Lugang Huang

Triage of pediatric injuries after the 2008 Wen-Chuan earthquake in China

PURPOSE The study aimed to review the effect of modifying triage strategies on the consultation and operation waiting times during the Wen-Chuan earthquake in China in 2008. METHOD The triage during the post-earthquake period was categorized into 3 phases. The consultation and operation waiting times were analyzed. RESULTS Of the 119 admitted children, there were 58 boys and 61 girls. Most of the victims were school-aged. In phase 1 (24 hours after the quake), the triage waiting time was 78 minutes. The waiting time for pediatric subspecialty consultation was 3.5 hours. There was an additional 7.5-hour delay before operation. In phase 2 (24-72 hours after the quake), senior pediatric surgeons carried out the triage and consultation. The consultation waiting time was reduced to 31 minutes. Four rotating teams operated 24 hours a day. The waiting time for operation was reduced to 4.5 hours. In phase 3 (4-19 days after the earthquake), gas gangrene screening was implemented. The triage waiting times for closed and open injuries were 47 and 64 minutes, respectively. Operation waiting times of 4.4 and 4.8 hours were recorded for closed and open injuries, respectively. Compared to that of phase 1, the waiting times for both consultation and operation of phases 2 and 3 were significantly shortened (P < .05). Most of the (89%) of the injuries were orthopedic traumas with lower limb fracture being the most common injury. Intraabdominal and thoracic injuries were relatively uncommon. CONCLUSIONS (1) Triage by pediatric surgeons in the reception area greatly reduced the delay of treatment and (2) the predominance of orthopedic injuries resulting from the earthquake indicates the focus of medical resource allocation in natural disasters of this type in the future.

Hyperleptinemia directly affects testicular maturation at different sexual stages in mice, and suppressor of cytokine signaling 3 is involved in this process

BackgroundLeptin plays an important role in reproductive function, and the mechanism of this phenomenon primarily focuses on the hypothalamic–pituitary–gonadal axis. However, until now, the direct effects of leptin on the testes during development from infancy to adulthood remained unclear. The aim of the present study was to explore the effects and molecular mechanisms that underlie leptin’s action in the testes during sexual maturation.MethodsWe used a monosodium glutamate (MSG)-treated mouse model to assess the effects of endogenous hyperleptinemia on the development of the testes from infancy to adulthood. Then, a variety of reproductive parameters were measured, including the concentration of testosterone, the weight and volume of the testicles, the diameter of the seminiferous tubules, and numbers of spermatogonia, spermatocytes, sperm, Leydig cells and offspring. In addition, we assessed the direct role of leptin and suppressor of cytokine signalling 3 (SOCS3)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3) on the testes in vitro.ResultsTestosterone secretion exhibited a diverse response: a low concentration of leptin induced testosterone secretion, and a high concentration inhibited testosterone secretion both in vivo and in vitro. A variety of reproductive parameters decreased in hyperleptinemic mice, including the weight and volume of the testicles, the diameter of the seminiferous tubules, and the numbers of spermatocytes, sperm, Leydig cells and offspring. The amount of spermatogonia was also elevated. The development of the testes was partially recovered after hyperleptinemia withdrawal. A high concentration of leptin induced SOCS3 expression and inhibited pSTAT3 expression in the testes.ConclusionsThe results indicated that MSG-induced hyperleptinemia directly affects testicular structure and function and that SOCS3/pSTAT3 played an important role in this process. These results also indicated the importance of monitoring and controlling leptin levels in obese male children. SOCS3 is a potential therapeutic target for leptin-induced dysgenesis.

Interleukin 23 regulates proliferation of lung cancer cells in a concentration-dependent way in association with the interleukin-23 receptor

A proinflammatory cytokine, interleukin 23 (IL-23), plays a role in tumor progression by inducing inflammation in the tumor microenvironment, although there is debate about its role in carcinogenesis. Direct effects of IL-23 on tumor cells have been reported rarely, and contradictory effects have been observed. Here, we studied such effects of IL-23 in lung cancer cells in vitro and in vivo and explored the underlying mechanism. We found IL-23 receptor expression in tissues from lung adenocarcinoma and small cell carcinoma but not in lung squamous cell carcinoma tissue. Interestingly, different concentrations of IL-23 had opposite effects in the same types of cells. We confirmed that the different effects could be explained by differences in binding to the IL-23 receptor (subunits IL-23r and IL-12Rβ1). Low concentrations of IL-23 promoted the proliferation of IL-23 receptor-positive A549 and SPCA-1 lung cancer cells by binding to IL-23r, whereas high concentrations of IL-23 inhibited proliferation of these cells by binding to both IL-23r and IL-12Rβ1. In contrast, IL-23 had no effect on IL-23 receptor-negative SK-MES-1 cells. IL-23 regulated the growth of human lung cancer cells through its effects on STAT3 expression and phosphorylation in a concentration-dependent way; the Ki-67 gene was involved in these processes. Our findings demonstrate for the first time that IL-23 affects the proliferation of IL-23 receptor-positive lung cancer cells and that this effect is dependent on the IL-23 concentration. This can explain at least part of the inconsistent reports on the role of IL-23 in the progression of carcinogenesis.

Zinc finger protein 637 protects cells against oxidative stress-induced premature senescence by mTERT-mediated telomerase activity and telomere maintenance.

Oxidative stress is believed to be an important inducer of cellular senescence and aging. Zinc finger protein 637 (Zfp637), which belongs to the Krüppel-like protein family, has been hypothesized to play a role in oxidative stress. Nevertheless, the precise function of Zfp637 has seldom been reported, and it remains unclear whether Zfp637 is involved in oxidative stress-induced premature senescence. In this study, we show that the endogenous expression levels of Zfp637 and mouse telomerase reverse transcriptase (mTERT) are downregulated during oxidative stress-induced premature senescence and in senescent tissues from naturally aged mice. The overexpression of Zfp637 markedly increases mTERT expression and telomerase activity, maintains telomere length, and inhibits both H2O2 and D-galactose-induced senescence accompanied by a reduction in the production of reactive oxygen species (ROS). In contrast, the knockdown of Zfp637 significantly aggravates cellular senescence by downregulating mTERT and telomerase activity, accelerating telomere shortening, and increasing ROS accumulation. In addition, the protective effect of Zfp637 against premature senescence is abrogated in the absence of mTERT. We further confirm that Zfp637 binds to and transactivates the mTERT promoter (−535/−502) specifically. As a result, the mTERT-mediated telomerase activity and telomere maintenance are responsible for the protective effect of Zfp637 against oxidative stress-induced senescence. We therefore propose that Zfp637 prevents oxidative stress-induced premature senescence in an mTERT-dependent manner, and these results provide a new foundation for the investigation of cellular senescence and aging.

IL-6 mediates differentiation disorder during spermatogenesis in obesity-associated inflammation by affecting the expression of Zfp637 through the SOCS3/STAT3 pathway.

Zfp637 is a recently identified zinc finger protein, and its functions remain largely unknown. Here, we innovatively demonstrate the effects of Zfp637 on the differentiation of mouse spermatogonia and on its downstream target gene SOX2 in vitro. Obesity has been recognized as a chronic inflammatory disease that leads to decreased sexual function and sexual development disorders. We observed higher levels of IL-6 in serum and testis homogenates from obese mice compared with control mice. We also demonstrated that high levels of IL-6 inhibited Zfp637 expression, and we elucidated the underlying mechanisms. SOCS3 overexpression and STAT3 phosphorylation inhibitor (AG490) were used to investigate the function of the SOCS3/STAT3 pathway during this process. Our results showed that exposure of mouse spermatogonial cells to high levels of IL-6 inhibited Zfp637 expression by increasing SOCS3 expression and inhibiting the phosphorylation of STAT3, further reducing cellular differentiation. Consistent with the in vitro results, we observed increasing expression levels of SOCS3 and SOX2, but a reduction of Zfp637 expression, in obese mouse testes. In conclusion, Zfp637 plays a crucial role in spermatogenesis by downregulating SOX2 expression, and IL-6 can decrease the expression of Zfp637 through the SOCS3/STAT3 signaling pathway.

ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription.

Reactive oxygen species (ROS)-driven oxidative stress has been recognized as a critical inducer of cancer cell death in response to therapeutic agents. Our previous studies have demonstrated that zinc finger protein (ZNF)32 is key to cell survival upon oxidant stimulation. However, the mechanisms by which ZNF32 mediates cell death remain unclear. Here, we show that at moderate levels of ROS, Sp1 directly binds to two GC boxes within the ZNF32 promoter to activate ZNF32 transcription. Alternatively, at cytotoxic ROS concentrations, ZNF32 expression is repressed due to decreased binding activity of Sp1. ZNF32 overexpression maintains mitochondrial membrane potential and enhances the antioxidant capacity of cells to detoxify ROS, and these effects promote cell survival upon pro-oxidant agent treatment. Alternatively, ZNF32-deficient cells are more sensitive and vulnerable to oxidative stress-induced cell injury. Mechanistically, we demonstrate that complement 1q-binding protein (C1QBP) is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway, thereby exerting the protective effects of ZNF32 on oxidative stress-induced apoptosis. Taken together, our findings indicate a novel mechanism by which the Sp1-ZNF32-C1QBP axis protects against oxidative stress and implicate a promising strategy that ZNF32 inhibition combined with pro-oxidant anticancer agents for hepatocellular carcinoma treatment.

A high-fat diet impairs reproduction by decreasing the IL1β level in mice treated at immature stage

Obesity causes low-grade inflammation that is involved in male infertility. Interleukin 1 beta (IL1β) plays an important role in this process. A high-fat diet (HFD) is the most common cause of obesity. However, the effect of a HFD on IL1β and its consequence in reproduction remain unclear. We established a HFD model in mice treated at immature stage (mice-TIS) and mice treated at mature stage (mice-TMS). Surprisingly, we found that a HFD decreased IL1β levels and was accompanied by an increase in testosterone in mice-TIS, while the reverse results were observed in mice-TMS. In addition, a HFD caused a reduction in testis macrophages and in the expression of inflammasome-related genes and proteins in mice-TIS. Furthermore, we found that IL1β inhibited testosterone secretion through down-regulating the gene expression of P450SCC and P450c17. However, the influence on mice-TIS that were induced by a HFD was recovered by stopping the HFD. In this study, we are the first to report that a HFD impairs the reproductive system by decreasing IL1β and enhancing testosterone levels in mice-TIS, which are different from the effects in mice-TMS. This provides new ideas for the treatment of obesity-induced infertility.

Establishment of a monoclonal antibody against a peptide of the novel zinc finger protein ZNF32 proved to be specific and sensitive for immunological measurements

Summary Background ZNF32 has been predicted to be a zinc finger protein and is involved in cell differentiation and tumor development, but its precise function is unknown. Specific monoclonal antibodies (mAbs) have been widely used in research and clinical diagnosis and treatments. Therefore, we established an anti-ZNF32 mAb to characterize this protein’s function. Material/Methods Peptide49–63, a specific small peptide of ZNF32, was chosen and the synthetic keyhole limpet hemocyanin (KLH)-peptide49–63 was used as an antigen to immunize mice. A mAb against peptide49–63 was generated by hybridoma technology, and hybridoma cells were screened by limiting dilution. The isoform of mAb-pZNF32-8D9 was identified by double agar diffusion. The sensitivity and specificity of the mAb and expressed levels of ZNF32 in various cells and tissues were identified by enzyme-linked immunosorbent assay (ELISA), immunocytochemistry, immunohistochemistry, and Western blotting. Results A stable anti-pZNF32-8D9 hybridoma secreting the anti-peptide49–63 mAb was established and the clone positive to the peptide49–63 in supernatant was 92% in ELISA. The mAb-pZNF32-8D9 is an immunoglobulin-1 that can be used for detecting the ZNF32 protein by immunocytochemistry, immunohistochemistry, and Western blotting and is highly sensitive and specific. We also found ZNF32 expressed at high levels in Jurkat and pulmonary squamous carcinoma cells, but it was not expressed in squamous epidermis cells. Conclusions mAb-pZNF32-8D9 can be used for the identification and expression of ZNF32. It might also provide a new tool for diagnostics or therapy for ZNF32-related diseases.

DDX17 nucleocytoplasmic shuttling promotes acquired gefitinib resistance in non-small cell lung cancer cells via activation of β-catenin

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations, almost all these patients will eventually develop acquired resistance to EGFR-TKI. However, the molecular mechanisms responsible for gefitinib resistance remain still not fully understood. Here, we report that elevated DDX17 levels are observed in gefitinib-resistant NSCLC cells than gefitinib-sensitive cells. Upregulation of DDX17 enhances the gefitinib resistance, whereas DDX17-silenced cells partially restore gefitinib sensitivity. Mechanistically, we demonstrate that DDX17 disassociates the E-cadherin/β-catenin complex, resulting in β-catenin nuclear translocation and subsequently augmenting the transcription of β-catenin target genes. Moreover, we identify two nuclear localization signal (NLS) and four nuclear export signal (NES) sequences mediated DDX17 nucleocytoplasmic shuttling via an exportin/importin-dependent pathways. Interruption of dynamic nucleocytoplasmic shuttling of DDX17 impairs DDX17-mediating the activation of β-catenin and acquired resistance in NSCLC cells. In conclusion, our findings reveal a novel and important mechanism by which DDX17 contributes to acquired gefitinib resistance through exportin/importin-dependent cytoplasmic shuttling and followed by activation of β-catenin, and DDX17 inhibition may be a promising strategy to overcome acquired resistance of gefitinib in NSCLC patients.

A New Modification of the Koyanagi Technique for the One-stage Repair of Severe Hypospadias

OBJECTIVE To describe a new modification of the Koyanagi technique for the one-stage repair of severe hypospadias and its short-term outcomes. PATIENTS AND METHODS Our modified Koyanagi technique was performed in 24 patients with severe hypospadias between February 2012 and January 2015. The age of the patients ranged from 1.9 to 11.9 years (mean = 3.5 years). The flap design was similar to the Koyanagi technique, but our modified technique highlighted the following points: after the chordee was completely corrected, the urethral plate was recreated using foreskin, and then a U-shaped incision was made on the original and recreated urethral plate (as in the Duplay technique); a pedicled flap of the tunica vaginalis or scrotal dartos was used for additional coverage of the neourethra. RESULTS The operation time lasted from 120 to 150 minutes (mean = 140 minutes). There were 5 patients (20.8%) who developed complications: 4 patients (16.7%) developed a fistula and 1 patient (4.2%) developed dehiscence of the urethra. There were no reported urethral strictures, meatal stenosis, or urethral diverticula. The complications in the 5 patients were successfully addressed with secondary repair, and all patients achieved satisfactory cosmetic and urethral functional results. CONCLUSION The modified Koyanagi technique simplified the operation and better preserved the blood supply to the flap. The additional coverage of the neourethra using a pedicled flap of the tunica vaginalis or scrotal dartos significantly decreased the rate of fistula formation. This technique is highly suitable for the one-stage repair of severe hypospadias with penoscrotal transposition.