Anti-Interleukin 17A Biologic Therapy Attempts on Livedoid Vasculopathy: A Report of Case Series.

The application of biologics such as anti-tumor necrosis factor (TNF) has shown great efficacy in livedoid vasculopathy (LV). However, new biological options need to be identified for those with a high tuberculosis reactivation risk. In this study, we evaluated the efficacy of anti-17A biologics for LV therapy. Two patients with LV who were irresponsive to traditional anticoagulation therapy were studied at the outpatient dermatology clinic of Peking Union Medical College Hospital. All patients received anti-17A biological therapy for at least two-four weeks. Both patients reported an exacerbation of the skin lesions, which might indicate that the IL-17 pathway plays a critical role in LV pathogenesis.

Classifying breast cancer using multi-view graph neural network based on multi-omics data.

Introduction: As the evaluation indices, cancer grading and subtyping have diverse clinical, pathological, and molecular characteristics with prognostic and therapeutic implications. Although researchers have begun to study cancer differentiation and subtype prediction, most of relevant methods are based on traditional machine learning and rely on single omics data. It is necessary to explore a deep learning algorithm that integrates multi-omics data to achieve classification prediction of cancer differentiation and subtypes. Methods: This paper proposes a multi-omics data fusion algorithm based on a multi-view graph neural network (MVGNN) for predicting cancer differentiation and subtype classification. The model framework consists of a graph convolutional network (GCN) module for learning features from different omics data and an attention module for integrating multi-omics data. Three different types of omics data are used. For each type of omics data, feature selection is performed using methods such as the chi-square test and minimum redundancy maximum relevance (mRMR). Weighted patient similarity networks are constructed based on the selected omics features, and GCN is trained using omics features and corresponding similarity networks. Finally, an attention module integrates different types of omics features and performs the final cancer classification prediction. Results: To validate the cancer classification predictive performance of the MVGNN model, we conducted experimental comparisons with traditional machine learning models and currently popular methods based on integrating multi-omics data using 5-fold cross-validation. Additionally, we performed comparative experiments on cancer differentiation and its subtypes based on single omics data, two omics data, and three omics data. Discussion: This paper proposed the MVGNN model and it performed well in cancer classification prediction based on multiple omics data.

A full-body transcription factor expression atlas with completely resolved cell identities in C. elegans.

Invariant cell lineage in C. elegans enables spatiotemporal resolution of transcriptional regulatory mechanisms controlling the fate of each cell. Here, we develop RAPCAT (Robust-point-matching- And Piecewise-affine-based Cell Annotation Tool) to automate cell identity assignment in three-dimensional image stacks of L1 larvae and profile reporter expression of 620 transcription factors in every cell. Transcription factor profile-based clustering analysis defines 80 cell types distinct from conventional phenotypic cell types and identifies three general phenotypic modalities related to these classifications. First, transcription factors are broadly downregulated in quiescent stage Hermaphrodite Specific Neurons, suggesting stage- and cell type-specific variation in transcriptome size. Second, transcription factor expression is more closely associated with morphology than other phenotypic modalities in different pre- and post-differentiation developmental stages. Finally, embryonic cell lineages can be associated with specific transcription factor expression patterns and functions that persist throughout postembryonic life. This study presents a comprehensive transcription factor atlas for investigation of intra-cell type heterogeneity.

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control.

N6-methyladenosine (m6A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m6A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m6A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels. Limited OGDH availability slows the tricarboxylic acid (TCA) cycle with accumulation of α-ketoglutarate (α-KG) and conversion of α-KG into L-2-hydroxyglutarate (L-2-HG). L-2-HG inhibits energy production in both murine and human hematopoietic cells in vitro. Impaired mitochondrial energy production confers competitive disadvantage to HSPCs and limits clonogenicity of Mll-AF9-induced leukemia. Our study uncovers a mechanism whereby the RNA m6A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia.

A rare case of intracranial solitary fibrous tumor that is still alive after multiple surgical resections: a case report and review of the literature.

A Solitary Fibrous Tumor (SFT) is a rare, aggressive, and metastasis- and recurrence- prone mesenchymal tumor. In this case report and review, we describe a rare instance of intracranial SFT, discovered for the first time. It was discovered in 2008 and following total surgical removal, the pathology was categorized as hemangiopericytoma cell tumor (HPC) at the time by WHO tumor criteria. An imaging review 8 months after surgery revealed a tumor recurrence: combined radiation and gamma-knife therapy was continued throughout this time. The tumor did not metastasis until June 2018 when it presented in the pancreas with ruptured bleeding and a postoperative pathology was suggestive of SFT. Fortunately, the patient is still alive nearly 3 years after the 2020 surgery, after staged surgical resection and combined multimedia therapy, with no imaging or clinical evidence of a recurrent intracranial primary lesions. To our knowledge, there is no previous record of using a combined treatment modality for Intracranial Solitary Fibrous Tumor (ISFT). Combined with an account of the patient's experience, we empirically describe a combined approach with a preference for gross-total resection (GTR), supplemented by multimodal assistance with stereotactic (radiotherapy), gamma knife (GK), molecular targeting, and immunization for patients admitted acutely, with accurate preoperative identification and aggressive management after intraoperative case response to maximize treatment of recurrent ISFT and improve prognosis. We recommend multimodal management for SFT with prolonged-term recurrence and metastases, both for the control benefits of GTR, RT, or GK for local recurrence and for the positive prognosis of targeted and immune metastases.

Tailoring the draw solution chemistry in the integrated electro-Fenton and forward osmosis for enhancing emerging contaminants removal: Performance, DFT calculation and degradation pathway.

Integrated electro-Fenton and forward osmosis is capable to simultaneously separate emerging contaminants and degrade accumulated ones. Thus, an understanding of how draw solution chemistry in forward osmosis influences electro-Fenton is vital for maximizing overall treatment. Therefore, this study aimed to determine the transport behavior of four trace organic contaminants (TrOCs) including Diuron, Atrazine, DEET and Sulfamethoxazole under several influencing factors. Alkalic NaCl severely deteriorated degradation because of the less generation of OH caused by the interfered iron redox cycle. pH-neutral NaCl resulted in the highest reverse salt flux, namely possible largest production of active chlorine, therefore leading to the highest degradation. Compared to NaCl, Na2SO4 presented a significant lower reverse diffusion due to the larger hydrated radius of SO42- than Cl-. Meanwhile, the large consumption of OH by SO42- decreased degradation. Dissolved organic matters in the secondary effluent acted as the scavenger for OH and resulted in a degradation decline. Water extraction resulted from forward osmosis deteriorated degradation kinetics of all compounds except Sulfamethoxazole. On the other hand, Density functional theory calculations and identified intermediates contributed to propose the possible degradation pathways for each TrOC in terms of understanding TrOCs removal mechanism.

Livedoid vasculopathy and peripheral neuropathy: A retrospective cohort study of 55 Chinese patients and literature review.

Livedoid vasculopathy (LV) is a thrombo-occlusive vascular disease with an uncertain aetiology. In addition to cutaneous manifestations, LV patients may develop peripheral neuropathy. This study aimed to examine features of peripheral neuropathy in Chinese LV patients. We retrospectively reviewed and analysed the clinical data of 55 LV patients treated at Peking Union Medical College Hospital and conducted a literature review of peripheral neuropathy in LV patients. The incidence of peripheral neuropathy in our cohort was 12.73%. Among the seven patients with neuropathy, five were women and two were men. Median age at enrollment and disease onset in these patients was 27.29 and 22.57 years, respectively. Mean time from the appearance of cutaneous manifestations to the development of neurological symptoms was 38.67 months. Peripheral neuropathy was generally refractory to treatment, asymmetric in the distal extremities, and slowly progressive. The main symptom was numbness; hypoesthesia and neuromuscular manifestations occurred occasionally. The proportion of patients reporting seasonal worsening of symptoms was significantly higher in LV patients with peripheral neuropathy than in LV patients without neuropathy (P < .05). Peripheral neuropathy is a potential complication of LV. LV patients with peripheral neuropathy require long-term follow-up.

RNA m6A demethylase ALKBH5 regulates the development of γδ T cells.

γδ T cells are an abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite γδ T cells' origin in the thymus, detailed mechanisms regulating γδ T cell development remain poorly understood. N6-methyladenosine (m6A) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in γδ T cell biology is still unclear. Here, we show that depletion of the m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells, which confers enhanced protection against gastrointestinal Salmonella typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of γδ T cell precursors by increasing the abundance of m6A RNA modification in thymocytes, which further reduces the expression of several target genes including Notch signaling components Jagged1 and Notch2. As a result, impairment of Jagged1/Notch2 signaling contributes to enhanced proliferation and differentiation of γδ T cell precursors, leading to an expanded mature γδ T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m6A modification in the regulation of γδ T cell early development.

Efficacy and safety of intravenous immunoglobulin for treating refractory livedoid vasculopathy: a systematic review.

Introduction: Intravenous immunoglobulin (IVIG) was reported to be the third most used monotherapy in livedoid vasculopathy (LV). There is currently a lack of randomized controlled clinical trials and no standardized therapeutic regimen for IVIG therapy in LV. Methods: We performed a systematic review of the efficacy and safety of IVIG in treating patients with LV using PubMed, Cochrane, and Embase databases. Results: Eighty LV patients from 17 articles were included, receiving IVIG therapy at a dose of 1-2.1 g/kg body weight every 4 weeks. The effective rate of IVIG therapy in LV patients was 95% (76/80) in published studies, showing a good clinical response for resolution of pain, skin ulcerations, and neurological symptoms, and reducing the dependence on glucocorticoids and immunosuppressive agents. IVIG therapy was well tolerated, and no severe adverse events were observed. Conclusion: Overall, to a certain degree, IVIG is probably a safe and effective treatment alternative for refractory LV patients, which still need to be confirmed by large-scale randomized controlled clinical trials.

Platelet count and plateletcrit: Potential haematological biomarkers for livedoid vasculopathy?

BACKGROUND: The pathogenesis of livedoid vasculopathy (LV) remains unknown. Although platelet activation occurs in LV, little research has been conducted on LV platelet morphology parameters. The purpose of this study was to investigate whether platelet morphology changes in LV and its clinical significance. METHODS: Twenty-seven LV patients and 21 cutaneous small vessel vasculitis (CSVV) patients, all at the active stage, were included. Platelet parameters in active- and stable-stage LV and CSVV patients were compared. Correlations between these platelet parameters and LV composite clinical scores were analysed. RESULTS: LV patients' mean age was 25.48 years (range: 9-62 years), and 81.48% (22/27) were women and 18.52% (5/27) were men. The platelet counts and plateletcrit (PCT) levels were significantly elevated in LV patients compared with CSVV patients and in active-stage LV patients compared with stable-stage LV patients after treatment. LV patient composite clinical scores that reflected disease severity and activity were positively correlated with the platelet count and PCT levels. CONCLUSION: Altered platelet morphology was detected in LV patients. Platelet count and PCT might be haematological biomarkers for early prediction of LV activity and relapses and for differential identification between LV and CSVV.

In vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2.

Treatment options for patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are scarce. Recurring mutations, such as mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2) are found in subsets of AML and MDS, are therapeutically targeted by mutant enzyme-specific small molecule inhibitors (IDHmi). IDH mutations induce diverse metabolic and epigenetic changes that drive malignant transformation. IDHmi alone are not curative and resistance commonly develops, underscoring the importance of alternate therapeutic options. We were first to report that IDH1/2 mutations induce a homologous recombination (HR) defect, which confers sensitivity to poly (ADP)-ribose polymerase inhibitors (PARPi). Here, we show that the PARPi olaparib is effective against primary patient-derived IDH1/2-mutant AML/ MDS xeno-grafts (PDXs). Olaparib efficiently reduced overall engraftment and leukemia-initiating cell frequency as evident in serial transplantation assays in IDH1/2-mutant but not -wildtype AML/MDS PDXs. Importantly, we show that olaparib is effective in both IDHmi-naïve and -resistant AML PDXs, critical given the high relapse and refractoriness rates to IDHmi. Our pre-clinical studies provide a strong rationale for the translation of PARP inhibition to patients with IDH1/2-mutant AML/ MDS, providing an additional line of therapy for patients who do not respond to or relapse after targeted mutant IDH inhibition.

Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies.

Splicing factor mutations are common among cancers, recently emerging as drivers of myeloid malignancies. U2AF1 carries hotspot mutations in its RNA-binding motifs; however, how they affect splicing and promote cancer remain unclear. The U2AF1/U2AF2 heterodimer is critical for 3' splice site (3'SS) definition. To specifically unmask changes in U2AF1 function in vivo, we developed a crosslinking and immunoprecipitation procedure that detects contacts between U2AF1 and the 3'SS AG at single-nucleotide resolution. Our data reveal that the U2AF1 S34F and Q157R mutants establish new 3'SS contacts at -3 and +1 nucleotides, respectively. These effects compromise U2AF2-RNA interactions, resulting predominantly in intron retention and exon exclusion. Integrating RNA binding, splicing, and turnover data, we predicted that U2AF1 mutations directly affect stress granule components, which was corroborated by single-cell RNA-seq. Remarkably, U2AF1-mutant cell lines and patient-derived MDS/AML blasts displayed a heightened stress granule response, pointing to a novel role for biomolecular condensates in adaptive oncogenic strategies.

Efficacy of an anti-TNF-alpha agent in refractory livedoid vasculopathy: a retrospective analysis.

BACKGROUND: Livedoid vasculopathy is a recurrent thrombo-occlusive vasculopathy of cutaneous blood vessels and its standard or first-line therapy is still controversial. Besides hypercoagulability, inflammatory factors may also play a secondary role in the pathogenesis of this disease. Monotherapy of thrombolytics cannot achieve satisfactory results because of concomitant inflammation. OBJECTIVE: This pilot study aimed to determine the efficacy of an anti-TNF-alpha agent in patients with refractory livedoid vasculopathy. METHODS: We studied five patients with livedoid vasculopathy who were resistant to steroids, antiplatelets, or danazol therapy, and were treated with etanercept 25-50 mg once a week for 12 consecutive weeks. We assessed clinical characteristics, laboratory findings, and etanercept's efficacy on skin lesions, pain, and quality of life. RESULTS: Etanercept therapy resulted in fast relief of pain in a mean time of 2 weeks. The median duration for the disappearance of erythema and ulcer healing was 8.8 weeks and 10.6 weeks, respectively. There was a reduction in pain by 34.3% after 12 consecutive weeks of etanercept treatment. Disease severity and quality of life significantly improved. CONCLUSIONS: In refractory livedoid vasculopathy patients, etanercept therapy is efficient for skin lesions and pain, and improvement of quality of life, especially in rapid relief of pain.

Neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and other hematological parameters in psoriasis patients.

BACKGROUND: Psoriasis is a chronic immune-mediated skin disorder. Systemic inflammation plays an important role in the pathogenesis of psoriasis. METHODS: A total of 477 patients with psoriasis vulgaris (PsV, n = 347), generalized pustular psoriasis (GPP, n = 37), erythrodermic psoriasis (PsE, n = 45), arthritic psoriasis (PsA, n = 25) and mixed psoriasis (n = 23), and 954 healthy control subjects were included in the study. Demographic, clinical, and laboratory information were collected and compared between subgroups. RESULTS: Compared with the healthy control group, patients with psoriasis had higher total white blood cell (WBC), neutrophil, platelet counts, neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR), but lower hemoglobin (Hb) levels, lymphocyte and red blood cell (RBC) counts. NLR values in the PsV group were significantly lower than those in the GPP, PsE, and PsA groups, with GPP group being the highest. PLR values in the PsV group were significantly lower than those in the GPP, PsE, and PsA groups. There was no significant correlation between the psoriasis area severity index (PASI) score and either the NLR or PLR in the PsV group. CONCLUSIONS: Elevated NLR and PLR were associated with psoriasis and differed between subtypes, suggesting that they could be used as markers of systemic inflammation in psoriasis patients.

Rivaroxaban for treatment of livedoid vasculopathy: A systematic review.

Rivaroxaban is a direct inhibitor of activated coagulation factor X and competitively targets factor Xa via reversible binding. We conducted a systematic review of the efficacy and safety of rivaroxaban for treatment of livedoid vasculopathy (LV) by searching the PubMed, Cochrane and Embase databases. A total of 22 articles and 1 registered clinical trial were identified in the search of which 13 were included. The studies included 73 LV patients receiving rivaroxaban therapy (10-20 mg per day). Overall, 60 patients (82.2%) had responses to therapy, achieving remission of both pain and ulceration. Few adverse effects were observed. Thus, the consensus of the clinical evidence is that rivaroxaban is a well-tolerated and effective treatment for LV. However, this still needs to be confirmed by large prospective and/or case control studies.

Factors Associated with Gestational Diabetes Mellitus: A Meta-Analysis.

Gestational diabetes mellitus (GDM) is a major public health issue, and the aim of the present study was to identify the factors associated with GDM. Databases were searched for observational studies until August 20, 2020. Pooled odds ratios (ORs) were calculated using fixed- or random-effects models. 103 studies involving 1,826,454 pregnant women were identified. Results indicated that maternal age ≥ 25 years (OR: 2.466, 95% CI: (2.121, 2.866)), prepregnancy overweight or obese (OR: 2.637, 95% CI: (1.561, 4.453)), family history of diabetes (FHD) (OR: 2.326, 95% CI: (1.904, 2.843)), history of GDM (OR: 21.137, 95% CI: (8.785, 50.858)), macrosomia (OR: 2.539, 95% CI: (1.612, 4.000)), stillbirth (OR: 2.341, 95% CI: (1.435, 3.819)), premature delivery (OR: 3.013, 95% CI: (1.569, 5.787)), and pregestational smoking (OR: 2.322, 95% CI: (1.359, 3.967)) increased the risk of GDM with all P < 0.05, whereas history of congenital anomaly and abortion, and HIV status showed no correlation with GDM (P > 0.05). Being primigravida (OR: 0.752, 95% CI: (0.698, 0.810), P < 0.001) reduced the risk of GDM. The factors influencing GDM included maternal age ≥ 25, prepregnancy overweight or obese, FHD, history of GDM, macrosomia, stillbirth, premature delivery, pregestational smoking, and primigravida.

Transcriptome-wide quantification of double-stranded RNAs in live mouse tissues by dsRIP-Seq.

Double-stranded RNAs (dsRNAs) are abundantly present in cells, playing multiple regulatory functions. dsRNAs of viral origin activate innate immune responses. Since RNA editing and modifications affect the structure and recognition of RNAs, their alteration can result in the accumulation of aberrant endogenous dsRNAs inducing a deleterious innate immune response. Here, we present a complete protocol for the measurement of dsRNAs in a live mouse tissue using dsRNA immunoprecipitation and sequencing (dsRIP-Seq). This protocol focuses on tissue isolation, dsRNA immunoprecipitation and downstream computational analysis. For complete details on the use and execution of this protocol, please refer to Gao et al. (2020).