The role of the indoleamine 2,3-dioxygenase gene in preventing ovarian transplant rejection in rats.

Indoleamine 2, 3-dioxygenase (IDO) plays important roles in maternal immune tolerance. Female Sprague Dawley rats (9-11 weeks old) were randomly divided into an autoplastic transplantation group (n = 75) and an allograft transplantation group (n = 300) further divided into subgroups of ovarian transplantation, allograft ovarian transplantation, allograft ovarian transplantation with cyclosporine A treatment, allograft ovarian transplantation and transfection with IDO-expressing lentiviruses, and allograft ovarian transplantation and transfection with control lentiviruses. IDO was successfully transfected intothe transplanted ovarian tissue. The survival rate, success rate of ovarian transplantation, period until estrous cycle restoration, and estrogen levels of rats that received IDO-expressing lentiviruseswere significantly different from those of rats that underwent allograft transplantation and with control transfection (all P < 0.05), but not significantly different from those of rats that received autoplastic transplantation (all P > 0.05). The number of ovarian follicles in the transplanted ovarian tissue of rats that received IDO-expressing lentiviruses was also significantly higher. The expression level of IDO protein detected by immunohistochemistry and western blotting was especially high in ovaries that had received IDO-containing lentiviruses. Naturally pregnant rats were found in each group postoperatively. These results indicate that IDO-expressing lentiviruses were successfully transfected into transplanted ovarian tissues of rats and that IDO was stably expressed within a certain time. These findings suggest that the expression level of IDO protein is associated with an enhanced success rate of ovarian tissue transplantation and a short restoration period of endocrine function.

Distinct FDG PET/CT avidity among newly diagnosed intravascular large B-cell lymphoma patients: a descriptive observational study.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of aggressive B-cell non-Hodgkin lymphoma that poses a great diagnostic challenge due to its highly heterogenous clinical manifestations. Although 18F-fluorodeoxyglucose (FDG) is widely used as a diagnostic tool for patients suspected of having lymphoma, as it reveals FDG-avid lesions, the FDG avidity of IVLBCL has not been extensively characterized. Here, we present a comprehensive report of FDG avidity in IVLBCL and its association with clinicopathological features and survival. This descriptive observational study included consecutive patients aged at least 18 years diagnosed with IVLBCL in Peking Union Medical Hospital across 9 years. Among 50 screened IVLBCL patients, 42 had undergone 18F-FDG PET/CT to detect possible lesions for biopsy before pathological diagnosis; their FDG PET/CT (positron emission computed tomography, PET/CT) reports were retrospectively reviewed. The primary endpoint was the clinical description of FDG avidity of newly diagnosed intravascular large B-cell lymphoma and frequency. A total of 73.8% patients showed FDG-avid lesions, with a median SUVmax of 7.4 (range 1-27.7), which was lower than that for other aggressive lymphomas. Clinicopathological features were the same between the FDG-avid group and the non-FDG-avid group, except that the latter had a higher Ki-67 index (median 90% in the nonavid group vs. 80% in the avid group, P = 0.043). The overall survival rate was not different between the PET/CT groups. Our findings demonstrate that FDG PET/CT is a useful diagnostic tool for detecting FDG-avid lesions in IVLBCL patients. A random skin biopsy is essential for assisting in the diagnosis of IVLBCL, even for those with negative PET/CT.

Three cases of late-onset post CAR-T therapy isolated CNS relapse in R/R large B-cell lymphoma.

CD19-chimeric antigen receptor T-cell (CAR T-cell) therapy has improved the outcomes of relapsed/refractory large B cell lymphoma significantly. However, about 50% of patients relapsed post-CAR-T therapy. Late relapse composed of 1/3 to 1/2 of CAR-T cell therapy failure, with no previous reports of isolated relapse in immune-privileged sites. Here, we report the first case series of late-onset post CAR-T cell therapy isolated central nervous system (CNS) relapses, in systemic relapsed/refractory large B cell lymphoma patients. With these cases, we suggest that additional CNS prophylaxis should be administrated for primary refractory patients on CAR-T cell therapy with previous neurological involvements, multiple extra-nodular lesions, and high CNS-IPI score pre-CAR, as well as early disappearance of circulating CAR-T cells post infusion.

Total cholesterol mediates the association between history of gestational diabetes mellitus and bone mineral density in US women aged 20-49 years.

OBJECTIVE: The aim of this study is to investigate the potential association between a history of gestational diabetes mellitus (GDM) and lumbar bone mineral density (BMD) among premenopausal women, with an additional examination of the mediating role of serum total cholesterol (TC). METHODS: In this cross-sectional study, 1809 women aged 20-49 years with at least one live birth between 2011 and 2018, drawn from the NHANES dataset, were analyzed. GDM history was identified through questionnaires. Using weighted multiple linear regression, we assessed the relationship between GDM history and lumbar BMD. Additionally, mediation analysis was performed to investigate the potential mediating role of TC. RESULTS: The fully adjusted linear regression model revealed a negative association between a history of GDM and lumbar BMD, indicating a reduction in lumbar BMD (ß = -0.023, 95% CI: -0.043, -0.003, P = 0.0275). Subgroup analysis highlighted a more pronounced trend in individuals aged ≥ 35 years and with a body mass index ≥ 30 kg/m². Furthermore, mediation analysis demonstrated a significant direct effect of a history of GDM on lumbar BMD (P < 0.0001), with serum TC playing a partial mediating role in this interaction (5.33%, P = 0.028). CONCLUSIONS: In women aged 20-49 years within the United States, a history of GDM was associated with diminished lumbar BMD, potentially mediated through serum TC.

Dietary supplements: clinical cholesterol-lowering efficacy and potential mechanisms of action.

This review aims to analyse the efficacy of dietary supplements in reducing plasma cholesterol levels. Focusing on evidence from meta-analyses of randomised controlled clinical trials, with an emphasis on potential mechanisms of action as supported by human, animal, and cell studies. Certain dietary supplements including phytosterols, berberine, viscous soluble dietary fibres, garlic supplements, soy protein, specific probiotic strains, and certain polyphenol extracts could significantly reduce plasma total and low-density lipoprotein (LDL) cholesterol levels by 3-25% in hypercholesterolemic patients depending on the type of supplement. They tended to be more effective in reducing plasma LDL cholesterol level in hypercholesterolemic individuals than in normocholesterolemic individuals. These supplements worked by various mechanisms, such as enhancing the excretion of bile acids, inhibiting the absorption of cholesterol in the intestines, increasing the expression of hepatic LDL receptors, suppressing the activity of enzymes involved in cholesterol synthesis, and activating the adenosine monophosphate-activated protein kinase signalling pathway.

Mutation profiling, tumour burden assessment, outcome prediction and disease monitoring by circulating tumour DNA in peripheral T-cell lymphoma.

In this prospective study, we aimed to evaluate the utility of circulating tumour DNA (ctDNA) in peripheral T-cell lymphomas (PTCLs). Plasma cell-free DNA (cfDNA) was obtained, and the mutational profile was assessed in 47 patients with newly diagnosed mature T- and NK-cell lymphoma. To validate the mutations detected in cfDNA, paired tumour tissue samples were available for 36 patients. Targeted next-generation sequencing was performed. A total of 279 somatic mutations involving 149 genes were identified in the 47 cfDNA samples. The overall sensitivity of plasma cfDNA in discovering biopsy-confirmed mutations was 73.9% with a specificity of 99.6%. When we considered only mutations with variant allele frequency >5% in the tumour biopsy, the sensitivity increased to 81.9%. Pretreatment ctDNA concentration and the number of mutations were highly correlated with tumour burden indicators including lactate dehydrogenase, Ann Arbor stage and International Prognostic Index score. Patients with high ctDNA level (>1.9 log ng/mL) had significantly lower overall response rates, inferior 1-year progression-free survival and overall survival rates than those with low level. Longitudinal analysis of ctDNA showed a strong agreement between ctDNA dynamics and the radiographic response. In conclusion, our study demonstrates that ctDNA may serve as a promising tool for mutational profiling, tumour burden assessment, outcome prediction and disease monitoring in PTCLs.

Evaluation of progression-free survival as a surrogate end point in primary CNS lymphoma: a systematic review and meta-analysis.

Purpose: To evaluate progression-free survival (PFS) as early surrogate endpoints for overall survival (OS) in primary CNS lymphoma (PCNSL). Methods: PubMed, Embase and Cochrane Central Library were searched up to 7 June 2022. Trial-level analyses were performed by weighted linear regression of logarithmic hazard ratios for PFS and OS. Treatment arm-level analyses were performed between PFS rates and 3- or 5-year OS rates. Results: 1471 PCNSL patients in nine randomized control trials were included. PFS was associated with OS (r = 0.750; 95% CI: 0.228-0.937). Strong linear correlations existed between 1-, 2- and 3-year PFS and 3-year OS (r = 0.896-0.928), moderate or weak correlations existed between 3- to 6-month PFS and 3-year OS, 3-month to 5-year PFS and 5-year OS. Conclusion: Short-term PFS can validly substitute for long-term OS in PCNSL.

Clinical Significance of Plasma Epstein-Barr Virus DNA in Peripheral T-Cell Lymphomas.

INTRODUCTION: The clinical implications of plasma Epstein-Barr virus (EBV) DNA in patients with peripheral T-cell lymphoma (PTCL) remain unclear. OBJECTIVE: This study aimed to explore the clinical correlations of pre- and post-treatment plasma EBV-DNA concentrations with treatment outcomes and prognosis in patients with PTCL. METHODS: We retrospectively reviewed 128 patients diagnosed with PTCL with available data on pre-treatment plasma EBV-DNA, including 63 patients for whom post-treatment plasma EBV-DNA data were also available. Patients with extra-nodal NK/T-cell lymphoma were excluded from this study. RESULTS: Pre-treatment plasma EBV-DNA was elevated (e.g., ≥500 copies/mL) in 35.2% of PTCL patients, with significant differences in positive rates between different subtypes of PTCL (p < 0.001). High pre-treatment EBV-DNA concentrations were associated with advanced age (>60 years), elevated lactate dehydrogenase levels, high International Prognostic Index (IPI), and positive EBV-encoded RNAs-ISH in tumor specimens. In multivariate analyses, pre-treatment EBV-DNA ≥500 copies/mL was an independent prognostic factor after adjusting for IPI and pathological subtypes (hazard ratio = 2.14, p = 0.032). For patients with elevated pre-treatment EBV-DNA, normalization of EBV-DNA concentrations after first-line chemotherapy was significantly associated with better overall response rate (81.3% vs. 22.2%, p = 0.014), progression-free survival (12.0 months vs. 3.7 months, p = 0.011), and overall survival (37.9 months vs. 7.8 months, p = 0.012). For patients achieving remission to first-line therapy, rebound of EBV-DNA levels during follow-up was associated with disease relapse or progression. CONCLUSIONS: These results suggest that pre-treatment plasma EBV-DNA concentration is a strong prognostic factor for PTCL. For patients with elevated pre-treatment EBV-DNA, dynamic monitoring of EBV-DNA changes after initiation of therapy is useful for predicting treatment outcome and disease relapse.

Association between complete right bundle branch block and atrial fibrillation development.

BACKGROUND: Complete right bundle branch block (CRBBB) is an important predictor of atrial fibrillation (AF) recurrence after pulmonary vein isolation. However, the association between CRBBB and AF development remains unclear. METHODS: We performed a retrospective study of 2639 patients (male, n = 1549; female, n = 1090; mean age, 58 ± 13 years). CRBBB was defined as a late R (R') wave in lead V1 or V2 with a slurred S wave in lead I and/or lead V6 with a prolonged QRS duration (≥120 ms). RESULTS: Among the 2639 patients, CRBBB was detected in 40 patients (1.5%), and the prevalence of AF was 7.4% (196/2639). The proportion of patients with AF and CRBBB was higher than the proportion of patients with AF without CRBBB (22.5% vs. 7.2%; p = 0.001). In the forward multivariate logistic analysis, CRBBB (odds ratio [OR], 3.329; 95% confidence interval [CI], 1.350-8.211; p = 0.009), complete left bundle branch block (OR, 2.209; 95% CI, 1.238-3.940; p = 0.007), age (OR, 1.020; 95% CI, 1.005-1.035; p = 0.009), valvular heart disease (OR, 2.332; 95% CI, 1.531-3.552; p < 0.001), left atrial diameter (OR, 1.133; 95% CI, 1.104-1.163; p < 0.001), left ventricular ejection fraction (OR, 1.023; 95% CI, 1.006-1.041; p = 0.007), and class I or III anti-arrhythmic drug use (OR, 10.534; 95% CI, 7.090-15.651; p < 0.001) were associated with AF. CONCLUSION: Complete right bundle branch block was significantly associated with AF development in hospitalized patients with cardiovascular diseases.

Metabolic characteristics of plasma bile acids in patients with intrahepatic cholestasis of pregnancy-mass spectrometric study.

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is one of the more common complications in the middle and late stages of pregnancy, which requires early detection and intervention. OBJECTIVE: The aim of the study is to investigate the changes in the metabolic profile of bile acids (BAs) in plasma of pregnant women with ICP and to look biomarkers for the diagnosis and grading of ICP, and to explore the disease mechanism. METHODS: The targeted metabolomics based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze plasma BAs. RESULTS: Twenty-seven BAs can be quantified in all participants. Among them, 22 BAs were identified as differential BAs between ICP and control groups. Five BAs include 3ß-CA, 3ß-DCA, CDCA-3Gln, NCA, and Tß-MCA, were found to be associated with ICP for the first time. Nine BAs include NCA, GCA, GCDCA, GHCA, GUDCA, HCA, TCA, TCDCA and THCA, can be used as possible ICP diagnostic biomarkers. Four BAs, i.e., GLCA, THCA, GHCA and TLCA-3S may be used as potential biomarkers for ICP grading. CONCLUSION: There were significant differences in plasma BA profiles between ICP patients and the control. The BA profiles of mild ICP group and severe ICP group partially overlapped. Potential diagnostic and grading BA markers were identified. A significant characteristic of ICP group was the increase of conjugated BAs. A mechanism to sustain the equilibrium of BA metabolism and adaptive response has been developed in ICP patients to accelerate excretion and detoxification.

Potential biomarkers identified in plasma of patients with gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common complication during pregnancy. Looking for reliable diagnostic markers for early diagnosis can reduce the impact of the disease on the fetus OBJECTIVE: The present study is designed to find plasma metabolites that can be used as potential biomarkers for GDM, and to clarify GDM-related mechanisms METHODS: By non-target metabolomics analysis, compared with their respective controls, the plasma metabolites of GDM pregnant women at 12-16 weeks and 24-28 weeks of pregnancy were analyzed. Multiple reaction monitoring (MRM) analysis was performed to verify the potential marker RESULTS: One hundred and seventy-two (172) and 478 metabolites were identified as differential metabolites in the plasma of GDM pregnant women at 12-16 weeks and 24-28 weeks of pregnancy, respectively. Among these, 40 metabolites were overlapped. Most of them are associated with the mechanism of diabetes, and related to short-term and long-term complications in the perinatal period. Among them, 7 and 10 differential metabolites may serve as potential biomarkers at the 12-16 weeks and 24-28 weeks of pregnancy, respectively. By MRM analysis, compared with controls, increased levels of 17(S)-HDoHE and sebacic acid may serve as early prediction biomarkers of GDM. At 24-28 weeks of pregnancy, elevated levels of 17(S)-HDoHE and L-Serine may be used as auxiliary diagnostic markers for GDM CONCLUSION: Abnormal amino acid metabolism and lipid metabolism in patients with GDM may be related to GDM pathogenesis. Several differential metabolites identified in this study may serve as potential biomarkers for GDM prediction and diagnosis.

Effect of catheter ablation on clinical outcomes in patients with atrial fibrillation and significant functional mitral regurgitation.

BACKGROUND: In patients with atrial fibrillation (AF) and functional mitral regurgitation (MR), catheter ablation reduces the severity of MR and improves cardiac remodeling. However, its effects on prognosis are uncertain. METHODS: This retrospective study included 151 consecutive patients with AF and functional MR, 82 (54.3%) of whom were treated by catheter ablation (Ablation group) and 69 (45.7%) with drug therapy without ablation (Non-ablation group). Forty-three pairs of these patients were propensity matched on the basis of age, CHA2DS2-VASc scores, and left ventricular ejection fraction. The primary outcome evaluated was severity of MR, cardiac remodeling and the combined incidence of subsequent heart failure-related hospitalization and strokes/transient ischemic attacks. RESULTS: Patients in the Ablation group showed a significant decrease in the severity of MR (p < 0.001), a significant decrease in the left atrial diameter (p = 0.010), and significant improvement in the left ventricular ejection fraction (p = 0.015). However, patients in the Non-ablation group showed only a significant decrease in the severity of MR (p = 0.004). The annual incidence of the studied events was 4.9% in the Ablation group and 16.7% in the Non-ablation group, the incidence being significantly lower in the ablation than Non-ablation group (p = 0.026) according to Kaplan-Meier curve analyses. According to multivariate Cox regression analysis, catheter ablation therapy (hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.09-0.84; p = 0.024) and heart failure at baseline (HR 3.84, 95% CI 1.07-13.74; p = 0.038) were independent predictors of the incidence of the studied events. CONCLUSIONS: Among patients with AF and functional MR, catheter ablation was associated with a significantly lower combined risk of heart failure-related hospitalization and stroke than in a matched cohort of patients receiving drug therapy alone.

[Analysis of a child with holoprosencephaly due to variant of SIX3 gene].

OBJECTIVE: To explore the genetic basis of a child with holoprosencephaly. METHODS: Genomic DNA of the child was extracted and subjected to whole exome sequencing. Suspected variant was verified by Sanger sequencing of her family members. RESULTS: Cranial MRI suggested lobulated holoprosencephaly with partial absence of corpus callosum. Genetic testing revealed that she has carried a heterozygous c.517C>G (p.His173Asp) variant of the SIX3 gene, for which both of her parents were of wild type. Based on the American College of Medical Genetics and Genomics guidelines, the c.517C>G variant of SIX3 gene was predicted to be pathogenic (PS2+PM1+PM2+PM5+PP3). CONCLUSION: The SIX3 gene c.517C>G variant probably underlay the multiple malformations in this child. Above finding has enabled her definite diagnosis.

Advances in Biomarker Studies in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurological and developmental condition that begins early in childhood and lasts throughout life. The epidemiology of ASD is continuously increasing all over the world with huge social and economical burdens. As the etiology of autism is not completely understood, there is still no medication available for the treatment of this disorder. However, some behavioral interventions are available to improve the core and associated symptoms of autism, particularly when initiated at an early stage. Thus, there is an increasing demand for finding biomarkers for ASD. Although diagnostic biomarkers have not yet been established, research efforts have been carried out in neuroimaging and biological analyses including genomics and gene testing, proteomics, metabolomics, transcriptomics, and studies of the immune system, inflammation, and microRNAs. Here, we will review the current progress in these fields and focus on new methods, developments, research strategies, and studies of blood-based biomarkers.

Germline defects of familial hemophagocytic lymphohistiocytosis-related genes presenting as adult-onset peripheral T-cell lymphoma.

Germline mutations in genes involved in perforin-granzyme-mediated cytotoxicity such as PRF1, UNC13D, STX11, and STXBP2 were known to cause familial hemophagocytic lymphohistiocytosis (FHL). In this study, we reported a unique group of 3 patients with germline mutations of UNC13D and STX11 genes and presented as adult-onset peripheral T-cell lymphoma (PTCL) with cytotoxic T-cell phenotype and atypical lymphoma presentations. CD107a degranulation assay and NK-cell activity analysis demonstrated impaired cytotoxic function of the NK/T-cells of the patients with FHL-related mutations. Gene expression profile study revealed that up-regulated genes of the cytotoxic T-cells were enriched in autoimmune-related pathways. It was possible that impaired cytotoxic lymphocyte-mediated immune surveillance and autoantigen stimulation may both participate in PTCL oncogenesis. Germline defects of FLH-related genes may represent a novel predisposing factor for PTCLs.

The role of upfront lenalidomide maintenance for primary central nervous system lymphoma following first-line methotrexate treatment: A retrospective study.

BACKGROUND: Consolidation therapy improves the duration of response among patients with primary central nervous system lymphoma (PCNSL). Lenalidomide maintenance has shown encouraging results in older patients with PCNSL. Herein, we performed a retrospective, single-center analysis to evaluate the effect of lenalidomide maintenance on the duration of response in patients with newly-diagnosed PCNSL. METHODS: Sixty-nine adult patients with PCNSL who achieved complete remission or partial remission (PR) after induction therapy were enrolled. The median age of patients was 58.0 years. The maintenance group (n = 35) received oral lenalidomide (25 mg/day) for 21 days, every 28 days for 24 months; the observation group did not undergo any further treatment. RESULTS: After a median follow-up of 32.6 months, the maintenance group experienced fewer relapse events. However, the median progression-free survival (PFS) was similar between groups (36.1 vs. 30.6 months; hazard ratio, 0.78; 95% confidence interval, 0.446). Lenalidomide maintenance significantly improved PFS and overall survival (OS) only among patients who experienced PR after induction. The median duration of lenalidomide maintenance was 18 months; lenalidomide was well tolerated and minimally impacted the quality of life. CONCLUSIONS: The present study was the first to evaluate lenalidomide maintenance as a frontline treatment among patients with PCNSL, PFS and OS did not improve, although the safety profile was satisfactory.

Lymphoma relapse 1 year or later after immunochemotherapy in DLBCL patients: clinical features and outcome.

Despite great advances in treatment, 30-40% of patients with DLBCL undergo relapses. Patients with a relapse within 1 year or beyond have a distinct outcome. Few clinical characteristics and survival data in the Chinese population have been published. We aimed to define the incidence and clinical features of DLBCL patients with very early relapse after front-line immunochemotherapy who may benefit greatly from the emerging chimeric antigen receptor T-cell therapy. Data of 564 DLBCL patients were analyzed. Among the 413 patients achieving a first complete remission, 59 underwent relapses: 32 patients (54.2%) relapsed within 1 year, and 27 patients (46.8%) relapsed 1 year or more. Patients relapsing within 1 year, in comparison with the other group, showed an inferior risk profile at diagnosis: elevated lactate dehydrogenase level (P = 0.002), high Eastern Cooperative Oncology Group performance score (P = 0.02), and high international prognosis index (P = 0.004). As expected, a worse overall survival was observed in the early relapse group. Multivariate analysis for OS showed that relapse within 1 year was an independent parameter for reduced overall survival (HR 0.241, P = 0.002).

Characteristics and prognostic value of gut microbiota in follicular lymphoma.

The pathogenesis and progression of follicular lymphoma (FL) depends on immune evasion mechanisms. The gut microbiota has been reported to be associated with the development and outcome of several human diseases by modulating host immunity. Thus, the present study investigated the characteristics and prognostic value of the gut microbiota in FL. Fecal samples from treatment-naïve patients with FL (n=28) and healthy controls (n=18) were prospectively collected. The gut microbiota diversity and composition were examined by 16S ribosomal RNA sequencing. The results demonstrated that patients with FL had distinct microbiota compositions. The relative abundance of the Ruminococcaceae family was significantly increased in patients with FL (P=0.01). Furthermore, a high level of Ruminococcus was identified as a strong indicator of tumor burden (P=0.001), and was related to the FL International Prognostic Index score and serum lactate dehydrogenase levels. The present results indicated an association between the gut microbiota and FL prognosis. Findings from the present study may provide a rational foundation for further investigation of the role of gut microbiota in lymphoma management.