolated from Chaenomeles speciosa (Sweet) Nakai (Rosaceae) fruits, exerts an effective treatment for gastric damage. OBJECTIVE: To investigate the gastroprotective effect of TA on indomethacin (IND) damaged GES-1 cells and rats, and explore potential mechanisms. MATERIALS AND METHODS: TA concentrations of 1.563-25 µM were used. Cell proliferation, apoptosis and migration were performed using MTT, colony formation, wound healing, migration, Hoechst staining assays. SD rats were divided into control, IND, TA (1, 2 and 4 mg/kg) + IND groups, once a day for 21 continuous days. Twenty-four hours after the last administration, all groups except the control group were given IND (100 mg/kg) by gavage. Gastric juice parameters, gastric ulcer, gastric blood flow (GBF), blood biochemical parameters and cytokine analysis and gastric mucosal histopathology were detected for 2 h and 6 h after IND oral administration. The mRNA and protein expression of miR-139 and the CXCR4/CXCL12/PLC/PKC/Rho A/MLC pathway were analyzed in the IND-damaged GES-1 cells and gastric tissue of rats. RESULTS: TA might ameliorate the gastric mucosal injury by accelerating the IND-damaged GES-1 cell proliferation and migration, ameliorating GBF, ulcer area and pathologic changes, the redox system and cytokine levels, the gastric juice parameters, elevating the gastric pH in IND damaged rats; suppressed miR-139 mRNA expression, elevated CXCR4 and CXCL12 mRNA and protein expression, p-PLC, p-PKC, Rho A, MLCK and p-MLC protein expression. DISCUSSION AND CONCLUSIONS: TA may have potential use as a clinical drug candidate for gastric mucosal lesion treatment.

Structural insights into the substrate binding sites of O-carbamoyltransferase VtdB from Streptomyces sp. NO1W98.

The O-carbamoyltransferase VtdB catalyzes the carbamoylation of venturicidin B, which is essential for the biosynthesis of the antibiotic venturicidin A. Here, the crystal structures of VtdB and VtdB in complex with the intermediate carbamoyladenylate (VtdBCAO) were determined at resolutions of 2.99 Å and 2.90 Å, respectively. The structures resemble the conserved YrdC-like and specific Kae1-like domains. A magnesium ion and the intermediate carbamoyladenylate were also observed in the Kae1-like domain of VtdB. The structure of VtdBCAO in complex with the substrate venturicidin B was modeled by a molecular docking method to better understand the substrate binding mode, revealing a novel venturicidin B binding pocket.

Analysis of clinical phenotype and genotype of Chinese children with disorders of sex development / 中华儿科杂志

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.

Organoids derived from the digestive system and their perspective applications in exercise physiology / 生理学报

Organoid, formed from organ-specific cells, is a group of self-renewal and self-organizing cells growing in a 3-dimensional structure. With the recent progress on microenvironment regulation, stem cell differentiation and organ development, organoids have been constructed and used as promising tools for a wide range of multidisciplinary biomedical applications. Exercise disrupts the internal environment homeostasis, which brings a series of physiological alterations to the digestive system. The current animal or human models are necessary, but not sufficient to monitor the fluctuating microenvironment of gastrointestinal epithelial cells or hepatocytes during exercise. This review described the construction and application of digestive system organoids, as well as the effect of exercise on the microenvironment of intestinal epithelial cells and hepatocytes. The perspective applications of digestive system organoids in exercise physiology were also stated. Using organoid technologies, the possible mechanisms of the exercise-induced dynamic physiological changes would be explored in a new dimension.

Retention of volunteers and factors influencing program performance of the Senior Care Volunteers Training Program in Jiangsu, China.

BACKGROUND: As the country with the largest aging population, China faces an enormous challenge with its elderly support and care. One of the proposed solutions is the development of volunteerism for elderly care. The Senior Care Volunteers Training Program (SCVTP) was initiated by the Red Cross Society of China with the purpose of training volunteers to care for community seniors. As one of the four pilot provinces, Jiangsu Province launched the program since 2017. AIMS: The present study was conducted to investigate the dropout rate of trained volunteer group leaders, the characteristics of the retained trained volunteer group leaders and the activities that their groups conducted. Additionally, the exploration of the factors influencing the SCVTP's performance was listed as another aim. METHODS: A cross-sectional study was designed. The study used purposive sampling to select participants who meet the criteria from all the trained volunteer group leaders (n = 623). Demographic questionnaire, volunteer role identity (VRI) scale, attitude toward helping others (AHO) scale, team climate and atmosphere (TCA) scale, and volunteer program performance evaluation (VPPE) questionnaire were used to collect the data online. Descriptive statistics were used to determine the dropout rate and general characteristics of the retained volunteers and the activities. A multiple linear regression equation was developed to study the factors that influence program performance. RESULTS: In total, 307 questionnaires were valid in the study. About 67.9%, 53.7%, and 30.0% of the trained volunteer group leaders dropped out of the program in the year of 2017, 2018, and 2019, respectively. The retained trained volunteer group leaders were more likely to be females (84.7%), those in excellent health (75.2%) and with a bachelor's degree or above (87.6%). Less attention has been paid to frailty care (n = 76) than other volunteer caring activities (e.g., safe care: n = 277, diet care: n = 250, drug management care: n = 226). VRI (ß = 0.118, p = 0.017), AHO (ß = 0.134, p = 0.021), TCA (ß = 0.459, p<0.001), and financial sustainability (ß = 0.179, p<0.001) affected the SCVTP's performance significantly (adjusted R2 = 0.356). CONCLUSION: High rate of trained volunteer group leaders' dropout should be brought to the policymaker's attention. The characteristics of the retained trained volunteer group leaders provide a useful reference for the recruitment of trainees in the future. Frailty care may need more training by the volunteer service provider. In order to enhance program performance, a better team climate and atmosphere, financial sustainability, and volunteers with appropriate attitude and role identity are also necessary for the volunteer program.

Vitamin D-vitamin D receptor system down-regulates expression of uncoupling proteins in brown adipocyte through interaction with Hairless protein.

Our previous study showed that feeding mice with vitamin D deficiency diet markedly alleviated high-fat-diet-induced overweight, hyperinsulinemia, and hepatic lipid accumulation. Moreover, vitamin D deficiency up-regulated the expression of uncoupling protein 3 (Ucp3) in white adipose tissue (WAT) and brown adipose tissue (BAT). The present study aimed to further investigate the effects of vitamin D and vitamin D receptor (Vdr) on Ucp1-3 (Ucps) expression in brown adipocyte and the mechanism involved in it. Rat primary brown adipocytes were separated and purified. The effects of the 1,25(OH)2D3 (1,25-dihydroxyvitamin D3; the hormonal form of vitamin D) and Vdr system on Ucps expression in brown adipocytes were investigated in basal condition and activated condition by isoproterenol (ISO) and triiodothyronine (T3). Ucps expression levels were significantly down-regulated by 1,25(OH)2D3 in the activated brown adipocyte. Vdr silencing reversed the down-regulation of Ucps by 1,25(OH)2D3, whereas Vdr overexpression strengthened the down-regulation effects. Hairless protein did express in brown adipocyte and was localized in cell nuclei. 1,25(OH)2D3 increased Hairless protein expression in the cell nuclei. Hairless (Hr) silencing notably elevated Ucps expression in activated condition induced by ISO and T3. Moreover, immunoprecipitation results revealed that Vdr could interact with Hairless, which might contribute to decreasing expression of Vdr target gene Ucps. These data suggest that vitamin D suppresses expression of Ucps in brown adipocyte in a Vdr-dependent manner and the corepressor Hairless protein probably plays a role in the down-regulation.

Efficacy of dexmedetomidine mixed with ropivacaine for brachial plexus block in patients undergoing upper limb surgery: a meta-analysis / 中华麻醉学杂志

Objective To systematically review the efficacy of dexmedetomidine mixed with ropivacaine for brachial plexus block in the patients undergoing upper limb surgery.Methods Medline,PubMed,Embase,Web of Science,Weipu,Wanfang,Zhiwang databases were searched for randomized controlled trials involving the efficacy of dexmedetomidine mixed with ropivacaine for brachial plexus block in patients undergoing upper limb surgery from the date of database establishment up to July 2017,and the trials were published in Chinese or in English.Evaluation indexes included onset time and duration of sensory and motor blocks and analgesia time when used for brachial plexus block.Trials were selected and data were extracted independently by 2 investigators,and meta-analysis was conducted using the Cochrane Collaboration's RevMan 5.3 software.Results Twelve randomized controlled trials were included in our metaanalysis.Compared with control group,the onset time of sensory and motor blocks was significantly shortened,the duration of sensory and motor blocks was prolonged,and analgesia time when used for brachial plexus block was prolonged in dexmedetomidine group (P＜0.01).Conclusion Dexmedetomidine mixed with ropivacaine can be effectively used for brachial plexus block in the patients undergoing upper limb surgery.

Effect of operation position change on heart index and stroke volume variation in patients monitored by FloTrac/Vigileo system / 重庆医学

Objective To investigate the effect of different operation positions on cardiac index (CI) and stroke volume variation (SVV) in the patients monitored by FloTrac/Vigileo system to provide some references for the hemodynamic management and liquid treatment of the patients.Methods Sixty patients scheduled for elective TV auxiliary thoracoscope radical operation of esophageal cancer.The CI and SVV changes were observed by using the FloTrac/Vigileo system.CI,SVV and CVP were recorded at 5 min after anesthesia induction (T0),5 min after converting to the position of head low feet high (T1),5 min after converting to the position of head high feet low (T2).Results Compared with T0,CI at T1 and T2 was decreased(P＜0.05);compared with T0,SVV at T1 was decreased and CVP was increased;SVV at T2 was increased and CVP was decreased(P＜0.05).Conclusion The operation position change may have a significant impact on the patient's CI,SVV and CVP.Focusing on the corresponding change can provide some references for the intraoperative hemodynamic management and liquid treatment.

The effects of different values of PEEP on heart index, stroke volume variation and oxygen transport index in patients monitored by FloTrac/Vigileo system / 天津医药

Objective To investigate the effects of different values of PEEP on cardiac index (CI), stroke volume variation (SVV) and oxygen transport index (DO2I) in patients monitored by FloTrac/Vigileo system, and to provide some references for the hemodynamic management and improvement of oxygenation for patients. Methods Sixty patients scheduled for elective television (TV) auxiliary thoracoscope radical operation for esophageal cancer were included in this study. Data of CI, SVV and DO2I were observed by the FloTrac/Vigileo system. Changes of CI, SVV and DO2I were recorded after anesthesia induction and turn left side (T0), artificial pneumothorax with 0 PEEP after 5 minutes (T1), artificial pneumothorax with 5 PEEP after 5 minutes (T2), artificial pneumothorax with 10 PEEP after 5 minutes (T3), and artificial pneumothorax with 15 PEEP after 5 minutes (T4). Results Compared with T0, CI decreased and SVV increased significantly at T1, T2, T3 and T4(P<0.05). Compared with T1, CI decreased and SVV increased at T4. DO2I increased at T2 and T3 compared with that of T1(P<0.05). Conclusion PEEP may have a certain influence on CI and SVV in the process of operation. The values of 5-10 PEEP can significantly improve oxygenation and have a less influence on hemodynamics, which can be appropriately used in clinical care.

Hexokinase 2 regulates G1/S checkpoint through CDK2 in cancer-associated fibroblasts.

Hexokinase 2 (HK2), a pivotal glycolytic enzyme, is often overexpressed in tumor cells and contributes to glycolysis. Emerging evidence has suggested that glycolysis is also enhanced in cancer-associated fibroblasts (CAF). However, it is not clear whether HK2 is involved in enhanced glycolysis in CAFs or what role HK2 plays in the CAFs. In this study, both time course experiments and dose response experiments demonstrated that the protein and mRNA levels of HK2 increase in CAF cells, according to western blot and quantitative PCR analyses, respectively. Additionally, miR-182 targets the 3' UTR of HK2, and its overexpression results in the degradation of HK2 mRNA, which eventually reduces the level of HK2 protein. On the other hand, knockdown of miR-182 increased the expression of HK2. Most importantly, HK2 regulated the protein level and T14 phosphorylation of CDK2, and knockdown of HK2 resulted in a G1 phase cell cycle arrest. These observations suggest that HK2 plays important roles in glycolysis regulation and in cell cycle checkpoint activation.

[Serum levels of tumor necrosis factor α and interferon γ in patients with hemophagocytic syndrome and its clinical significance].

In order to explore the serum levels and clinical significance of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in patients with hemophagocytic syndrome (HPS). The clinical data of HPS patients in Capital Medical University Beijing Friendship Hospital from October 2008 to October 2010 were collected. The serum concentration of TNF-α and IFN-γ in HPS patients and 20 healthy controls was measured with enzyme-linked immunosorbent assay (ELISA). The correlations between the levels of TNF-α and primary disease were analyzed, the levels of hemoglobin, ferritin, triglyceride, NK cell activity and sCD25 were detected on the same day, the correlations between the concentrations of TNF-α and IFN-γ and these laboratory indicators were analyzed. The results indicated that the serum levels of TNF-α and IFN-γ in 30 cases of HPS was higher than that in control group (p < 0.05, p < 0.01); the difference of TNF-α concentration was statistically significant in rheumatism-related and tumor-related HPS groups(p = 0.04), the level of TNF-α in HPS patients showed negative correlation with hemoglobin. It is concluded that the high levels of TNF-α and IFN-γ in HPS patients may play certain roles in the pathogenesis and progress of HPS. These data indicated that the high level of TNF-α may be the main factor for anemia in patients with HPS.

[Expression of serum sHLA-G in patients with hemophagocytic syndrome and its clinical significance].

In order to investigate the expression of serum sHLA-G in hemophagocytic syndrome (HPS) patients and to evaluate its clinical significance, the clinical data of HPS patients in Capital Medical University Beijing Friendship Hospital during the period from September 2008 to July 2010 were collected. They were divided into infection-associated HPS, tumor-associated HPS and rheumatological disease-associated HPS according to cause of diseases. The serum concentration of sHLA-G in HPS patients and 25 healthy controls was measured by enzyme-linked immunosorbent assay (ELISA), the correlations between sHLA-G level and laboratory indicators were analyzed. The results showed that the level of serum sHLA-G in HPS patients was significantly higher than that in healthy controls (p = 0.003), but the difference was not statistically significant between HPS groups of different causes (p = 0.233). The positive correlation of sHLA-G level in HPS patients with platelet count was found, but there was no positive correlation of their sHLA-G levels with WBC, Hb, Plt, ALT, AST, LDH, Alb, TBil, DBil, IBil, Cr, BUN, TG, fibrinogen and ferritin levels detected on same day. It is concluded that the the increase of serum sHLA-G levels in HPS patients may be caused by different factors such as infection, tumor, T cell activation and over-stimulation of several cytokines. sHLA-G can inhibit NK cell activity, resulting in formation of abnormal immune storm, and may be play a role in the pathogenesis of HPS.

Expression of serum sHLA-G in patients with hemophagocytic syndrome and its clinical significance / 中国实验血液学杂志

In order to investigate the expression of serum sHLA-G in hemophagocytic syndrome (HPS) patients and to evaluate its clinical significance, the clinical data of HPS patients in Capital Medical University Beijing Friendship Hospital during the period from September 2008 to July 2010 were collected. They were divided into infection-associated HPS, tumor-associated HPS and rheumatological disease-associated HPS according to cause of diseases. The serum concentration of sHLA-G in HPS patients and 25 healthy controls was measured by enzyme-linked immunosorbent assay (ELISA), the correlations between sHLA-G level and laboratory indicators were analyzed. The results showed that the level of serum sHLA-G in HPS patients was significantly higher than that in healthy controls (p = 0.003), but the difference was not statistically significant between HPS groups of different causes (p = 0.233). The positive correlation of sHLA-G level in HPS patients with platelet count was found, but there was no positive correlation of their sHLA-G levels with WBC, Hb, Plt, ALT, AST, LDH, Alb, TBil, DBil, IBil, Cr, BUN, TG, fibrinogen and ferritin levels detected on same day. It is concluded that the the increase of serum sHLA-G levels in HPS patients may be caused by different factors such as infection, tumor, T cell activation and over-stimulation of several cytokines. sHLA-G can inhibit NK cell activity, resulting in formation of abnormal immune storm, and may be play a role in the pathogenesis of HPS.

Serum levels of tumor necrosis factor α and interferon γ in patients with hemophagocytic syndrome and its clinical significance / 中国实验血液学杂志

In order to explore the serum levels and clinical significance of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in patients with hemophagocytic syndrome (HPS). The clinical data of HPS patients in Capital Medical University Beijing Friendship Hospital from October 2008 to October 2010 were collected. The serum concentration of TNF-α and IFN-γ in HPS patients and 20 healthy controls was measured with enzyme-linked immunosorbent assay (ELISA). The correlations between the levels of TNF-α and primary disease were analyzed, the levels of hemoglobin, ferritin, triglyceride, NK cell activity and sCD25 were detected on the same day, the correlations between the concentrations of TNF-α and IFN-γ and these laboratory indicators were analyzed. The results indicated that the serum levels of TNF-α and IFN-γ in 30 cases of HPS was higher than that in control group (p < 0.05, p < 0.01); the difference of TNF-α concentration was statistically significant in rheumatism-related and tumor-related HPS groups(p = 0.04), the level of TNF-α in HPS patients showed negative correlation with hemoglobin. It is concluded that the high levels of TNF-α and IFN-γ in HPS patients may play certain roles in the pathogenesis and progress of HPS. These data indicated that the high level of TNF-α may be the main factor for anemia in patients with HPS.

Influence of Human Cytomegalovirus Infection during First Trimester on Neurobehavior of Mice / 实用儿科临床杂志

Objective To explore the neurobehavioral change of mice from dams with human cytomegalovirus(HCMV) infection during first trimester. Methods Eight-week-old fertilized female Kunming mice were randomly divided into infected group and control group.On the 4th gestation day mice in infected group were injected intraperitoneally with 0.5 mL HCMV (1?10-6 50 percent of tissue cultured infective dose),and those in control group were injected intraperitoneally with 0.5 mL supernatant of cultured human fibroblast.Caesarean birth operation was performed on 3 randomly chosen fertilized mice before delivery. Fetuses were observed and their brain tissue were collected and analyzed under light and electron microscope separately.PCR test was used to determine HCMV pp65 antigen of offspring′s sera.Neurobeha-vioral test such as Morris Water Maze and Lashley Ⅲ Water Maze were performed on offspring mice of 6-7 weeks old.Results Compared with control group,the pathological changes such as degeneration,necrosis,and nucleus disappearance of nerve cells and giant cells were found in offspring′s brain of mice in infected group under light microscope. Under electron microscope,swelling of nerve cells and spherical virus particle in the cytoplasm were found in the brain of mice in infected group. HCMV pp65 antigen was detected in 7 offspring mouse′s se-rum in infected group.Offspring′s swimming time and speed were(30.21?12.74) s and(19.10?1.90) cm/s in infected group,while those in control group were (11.87?3.62) s and (23.21?1.02) cm/s by Morris Water Maze test,there were significantly differences between 2 groups (Pa

Significance of Detection of Levels of Anti-Endomysial Antibody Immunoglobulin A,Immunoglobulin G in Diagnosis of Celiac Disease / 实用儿科临床杂志

Objective To investigate whether iceberg phenomenon of celiac disease(gluten-sensitive enterpathy,GSE) exists among the people of China,and study on the levels of anti endomysial antibody(AEA)IgA and IgG,which provide the foundation for studying functional genome of GSE.Methods One hundred and thirty-six cases liability crowd,which showed part symptoms of GSE,were selected as case group and 50 cases of normal were selected as control group.Enzyme-linked immunosorbent assay was used to detect the level of 2 groups and positive rate of AEA was compared between 2 groups.Results The levels of AEA IgA and IgG in case group(17.69?2.97,15.23?2.36)were significantly higher than those of control group(11.65?2.75,12.25?1.86),especially 2 strong positive cases were found in case group.Conclusion Iceberg phenomenon of celiac disease exists in the people of China,which means many celiac disease patients have not been diagnosed and it need us far more research.