[Impact of SARS-CoV-2 infection on graft composition and early transplant outcomes following allogeneic hematopoietic stem cell transplantation].

Objective: To assess the feasibility of using donors with novel coronavirus disease 2019 (COVID-19) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) when there are no other available donors and allo-HSCT cannot be delayed or discontinued. Methods: Seventy-one patients with malignant hematological diseases undergoing allo-HSCT between December 8, 2022, and January 10, 2023, were included. Of these, 16 received grafts from donors with mild COVID-19 (D-COVID(+) group) and 55 received grafts from donors without COVID-19 (D-COVID(-) group). The graft compositions were compared between the two groups. Engraftment, acute graft-versus-host disease (aGVHD), overall survival (OS), and relapse were also evaluated. Results: There were no serious side effects or adverse events in the D-COVID(+) group. The mononuclear cell dose and CD34(+) cell dose were comparable between the two groups, and no additional apheresis was required. There were no significant differences in the lymphocyte, monocyte, and T-cell subset doses between the two groups. The median natural killer cell dose in the D-COVID(+) group was significantly higher than that in the D-COVID(-) group (0.69×10(8)/kg vs. 0.53×10(8)/kg, P=0.031). The median follow-up time was 72 (33-104) days. All patients achieved primary engraftment. The 60-day platelet engraftment rates in the D-COVID(+) and D-COVID(-) groups were 100% and (96.4±0.2) %, respectively (P=0.568). There were no significant differences in neutrophil (P=0.309) and platelet (P=0.544) engraftment times. The cumulative incidence of grade 2-4 aGVHD was (37.5±1.6) % vs. (16.4±0.3) % (P=0.062), and of grade 3-4 aGVHD was 25.0% ±1.3% vs. 9.1% ±0.2% (P=0.095) in the D-COVID(+) and D-COVID(-) groups, respectively. The probabilities of 60-day OS were 100% and 98.1% ±1.8% (P=0.522) in the D-COVID(+) and D-COVID(-) groups, respectively. There was no relapse of primary disease during the study period. Conclusion: When allo-HSCT cannot be delayed or discontinued and no other donor is available, a donor with mild COVID-19 should be considered if tolerable. Larger sample sizes and longer follow-up periods are required to validate these results.

Prognostic impact of prognostic nutritional index in advanced (stage IIIB/IV) non-small cell lung cancer patients.

Prognostic nutritional index (PNI) is a parameter reflecting prognosis for various cancers, including resected lung cancer. However, there were few reports to study the relationship between the PNI and overall survival (OS) in patients with advanced (stage IIIB/IV) non-small lung cancer (NSCLC). In this study, we collected the clinical data of 315 patients with advanced (stage IIIB/IV) NSCLC who had received chemotherapy or epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) between January 2010 and June 2011. Survival curves were plotted using the Kaplan-Meier method. Multivariate analyses were used to evaluate prognostic significance of PNI in patients with advanced (stage IIIB/IV) NSCLC. In our analysis, we found that PNI (p=0.001) was significantly associated with OS in patients with advanced (stage IIIB/IV) NSCLC, so was smoking (p<0.001) and disease stage (p=0.005). We demonstrated that PNI could be utilized to predict survival outcomes in patients with advanced (stage IIIB/IV) NSCLC. Patients with a lower PNI may have worse prognosis.

Integrated network analysis to identify the key genes, transcription factors, and microRNAs involved in hepatocellular carcinoma.

HCC (hepatocellular carcinoma), which can be induced by cirrhosis and viral hepatitis infection, is the most frequent form of liver cancer. This study is performed to investigate the mechanisms of HCC. GSE57957 was obtained from Gene Expression Omnibus database, including 39 HCC samples and 39 adjacent non-tumorous samples. The DEGs (differentially expressed genes) were screened using the limma package in R, and then were conducted with enrichment analysis using "BioCloud" platform. Using STRING database, WebGestalt tool, as well as ITFP and TRANSFAC databases, PPI (protein-protein interaction) pairs, miRNA (microRNA)-target pairs, and TF (transcription factor)-target pairs separately were predicted. Followed by integrated network was constructed by Cytoscape software and module analysis was performed using the MCODE plugin of Cytoscape software. There were 518 DEGs identified from the HCC samples, among which 17 up-regulated genes (including MCM2, MCM6, and CDC20) and 5 down-regulated genes could also function as TFs. In the integrated network for the down-regulated genes, FOS and ESR1 had higher degrees, and both of them were targeted by miR-221 and miR-222. Additionally, MCM2 had interaction with MCM6 in the up-regulated module with the highest score. MCM2, MCM6, CDC20, FOS, ESR1, miR-221 and miR-222 might affect the pathogenesis of HCC.

Genetic study of early-onset Graves' disease in the Chinese Han population.

Graves' disease (GD) is a complex autoimmune disorder in which genetic and environmental factors are both involved in the pathogenesis. Early-onset patients have a shorter exposure time to environmental factors and are, therefore, good models to help understand the genetic architecture of GD. Based on previous studies of early-onset GD, 11 single nucleotide polymorphisms (SNPs) and their related SNPs (R2 > .6), SNPs located within a ±1-Mb region of the FOXP3 gene, and 20 validated GD-risk SNPs were selected and screened for genotyping in 3735 GD and 4893 control patients to investigate whether early-onset GD is a subtype of GD with distinct susceptibility genes. Ultimately, we did not confirm the reported genetic markers of early-onset GD in our Chinese Han population but found that a GD-risk SNP located in the human leukocyte antigen class I region-rs4947296-was more strongly correlated with early-onset GD than non-early-onset GD. In addition, heterogeneity analysis of GD patients suggests that it may be more reasonable to define early-onset GD as an onset age ≤20 years.

Egr-1 regulates irradiation-induced autophagy through Atg4B to promote radioresistance in hepatocellular carcinoma cells.

Although hepatocellular carcinoma (HCC) is usually response to radiation therapy, radioresistance is still the major obstacle that limits the efficacy of radiotherapy for HCC patients. Therefore, further investigation of underlying mechanisms in radioresistant HCC cells is warranted. In this study, we determined the effect of early growth response factor (Egr-1) on irradiation-induced autophagy and radioresistance in HCC cell lines SMMC-7721 and HepG2. We showed that autophagy-related gene 4B (Atg4B) is induced by Egr-1 upon ionizing radiation (IR) in HCC cells. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) revealed that Egr-1 binds to the Atg4B promoter to upregulate its expression in HCC cells. Suppression of Egr-1 function by dominant-negative Egr-1 dampens IR-induced autophagy, cell migration, and increases cell sensitivity to radiotherapy. Together, these results suggest that Egr-1 contributes to HCC radioresistance through directly upregulating target gene Atg4B, which may serve as a protective mechanism by preferential activation of the autophagy.

Value of microsurgical varicocelectomy for severe oligo-asthenospermia patients failed in fertilization assisted by in vitro fertilization.

OBJECTIVE: To investigate the clinical effect of microsurgical varicocelectomy on severe oligo-asthenospermia patients failing in fertilization assisted by intracytoplasmic sperm injection. PATIENTS AND METHODS: From January 2013 to August 2014, forty-nine patients with severe oligo-asthenospermia and serious varicoceles were treated by microsurgical varicocelectomy after failing in fertilization assisted by intracytoplasmic sperm injection (ICSI), eleven of whom had varicoceles on the left side and thirty-eight had bilateral varicoceles. Patients were followed up for the natural pregnancy condition, changes of routine semen parameters and reproductive hormone level and the embryonic development and outcome of next IVF-ET (ICSI) cycles within 6 months. RESULTS: After surgery, 61.2% (30/49) of spouses obtained clinical pregnancy. Among whom 22.4% (11/49) were naturally pregnant, 32.65% (16/49) were conceived after second IVF-ET assistance, and 6.1% (3/49) were conceived with the third or further assistance of ICSI-ET. The overall miscarriage rate was 16.7% (5/30). All of the patients had improvement in the sperm concentration and forward motility. The sperm concentration increased from (10.53 ± 8.76) × 106/ml to (20.23 ± 11.76) × 106/ml. The ratio of forward motile sperm was increased to (30.52 ± 18.78) % from (8.75.52 ± 6.36) % (p < 0.01). The serum total testosterone (T) improved from (2.19 ± 1.03) ng/ml to (4.05 ± 0.64) ng/ml (p < 0.05). Serum follicle-stimulating hormone (FSH) changed from (5.23 ± 1.26) mIU/ml to (3.76 ± 2.22) mIU/ml after the procedure. Luteinizing hormone (LH) changed from (4.38 ± 1.36) to (3.98 ± 1.38) mIU/ml. Estrogen (E2) changed from 40.28 ± 7.26 pg/ml to 35.24 ± 5.75 pg/ml. Prolactin (PRL) level elevated from (18.24 ± 4.28) to (17.16 ± 2.16) ng/ml (p > 0.05). The fertility rate of in vitro fertilization significantly improved to (83.36 ± 19.36) % from (72.36 ± 17.88) % (p < 0.05). The rate of 2PN ratio increased from (66.73 ± 17.93) % to (75.96 ± 20.39) %. The cleavage rate increased from (83.26 ± 32.33) % to (90.35 ± 23.66). The abnormal fertility rate were (5.36 ± 12.58) % and (7.26 ± 13.89) % before and after the procedure (p > 0.05), while the rate of high-quality embryos increased significantly from (34.36 ± 33.27) % to (55.67 ± 23.36) % (p < 0.05). The rate of transferable embryos remained without significant change (70.67 ± 30.6% before and 60.53 ± 30.27% after the procedure). The anabiosis rate of frozen embryo increased from (66.32 ± 30.69) % to (89.72 ± 29.69) %. The further blastocyst rate improved from (10.98 ± 9.7) % to (30.27 ± 15.33) % (p < 0.01). CONCLUSIONS: The microsurgical varicocelectomy effectively improved sperm parameters, the fertility rate of oocyte fertilized in vitro and the anabiosis rate and blastocyst rate of the frozen embryo for on patients with severe oligo-asthenospermic, and further increased the odds of natural pregnancy, the rate of high-quality embryos and the success rate of in vitro fertilization.

Association between the c.1564A>T genetic polymorphism of the MDR1 gene and hepatocellular carcinoma in Chinese population.

The objective of this study was to evaluate the influence of c.1564A>T genetic polymorphisms in the multidrug resistance 1 gene (MDR1) on hepatocellular carcinoma (HCC) susceptibility through association analysis. A total of 632 HCC patients and 645 cancer-free controls were enrolled in this study. The c.1564A>T genetic polymorphisms were genotyped by created restriction site-polymerase chain reaction (CRS-PCR) and confirmed using DNA sequencing methods. The potential associations of c.1564A>T genetic polymorphisms with the risk of HCC were analyzed by different genetic models. Statistically significantly increased risks of HCC were detected in the homozygote comparison (TT versus AA: OR = 1.70, 95%CI = 1.17-2.45, χ(2) = 7.99, P = 0.005), recessive model (TT versus AT/AA: OR = 1.64, 95%CI = 1.15-2.33, χ(2) = 7.66, P = 0.006), and allele contrast (T versus A: OR = 1.23, 95%CI = 1.04-1.45, χ(2) = 6.09, P = 0.014). Our data suggest that the genotypes/alleles from c.1564A>T genetic polymorphisms are statistically associated with HCC risk. The allele-T and genotype TT may contribute to susceptibility to HCC in the Chinese Han population.

Fibroblast growth factor receptor 4 Gly388Arg polymorphism associated with severity of gallstone disease in a Chinese population.

The etiology of gallstone disease is multifactorial; supersaturation of bile with cholesterol is a primary cause for gallstone formation. In previous studies, we found that fibroblast growth factor receptor 4 (FGFR4) plays an important role in maintaining bile acid homeostasis by regulating the expression of cholesterol 7α-hydroxylase (CYP7A1), a rate-limiting enzyme for bile acid biosynthesis. The Gly388Arg (G-388R) polymorphism of FGFR4 affects stabilization and activation of FGFR4. Consequently, we studied the FGFR4 gene as a candidate gene for genetic susceptibility to gallstone disease. We found that overexpression of FGFR4, especially the G-388R mutant of FGFR4, inhibits luciferase activity of CYP7A1 reporter in HepG2 cells, indicating that the G-388R mutant of FGFR4 may have greater inhibitory activity against bile acid biosynthesis. To investigate the association of FGFR4 polymorphism with gallstone disease, 117 patients with gallstone disease and 457 controls were genotyped for FGFR4 polymorphism G-388R by PCR-RFLP. Although the incidence of gallstone disease was not greater in patients with the FGFR4 RR genotype, the ratio of gallstone patients with acute cholecystitis in the FGFR4 RR genotype (42%) was significantly higher than that in other genotypes of FGFR4 (P = 0.019). In conclusion, the FGFR4 polymorphism is a genetic risk factor contributing to aggravation of gallstone disease.

Transgenic expression of the coxsackie/adenovirus receptor enables adenoviral-mediated gene delivery in naive T cells.

The inability to easily and efficiently introduce genes into primary T cells has hampered the investigation of the pathways controlling T cell fate. To enable adenoviral-mediated gene transfer into normal naive T cells, transgenic (Tg) mice expressing the coxsackie/adenovirus receptor (CAR) in their T cell compartment were constructed. Whereas naive T cells are resistant to adenoviral infection, Tg expression of CAR on T cells greatly facilitates adenoviral-mediated gene expression ex vivo, in vivo, and in differentiated T helper cells. Thus we have developed a technology for efficient gene delivery to naive T cells. By using adenoviral vectors encoding specific inhibitors, we show that G1 cyclin-dependent kinase, NF-kappaB, and caspase activities are required for the proliferation of primary T cells. In addition, by expressing Bcl-x(L) protein at a level that closely approximates mitogen-induced levels, we demonstrate that Bcl-x(L) expression is sufficient to account for mitogen-mediated survival of primary T cells. Thus, adenoviral-mediated gene delivery to CAR Tg T cells should be useful for the analysis of many genes controlling T cell fate.

Effect of acupuncture at Hsien-Ku (St-43) on the pulse spectrum and a discussion of the evidence for the frequency structure of Chinese medicine.

We investigated the pulse spectrum variation of the human radial artery when Hsien- Ku (St 43), an acupoint on the stomach meridian, was needled and compared the results with the acupuncture effects of two other acupoints, Tsu-San-Li (St-36) and Tai-Shih (K-3), reported previously. For Hsien-Ku, the harmonic proportions were redistributed: the second harmonic (C2) decreased, C3, C5, C6, C7, C8 and C9 increased, C3, C6 and C9 became the relative peaks to their neighboring harmonics and C2, C4 became the relative minimums. The phase angles of the 2nd harmonic (P2) and 5th harmonic (P5) decreased, propagating faster. These effects were similar to that of Tsu-San-Li which is also on the stomach meridian. A totally different pattern was found for Tai-Shih on the kidney meridian. These results strengthen the theory that a meridian can be classified according to its effects on the pulse spectrum, and that all the meridian related effects such as those caused by acupuncture or meridian specific herbs are frequency specific.

A role for E2F1 in the induction of ARF, p53, and apoptosis during thymic negative selection.

E2F transcriptional activity controls the expression of many of the genes required for G1 to S phase progression. E2F1, one member of the E2F family, plays an important role in the induction of apoptosis. We have examined the role of the E2F1 transcription factor in apoptosis during T-cell maturation in the thymus. We show that E2F1 is required for the apoptosis of autoimmune immature T cells during thymic negative selection in vivo. This T-cell receptor-mediated apoptosis coincides with the E2F1-dependent increase of p19-ARF mRNA and p53 protein levels. In contrast, E2F1 is not required for the induction of apoptosis by glucocorticoids or DNA damage. These results demonstrate a specific role for E2F1, which triggers a pathway leading to ARF and p53 induction, in a physiological apoptosis pathway that is uncoupled from a normal proliferative event.