Loss of FUT8 in renal tubules ameliorates ischemia-reperfusion injury-induced renal interstitial inflammation transition to fibrosis via the TLR3-NF-κB pathway.

Renal ischemia-reperfusion injury (IRI) is a common reason of acute kidney injury (AKI). AKI can progress to chronic kidney disease (CKD) in some survivors. Inflammation is considered the first-line response to early-stage IRI. We previously reported that core fucosylation (CF), specifically catalyzed by α-1,6 fucosyltransferase (FUT8), exacerbates renal fibrosis. However, the FUT8 characteristics, role, and mechanism in inflammation and fibrosis transition remain unclear. Considering renal tubular cells are the trigger cells that initiate the fibrosis in the AKI-to-CKD transition in IRI, we targeted CF by generating a renal tubular epithelial cell (TEC)-specific FUT8 knockout mouse and measured FUT8-driven and downstream signaling pathway expression and AKI-to-CKD transition. During the IRI extension phase, specific FUT8 deletion in the TECs ameliorated the IRI-induced renal interstitial inflammation and fibrosis mainly via the TLR3 CF-NF-κB signaling pathway. The results firstly indicated the role of FUT8 in the transition of inflammation and fibrosis. Therefore, the loss of FUT8 in TECs may be a novel potential strategy for treating AKI-CKD transition.

TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

The Phenotypic and Genetic Spectrum of Paroxysmal Kinesigenic Dyskinesia in China.

BACKGROUND: Paroxysmal kinesigenic dyskinesia is a spectrum of involuntary dyskinetic disorders with high clinical and genetic heterogeneity. Mutations in proline-rich transmembrane protein 2 have been identified as the major pathogenic factor. OBJECTIVES: We analyzed 600 paroxysmal kinesigenic dyskinesia patients nationwide who were identified by the China Paroxysmal Dyskinesia Collaborative Group to summarize the clinical phenotypes and genetic features of paroxysmal kinesigenic dyskinesia in China and to provide new thoughts on diagnosis and therapy. METHODS: The China Paroxysmal Dyskinesia Collaborative Group was composed of departments of neurology from 22 hospitals. Clinical manifestations and proline-rich transmembrane protein 2 screening results were recorded using unified paroxysmal kinesigenic dyskinesia registration forms. Genotype-phenotype correlation analyses were conducted in patients with and without proline-rich transmembrane protein 2 mutations. High-knee exercises were applied in partial patients as a new diagnostic test to induce attacks. RESULTS: Kinesigenic triggers, male predilection, dystonic attacks, aura, complicated forms of paroxysmal kinesigenic dyskinesia, clustering in patients with family history, and dramatic responses to antiepileptic treatment were the prominent features in this multicenter study. Clinical analysis showed that proline-rich transmembrane protein 2 mutation carriers were prone to present at a younger age and have longer attack duration, bilateral limb involvement, choreic attacks, a complicated form of paroxysmal kinesigenic dyskinesia, family history, and more forms of dyskinesia. The new high-knee-exercise test efficiently induced attacks and could assist in diagnosis. CONCLUSIONS: We propose recommendations regarding diagnostic criteria for paroxysmal kinesigenic dyskinesia based on this large clinical study of paroxysmal kinesigenic dyskinesia. The findings offered some new insights into the diagnosis and treatment of paroxysmal kinesigenic dyskinesia and might help in building standardized paroxysmal kinesigenic dyskinesia clinical evaluations and therapies. © 2020 International Parkinson and Movement Disorder Society.

Inhibition of core fucosylation limits progression of diabetic kidney disease.

BACKGROUND: FUT8-mediated core fucosylation, which transfers a fucose residue from GDP-fucose to core-GlcNAc of the N-linked type glycoproteins, is crucial for signaling receptors function. Core fucosylation is involved in various biological processes such as cell proliferation, apoptosis, differentiation and immune regulation. Our previous studies demonstrated that inhibiting core fucosylation prevented renal interstitial fibrosis of UUO murine models, but its role in the development of diabetic kidney disease (DKD) remains unclear. This study aimed to clarify the protective effects and molecular mechanisms during the progress of DKD by inhibiting core fucosylation in vivo. METHODS: Core fucosylation was examined in streptozotocin (STZ)-induced diabetic mouse model. Then a new Fut8 mutation mouse model in which exon 7 of Fut8 gene is deleted was constructed for diabetes induction. Metabolic and renal parameters were measured. Renal structure, fibrosis, and podocyte injury were assessed, and underlying mechanisms were investigated. RESULTS: The levels of fasting blood glucose, glycated hemoglobin, kidney-weight-to- body-weight (KW/BW) and urine albumin-to-creatinine (ACR) were increased at 16 weeks post injection. KW/BW and urine ACR were decreased significantly by inhibiting core fucosylation. The renal pathology, fibrosis, and podocyte injury were mitigated significantly by inhibiting core fucosylation. The protective effects of inhibiting core fucosylation were mediated by downregulated of the phosphorylation of Smad2/3 and extracellular signal-regulated kinase (ERK). CONCLUSIONS: Our results indicate that FUT8-based treatment might be a promising intervention strategy in therapeutic paradigm of DKD.

Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 163 patients.

BACKGROUND: Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal dyskinesia. Approximately half of the cases of paroxysmal kinesigenic dyskinesia worldwide are attributable to proline-rich transmembrane protein 2 mutations. OBJECTIVE: The objective of this study was to investigate potential causative genes and clinical characteristics in proline-rich transmembrane protein 2-negative patients with paroxysmal kinesigenic dyskinesia. METHODS: We analyzed clinical manifestations and performed exome sequencing in a cohort of 163 proline-rich transmembrane protein 2-negative probands, followed by filtering data with a paroxysmal movement disorders gene panel. Sanger sequencing, segregation analysis, and phenotypic reevaluation were used to substantiate the findings. RESULTS: The clinical characteristics of the enrolled 163 probands were summarized. A total of 39 heterozygous variants were identified, of which 33 were classified as benign, likely benign, and uncertain significance. The remaining 6 variants (3 novel, 3 documented) were pathogenic and likely pathogenic. Of these, 3 were de novo (potassium calcium-activated channel subfamily M alpha 1, c.1534A>G; solute carrier family 2 member 1, c.418G>A; sodium voltage-gated channel alpha subunit 8, c.3640G>A) in 3 sporadic individuals, respectively. The other 3 (paroxysmal nonkinesiogenic dyskinesia protein, c.956dupA; potassium voltage-gated channel subfamily A member 1, c.765C>A; Dishevelled, Egl-10, and Pleckstrin domain containing 5, c.3311C>T) cosegregated in 3 families. All 6 cases presented with typical paroxysmal kinesigenic dyskinesia characteristics, except for the Dishevelled, Egl-10, and Pleckstrin domain containing 5 family, where the proband's mother had abnormal discharges in her temporal lobes in addition to paroxysmal kinesigenic dyskinesia episodes. CONCLUSIONS: Our findings extend the genotypic spectrum of paroxysmal kinesigenic dyskinesia and establish the associations between paroxysmal kinesigenic dyskinesia and genes classically related to other paroxysmal movement disorders. De novo variants might be a cause of sporadic paroxysmal kinesigenic dyskinesia. © 2018 International Parkinson and Movement Disorder Society.

First-line CDK4/6 inhibitor-based combinations for HR+/HER2- advanced breast cancer: A Bayesian network meta-analysis.

BACKGROUND: International guidelines recommend cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)-based first-line therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, direct drug comparisons are lacking. We aimed to identify the most effective and safe therapy through network meta-analysis (NMA). METHODS: We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and OpenGrey up to September 30, 2023. Eligible studies included randomized controlled trials (RCTs) assessing endocrine therapy alone or in combination with CDK4/6i as first-line endocrine treatment for HR+/HER2- ABC patients. The hazard ratios for progression-free survival (PFS) and overall survival (OS) and relative risks for objective response rate and adverse events (AEs) were available in selected trials. We performed a Bayesian NMA following PRISMA guidelines. RESULTS: Thirteen RCTs, involving 10 treatments, were included. Most studies were at low risk of bias. Regarding PFS, ribociclib+fulvestrant ranked first with a surface under the cumulative ranking curve (SUCRA) of 85.0%, followed by dalpiciclib+nonsteroidal aromatase inhibitor (NSAI) (SUCRA = 78.9%). Considering OS, the top three ranked treatments were ribociclib+fulvestrant (SUCRA = 94.1%), abemaciclib+NSAI (SUCRA = 69.9%), and ribociclib+NSAI (SUCRA = 68.5%). Out of four CDK4/6is, ribociclib minimized the grade 3/4 AEs, while dalpiciclib demonstrated the worst safety. Publication bias could not be ignored in our analyses, and the certainty of evidence was downgraded primarily due to imprecision. CONCLUSIONS: Ribociclib+fulvestrant probably represents the best option in a first-line setting. When combined with NSAI, dalpiciclib likely showed the best efficacy but the worst safety. Abemaciclib+NSAI and ribociclib+NSAI could also be promising treatments, while palbociclib presented inferiority. (PROSPERO Registration No. CRD42022370271).

Predictive Significance of Systemic Immune-Inflammation Index in Patients with Breast Cancer: A Retrospective Cohort Study.

Background: Peripheral blood inflammation indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have become research hotspots in the diagnosis, treatment, and prognosis prediction of breast cancer, whereas existing research findings remain controversial. Methods: Data pertaining to 1808 breast cancer patients were collected retrospectively to analyze the predictive value of NLR/PLR/SII for breast cancer clinicopathological characteristics, chemotherapy response, and relapse. 1489, 258, and 53 eligible breast cancer patients entered into the three analyses, respectively. Logistic regression analyses were used to assess the correlation between these indices and poor response to chemotherapy. A predictive scoring model was established to predict chemotherapeutic responses based upon the odds ratio values of significant variables identified in logistic regression analyses. Results: Higher pretherapeutic NLR/PLR/SII values were significantly correlated with higher tumor stage, triple-negative breast cancer, premenopausal status, and younger age. Logistic regression analyses indicated that pretherapeutic high SII (as a continuous variable or with a cut-off value of 586.40) and HER2-negative status were independent predictors of poor response to neoadjuvant chemotherapy. A first-in-class SII-based predictive scoring model well distinguished patients who might not benefit from neoadjuvant chemotherapy, with an area under the curve of 0.751. In HR-positive cancers, SII was more strongly associated with clinicopathological features and chemotherapy response. In addition, a receiver operating characteristic curve analysis indicated that the specificity of follow-up SII in identifying cancer relapse was greater than 98.0% at a cut-off value of 900. Conclusion: As a predictor of breast cancer, especially in the HR-positive subtype, SII may eclipse NLR/PLR. SII-high patients are more likely to have a worse chemotherapy response and a higher risk of recurrence.

Cyclin-dependent kinase inhibition and its intersection with immunotherapy in breast cancer: more than CDK4/6 inhibition.

INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) have had clinical success in treating hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Notably, CDK4/6i have expanded to the neoadjuvant setting for early breast cancer and other cancer types and potently synergize with immunotherapy. Other CDKs, including CDK7, CDK9, and CDK12/13, mainly function in transcriptional processes as well as cell cycle regulation, RNA splicing, and DNA damage response. Inhibiting these CDKs aids in suppressing tumors, reversing drug resistance, increasing drug sensitivity, and enhancing anti-tumor immunity in breast cancer. AREAS COVERED: We reviewed the applications of CDK4/6i, CDK7i, CDK9i and CDK12/13i for various breast cancer subtypes and their potentials for combination with immunotherapy. A literature search of PubMed, Embase, and Web of Science was conducted in April 2022. EXPERT OPINION: The use of CDK4/6i represents a major milestone in breast cancer treatment. Moreover, transcription-related CDKs play critical roles in tumor development and are promising therapeutic targets for breast cancer. Some relevant clinical studies are underway. More specific and efficient CDKis will undoubtedly be developed and clinically tested. Characterization of their immune-priming effects will promote the development of combination therapies consisting of CDKi and immunotherapy.

Functional assessment of missense variants of uncertain significance in the cancer susceptibility gene PALB2.

Germline PALB2 pathogenic variants are associated with an increased lifetime risk for breast, pancreatic, and ovarian cancer. However, the interpretation of the pathogenicity of numerous PALB2 missense variants of uncertain significance (VUSs) identified in germline genetic testing remains a challenge. Here we selected ten potentially pathogenic PALB2 VUSs identified in 2279 Chinese patients with breast cancer and evaluated their impacts on PALB2 function by systematic functional assays. We showed that three PALB2 VUSs p.K16M [c.47 A > T], p.L24F [c.72 G > C], and p.L35F [c.103 C > T] in the coiled-coil domain impaired PALB2-mediated homologous recombination. The p.L24F and p.L35F variants partially disrupted BRCA1-PALB2 interactions, reduced RAD51 foci formation in response to DNA damage, abrogated ionizing radiation-induced G2/M checkpoint maintenance, and conferred increased sensitivity to olaparib and cisplatin. The p.K16M variant presented mild effects on BRCA1-PALB2 interactions and RAD51 foci formation. Altogether, we identify two novel PALB2 VUSs, p.L24F and p.L35F, that compromise PALB2 function and may increase cancer risk. These two variants display marked olaparib and cisplatin sensitivity and may help predict response to targeted therapy in the clinical treatment of patients with these variants.

Positive association of serum FUT8 activity with renal tubulointerstitial injury in IgA nephropathy patients.

BACKGROUND: α-1,6 Fucosyltransferase (FUT8) appears to play an essential role in the pathogenesis of renal fibrosis. However, it remained unknown whether FUT8 also contributed to renal fibrosis in immunoglobulin A nephropathy (IgAN). In the present study, we explored the association of serum FUT8 activity with renal tubulointerstitial injury in IgAN patients. METHODS: Serum FUT8 activity was measured in 135 IgAN patients and 68 healthy controls from January 2016 to December 2018. The relationships of serum FUT8 activity with clinical and pathological features were analyzed. RESULTS: Relative to healthy controls, IgAN patients had significantly higher serum FUT8 activity and upregulation of renal FUT8 protein (p < .05). Among IgAN patients, there was a positive correlation of serum FUT8 activity with renal FUT8 protein expression (p < .05). Multivariable logistic regression analyses showed that serum FUT8 activity was significantly associated with serum creatinine and eGFR (p < .05). Based on a cut-off value determined from ROC curve analysis, we divided IgAN patients into a low serum FUT8 activity group (≤12.2 pmol/h/mL, n = 40) and a high serum FUT8 activity group (>12.2 pmol/h/ml, n = 95). The high serum FUT8 activity group had a higher Oxford T score, increased inflammatory cell infiltration, more severe fibrosis and poor renal function (p < .05). CONCLUSION: Serum FUT8 activity was positive association with renal tubulointerstitial injury in IgAN patients.

Retrieving zinc concentrations in topsoil with reflectance spectroscopy at Opencast Coal Mine sites.

Heavy metals contaminations in mining areas aroused wide concerns globally. Efficient evaluation of its pollution status is a basis for further soil reclamation. Visible and near-infrared reflectance (Vis-NIR) spectroscopy has been diffusely used for retrieving heavy metals concentrations. However, the reliability and feasibility of calibrated models were still doubtful. The present study estimated zinc (Zn) concentrations via the random forest (RF) and partial least squares regression (PLSR) using ground in-situ Zn concentrations as well as soil spectral reflectance at an Opencast Coal Mine of Ordos, China in February 2020. The coefficient of determination (R2), root mean square error (RMSE), mean absolute error (MAE), and the ratio of performance to deviation (RPD) were selected to assess the robustness of the methods in estimating Zn contents. Moreover, the characteristic bands were chosen by Pearson correlation analysis and Boruta Algorithm. Finally, the comparison between RF and PLSR combined with eight spectral reflectance transformation methods was conducted for four concentration groups to determine the optimal model. The results indicated that: (1) Zn contents represented a skewed distribution (coefficient of variation (CV) = 33%); (2) the spectral reflectance tended to decrease with the increase of Zn contents during 580-1850 nm based on Savitzky-Golay smoothing (SG); (3) the continuous wavelet transform (CWT) demonstrated higher effectiveness than other spectral reflectance transformation methods in enhancing spectral responses, the R2 between Zn contents and the soil spectral reflectance achieved the highest (R2 = 0.71) by using CWT; (4) the RF combined with CWT exhibited the best performance than other methods in the current study (R2 = 0.97, RPD = 3.39, RMSE = 1.05 mg kg-1, MAE = 0.79 mg kg-1). The current study supplied a scientific scheme and theoretical support for predicting heavy metals concentrations via the Vis-NIR spectral method in possible contaminated areas such as coal mines and metallic mineral deposit areas.

A proposed synergistic effect of CSF1R and NMUR2 variants contributes to binge eating in hereditary diffuse leukoencephalopathy with spheroids.

BACKGROUND: The genetic mechanisms of binge eating (BE) as a disease identity remain obscure. BE is usually viewed as a part of the behavioral variant of frontotemporal dementia (bvFTD) features. We encountered a family with hereditary diffuse leukoencephalopathy with spheroids (HDLS) that manifested uniformly with binge-eating-onset dementia. The genetic factors associated with the rare phenotype were investigated. METHODS: The detailed phenotypes of the patients were described. We performed whole-exome sequencing (WES) of family members and repeat-primed PCR to analyze the patients' expansion size of C9orf72, a well-established gene causing FTD. The WES results of additional HDLS patients without BE manifestations were also investigated. RESULTS: All affected individuals had a BE-dementia-epilepsy pattern of disease progression. A recurrent disease-causing mutation in CSF1R established the diagnosis of HDLS in the family. No abnormalities in the expansion size of C9orf72 were detected. The concurrence of a recurrent CSF1R mutation and a rare variant in NMUR2, a gene functionally related to BE, was revealed in the affected family members. No potentially pathogenic variants in other known BE-associated genes were identified. Both the NMUR2 variant and the CSF1R mutation cosegregated with the BE-dementia-epilepsy phenotype in the family. In three additional HDLS patients without BE, no pathogenic variants in NMUR2 were detected. CONCLUSIONS: We propose that synergistic genetic effects of NMUR2 and CSF1R variants may exist and contribute to the development of the BE phenotype in HDLS. NMUR2 is one of the potential susceptible genes in BE and may contribute in a background of a disrupted structural neuronetwork. Further studies in other BE-related disorders are required.

Association between a novel mutation in SLC20A2 and familial idiopathic basal ganglia calcification.

Familial idiopathic basal ganglia calcification (FIBGC) is a rare, autosomal dominant disorder involving bilateral calcification of the basal ganglia. To identify gene mutations related to a Chinese FIBGC lineage, we evaluated available individuals in the family using CT scans. DNA was extracted from the peripheral blood of available family members, and both exonic and flanking intronic sequences of the SLC20A2 gene were amplified by PCR and then sequenced. Non-denaturing polyacrylamide gel electrophoresis (PAGE) was used to confirm the presence of mutations. Allele imbalances of the SLC20A2 gene or relative quantity of SLC20A2 transcripts were evaluated using qRT-PCR. A novel heterozygous single base-pair deletion (c.510delA) within the SLC20A2 gene was identified. This deletion mutation was found to co-segregate with basal ganglia calcification in all of the affected family members but was not detected in unaffected individuals or in 167 unrelated Han Chinese controls. The mutation will cause a frameshift, producing a truncated SLC20A2 protein with a premature termination codon, most likely leading to the complete loss of function of the SLC20A2 protein. This mutation may also lead to a reduction in SLC20A2 mRNA expression by approximately 30% in cells from affected individuals. In conclusion, we identified a novel mutation in SLC20A2 that is linked to FIBGC. In addition to the loss of function at the protein level, decreasing the expression of SLC20A2 mRNA may be another mechanism that can regulate SLC20A2 function in IBGC individuals. We propose that the regional expression pattern of SLC20A1 and SLC20A2 might explain the unique calcification pattern observed in FIBGC patients.