Causal relationship between genetically predicted type 2 diabetes mellitus and male infertility.

Background: Diabetes mellitus (DM) stands as the most prevalent endocrine abnormality affecting the physiological systems and organs and impairing the male reproductive functions. Type 2 Diabetes Mellitus (T2DM), accounting for about 90-95% of DM, is closely associated with male infertility. However, the magnitude of the causal relationships between T2DM and male infertility remains unclear. The current investigation was to explore the causal relationship between T2DM and male infertility utilizing the Mendelian Randomization (MR) analysis. Methods: A two-sample MR (2SMR) analysis was conducted to investigate the causal relationship between T2DM and male infertility in the European population from the genome-wide association study (GWAS) summary data that was publicly accessible. GWAS for T2DM and male infertility were extracted from the IEU Open GWAS Project database, with the resulting data encompassing 680 cases and 72,799 controls as the outcome data. Five MR methods were employed for the 2SMR analyses, namely the MR-Egger, weighted median estimation (WME), weighted mode (WM), inverse-variance weighted (IVW), and simple mode. The primary analytical technique utilized in this study was the IVW method, and a multivariate MR analysis was executed to examine the potential mediating influences of T2DM on male infertility. Results: Following were the odds ratios (ORs) and associated 95% CIs derived from IVW (fixed effects), MR-Egger, WM, WME, and simple mode approaches: 0.824 (95% CI 0.703-0.966), 0.726 (95% CI 0.527-1.001), 0.827 (95% CI 0.596-1.150), 0.841 (95% CI 0.654-1.082), and 0.875 (95% CI 0.544-1.405), respectively. The outcomes of the heterogeneity tests were P=0.378 and P=0.384, respectively, implying no heterogeneity. Egger-intercept outcomes were P=0.374, highlighting the absence of pleiotropy. The stability of the results was affirmed through the leave-one-out analysis. Notably, all F-values surpassed 10, indicating the absence of weak bias attributed to instrument variables(IVs). Conclusions: This research furnishes evidence supporting a causal association between T2DM and male infertility. These insights offer a foundation for future investigations aiming to establish the association between genetically predicted T2DM and male infertility. These outcomes suggest the significance of active monitoring and proactive measures for preventing infertility in male individuals with T2DM. Furthermore, careful consideration is required for individuals of reproductive age to prevent and treat T2DM.

LncRNA LBX2-AS1 inhibits acute myeloid leukemia progression through miR-455-5p/MYLIP axis.

Acute myeloid leukemia (AML) is a common blood cancer primarily affecting the bone marrow and blood cells, which is prevalent among adults. Long non-coding RNAs (lncRNAs) have been shown to play a crucial role in the development and progression of AML. LBX2-AS1 is a recently discovered lncRNA that has been linked to the pathogenesis and progression of several types of cancer. This study aimed to investigate the role and possible mechanisms of LBX2-AS1 in AML. Expression levels of LBX2-AS1, miR-455-5p, and their target genes were detected in AML samples and cells by RT-qPCR. Cell proliferation and apoptosis were determined by Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays, and flow cytometry, respectively. LBX2-AS1 was downregulated in AML specimens and cells, and overexpression of LBX2-AS1 significantly inhibited cell proliferation and enhanced apoptosis in vitro. We also determined the effects of LBX2-AS1 overexpression in an AML mouse model by in vivo bioluminescence imaging. Mechanistically, LBX2-AS1 acts as a competitive endogenous RNA, which promotes myosin regulatory light chain interacting protein (MYLIP) expression by sponging miR-455-5p. Knockdown of MYLIP or upregulation of miR-455-5p antagonized the effect of LBX2-AS1 overexpression on the progression of AML. LBX2-AS1 may thus be a valuable therapeutic target for AML.

Gilteritinib-based combination therapy in adult relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Gilteritinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib-based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3-mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3-mutated AML, and it may be considered an effective therapy bridge to transplantation.

[Correlation between Serum Interleukin-33, ß2-Microglobulin Levels and DS Stage in Patients with Multiple Myeloma].

OBJECTIVE: To investigate the correlation between serum interleukin-33 (IL-33), ß2microglobulin (ß2-MG) levels and Durie-Salmon (DS) stage in patients with multiple myeloma (MM). METHODS: 100 MM patients admitted to the First Affiliated Hospital of Fujian Medical University from March 2019 to January 2021 were selected and divided into stage I, stage II and stage III groups according to the DS staging system. A baseline data questionnaire of patients was designed, then the relevant baseline data and laboratory test results of patients were recorded. The levels of serum IL-33 and ß2-MG of all patients were detected, and the correlation between serum IL-33, ß2-MG levels and DS stage of MM patients was analyzed. RESULTS: Among the 100 patients with MM, there were 32 cases in stage I, 39 cases in stage II and 29 cases in stage III. The levels of serum CRP and ß2-MG of patients in stage III were significantly higher than those of patients in stage I and II, and the levels of serum CRP and ß2-MG of patients in stage II were significantly higher than those of patients in stage I, the differences were statistically significant (P <0.05). The level of serum IL-33 of patients in stage III was significantly lower than that of patients in stage I and II, and the level of serum IL-33 of patients in stage II was significantly lower than that of patients in stage I, the differences were statistically significant (P <0.05). There was no statistical significant difference in other data between groups (P >0.05). Kendall's tau-b correlation analysis showed that the levels of serum CRP and ß2-MG were positively correlated with DS stage in MM patients (r =0.534, 0.776), the level of serum IL-33 was negatively correlated with DS stage in MM patients (r =-0.759). Ordered logistic regression analysis and forest plot showed that the low level of serum IL-33 and the high level of ß2-MG were the influencing factors of high DS stage in MM patients (P <0.05 ). CONCLUSION: DS stage of MM patients is closely related to the levels of serum IL-33 and ß2-MG, that is, the lower the serum IL-33 level and the higher the ß2-MG level, and the higher the DS stage of MM patients.

Associations of long-term cadmium exposure with peripheral white blood cell subtype counts and indices in residents of cadmium-polluted areas.

BACKGROUND: Experimental evidence suggests that exposure to cadmium (Cd) could affect immune cells in vivo and in vitro. However, the associations of long-term Cd exposure with white blood cell (WBC) subtype counts and hemogram-derived indices have been rarely investigated. Therefore, we evaluated these relationships in residents of cadmium-polluted areas. METHODS: This cross-sectional study included 431 participants aged 45-75 years without occupational exposure histories from Cd-contaminated areas of southern China. We detected WBC, neutrophil, lymphocyte, and monocyte counts using routine blood tests and calculated neutrophil-lymphocyte ratio (NLR), systemic inflammation response index (SIRI), and lymphocyte-monocyte ratio (LMR). Urinary Cd (U-Cd) was measured with inductively coupled plasma mass spectrometry and adjusted for creatinine. To evaluate the associations of U-Cd with peripheral WBC subtype counts and indices, we performed multivariate linear regression, logistic regression and subgroup analyses using U-Cd categorized into quartiles. RESULTS: In models adjusted for all potential confounders, U-Cd was negatively associated with WBC, neutrophil, and monocyte counts in Q2, compared with Q1 of U-Cd (p < 0.05). A similar relationship was observed between U-Cd and NLR and SIRI, whereas the corresponding association for LMR was positive (p < 0.05). In subgroup analyses, U-Cd was negatively associated with neutrophil count, except for never smokers, after full adjustment. CONCLUSIONS: U-Cd was negatively associated with WBC count, neutrophil count, monocyte count, NLR, and SIRI, and positively associated with LMR. Therefore, neutrophil count could be a potential indicator of long-term Cd exposure-associated immunosuppressive effect.

Leukemia cutis with IDH1, DNMT3A and NRAS mutations conferring resistance to venetoclax plus 5-azacytidine in refractory AML.

Recently, novel drugs like venetoclax plus 5-azacytidine (VA) were reported to have promising efficacy in refractory acute myeloid leukemia (AML). However, there are still some cases presented with novel drugs resistance, and its genetics composition and clinical phenotype are urging to study. We described a 58-year-old patient who was resistant to intensive chemotherapy. This refractory AML was presented with the persistence of RUNX1, IDH1 and DNMT3A mutations. RUNX1 mutations disappeared and leukemia cutis ensued after multiple chemotherapies. Leukemia cutis exhibited NRAS mutations in addition to IDH1 and DNMT3A mutations. With the VA salvage treatment, platelets were recovered to the normal level and blasts in bone marrow and peripheral blood were moderately controlled. However, leukemia cutis did not resolve. Unexpectedly, BM blasts obtained the new NRAS mutations after VA treatment, and consequently experienced leukostasis with two distinct leukemia clones. After survival of 230 days, this patient died because of spontaneous cerebral hemorrhage. This case highlights presentation of leukemia cutis with simultaneous mutations of IDH1, DNMT3A and NRAS in AML patients might act as a resistant niche to avoid the toxicity of multiple drugs including VA. There is unmet need to validate this result in the clinical trials or a large cohort of patients in the future.

Improvement and Evaluation of a Staining Method for Measuring Sperm Lactate Dehydrogenase C4 Activity.

BACKGROUND: This study sought to improve and evaluate a 2-hydroxyvaleric acid based staining method for detection of lactate dehydrogenase C4 (LDH-C4) activity in human spermatozoa. METHODS: A staining method for measuring sperm LDH-C4 activity with the substrate 2-hydroxyvaleric acid was improved. Expression level of LDH-C4 was assessed by Western blotting. The diagnostic performance was evaluated by plotting the receiver operating characteristic (ROC) curve. RESULTS: The positive products were black purple lumps concentrated in the neck segment of spermatozoa. Expression level of LDH-C4 was significantly reduced in the low activity infertile cases as compared to the matched contrasts. Decreased LDH-C4 level was significantly correlated with the declined enzyme activity (r = 0.702, p = 0.000). The ROC curve allowed for the discrimination between low and normal LDH-C4 activity cases with a sensitivity of 0.912 and specificity of 0.895, corresponding to an area under curve (AUC) of 0.941. CONCLUSIONS: The improved method hallmarks a promising accuracy in evaluating sperm LDH-C4 activity. Down-regulated LDH-C4 level is a culprit for the decreased LDH-C4 activity in spermatozoa.

Pathological Effects of the FMR1 CGG-Repeat Polymorphism (5-55 Repeat Numbers): Systematic Review and Meta-Analysis.

The fragile X mental retardation 1 (FMR1) gene contains a highly polymorphic trinucleotide (CGG) repeat and consists of various allelic forms. Traditionally, 55-200 repeats and over 200 CGG repeats have been highlighted to be associated with ovarian dysfunction and neuro-psychiatric risks. However, previous studies had paid little attention to the allelic forms of 5-55 CGG repeats. Herein, we sought to evaluate the pathological features of FMR1 allelic category with a range of 5-55 CGG repeats. We further classified the spectrum of CGG sizes (5-55 repeats) into three sub-groups as low numbers of CGG repeat (< 26 repeats), normal CGG count (26-34 repeats), and small CGG expansion (35-54 repeats). Our systematic review documented that low numbers of CGG repeat (< 26 repeats) revealed a close relationship with premature ovarian failure. Correspondingly, the meta-analysis showed that small CGG expansion, involving allelic sizes with 35-54 (n = 8, OR = 1.22, 95% CI: 0.75-2.00, P > 0.05) and 41-54 (n = 7, OR = 1.62, 95% CI: 1.14-2.30, P < 0.05), was both linked to the risk of ovarian dysfunction. Additionally, small CGG expansion exerts significant influence on male Parkinsonism cohorts (OR = 2.17, 95% CI: 1.50-3.14, P < 0.05), mental retardation, and repeat instability. Our data provide evidence that the CGG-repeat numbers below 26 or above 34 of FMR1 gene are also associated with disease risks and thus should be regarded as pathological genotypes for a routine test.

[Efficacy of HAA regimen in the treatment of 64 patients with refractory/relapsed acute myeloid leukemia].

OBJECTIVE: To evaluate the efficacy and safety of the HAA regimen (homoharringtonine,cytarabine and aclarubicin)as salvage chemotherapy in the treatment of refractory/relapsed acute myeloid leukemia (AML). METHODS: We retrospectively analyzed 64 patients with refractory/relapsed AML who received the HAA regimen as salvage chemotherapy. The complete remission (CR)rate was analyzed. Kaplan-Meier method was used to estimate overall survival (OS) and relapse free survival (RFS), and the differences were compared by Log-rank test. RESULTS: The overall CR rate was 70.1%, and 67.1% of the patients attained CR after the first induction course. The early death rate was 0. The median follow-up time was 61 (range:6-120) months. The estimated 3-year OS rate was 46.8% and the estimated 3-year RFS rate was 42.8%. The CR rates of patients with favorable/intermediate and unfavorable cytogenetics were 76.4% and 33.3%, respectively. The 3-year OS of favorable/intermediate and unfavorable group were 53.7% and 10.0%, respectively. The median survival time of unfavorable group was only 8 months. The side effects associated with the HAA regimen were tolerable, in which the most common toxicities were myelosuppression and infection. CONCLUSION: HAA regimen is associated with a higher rate of CR and longer-term survival and its toxicity can be tolerated. The regimen is suitable for refractory/relapsed AML patients with favorable or intermediate risk .

[Advances in the studies of spermatogonial stem cells in primate mammals].

Spermatogonial stem cells(SSCs) are a type of spermatogonial cells that play an important role in the spermatogenesis of males. SSCs not only possess the properties of stem cells but also differentiate into sperm. They are the unique adult stem cells that transmit genetic information to subsequent generations. Therefore,SSCs are regarded as an ideal alternative source of pluripotent stem cells according with moral and ethical issues,legality,and safety. Long-term in vitro culture systems and identification of SSCs have paved the ground for the studies of their transplantation and pluripotency. Early relevant studies mainly focused on non-primate mammals. Recently,researches on SSCs have made great progress in primate mammals,especially in humans. This review focuses on the characterization,isolation,purification,cultivation,identification,and biological markers of SSCs,with a discussion on their unlimited pluripotency and application,and meanwhile provides an insight into the application potential of SSCs in the treatment of male infertility and human regenerative medicine.