Molecular characteristics, clinical significance, and cancer immune interactions of cuproptosis and ferroptosis-associated genes in colorectal cancer.

Objective: To systematically analyze the expression of cuproptosis and ferroptosis genes and their impact on the development, prognosis, tumor microenvironment (TME), and treatment response in colorectal cancer (CRC) patients. Methods: We systematically evaluated 33 cuproptosis and ferroptosis-related genes and comprehensively identified the correlations between cuproptosis and ferroptosis-related genes and transcriptional patterns, prognosis, and clinical features. Three distinct subgroups were identified in CRC using the TCGA database and the GEO database. We next assessed the relationship between the molecular features, prognostic significance, and clinical indicators of the prognostic genes in the cuproptosis and ferroptosis-related gene clusters. In addition, a PAC_score, which accurately predicted the prognosis of CRC patients and the efficacy of immunomodulatory mAbs, was obtained. Results: Patients in the low expression group (low expression of cuproptosis and ferroptosis-related genes) had a longer survival compared to the high expression group. We identified two distinct prognosis-associated molecular subtypes and observed an association between clinical information and prognosis. The enrichment analysis of differential genes associated with prognosis showed that the main enrichment was related to biological processes such as metastasis and metabolism. Next, the PCA_score for predicting overall survival (OS) was established and its reliable predictive value in CRC patients was confirmed. Furthermore, highly reliable nomogram was created to facilitate the clinical feasibility of the PCA_score. It was found that the immunomodulatory mAbs, PD-L1 and CTLA4 were highly expressed in the low PCA_score score group with statistically significance. Conclusion: Overall, the PCA scores of prognostic differential genes in the cuproptosis and ferroptosis-related gene clusters were strongly associated with clinical characteristics, prognosis, and immunotherapy in CRC patients. This data may promote further exploration of more effective immunotherapy strategies for CRC.

Hemolytic Disease of the Fetus and Newborn Caused by Anti-Group A IgG From a Group B Mother.

ABO incompatibility has emerged as the premier reason for hemolytic disease of the fetus and newborn (HDFN). It always occurs in the offspring of blood group O mother. We present a rare case that the fetus of group A got HDFN caused by the anti-group A immunoglobulin G from a group B mother. The direct Coombs test of the fetus blood was negative, but the indirect Coombs test on A1 standard blood cells was strong positive (4+). The acid release test of antibody on the membrane of red blood cells to A1 standard blood cells was also strong positive (4+). Bilirubin of the fetus reached the threshold of exchange transfusion, but she just received 4 days' phototherapy and 2.2 g albumin intravenous injection, with no packed blood cells transfusion, because her family refused, and came to a favorable outcome. This case reminds us not to ignore the possibility of HDFN in offspring of mothers with non-O blood group.

Microsatellite and Single Nucleotide Polymorphisms in the Insulin-Like Growth Factor 1 Promoter with Insulin Sensitivity and Insulin Secretion.

BACKGROUND To investigate associations of the CA microsatellite and rs35767, rs5742612, and rs2288377 polymorphisms and the single nucleotide polymorphism (SNP) haplotypes with and without the CA microsatellite in the IGF1 promoter with insulin sensitivity and secretion. MATERIAL AND METHODS The CA microsatellite and SNPs were genotyped in 389 type 2 diabetes mellitus (T2DM) patients. A 75 g oral glucose tolerance test (OGTT) was given to all the participants. Associations of the genotypes and haplotypes with insulin sensitivity, insulin secretion, glucose tolerance, and insulin-like growth factor 1 (IGF1) were analyzed by ANCOVA (general linear model) and multiple linear regression, after controlling for gender, age, and BMI. RESULTS The CA microsatellite, rs35767 polymorphisms, and SNP haplotypes with or without CA showed no significant association with metabolic parameters. The C allele of rs5742612 was found to be associated with decreased insulin sensitivity (HOMA-S index, ß=-0.131, P=0.008; fasting insulin level, ß=0.022, P=0.006) and increased insulin secretion (HOMA-B index, ß=0.099, P=0.008; insulin AUC, ß=0.112, P=0.012). The linear regression model also indicated that the A allele of rs2288377 was associated with decreased insulin sensitivity (HOMA-S index, ß=-0.159, P=0.001; fasting insulin, ß=0.143, P=0.001) and increased insulin secretion (HOMA-B index, ß=0.114, P=0.017; insulin AUC, ß=0.042, P=0.002). CONCLUSIONS The CA microsatellite and rs35767 have no genotype-related difference in insulin sensitivity or secretion. The rs5742612 and rs2288377 polymorphisms are significantly associated with insulin biology, with the TT genotype exhibiting higher insulin sensitivity and lower insulin secretion compared with carriers of the C allele and A allele, respectively, mostly attributed to the direct functional roles of the two loci.

Influence of type 2 diabetes mellitus on Khorana venous thromboembolism risk in colorectal cancer patients

Background: Many studies have documented the association between venous thromboembolism (VTE) and colorectal cancer (CRC). The Khorana model is a VTE risk assessment model for predicting cancer-associated thrombosis. Type 2 diabetes (T2DM) has also been reported to increase the risk of VTE. Purpose: The aim of this study was to investigate the influence of T2DM on Khorana VTE risk in CRC patients and to explore the relationship between Khorana VTE category and CRC clinicopathological factors. Methods: This analysis included 615 CRC patients (205 with T2DM). Fibrinogen and D-dimer levels were compared within each group. A comparison was made of the proportion of patients in different Khorana VTE risk categories in CRC patients with and without T2DM. The association between Khorana VTE risk category and clinicopathological factors among all the CRC patients was evaluated. Results: Fibrinogen levels of CRC patients with T2DM were significantly higher than those of non-diabetes patients (4.13 ± 1.06 vs 3.94 ± 0.98, p < 0.001). A higher proportion of CRC patients with T2DM were in the Khorana intermediate-to-high risk category (H = 4.749, p = 0.029). Female sex, diabetes, colon location (compared with rectum), larger tumor size, advanced pT stage and pN stage were correlated with the intermediate-to-high Khorana VTE risk category, with odd ratios (95% confidence intervals [CI]) of 1.537 (1.064-2.220), 1.499 (1.027-2.186), 2.313 (1.588-3.370), 2.284 (1.542-3.383), 4.429 (2.088-9.396) and 1.822 (1.230-2.698), respectively. Conclusion: T2DM increases Khorana VTE risk in CRC patients. Female sex, diabetes, colon location, large tumor size and poor stage are associated with the intermediate-to-high Khorana VTE risk category (AU)

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Influence of type 2 diabetes mellitus on Khorana venous thromboembolism risk in colorectal cancer patients.

BACKGROUND: Many studies have documented the association between venous thromboembolism (VTE) and colorectal cancer (CRC). The Khorana model is a VTE risk assessment model for predicting cancer-associated thrombosis. Type 2 diabetes (T2DM) has also been reported to increase the risk of VTE. PURPOSE: The aim of this study was to investigate the influence of T2DM on Khorana VTE risk in CRC patients and to explore the relationship between Khorana VTE category and CRC clinicopathological factors. METHODS: This analysis included 615 CRC patients (205 with T2DM). Fibrinogen and D-dimer levels were compared within each group. A comparison was made of the proportion of patients in different Khorana VTE risk categories in CRC patients with and without T2DM. The association between Khorana VTE risk category and clinicopathological factors among all the CRC patients was evaluated. RESULTS: Fibrinogen levels of CRC patients with T2DM were significantly higher than those of non-diabetes patients (4.13 ± 1.06 vs 3.94 ± 0.98, p < 0.001). A higher proportion of CRC patients with T2DM were in the Khorana intermediate-to-high risk category (H = 4.749, p = 0.029). Female sex, diabetes, colon location (compared with rectum), larger tumor size, advanced pT stage and pN stage were correlated with the intermediate-to-high Khorana VTE risk category, with odd ratios (95% confidence intervals [CI]) of 1.537 (1.064-2.220), 1.499 (1.027-2.186), 2.313 (1.588-3.370), 2.284 (1.542-3.383), 4.429 (2.088-9.396) and 1.822 (1.230-2.698), respectively. CONCLUSION: T2DM increases Khorana VTE risk in CRC patients. Female sex, diabetes, colon location, large tumor size and poor stage are associated with the intermediate-to-high Khorana VTE risk category.

[Reference values of semen parameters for normal fertile men in Shanghai].

OBJECTIVE: To analyze the distribution characteristics of the main semen parameters of healthy semen donors and normal fertile men in Shanghai, compare the semen quality between the two groups, and investigate the normal reference values of the semen parameters of the fertile population in Shanghai. METHODS: We obtained semen samples from 100 healthy donors and 41 fertile men, performed semen analyses according to the WHO (2010) guidelines, and determined the semen volume, sperm concentration, sperm progressive motility, total sperm count and total progressively motile sperm count. We analyzed the distribution of the semen parameters of the normal fertile men, and obtained the lower limits of their normal reference values. RESULTS: There were no statistically significant differences in the main semen parameters between the healthy donors and normal fertile men (P < 0.05). The lower reference limits for the semen parameters of normal fertile men in Shanghai (P < 0.05) were as follows: sperm concentration > or = 27.3 x 10(6)/ml, sperm progressive motility > or = 8.1%, semen volume > or = 0.82 ml, total sperm count > or = 44.73 x 10(6) per ejaculate, and total progressively motile sperm count > or = 24.68 x 10(6) per ejaculate. CONCLUSION: For the evaluation of male fecundity, total sperm count and total progressively motile sperm count may be two better predictors than others.

[Direct fumigation for freeze-thawing of human sperm: an experimental study].

OBJECTIVE: To study the effect of direct fumigation on the post-thaw recovery rate of cryopreserved spermatozoa, and to search for a best method for human sperm cryopreservation. METHODS: We collected semen samples from 100 donors conforming to the normal reference values in WHO Laboratory Manual for the Examination and Processing of Human Semen (5th Ed), divided them into two groups, and subjected them to cryopreservation by programmable freezing (Group A) and direct fumigation (Group B), respectively. We detected the progressive motility of pre-freezing and post-thaw sperm with a computer-assisted semen analyzer, and compared the effects of the two methods on the functional integrity of sperm membrane and the rate of abnormal sperm using the percentage of hypo-osmotic swelling sperm and modified Papanicolaou staining. RESULTS: Statistically significant differences were found in post-thaw sperm progressive motility between the Groups A and B ([34.0 +/- 18.4]% vs [43.0 +/- 19.5]%, P<0.05), both remarkably decreased as compared with pre-freezing ([57.0 +/- 16.7]%, P<0.05). Such differences were also found in the post-thaw recovery rate of progressively motile sperm between the two groups ([52.2 +/- 20.6]% vs [67.1 +/- 20.0]%, P<0.05). The post-thaw percentage of hypo-osmotic swelling sperm was obviously decreased in both Groups A and B ([67.1 +/- 11.1]% and [70.6 +/- 10.0]%) in comparison with pre-freezing ([84.5 +/- 7.5]%, P<0.05), with significant differences between A and B (P<0.05). However, the rate of sperm abnormality was evidently increased in Groups A and B ([85.0 +/- 8.7% and [85.7 +/- 9.1]%), significantly higher than pre-freezing ([77.8 +/- 9.6]%, P<0.05), but with no significant differences between A and B (P>0.05). CONCLUSION: Direct fumigation is superior to programmable freezing for its easier operation, wider application, and higher sperm recovery rate.

[Estrogens affect Sertoli cells and the blood-testis barrier in pubertal rats].

OBJECTIVE: To investigate the correlation of exogenous estrogens with the expression of FasL in Sertoli cells and the blood-testis barrier during the differentiation and maturation period of Sertoli cells, and to discuss the related factors that influence the blood-testis barrier of pubertal rats. METHODS: Super-physiological doses of exogenous estrogenic compounds (diethylstilbestrol and estradiol) were administered to pubertal Sprague-Dawley rats in vitro and in vivo, the FasL expression in the Sertoli cells of the rats detected by immunohistochemistry and Western blot, and the changes in the blood-testis barrier observed with the electron microscope. RESULTS: After the exposure to exogenous estrogens, the FasL expression was markedly up-regulated in the immature Sertoli cells (P < 0.05) as well as in the Sertoli cell membrane and the blood-testis barrier of the epithelium. The tracer lanthanum passed through the blood-testis barrier and reached the whole layer of the epithelium at 18 days. CONCLUSION: Super-physiological dose of exogenous estrogens can change the expression and distribution of FasL in immature Sertoli cells and affect the structure of the blood-testis barrier.

Expression of the retinoic acid-metabolizing enzymes RALDH2 and CYP26b1 during mouse postnatal testis development.

AIM: To study the expression pattern of the retinoic acid metabolizing enzymes RALDH2 and CYP26b1 during mouse postnatal testis development at both mRNA and protein levels. METHODS: Real-time polymerase chain reaction and Western blot analysis were performed to determine the relative quantity of RALDH2 and CYP26b1 at both mRNA and protein levels at postnatal day 1, 5, 10, 20, and in adult mice (70 days testes). Testicular localization of RALDH2 and CYP26b1 during mouse postnatal development was examined using immunohistochemistry assay. RESULTS: Aldh1a2 transcripts and its protein RALDH2 began to increase at postnatal day 10, and remained at a high level through postnatal day 20 to adulthood. Cyp26b1 transcripts and CYP26b1 protein did not change significantly during mouse postnatal testis development. RALDH2 was undetectable in the postnatal 1, 5 and 10 day testes using immunohistochemistry assay. At postnatal day 20 it was detected in pachytene spermatocytes. Robust expression of RALDH2 was restricted in round spermatids in the adult mouse testis. In the developing and adult testis, CYP26b1 protein was confined to the peritubular myoepithelial cells. CONCLUSION: Our results indicate that following birth, the level of retinoic acid in the seminiferous tubules might begin to increase at postnatal day 10, and maintain a high level through postnatal day 20 to adulthood.