Section E6.1-6.6 of the American College of Medical Genetics and Genomics (ACMG) Technical Laboratory Standards: Cytogenomic studies of acquired chromosomal abnormalities in neoplastic blood, bone marrow, and lymph nodes.

Cytogenomic analyses of acquired clonal chromosomal abnormalities in neoplastic blood, bone marrow, and/or lymph nodes are instrumental in the clinical management of patients with hematologic neoplasms. Cytogenetic analyses assist in the diagnosis of such disorders and can provide important prognostic information. Furthermore, cytogenetic studies can provide crucial information regarding specific genetically defined subtypes of these neoplasms that may have targeted therapies. At time of relapse, cytogenetic analysis can confirm recurrence of the original neoplasm, detect clonal disease evolution, or uncover a new unrelated neoplastic process. This section deals specifically with the technical standards applicable to cytogenomic studies of acquired clonal chromosomal abnormalities in neoplastic blood, bone marrow, and/or lymph nodes. This updated Section E6.1-6.6 supersedes the previous Section E6 in Section E: Clinical Cytogenetics of the American College of Medical Genetics and Genomics Technical Standards for Clinical Genetics Laboratories.

Section E6.7-6.12 of the American College of Medical Genetics and Genomics (ACMG) Technical Laboratory Standards: Cytogenomic studies of acquired chromosomal abnormalities in solid tumors.

Clinical cytogenomic studies of solid tumor samples are critical to the diagnosis, prognostication, and treatment selection for cancer patients. An overview of current cytogenomic techniques for solid tumor analysis is provided, including standards for sample preparation, clinical and technical considerations, and documentation of results. With the evolving technologies and their application in solid tumor analysis, these standards now include sequencing technology and optical genome mapping, in addition to the conventional cytogenomic methods, such as G-banded chromosome analysis, fluorescence in situ hybridization, and chromosomal microarray analysis. This updated Section E6.7-6.12 supersedes the previous Section E6.5-6.8 in Section E: Clinical Cytogenetics of the American College of Medical Genetics and Genomics Standards for Clinical Genetics Laboratories.

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. OBJECTIVES: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. RESULTS: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], -90.90 mg/g, 95% CI, -140.17 to -41.64 mg/g), 24-h urinary protein excretion (WMD, -0.20 g, 95% CI, -0.28 to -0.12 g), estimated glomerular filtration rate (eGFR) (WMD, -1.99 mL/min/1.73 m2, 95% CI, -3.28 to -0.70 mL/min/1.73 m2), chronic renal failure events (RR, 0.86, 95% CI, 0.79-0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77-0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73-2.40) and hypotension (RR, 1.80, 95% CI, 1.41-2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56-0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79-1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57-0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02-1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26-25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22-1.22) increased the risk of breast disorders. CONCLUSIONS: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.

Development and application of an indirect ELISA for detection of antibodies against emerging atypical porcine pestivirus.

BACKGROUND: Atypical porcine pestivirus (APPV) is a newly discovered swine pestivirus, which can cause congenital tremor and high mortality in newborn piglets and subclinical infection in adult pigs, leading to significant impacts on the pig industry. Currently, there is no approved serological method to assess APPV infection status in pig farms. METHODS: In this study, the envelope glycoprotein E2 of APPV was highly expressed in suspension HEK293 cells, and further an indirect enzyme-linked immunosorbent assay based on the recombinant E2 protein (E2-iELISA) was developed and evaluated. RESULTS: The reaction parameters of the E2-iELISA were optimized, and the cutoff value was determined to be 0.2 by analyzing S/P values of 165 negative sera against APPV that were confirmed by virus neutralization test (VNT). Specificity test showed that the method had no cross-reaction with other common swine viruses. The E2-iELISA was evaluated using a panel of swine sera, and showed high sensitivity (113/120, 94.2%) and specificity (65/70, 92.9%), and the agreement rate with VNT was 93.7% (178/190). Subsequently, the E2-iELISA was utilized to investigate the seroprevalence of APPV in pig herds of China. When detecting 1368 pig serum samples collected from nine provinces in China, the overall seroprevalence of APPV was 73.9% (1011/1368). CONCLUSION: Our findings suggest that the E2-iELISA is specific and sensitive, and could be a valuable tool for serological surveillance of APPV infection in pigs.

Osteoblast Jmjd3 regulates osteoclastogenesis via EphB4 and RANKL signalling.

BACKGROUND: Osteoblasts suppress osteoclastogenesis during the reversal phase of bone remodelling and the mechanism needs to be further investigated. Here, we investigated the role of histone demethylase Jumonji domain-containing 3 (Jmjd3) in osteoblasts on regulating osteoclastogenesis. METHODS: Jmjd3 expression was silenced in osteoblasts. Osteoblasts and osteoclasts were co-cultured in direct or indirect contact ways, and osteoclastogenesis was determined by tartrate-resistant acid phosphatase (TRAP) staining and Western blotting. Additionally, Ephrin receptor B4 (EphB4) and receptor activator of nuclear factor-kappa Β ligand (RANKL) expression were quantified in osteoblasts via real-time PCR, Western blotting, and enzyme-linked immunosorbent assay. Subsequently, EphB4 was overexpressed in osteoblasts and RANKL expression and osteoclastogenesis was quantified. RESULTS: Osteoclastogenesis and marker protein expression levels was promoted when osteoclasts were co-cultured with Jmjd3-silenced osteoblasts. Silencing of Jmjd3 expression in osteoblasts decreased EphB4 expression, owing to suppression of demethylation of H3K27me3 on the promoter region of EphB4. Whereas RANKL expression was upregulated in Jmjd3-silenced osteoblasts. Overexpression of EphB4 in osteoblasts inhibited osteoclastogenesis and RANKL expression. CONCLUSION: Jmjd3 in osteoblasts is a crucial regulator of osteoblast-to-osteoclast communication through EphB4-EphrinB2, RANKL-RANK and EphB4-RANKL signalling axes, suggesting the pivotal role of Jmjd3 in bone remodelling process in bone destruction disease such as chronic apical periodontitis.

A study on the factors influencing the utilization of public health services by China's migrant population based on the Shapley value method.

BACKGROUND: The health of migrants has received significant global attention, and it is a particularly significant concern in China, which has the largest migrant population in the world. Analyzing data on samples from the Chinese population holds practical significance. For instance, one can delve into an in-depth analysis of the factors impacting (1) the health records of residents in distinct regions and (2) the current state of family doctor contracts. This study explores the barriers to access these two health services and the variations in the effects and contribution magnitudes. METHODS: This study involved data from 138,755 individuals, extracted from the 2018 National Migration Population Health and Family Planning Dynamic Monitoring Survey database. The theoretical framework employed was the Anderson health service model. To investigate the features and determinants of basic public health service utilization among the migrant population across different regions of China, including the influence of enabling resources and demand factors, x2 tests and binary logistic regression analyses were conducted. The Shapley value method was employed to assess the extent of influence of each factor. RESULTS: The utilization of various service types varied among the migrant population, with significant regional disparities. The results of the decomposition of the Shapley value method highlighted variations in the mechanism underlying the influence of propensity characteristics, enabling resources, and demand factors between the two health service types. Propensity characteristics and demand factors were found to be the primary dimensions with the highest explanatory power; among them, health education for chronic disease prevention and treatment was the most influential factor. CONCLUSION: To better meet the health needs of the migrant population, regional barriers need to be broken down, and the relevance and effectiveness of publicity and education need to be improved. Additionally, by considering the education level, demographic characteristics, and mobility characteristics of the migrant population, along with the relevant health policies, the migrant population needs to be guided to maintain the health records of residents. They should also be encouraged to sign a contract with a family doctor in a more effective manner to promote the equalization of basic health services for the migrant population.

Acute kidney injury in patients with cancer receiving anti-PD-1/PD-L1 antibodies: incidence, risk factors, and prognosis.

Anti-PD-1/PD-L1 antibodies are widely used in anti-cancer therapy. While they have improved cancer prognoses, immune-related adverse events, which can cause acute kidney injury (AKI), cannot be ignored. The purpose of this retrospective cohort study was to assess the incidence, risk factors, and prognosis of AKI associated with anti-PD-1/PD-L1 antibodies. Patients who received anti-PD-1/PD-L1 antibody treatment at our hospital between January 2018 and December 2022 were enrolled. Clinical information, combined medications, concomitant diseases, tumor types, and laboratory indicators were collected from patient records, and the incidence of AKI was determined. The risk factors for AKI were assessed using univariate and multivariate logistic regression analyses. Overall, 1418 patients were enrolled. The median follow-up time was 112 days and 92 (6.5%) developed AKI. The median time from the initial anti-PD-1/PD-L1 antibody treatment to AKI was 99.85 days. Head and neck cancer and combined use of diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), lower hemoglobin level, and other types of chemotherapeutic drugs were independent risk factors for AKI. The complete recovery, partial recovery, non-recovery, and unknown AKI rates were 7.6%, 28.3%, 52.2%, and 11.9%, respectively. Kidney biopsies were performed on two patients with AKI and pathology confirmed diagnosis of acute tubulointerstitial nephritis. In this cohort, AKI was not uncommon in patients treated with anti-PD-1/PD-L1 antibodies; therefore, it is necessary to monitor renal function and identify AKI early, especially in patients with head and neck tumors. Improving anemia and minimizing the use of diuretics, NSAIDs, and chemotherapeutics may reduce AKI.

Plasma D-dimer levels are associated with disease progression in diabetic nephropathy: a two-center cohort study.

BACKGROUND: This study aimed to investigate the relationship between plasma D-dimer levels, clinicopathological features, and clinical outcomes in patients with biopsy-proven diabetic nephropathy (DN). METHODS: A total of 137 patients with biopsy-proven DN were enrolled in this two-center cohort study. Patients were stratified into tertiles based on plasma D-dimer levels. We investigated the relationship between plasma D-dimer levels and clinical outcomes, including a composite of death, a 40% decline in estimated glomerular filtration rate (e-GFR) from baseline, or end-stage renal disease (ESRD) (defined as e-GFR < 15 mL/min/1.73 m2 or need for renal replacement therapy including hemodialysis, peritoneal dialysis, or kidney transplantation), assessed using Cox regression models with adjustment for confounders. RESULTS: At baseline, the mean age was 52.61 ± 11.63 years, and the mean e-GFR was 58.02 ± 28.77 mL/min/1.73 m2. During a median 26-month follow-up period, 65 (47% of patients) achieved clinical outcomes. Compared with the low plasma D-dimer level group, those with higher plasma D-dimer levels were more likely to have higher 24-h proteinuria (p = .002), lower e-GFR (p = .001), lower hemoglobin (p = .001), a higher glomerular lesion class (p = .03), and higher interstitial fibrosis and tubular atrophy (IFTA) scores (p = .002). After adjustment for demographic, DN-specific covariates, and treatments, it was observed that a higher tertile of plasma D-dimer was nonlinearly associated with an increased risk of the clinical outcomes (Hazard Ratio (HR) for tertile 2 vs. 1, 1.7; 95% Confidence Interval (CI), 0.80-3.75; HR for tertile 3 vs. 1, 2.2; 95% CI, 0.93-5.27; p for trend = .001) in the Cox proportional hazards models. CONCLUSION: In this study, DN patients with higher levels of plasma D-dimer had higher 24-h proteinuria, lower e-GFR, a higher glomerular lesion class, and higher IFTA scores. Furthermore, a high level of plasma D-dimer was nonlinearly associated with DN progression.

ERG amplification is a secondary recurrent driver event in myeloid malignancy with complex karyotype and TP53 mutations.

ERG is a transcription factor encoded on chromosome 21q22.2 with important roles in hematopoiesis and oncogenesis of prostate cancer. ERG amplification has been identified as one of the most common recurrent events in acute myeloid leukemia with complex karyotype (AML-CK). In this study, we uncover three different modes of ERG amplification in AML-CK. Importantly, we present evidence to show that ERG amplification is distinct from intrachromosomal amplification of chromosome 21 (iAMP21), a hallmark segmental amplification frequently encompassing RUNX1 and ERG in a subset of high-risk B-lymphoblastic leukemia. We also characterize the association with TP53 aberrations and other chromosomal aberrations, including chromothripsis. Lastly, we show that ERG amplification can initially emerge as subclonal events in low-grade myeloid neoplasms. These findings demonstrate that ERG amplification is a recurrent secondary driver event in AML and raise the tantalizing possibility of ERG as a therapeutic target.

Association of central arterial blood pressure and left ventricular hypertrophy in patients with chronic kidney disease.

AIMS: In the general population, central arterial blood pressure has proved to be more closely related to left ventricular hypertrophy (LVH) than brachial arterial blood pressure. We aimed to investigate whether this relationship was true in patients with chronic kidney disease (CKD). METHODS: In this retrospective study, we reviewed the medical records of 289 adult patients with CKD from the Zhejiang Provincial People's Hospital in Zhejiang, China. Demographic, echocardiographic and brachial and central blood pressure parameters were retrieved from medical records. Central blood pressure was measured using the SphygmoCor® CvMS (AtCor, Australia) device and its corresponding software. Multivariate logistic regression analyses were performed to identify independent predictors of LVH. Receiver operating characteristic curves were used to determine the ability of central and brachial blood pressure to predict LVH. RESULTS: The left ventricular mass index was positively associated with both central and brachial blood pressures. However, multiple logistic regression analysis demonstrated that a central pulse pressure (CPP) ≥ 58 mm Hg was an independent risk factor for LVH (OR = 5.597, 95%CI 2.363-13.259, p < .001). Brachial pulse pressure is not superior to CPP in predicting LVH (area under the curve [AUC] = 0.695, 95%CI 0.634-0.756, p < .001 vs. AUC = 0.687, 95%CI: 0.626-0.748, p < .001, respectively; p = .4824). CONCLUSION: Our results suggested that, similarly to the general population, CPP is a better parameter for predicting the occurrence of LVH in patients with CKD.

LASSO-derived nomogram predicting new-onset diabetes mellitus in patients with kidney disease receiving immunosuppressive drugs.

WHAT IS KNOWN AND OBJECTIVE: Patients with kidney disease receiving immunosuppressive drugs (ISDs) (tacrolimus, cyclosporine and glucocorticoids) have a high risk of developing new-onset diabetes mellitus (NODM). We aimed to establish a precise and convenient model for predicting NODM in patients receiving immunosuppressive drugs. METHODS: This retrospective study recruited 1883 patients receiving ISDs between January 2010 and October 2018. The occurrence of NODM was the primary endpoint. The patients were randomly divided into training (n = 1318) and validation cohorts (n = 565) at a 7:3 ratio. A nomogram was established based on a least absolute shrinkage and selection operator (LASSO)-derived logistic regression model. The nomogram's discrimination and calibration abilities were evaluated in both cohorts using the Hosmer-Lemeshow test and calibration curves. Decision curve analysis (DCA) was used to evaluate the net benefit of the predictive efficacy. RESULTS AND DISCUSSION: Amongst the 1883 patients with kidney disease receiving immunosuppressive drugs, 375 (28.5%) and 169 (29.9%) developed NODM in the training (n = 1318) and validation cohorts (n = 565), respectively. Nine clinic predictors were included in this LASSO-derived nomogram, which is easy to be operated clinically. The discriminative ability, determined by the area under the receiver operating characteristic curve (AUC), was 0.816 (95% confidence interval [CI] 0.790-0.841) and 0.831 (95%CI 0.796-0.867) in the training and validation cohorts, respectively. Calibration was confirmed with the Hosmer-Lemeshow test in the training and validation cohorts (p = 0.238, p = 0.751, respectively). WHAT IS NEW AND CONCLUSION: Nearly one-third of patients with kidney disease receiving immunosuppressive drugs developed NODM. The nomogram established in this study may aid in predicting the occurrence of NODM in patients with kidney disease receiving immunosuppressive drugs.

Single nucleotide polymorphism array and cytogenetic analyses of ovarian teratomas in children.

Teratomas are the most common tumors in the ovary during childhood. Previous studies suggested that they may be derived from germ cells at any developmental stage from premeiotic oogonia through meiotic oocytes to post-meiotic ova. The majority of mature teratomas reveal normal karyotypes and immature teratomas show higher frequency of chromosomal abnormalities. We analyzed fresh tissue samples from 25 primary ovarian teratomas and three extraovarian deposits using whole genome single nucleotide polymorphism (SNP) array and karyotype. SNP array detected five patterns of copy neutral loss of heterozygosity (CN-LOH): failure of meiosis I (type I) in 12 tumors, failure of meiosis II (type II) in six tumors, endoreduplication of a haploid ovum (type III) in two tumors, premeiotic error (type IV) in four tumors, and both meiotic I and meiotic II errors in one tumor (type V). Three tumors with type I error had a single chromosome showing meiotic II error, and two tumors with type II error had a single chromosome showing premature sister-chromatid separation in meiosis I. Lack of recombination in multiple chromosomes in meiosis I were common, chromosomes 17, 7, 8, 21, and 22 were most commonly involved. Abnormal karyotypes were observed in four teratomas including +3, del(3q), +7, +8, +12, and i(18q). The extraovarian deposits revealed the same CN-LOH pattern as the primary teratoma. In summary, SNP array reveals the origin of ovarian teratoma and we propose a new mechanism that consecutive meiotic I and II errors occur frequently in ovarian teratomas.

Myelodysplastic syndrome with t(6;9)(p22;q34.1)/DEK-NUP214 better classified as acute myeloid leukemia? A multicenter study of 107 cases.

t(6;9)(p22;q34.1)/DEK-NUP214 is a recurrent genetic abnormality that occurs in 1-2% of patients with acute myeloid leukemia (AML), and rarely in myelodysplastic syndrome (MDS). It has been suggested by others that all myeloid neoplasms with t(6;9)/DEK-NUP214 may be considered as AML, even when blast count is <20%. In this study, we compared the clinicopathologic features of 107 patients with myeloid neoplasms harboring t(6;9)/DEK-NUP214: 33 MDS and 74 AML. Compared with patients with AML, patients with MDS were older (p = 0.10), had a lower white blood cell count (p = 0.0017), a lower blast count in the peripheral blood (p < 0.0001) and bone marrow (p < 0.0001), a higher platelet count (p = 0.022), and a lower frequency of FLT3-ITD mutation (p = 0.01). In addition, basophilia was not a common feature in the patients of this cohort. Although there was no difference in overall survival between MDS and AML patients (p = 0.18) in the entire cohort, the survival curves did show a trend toward favorable survival in MDS patients. Multivariate analyses showed that initial diagnosis of MDS vs. AML and allogeneic hematopoietic stem cell transplantation were prognostic factors for survival of patients with t(6;9)/DEK-NUP214 (p = 0.008 and p < 0.0001, respectively). Our data suggest that MDS with t(6;9)/DEK-NUP214 is prognostically not equivalent to AML with t(6;9)/DEK-NUP214. These data also show that stem cell transplantation greatly improves the survival of MDS and AML patients with myeloid neoplasms associated with t(6;9)/DEK-NUP214.

TRIM63 is a sensitive and specific biomarker for MiT family aberration-associated renal cell carcinoma.

Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carcinoma (MiTF-RCC) is a subtype of renal cell carcinoma harboring recurrent chromosomal rearrangements involving TFE3 or TFEB genes. MiTF-RCC is morphologically diverse, can histologically resemble common RCC subtypes like clear cell RCC and papillary RCC, and often poses a diagnostic challenge in genitourinary clinical and pathology practice. To characterize the MiTF-RCC at the molecular level and identify biomarker signatures associated with MiTF-RCC, we analyzed RNAseq data from MiTF-RCC, other RCC subtypes and benign kidney. Upon identifying TRIM63 as a cancer-specific biomarker in MiTF-RCC, we evaluated its expression independently by RNA in situ hybridization (RNA-ISH) in whole tissue sections from 177 RCC cases. We specifically included 31 cytogenetically confirmed MiTF-RCC cases and 70 RCC cases suspicious for MiTF-RCC in terms of clinical and morphological features, to evaluate and compare TRIM63 RNA-ISH results with the results from TFE3/TFEB fluorescence in situ hybridization (FISH), which is the current clinical standard. We confirmed that TRIM63 mRNA was highly expressed in all classes of MiTF-RCC compared to other renal tumor categories, where it was mostly absent to low. While the TRIM63 RNA-ISH and TFE3/TFEB FISH results were largely concordant, importantly, TRIM63 RNA-ISH was strongly positive in TFE3 FISH false-negative cases with RBM10-TFE3 inversion. In conclusion, TRIM63 can serve as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. We suggest a combination of TFE3/TFEB FISH and TRIM63 RNA-ISH assays to improve the accuracy and efficiency of MiTF-RCC diagnosis. Accurate diagnosis of MiTF-RCC and other RCC subtypes would enable effective targeted therapy and avoid poor therapeutic response due to tumor misclassification.

Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Chromosomal microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism array, are widely applied in the diagnostic evaluation for both constitutional and neoplastic disorders. In a constitutional setting, this technology is accepted as the first-tier test for the evaluation of chromosomal imbalances associated with intellectual disability, autism, and/or multiple congenital anomalies. Furthermore, chromosomal microarray analysis is recommended for patients undergoing invasive prenatal diagnosis with one or more major fetal structural abnormalities identified by ultrasonographic examination, and in the evaluation of intrauterine fetal demise or stillbirth when further cytogenetic analysis is desired. This technology also provides important genomic data in the diagnosis, prognosis, and therapy of neoplastic disorders, including both hematologic malignancies and solid tumors. To assist clinical laboratories in the validation of chromosomal microarray methodologies for constitutional and neoplastic applications, the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee has developed these updated technical laboratory standards, which replace the ACMG technical standards and guidelines for microarray analysis in constitutional and neoplastic disorders previously published in 2013.

Lactobacillus rhamnosus GG defense against Salmonella enterica serovar Typhimurium infection through modulation of M1 macrophage polarization.

Lactobacillus rhamnosus GG (LGG), a model probiotic strain, plays an important role in immune regulatory activity to prevent and treat intestinal inflammation or diarrhea. However, the effect of the immune modulation of LGG on macrophages to prevent Salmonella infection has not been thoroughly studied. In this study, C57BL/6 mice were pre-administered LGG for 7 days continuously, and then infected with Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium). The results of the in vivo study indicated that LGG could reduce body weight loss, death rate and intestinal inflammatory response caused by S. Typhimurium. LGG also limited S. Typhimurium dissemination to liver and spleen, and thereby protected against infection. In vitro study, we observed that LGG enhanced the phagocytic and bactericidal ability of macrophages and upregulated M1 macrophage characters (e.g. iNOS, NO and IL-12) against S. Typhimurium. In addition, LGG also elevated IL-10 secretion, which was helpful to ameliorate intestinal inflammatory injury caused by S. Typhimurium. In conclusion, LGG could modulate M1 macrophage polarization and offer protective effects against S. Typhimurium infection.

Genetic reduction of cilium length by targeting intraflagellar transport 88 protein impedes kidney and liver cyst formation in mouse models of autosomal polycystic kidney disease.

Polycystin-1 (PC1) and -2 (PC2), products of the PKD1 and PKD2 genes, are mutated in autosomal dominant polycystic kidney disease (ADPKD). They localize to the primary cilia; however, their ciliary function is in dispute. Loss of either the primary cilia or PC1 or PC2 causes cyst formation. However, loss of both cilia and PC1 or PC2 inhibits cyst growth via an unknown pathway. To help define a pathway, we studied cilium length in human and mouse kidneys. We found cilia are elongated in kidneys from patients with ADPKD and from both Pkd1 and Pkd2 knockout mice. Cilia elongate following polycystin inactivation. The role of intraflagellar transport proteins in Pkd1-deficient mice is also unknown. We found that inactivation of Ift88 (a gene expressing a core component of intraflagellar transport) in Pkd1 knockout mice, as well as in a new Pkd2 knockout mouse, shortened the elongated cilia, impeded kidney and liver cystogenesis, and reduced cell proliferation. Multi-stage in vivo analysis of signaling pathways revealed ß-catenin activation as a prominent, early, and sustained event in disease onset and progression in Pkd2 single knockout but not in Pkd2.Ift88 double knockout mouse kidneys. Additionally, AMPK, mTOR and ERK pathways were altered in Pkd2 single knockout mice but only AMPK and mTOR pathway alteration were rescued in Pkd2.Ift88 double knockout mice. Thus, our findings advocate an essential role of polycystins in the structure and function of the primary cilia and implicate ß-catenin as a key inducer of cystogenesis downstream of the primary cilia. Our data suggest that modulating cilium length and/or its associated signaling events may offer novel therapeutic approaches for ADPKD.

Cytogenomic array detects a subset of myelodysplastic syndrome with increased risk that is invisible to conventional karyotype.

Conventional karyotyping is essential standard practice in the initial evaluation of myelodysplastic syndrome (MDS) and is the most impactful single component of the Revised International Prognostic Scoring System (IPSS-R). While single nucleotide polymorphism array (SNP-A) has demonstrated the ability to detect chromosomal defects with greater sensitivity than conventional karyotype, widespread adoption is limited by the unknown additional prognostic impact of SNP-A analysis. Here, we investigate the significance of additional SNP-A abnormalities in the setting of MDS and demonstrate differences in survival of patients with additional abnormalities, even those initially characterized as relatively lower risk either by cytogenetic score or IPSS-R. Our findings identify specific abnormalities, particularly KMT2A partial tandem duplication, that are invisible to conventional karyotype and potentially contribute to the poor prognosis of MDS patients. Furthermore, these results demonstrate the added value of SNP-A analysis in identifying patients who may benefit from more aggressive therapy, particularly those who would otherwise be classified into lower risk categories.

Technical laboratory standards for interpretation and reporting of acquired copy-number abnormalities and copy-neutral loss of heterozygosity in neoplastic disorders: a joint consensus recommendation from the American College of Medical Genetics and Genomics (ACMG) and the Cancer Genomics Consortium (CGC).

The detection of acquired copy-number abnormalities (CNAs) and copy-neutral loss of heterozygosity (CN-LOH) in neoplastic disorders by chromosomal microarray analysis (CMA) has significantly increased over the past few years with respect to both the number of laboratories utilizing this technology and the broader number of tumor types being assayed. This highlights the importance of standardizing the interpretation and reporting of acquired variants among laboratories. To address this need, a clinical laboratory-focused workgroup was established to draft recommendations for the interpretation and reporting of acquired CNAs and CN-LOH in neoplastic disorders. This project is a collaboration between the American College of Medical Genetics and Genomics (ACMG) and the Cancer Genomics Consortium (CGC). The recommendations put forth by the workgroup are based on literature review, empirical data, and expert consensus of the workgroup members. A four-tier evidence-based categorization system for acquired CNAs and CN-LOH was developed, which is based on the level of available evidence regarding their diagnostic, prognostic, and therapeutic relevance: tier 1, variants with strong clinical significance; tier 2, variants with some clinical significance; tier 3, clonal variants with no documented neoplastic disease association; and tier 4, benign or likely benign variants. These recommendations also provide a list of standardized definitions of terms used in the reporting of CMA findings, as well as a framework for the clinical reporting of acquired CNAs and CN-LOH, and recommendations for how to deal with suspected clinically significant germline variants.

New-Onset Diabetes Mellitus in Patients with Idiopathic Membranous Nephropathy Undergoing Tacrolimus and Low-Dose Corticosteroid Therapy.

BACKGROUND: Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Although various studies have demonstrated the efficacy of tacrolimus combined with corticosteroids for treating IMN, both tacrolimus and corticosteroids have been shown to be diabetogenic, particularly following organ transplantation. Furthermore, the frequency and risk factors for new-onset diabetes mellitus (NODM) in IMN patients treated with tacrolimus plus low-dose corticosteroids remain unclear. OBJECTIVES: To evaluate the incidence of NODM in IMN patients undergoing tacrolimus plus low-dose corticosteroid therapy and to confirm the risk factors for NODM development. METHODS: This retrospective study recruited 72 eligible patients with biopsy-proven IMN from our center, between September 2013 and June 2018. All subjects were treated with tacrolimus plus low-dose corticosteroids for a minimum of 3 months. The primary outcome was NODM development during the follow-up period. The secondary outcome was complete or partial remission. Patients were divided into 2 groups: patients with NODM (NODM group) and those without NODM (No-NODM group). Demographic and clinical data at baseline and follow-up were assessed. RESULTS: During follow-up, 31 of the 72 patients developed NODM (43.0%). The median time to occurrence was 3 months after treatment initiation. NODM patients were significantly older (median age 59 vs. 40 years) than No-NODM patients. Baseline fasting blood glucose levels were slightly higher in the NODM group; however, the difference was not significant (p = 0.07). Older age was an independent risk factor for NODM (OR 1.73 and 95% CI 1.20-2.47, p = 0.003). Overall kidney remission rates were 80.6%. There was no significant difference in remission rate between groups. There was a significant difference in development of pulmonary infection, which occurred in 7 NODM patients and only in 1 No-NODM patient (p = 0.018). IMN reoccurred in 5 NODM patients but only 1 No-NODM patient. CONCLUSIONS: Tacrolimus plus low-dose corticosteroid therapy was an efficient treatment for IMN; however, it was accompanied by increased NODM morbidity, which should be considered serious, due to the increased risk of life-threatening complications. Increasing age was a major risk factor for NODM in IMN patients treated with tacrolimus plus low-dose corticosteroid therapy.