Diagnostic value of the creatine kinase-MB/creatine kinase and neutrophil/lymphocyte ratios in acute myocardial infarction.

OBJECTIVE: To investigate the clinical significance of the creatine kinase (CK)-MB/total CK ratio, neutrophil/lymphocyte ratio (NLR) and red blood cell distribution width in acute myocardial infarction (AMI). METHODS: A retrospective analysis was conducted of 196 AMI cases from our hospital's cardiology department; healthy people were selected over the same period as the control. The two groups' test indexes were compared through multivariate logistic regression analysis to screen for AMI risk factors; the receiver operating characteristic (ROC) curve was used to evaluate their AMI predictive values. RESULTS: The serum CK, CK-MB, CK index, neutrophils and NLR values in the AMI group were significantly higher compared with those in the control group (p < 0.05); however, the levels of serum lymphocytes were significantly lower compared with those in the control group (p < 0.05). Multivariate logistic regression analysis showed that elevated CK-MB and NLR levels were risk factors for AMI (p < 0.05). The ROC curve showed that the area under the curve of the NLR and CK levels were 0.917 and 0.594, respectively. CONCLUSION: The CK index and NLR have a clinical predicting value for AMI and could be used as a clinical auxiliary diagnostic index for the assessment of patients with AMI.

Hepatocellular carcinoma cells downregulate NADH:Ubiquinone Oxidoreductase Subunit B3 to maintain reactive oxygen species homeostasis.

BACKGROUND: HCC is a leading cause of cancer-related death. The role of reactive oxygen species (ROS) in HCC remains elusive. Since a primary ROS source is the mitochondrial electron transport chain complex Ι and the NADH:ubiquinone Oxidoreductase Subunit B3 (NDUFB3), a complex I subunit, is critical for complex I assembly and regulates the associated ROS production, we hypothesize that some HCCs progress by hijacking NDUFB3 to maintain ROS homeostasis. METHODS: NDUFB3 in human HCC lines was either knocked down or overexpressed. The cells were then analyzed in vitro for proliferation, migration, invasiveness, colony formation, complex I activity, ROS production, oxygen consumption, apoptosis, and cell cycle. In addition, the in vivo growth of the cells was evaluated in nude mice. Moreover, the role of ROS in the NDUFB3-mediated changes in the HCC lines was determined using cellular and mitochondrion-targeted ROS scavengers. RESULTS: HCC tissues showed reduced NDUFB3 protein expression compared to adjacent healthy tissues. In addition, NDUFB3 knockdown promoted, while its overexpression suppressed, HCC cells' growth, migration, and invasiveness. Moreover, NDUFB3 knockdown significantly decreased, whereas its overexpression increased complex I activity. Further studies revealed that NDUFB3 overexpression elevated mitochondrial ROS production, causing cell apoptosis, as manifested by the enhanced expressions of proapoptotic molecules and the suppressed expression of the antiapoptotic molecule B cell lymphoma 2. Finally, our data demonstrated that the apoptosis was due to the activation of the c-Jun N-terminal kinase (JNK) signaling pathway and cell cycle arrest at G0/G1 phase. CONCLUSIONS: Because ROS plays essential roles in many biological processes, such as aging and cancers, our findings suggest that NDFUB3 can be targeted for treating HCC and other human diseases.

SMYD2 Imparts Gemcitabine Resistance to Pancreatic Adenocarcinoma Cells by Upregulating EVI2A.

Although gemcitabine (GEM) is the first­line drug for advanced pancreatic adenocarcinoma (PAAD), the development of GEM resistance severely limits the effectiveness of this chemotherapy. This study investigated the mechanisms of ecotropic viral integration site 2 A (EVI2A) for resistance to GEM and immune evasion in PAAD. GEM resistance-related biomarkers were predicted using GEO datasets, and GEM-resistant PAAD cells were generated. EVI2A was found expressed highly in GEM-resistant PAAD cells. Gain-of-function analyses revealed that EVI2A encouraged the proliferation and motility of GEM-resistant cells and prevented apoptosis. In addition, EVI2A reduced T cell effector activation. SMYD2 was overexpressed in GEM-resistant cells, and SMYD2 enhanced H3K36me2 modification of EVI2A, thereby promoting EVI2A expression. SMYD2 reduced the sensitivity of GEM-resistant cells, which was reversed by EVI2A knockdown. SMYD2 increased the amount of M2 macrophages (co-cultured with PAAD cells) and decreased T cell effector activation (co-cultured with macrophage supernatant), and the number of M2 macrophages was decreased and T cell effectors were activated following EVI2A knockdown. Our findings indicate that EVI2A, manipulated by the SMYD2-H3K36me2 epigenetic axis, promoted GEM resistance and M2 macrophage-mediated immune evasion in PAAD. Therefore, EVI2A might represent a therapeutic target for overcoming GEM resistance and immunosuppressive environment in PAAD.

[Screening and obataining of aptamers for the blood group antigen-binding adhesin (BabA) to block Helicobacter pylori (H.pylori) colonization in the stomach of mice].

Objective To explore the aptamer specific binding blood group antigen-binding adhesin (BabA) of Helicobacter pylori (H.pylori) for blocking of H.pylori adhering host cell. Methods H.pylori strain was cultured and its genome was extracted as templates to amplify the BabA gene by PCR with designed primers. The BabA gene obtained was cloned and constructed into prokaryotic expression plasmid, which was induced by isopropyl beta-D-galactoside (IPTG) and purified as target. The single stranded DNA (ssDNA) aptamers that specifically bind to BabA were screened by SELEX. Enzyme-linked oligonucleotide assay (ELONA) was used to detect and evaluate the characteristics of candidate aptamers. The blocking effect of ssDNA aptamers on H.pylori adhesion was subsequently verified by flow cytometry and colony counting at the cell level in vitro and in mouse model of infection, respectively. Meanwhile, the levels of cytokines, interleukin 6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), IL-10 and IL-4 in the homogenate of mouse gastric mucosa cells were detected by ELISA. Results The genome of H.pylori ATCC 43504 strains was extracted and the recombinant plasmid pET32a-BabA was constructed. After induction and purification, the relative molecular mass (Mr) of the recombinant BabA protein was about 39 000. The amino acid sequence of recombinent protein was consistent with BabA protein by peptide mass fingerprint (PMF). Five candidate aptamers were selected to bind to the above recombinent BabA protein by SELEX. The aptamers A10, A30 and A42 identified the same site, while A3, A16 and the above three aptamers identified different sites respectively. The aptamer significantly blocked the adhesion of H.pylori in vitro. Animal model experiments showed that the aptamers can block the colonization of H.pylori in gastric mucosa by intragastric injection and reduce the inflammatory response. The levels of IL-4, IL-6, IL-8 and TNF-α in gastric mucosal homogenates in the model group with aptamer treatment were lower than that of model group without treatment. Conclusion Aptamers can reduce the colonization of H.pylori in gastric mucosa via binding BabA to block the adhesion between H.pylori and gastric mucosal epithelial cells.

Targeting histone deacetylases for cancer therapy: Trends and challenges.

Dysregulation of histone deacetylases (HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors (HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.

[Helicobacter pylori promotes gastric cancer metastasis via up-regulating the expression of Bmi-1].

Objective To clarify whether Helicobacter pylori (H. pylori) can promote metastasis of gastric cancer cells via the high-expression of induced B cell specific Moloney murine leukemia virus integration site 1 (Bmi-1). Methods The gastric cancer tissue specimens from 82 patients were collected for this study. The protein and gene expression level of Bmi-1 in gastric adenocarcinoma tissue were detected by immunohistochemistry and real time quantitative PCR, respectively. And meanwhile the correlation between Bmi-1 levels and pathological features, and prognosis of gastric cancer were analyzed retrospectively. Then, the GES-1 cells were transfected with pLPCX-Bmi-1 plasmid and infected with H. pylori respectively. After the Bmi-1 overexpression in GES-1 cells, the invasion ability of the GES-1 cells was detected by Transwell assay, and the cell cycle and apoptosis were detected by flow cytometry. Results The mRNA and protein of Bmi-1 expression in gastric cancer tissues were higher than tumor-adjacent tissue, and the high expression of Bmi-1 was positively correlated with tumor invasion, TNM stage, tumor differentiation, lymph node metastasis and H. pylori infection. When expression of Bmi-1 was up-regulated as a result of H.pylori infection or pLPCX-Bmi-1 transfection, the GES-1 cells had higher invasiveness and lower apoptosis rate with the above treatment respectively. Conclusion H. pylori infection can inhibit the apoptosis of gastric cancer cells and promote their invasion via up-regulating expression of Bmi-1.

Sulfotransferase 1C2 promotes hepatocellular carcinoma progression by enhancing glycolysis and fatty acid metabolism.

BACKGROUND: Hepatocellular carcinoma (HCC) is aggressive liver cancer. Despite advanced imaging and other diagnostic measures, HCC in a significant portion of patients had reached the advanced stage at the first diagnosis. Unfortunately, there is no cure for advanced HCC. As a result, HCC is still a leading cause of cancer death, and there is a pressing need for new diagnostic markers and therapeutic targets. METHODS: We investigated sulfotransferase 1C2 (SUTL1C2), which we recently showed was overexpressed in human HCC cancerous tissues. Specifically, we analyzed the effects of SULT1C2 knockdown on the growth, survival, migration, and invasiveness of two HCC cell lines, i.e., HepG2 and Huh7 cells. We also studied the transcriptomes and metabolomes in the two HCC cell lines before and after SULT1C2 knockdown. Based on the transcriptome and metabolome data, we further investigated the SULT1C2 knockdown-mediated shared changes, i.e., glycolysis and fatty acid metabolism, in the two HCC cell lines. Finally, we performed rescue experiments to determine whether the inhibitory effects of SULT1C2 knockdown could be rescued via overexpression. RESULTS: We showed that SULT1C2 overexpression promoted the growth, survival, migration, and invasiveness of HCC cells. In addition, SULT1C2 knockdown resulted in a wide range of gene expression and metabolome changes in HCC cells. Moreover, analysis of shared alterations showed that SULT1C2 knockdown significantly suppressed glycolysis and fatty acid metabolism, which could be rescued via SULT1C2 overexpression. CONCLUSIONS: Our data suggest that SULT1C2 is a potential diagnostic marker and therapeutic target for human HCC.

Smoking Bans and Circulatory System Disease Mortality Reduction in Macao (China): Using GRA Models.

This study evaluates the association between smoking rates and mortality from circulatory system diseases (CSD) after implementing a series of smoking bans in Macao (China). (1) Background: Macao phased in strict total smoking bans since 2012. During the past decade, smoking rates among Macao women have dropped by half. CSD mortalities in Macao also show a declining trend. (2) Method: Grey relational analysis (GRA) models were adopted to rank the importance of some key factors, such as income per capita, physician density, and smoking rates. Additionally, regressions were performed with the bootstrapping method. (3) Results: Overall, smoking rate was ranked as the most important factor affecting CSD mortality among the Macao population. It consistently remains the primary factor among Macao's female population. Each year, on average 5 CSD-caused deaths were avoided among every 100,000 women, equivalent to about 11.45% of the mean annual CSD mortality. (4) Conclusions: After the implementation of smoking bans in Macao, the decrease in smoking rate among women plays a primary role in the reduction in CSD mortality. To avoid excess CSD mortality due to smoking, Macao needs to continue to promote smoking cessation among the male population.

Case report of a pediatric Chinese cystic fibrosis patient with the c.1521_1523delCTT/c.3874-4522A>G genotype.

This report describes a case of an 11-year-old Chinese boy with cystic fibrosis (CF) bearing the c.1521_1523delCTT/c.3874-4522A>G genotype, an extremely rare CF genotype in the Chinese population. Notably, the deep intron mutation c.3874-4522A>G, which has mainly been reported in patients with phenotypically mild CF, is identified here for the first time in a Chinese patient with severe CF. In the case discussed here, the c.3874-4522A>G mutation was associated with severe pulmonary disease with early symptoms onset, progressive bronchiectasis, recurrent airway infection with both Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus, rapid decline of lung function and poor weight gain. Despite intensive hospital-based pulmonary care and optimized therapy, the child died of cardiopulmonary failure 3 months after discharge.

Major ginsenosides from Panax ginseng promote aerobic cellular respiration and SIRT1-mediated mitochondrial biosynthesis in cardiomyocytes and neurons.

Background: Aerobic cellular respiration provides chemical energy, adenosine triphosphate (ATP), to maintain multiple cellular functions. Sirtuin 1 (SIRT1) can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) to promote mitochondrial biosynthesis. Targeting energy metabolism is a potential strategy for the prevention and treatment of various diseases, such as cardiac and neurological disorders. Ginsenosides, one of the major bioactive constituents of Panax ginseng, have been extensively used due to their diverse beneficial effects on healthy subjects and patients with different diseases. However, the underlying molecular mechanisms of total ginsenosides (GS) on energy metabolism remain unclear. Methods: In this study, oxygen consumption rate, ATP production, mitochondrial biosynthesis, glucose metabolism, and SIRT1-PGC-1α pathways in untreated and GS-treated different cells, fly, and mouse models were investigated. Results: GS pretreatment enhanced mitochondrial respiration capacity and ATP production in aerobic respiration-dominated cardiomyocytes and neurons, and promoted tricarboxylic acid metabolism in cardiomyocytes. Moreover, GS clearly enhanced NAD+-dependent SIRT1 activation to increase mitochondrial biosynthesis in cardiomyocytes and neurons, which was completely abrogated by nicotinamide. Importantly, ginsenoside monomers, such as Rg1, Re, Rf, Rb1, Rc, Rh1, Rb2, and Rb3, were found to activate SIRT1 and promote energy metabolism. Conclusion: This study may provide new insights into the extensive application of ginseng for cardiac and neurological protection in healthy subjects and patients.

Ginseng-derived nanoparticles inhibit lung cancer cell epithelial mesenchymal transition by repressing pentose phosphate pathway activity.

It is unclear whether ginseng-derived nanoparticles (GDNPs) can prevent tumor cell epithelial-mesenchymal transition (EMT). Here, we describe typical characteristics of GDNPs and possible underlying mechanisms for GDNP antitumor activities. First, GDNPs particle sizes and morphology were determined using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM), respectively, while cellular uptake of PKH67-labeled GDNPs was also assessed. Next, we evaluated GDNPs antitumor effects by determining whether GDNPs inhibited proliferation and migration of five tumor cell lines derived from different cell types. The results indicated that GDNPs most significantly inhibited proliferation and migration of lung cancer-derived tumor cells (A549, NCI-H1299). Moreover, GDNPs treatment also inhibited cell migration, invasion, clonal formation, and adhesion tube formation ability and reduced expression of EMT-related markers in A549 and NCI-H1299 cells in a dose-dependent manner. Meanwhile, Kaplan-Meier analysis of microarray data revealed that high-level thymidine phosphorylase (TP) production, which is associated with poor lung cancer prognosis, was inhibited by GDNPs treatment, as reflected by decreased secretion of overexpressed TP and downregulation of TP mRNA-level expression. In addition, proteomic analysis results indicated that GDNPs affected pentose phosphate pathway (PPP) activity, with ELISA results confirming that GDNPs significantly reduced levels of PPP metabolic intermediates. Results of this study also demonstrated that GDNPs-induced downregulation of TP expression led to PPP pathway inhibition and repression of lung cancer cell metastasis, warranting further studies of nano-drugs as a new and promising class of anti-cancer drugs.

Long-term use of broad-spectrum antibiotics affects Ly6Chi monocyte recruitment and IL-17A and IL-22 production through the gut microbiota in tumor-bearing mice treated with chemotherapy.

The protective effects of antibiotics against infection in cancer patients treated with chemotherapy remains unclear and related studies have been performed in healthy or pathogen-infected animal models. Here, we aimed to study the effects of antibiotic use on intestinal infection in tumor-bearing mice treated with chemotherapy and to determine the underlying mechanisms. Subcutaneous CT26 tumor-bearing mice were assigned to four groups: the control (Ctrl) group without any treatment, the antibiotic (ATB) group treated with a mixture of ampicillin, streptomycin, and colistin, the 5-fluorouracil (FU) group treated with four cycles of intraperitoneal injections of FU, and the ATB + FU group treated with the combination of ATB and FU. Gut microbial composition was determined and mesenteric lymph nodes (mLNs) were isolated for bacterial culturing. Intestinal permeability and integrity were assessed and the expression of cytokines was analyzed by quantitative PCR, ELISA, or flow cytometry (FCM). Monocytes in the colonic lamina propria (LP) were measured by FCM. Compared with the Ctrl and FU groups, the numbers of positive bacterial culturing results for mLNs were higher, and gut bacterial compositions were altered in the ATB and ATB + FU groups, with significantly decreased alpha diversity in the ATB + FU group. Intestinal integrity regarding the expression of tight junction proteins and intestinal permeability were not impaired significantly after treatments, but the colons were shorter in the ATB + FU group. The expression levels of intestinal IL-17A and IL-22, as well as the percentages of IL-17A+ cells in the colonic LP of the ATB + FU group, were lower than those in the FU group. The percentages of Ly6Chi monocytes in the colonic LP were lower, but those in the spleen were higher in the ATB + FU group than in the FU group. The mRNA levels of colonic CCL8 were reduced in the ATB + FU group. Antibiotic use is associated with an increased incidence of intestinal infections in tumor-bearing mice treated with chemotherapy, which might in turn be associated with a dysregulated gut microbiota that inhibits colonic monocyte recruitment and IL-17A and IL-22 production.

The prevalence and influencing factors of the oropharyngeal carriage of Haemophilus influenzae in healthy children in a high-altitude area of China: A cross-sectional study.

Haemophilus influenzae is a common commensal organism of the human upper respiratory tract and an important cause of human disease. No data on H influenzae carriage rate has been carried out on the Qinghai-Tibet Plateau of China. This study aims to present the H influenzae carriage rate and influencing factors of H influenzae in healthy children <15 years of age in Qinghai Province, an area located on the Qinghai-Tibet Plateau in China. Oropharyngeal swabs for the detection of H influenzae DNA were collected between September and October 2019. Taqman real-time polymerase chain reaction was used to detect the nucleic acids from the oropharyngeal swabs. Self-designed questionnaires were used to investigate the related information among this group of children. A number of 284 children were enrolled in this study. The carriage rate of H influenzae was 44.7%. The carriage rate in cities was 47.5%, in rural areas was 21.9%, and in pastoral areas was 52.8%. The carriage rate was found to be higher among children of minority ethnic groups than those of Han ethnicity (55.6% vs 38.1%). H influenzae carriage rate was influenced by tobacco smoke exposure (adjusted odds ratio [aOR] = 2.31, 95% CI [confidence interval]: 1.14-4.70), having siblings <5 years of age (aOR = 2.36, 95% CI: 1.21-4.59), respiratory infections during the last 30 days (aOR = 2.37, 95% CI: 1.11-5.06), and parent/guardian education level (aOR = 0.08, 95% CI: 0.02-0.27). H influenzae was highly prevalent in healthy children in Qinghai Province, especially among children of minority ethnicities and those living in pastoral areas. Tobacco smoke exposure, having siblings <5 years of age, and respiratory infections during the last 30 days were risk factors for H influenzae carriage. Parents or guardians having education levels of college or higher was a protective factor for H influenzae carriage. It is of critical importance that the government take effective measures to reduce the carriage rate and the occurrence of H influenzae related diseases in susceptible populations.

Hemostatic Effect of 20(S)-Panaxadiol by Induced Platelet Aggregation Depending on Calcium Signaling Pathway.

Panax notoginseng (Burk.) F.H. Chen is the most traditional hemostatic herb in China. Our previous research found that 20(S)-protopanaxadiol showed the hemostatic effect. And 20(S)-panaxadiol (PD) has a similar structure to 20(S)-protopanaxadiol with a dammarane skeleton. So, this article mainly studies the hemostatic effect of PD. The mouse tail amputation and liver scratch models were used to detect the hemostatic effect of PD. Blood routine and plasma coagulation parameters were measured by using a blood analyzer. The platelet aggregometer analyzed the platelet aggregation rate and adenosine triphosphate (ATP) concentration. Moreover, the intracellular calcium concentration ([Ca2+] i ), P-selectin (CD62P), PAC-1 (GP IIb/IIIa receptor marker), and cyclic adenosine monophosphate (cAMP) of platelets were also detected. The results showed that PD obviously shortened the bleeding time of the model mouse, affected the RBC and PLT parameters of rats, reduced APTT and TT, elevated FIB concentration, and promoted human/rat-washed platelet aggregation in vitro. PD promoted the release of ATP and [Ca2+] i and slightly increased the expression of CD62P and PAC-1 of platelets without 1 mM Ca2+. After adding 1 mM Ca2+, PD obviously increased ATP releasing and CD62P and GP IIb/IIIa expression rate and decreased the cAMP level of platelets. These parameter changes of PD-caused platelet were inhibited by vorapaxar. Besides, PD increased the phosphorylation of phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase 3ß (PI3K/Akt/GSK3ß) of human platelets. PD is an important hemostatic ingredient in Panax notoginseng, which induced platelet aggregation by affecting the calcium signaling and activating the PI3K/Akt/GSK3ß signaling pathway.

Genetic spectrum of Chinese children with cystic fibrosis: comprehensive data analysis from the main referral centre in China.

BACKGROUND AND OBJECTIVES: Cystic fibrosis (CF) is a heterogeneous disease with a diverse genetic spectrum among populations. Few patients with CF of Chinese origin have been reported worldwide. The objective of this study is to characterise the genotypic features of CF in Chinese children. METHODS: We recruited and characterised the genetic manifestations of 103 Chinese children with CF in Beijing Children's Hospital from 2010 to 2022. Whole-exome sequencing were performed to define the genotypes. Meanwhile, other 99 genetically confirmed patients with Chinese origin described in 45 references were also summarised. RESULTS: 158 different variants including 23 novel observations were identified after sequencing. The majority of CFTR variants (82.3%) in Chinese have been observed only once or twice. 43.7% of the variants were only identified in patients of Chinese origin. The c.2909G>A(p.Gly970Asp), c.1766+5G>T and c.1657C>T(p.Arg553X) were the most frequent variants among Chinese patients, with allele frequency of 12.1%, 5.4% and 3.6%, respectively. The first two variants both showed significant Chinese ethnic tendency, while the latter one most likely came from Europeans for historical reasons. They also demonstrated significant differences in geographical distribution. c.1521_1523delCTT(p.F508del) was rarely observed in patients of pure Chinese origin, with an allele frequency of 1.8%. Two de novo variants (c.960dupA[p.Ser321IlefsX43] and c.2491-2A>G) and two deep-intronic variants (c.3718-2477C>T and c.3874-4522A>G) were identified, which were also quite rare among Chinese. CONCLUSIONS: The genetic spectrum of CF in Chinese is unique and quite different from that observed in Caucasians. The geographical distributions of the most frequent variants were reported for the first time.

Calcium released by osteoclastic resorption stimulates autocrine/paracrine activities in local osteogenic cells to promote coupled bone formation.

A major cause of osteoporosis is impaired coupled bone formation. Mechanistically, both osteoclast-derived and bone-derived growth factors have been previously implicated. Here, we hypothesize that the release of bone calcium during osteoclastic bone resorption is essential for coupled bone formation. Osteoclastic resorption increases interstitial fluid calcium locally from the normal 1.8 mM up to 5 mM. MC3T3-E1 osteoprogenitor cells, cultured in a 3.6 mM calcium medium, demonstrated that calcium signaling stimulated osteogenic cell proliferation, differentiation, and migration. Calcium channel knockdown studies implicated calcium channels, Cav1.2, store-operated calcium entry (SOCE), and calcium-sensing receptor (CaSR) in regulating bone cell anabolic activities. MC3T3-E1 cells cultured in a 3.6 mM calcium medium expressed increased gene expression of Wnt signaling and growth factors platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and bone morphogenic protein-2 (BMP 2). Our coupling model of bone formation, the receptor activator of nuclear factor-κΒ ligand (RANKL)-treated mouse calvaria, confirmed the role of calcium signaling in coupled bone formation by exhibiting increased gene expression for osterix and osteocalcin. Critically, dual immunocytochemistry showed that RANKL treatment increased osterix-positive cells and increased fluorescence intensity of Cav1.2 and CaSR protein expression per osterix-positive cell. The above data established that calcium released by osteoclasts contributed to the regulation of coupled bone formation. CRISPR/Cas-9 knockout of Cav1.2 in osteoprogenitor cells cultured in basal calcium medium caused a >80% decrease in the expression of downstream osteogenic genes, emphasizing the large magnitude of the effect of calcium signaling. Thus, calcium signaling is a major regulator of coupled bone formation.

BCAT1 knockdown-mediated suppression of melanoma cell proliferation and migration is associated with reduced oxidative phosphorylation.

Malignant melanoma has a high mutational rate. As a result, resistance to current therapies is common. Consequently, there is an unmet medical need to develop novel therapies. Recent data suggest that branched-chain amino acid transaminase 1 (BCAT1) is overexpressed in multiple cancers, and such overexpressed BCAT1 is necessary for individual cancer progression. Therefore, BCAT1 appears to be a good target in cancer treatment. Additionally, because its expression in healthy tissues is highly restricted in adults and is limited to the brain, ovary, and placenta, BCAT1 is especially an ideal target in cancer therapies. Currently, the function of BCAT1 in malignant melanoma has not been demonstrated. Therefore, we investigated the role of BCAT1 in the proliferation and migration of malignant melanomas using human samples and mouse malignant B16 melanoma cell line. Our data showed that BCAT1 was overexpressed in malignant melanoma tissues both in humans and mice. Besides, BCAT1 knockdown suppressed melanoma cell proliferation and migration, which was associated with reduced oxidative phosphorylation. Collectively, our data indicate that BCAT1 is a promising therapeutic target for the treatment of malignant melanomas.

Prognosis and treatment of 46 Chinese pediatric cystic fibrosis patients.

BACKGROUND: Since public awareness of cystic fibrosis (CF) has increased, more children have been diagnosed with CF in China. This study aimed to investigate medical and other challenges faced by pediatric CF patients in China. METHOD: Treatments and treatment outcomes were retrospectively analyzed for 46 pediatric CF patients diagnosed from August 2009 to June 2019. Pre- and post-treatment results were compared using independent samples t-test. RESULTS: Of 46 pediatric CF study patients, four died and five were lost to follow-up. Thirty-seven patients were monitored for 0.03 to 9.21 years; patients exhibited fewer attacks of respiratory tract infections after diagnosis (4.49 ± 2.13 episodes/year before diagnosis vs 1.97 ± 1.87 times/year after 1-year treatment, p < 0.05), significantly reduced sputum production and experienced 1.62 ± 1.71 exacerbations/year. Patient mean body mass index was 16.87 ± 3.53 and pancreatic malfunction persisted in 15 patients. For 17 children, no significant differences in lung function were found at follow-up as compared to lung function at diagnosis (FEV1: 82.45% ± 16.56% vs 75.26% ± 22.34%, FVC: 87.18% ± 13.64% vs 86.99% ± 19.95%, FEF75%: 46.51% ± 28.78% vs 36.63% ± 24.30%, P = 0.27, 0.97, 0.20, respectively). Pseudomonas aeruginosa (17/27) and bronchiectasis (22/22) were found during follow-up evaluation. Twenty-four patients (64.8%) maintained good adherence to therapies. Overall, azithromycin and tobramycin treatments were administered for 0.5-62 months and 0.5-48 months, respectively, and triggered no obvious adverse reactions. CONCLUSION: No obvious declines in clinical presentation or lung function were found in Chinese pediatric CF patients after receiving standard therapeutic and active treatments, although malnutrition and low compliance were persistent challenges.