Gene expression prognostic of early relapse risk in low-risk B-cell acute lymphoblastic leukaemia in children.

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukaemia (ALL) and is associated with favorable outcomes, especially in low-risk children. However, as many as 10% of children relapse within 3 years, and such early relapses have poor survival. Identifying children at risk for early relapse is an important challenge. We interrogated data from 87 children with low-risk ETV6::RUNX1-positive B-cell ALL and with available preserved bone marrow samples (discovery cohort). We profiled somatic point mutations in a panel of 559 genes and genome-wide transcriptome and single-nucleotide variants. We found high TIMD4 expression (> 85th-percentile value) at diagnosis was the most important independent prognostic factor of early relapse (hazard ratio [HR] = 5.07 [1.76, 14.62]; p = 0.03). In an independent validation cohort of low-risk ETV6::RUNX1-positive B-cell ALL (N = 68) high TIMD4 expression at diagnosis had an HR = 4.78 [1.07, 21.36] (p = 0.04) for early relapse. In another validation cohort including 78 children with low-risk ETV6::RUNX1-negative B-cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 [1.31, 11.79] (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low-risk B-cell ALL in children might be associated with high risk for early relapse.

Low toxicity contributes to Sporothrix globosa invade the skin of patients in low-epidemic areas of China.

OBJECTIVE: This study aims to assess the clinical characteristics of sporotrichosis in low-endemic areas of China, including the prevalence geography, genotypic traits of patients, clinical manifestations, and strain virulence and drug sensitivities. The objective is to improve the currently used clinical management strategies for sporotrichosis. METHODS: Retrospective data were collected from patients diagnosed with sporotrichosis through fungal culture identification. The isolates from purified cultures underwent identification using CAL (Calmodulin) gene sequencing. Virulence of each strain was assessed using a Galleria mellonella (G. mellonella) larvae infection model. In vitro susceptibility testing against commonly used clinical antifungal agents for sporotrichosis was conducted following CLSI criteria. RESULTS: In our low-endemic region for sporotrichosis, the majority of cases (23) were observed in middle-aged and elderly women with a history of trauma, with a higher incidence during winter and spring. All clinical isolates were identified as Sporothrix globosa (S. globosa). The G. mellonella larvae infection model indicated independent and dose-dependent virulence among strains, with varying toxicity levels demonstrated by the degree of melanization of the G. mellonella. Surprisingly, lymphocutaneous types caused by S. globosa exhibited lower in vitro virulence but were more common in affected skin. In addition, all S.globosa strains displayed high resistances to fluconazole, while remaining highly susceptible to terbinafine, itraconazole and amphotericin B. CONCLUSION: Given the predominance of elderly women engaged in agricultural labour in our region, which is a low-epidemic areas, they should be considered as crucial targets for sporotrichosis monitoring. S. globosa appears to be the sole causative agent locally. However, varying degrees of melanization in larvae were observed among these isolates, indicating a divergence in their virulence. Itraconazole, terbinafine and amphotericin B remain viable first-line antifungal options for treating S.globosa infection.

Tetrahydrobiopterin metabolism attenuates ROS generation and radiosensitivity through LDHA S-nitrosylation: novel insight into radiogenic lung injury.

Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice (Gch1fl/fl; Sftpa1-Cre+/- mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice (Gch1lsl/lsl; Sftpa1-Cre+/- mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. Overall, the results of the present study showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced lung injury.

Two Cases of Superficial Fungal Infection Caused by Non-Albicans Candida Species Manifest Greenish-black Discoloration.

The clinical manifestation of superficial candidiasis varies depending on the infectious sites and causative Candida species that brings a great challenge to diagnose or treat without mycological or pathological evidence in clinical settings. Oral mucosal candidiasis and onychomycosis are most common types of superficial candidiasis. Typically, oral mucosal candidiasis manifests as white or erythematous thrush coated on the tongue and other interior oral cavity; and onychomycosis caused by Candida spp. presents with thick, fragile, or cracked fingernails or toenails in yellow or white discoloration. Here, we report one case of patient with a black hairy tongue caused by Candida tropicalis and one case of greenish discolored onychomycosis caused by Candida parapsilosis. The cases of superficial candidiasis with the same discolored lesions were searched in literature and compared with our cases in clinical manifestation, causative pathogen and treatment. These cases highlight the importance of mycological diagnosis for identifying non-Candida albicans Candida species (NCAC) in superficial infections to guide an effective therapy.

Fault Diagnosis of Rolling Bearings in Primary Mine Fans under Sample Imbalance Conditions.

Rolling bearings are crucial parts of primary mine fans. In order to guarantee the safety of coal mine production, primary mine fans commonly work during regular operation and are immediately shut down for repair in case of failure. This causes the sample imbalance phenomenon in fault diagnosis (FD), i.e., there are many more normal state samples than faulty ones, seriously affecting the precision of FD. Therefore, the current study presents an FD approach for the rolling bearings of primary mine fans under sample imbalance conditions via symmetrized dot pattern (SDP) images, denoising diffusion probabilistic models (DDPMs), the image generation method, and a convolutional neural network (CNN). First, the 1D bearing vibration signal was transformed into an SDP image with significant characteristics, and the DDPM was employed to create a generated image with similar feature distributions to the real fault image of the minority class. Then, the generated images were supplemented into the imbalanced dataset for data augmentation to balance the minority class samples with the majority ones. Finally, a CNN was utilized as a fault diagnosis model to identify and detect the rolling bearings' operating conditions. In order to assess the efficiency of the presented method, experiments were performed using the regular rolling bearing dataset and primary mine fan rolling bearing data under actual operating situations. The experimental results indicate that the presented method can more efficiently fit the real image samples' feature distribution and generate image samples with higher similarity than other commonly used methods. Moreover, the diagnostic precision of the FD model can be effectively enhanced by gradually expanding and enhancing the unbalanced dataset.

Scalp Infection Caused by Mycobacterium abscessus Manifested as Patchy Alopecia in an Immunocompetent Female.

Mycobacterium abscessus (M. abscessus) is a fast-growing, non-tuberculous mycobacterium (NTM) that can cause human infections varying from superficial infection to pulmonary or even systemic infections. The latter is more commonly appeared in immunocompromised patients. The skin infection caused by M. abscessus often appears after trauma or surgical procedure. It is often manifested by subcutaneous nodules, papules, erythema, tender erythematous or violaceous plaques, cellulitis, abscesses, ulcerations, and draining sinuses. Herein, we present a non-typical cutaneous manifestation of M. abscessus infection in a 46-year-old woman who presented with alopecia on the scalp with no itching or pain. The pathogen was isolated and identified as M. abscessus by morphology and DNA sequencing. To our best knowledge, there was no report that this organism could cause skin lesions mimicking patchy alopecia. After 3 months of antibacterial treatment, the cutaneous lesion disappeared, and new growth of hair occurred in this patient.

Construction of an immune-related lncRNA-miRNA-mRNA regulatory network in radiation-induced esophageal injury in rats.

Radiation-induced esophageal injury (RIEI) is an adverse reaction of radiation therapy in patients with esophageal cancer, lung cancer and other malignant tumors. Competitive endogenous RNA (ceRNA) network is known to play a significant role in the onset and progression of many diseases, but the exact mechanism of ceRNA in RIEI has not been fully elucidated. In this study, rat esophaguses were obtained after conducting irradiation under different doses (0 Gy, 25 Gy, 35 Gy). Total RNA was extracted and mRNA, lncRNA, circRNA, and miRNA sequencing was performed. Multiple dose-dependent differentially expressed RNAs (dd-DERs), including 870 lncRNAs, 82 miRNAs, 2478 mRNAs, were obtained through the integration of differential expression analysis and dose-dependent screening (35 Gy ≥ 25 Gy > 0 Gy, or 35 Gy ≤ 25 Gy < 0 Gy). Co-expression analysis and prediction of the binding site in dd-DER were conducted and 27 lncRNAs, 20 miRNAs, and 168 mRNAs were selected to construct a ceRNA network. As the immune microenvironment is crucial for RIEI progression, we constructed an immune-related ceRNA network consisting of 11 lncRNAs, 9 miRNAs, and 9 mRNAs. The expression levels of these immune-related RNAs were verified by RT-qPCR. Immune infiltration analysis showed that the RNAs in the immune-related ceRNA network were mainly associated with the proportion of monocytes, M2 macrophages, activated NK cells, and activated CD4+ memory T cells. Drug sensitivity analysis was conducted based on the expression levels of mRNAs in the immune-related ceRNA network, and small molecule drugs with preventive and therapeutic effects on RIEI were identified. In summary, an immune-related ceRNA network associated with RIEI progression was constructed in this study. The findings provide useful information on new potential targets for the prevention and treatment of RIEI.

Refining eligibility criteria of unit selection for myeloablative cord blood transplantation in acute leukemia: Real-world experience of a referral center.

The algorithm for cord blood (CB) unit selection is still somewhat ambiguous. We retrospectively analyzed 620 cases of acute leukemia between 2015 and 2020, who were treated with myeloablative single-unit umbilical CB transplantation (UCBT). We found that, when human leukocyte antigen (HLA) mismatch was ≤3/10, CD34+ cell dosage <0.83 × 105/kg-considerably lower than prevalent guidelines-was permissible without affecting survival. Moreover, synergy between donor killer-cell immunoglobulin-like receptors (KIR) haplotypes-B and donor-recipient HLA-C mismatch protected against relapse-related mortality. We submit that minimum required CD34+ cell dosage can possibly be relaxed to broaden access to UCBT, and donor KIR genotyping should be considered during unit selection.

Successful application of photodynamic therapy for skin infection caused by Corynespora cassiicola in an immunosuppressed patient and literature review.

Corynespora cassiicola (C. cassiicola) is a common plant pathogen but occasionally causes infections in human skin. Poor outcome and death in such cases were then often reported even after a long course of antifungal treatment. In the present case, the patient was a 54-year-old farmer who presented with a ten-month history of an ulcerative lesion in the right lower extremity after a minor skin trauma. The patient had been undergoing immunosuppressive treatment for nephrotic syndrome for 2 months before the onset of the skin lesion. The fungal isolate from the lesion was identified as C. cassiicola by morphology and molecular sequencing. The patient was treated with ALA-PDT 5 times at 10 days intervals. The lesion disappeared and has not recurred in the 8-month follow-up. To our knowledge, it is the first time ALA-PDT has been used for treatment of a skin lesion caused by C. cassiicola. A retrospective analysis of the literature found 9 cases of C. cassiicola infection. All 9 patients had a history of immunodeficient conditions and had experienced a long course of antifungal therapy. Despite the rigorous antifungal treatment, 2 patients with CARD9 gene deficiency ultimately died. Our case suggests that photodynamic therapy is a potentially beneficial approach for treatment of fungal infection in immunosuppressed patients who failed to respond to antifungal agents.

The Composite Immune Risk Score predicts overall survival after allogeneic hematopoietic stem cell transplantation: A retrospective analysis of 1838 cases.

There has been little consensus on how to quantitatively assess immune reconstitution after hematopoietic stem cell transplantation (HSCT) as part of the standard of care. We retrospectively analyzed 11 150 post-transplant immune profiles of 1945 patients who underwent HSCT between 2012 and 2020. 1838 (94.5%) of the cases were allogeneic HSCT. Using the training set of patients (n = 729), we identified a composite immune signature (integrating neutrophil, total lymphocyte, natural killer, total T, CD4+ T, and B cell counts in the peripheral blood) during days 91-180 after allogeneic HSCT that was predictive of early mortality and moreover simplified it into a formula for a Composite Immune Risk Score. When we verified the Composite Immune Risk Score in the validation (n = 284) and test (n = 391) sets of patients, a high score value was found to be associated with hazard ratios (HR) of 3.64 (95% C.I. 1.55-8.51; p = .0014) and 2.44 (95% C.I., 1.22-4.87; p = .0087), respectively, for early mortality. In multivariate analysis, a high Composite Immune Risk Score during days 91-180 remained an independent risk factor for early mortality after allogeneic HSCT (HR, 1.80; 95% C.I., 1.28-2.55; p = .00085). In conclusion, the Composite Immune Risk Score is easy to compute and could identify the high-risk patients of allogeneic HSCT who require targeted effort for prevention and control of infection.

Surgery plus photodynamic therapy for a diabetic patient with cutaneous infectious granuloma caused by Curvularia lunata.

Curvularia lunata (C. lunata) can be easily found in environment and plants and rarely causes human infections. Antifungal agents have been the primary approach to treat such infections; however, adverse hepatotoxic reactions may require discontinuation of the long-term use of antifungal agents in patients with pre-existing liver diseases. New therapeutic approaches are thus needed to cope with these circumstances. Here, we report a 66-year-old diabetic female patient, suffering from a rapidly growing lesion on the nose for 2 months. The patient was diagnosed with cutaneous fungal infection caused by C. lunata, which was based on mycological study and ITS sequencing. The lesion was completely disappeared after a combination of surgery and 3 times of photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) at 9- day intervals. The patient did not receive any antifungal agents during the treatment. There was no recurrence at 6-month fellow-up. In the following in vitro study, C. Lunata growth was significantly inhibited by ALA-PDT treatment. Therapeutic success in this patent suggests that the ALA-PDT method could be a promising treatment for cutaneous fungal infection caused by C. Lunata and others.

'Dynamic zero-COVID' policy and viral clearance during an omicron wave in Tianjin, China: a city-wide retrospective observational study.

OBJECTIVE: To report how the Chinese mainland battled its first omicron wave, which happened in Tianjin, a metropolis with 14 million residents. We also sought to better understand how clinical features affected the timing of viral clearance. DESIGN: A retrospective study of the omicron wave in Tianjin between 8 January 2022 and 3 March 2022. SETTING: Except for the first cases on 8 January, all the omicron cases were identified through PCR mass testing in the residential communities. Residential quarantine and serial PCR mass testing were dynamically adjusted according to the trends of new cases. PARTICIPANTS: All the 417 consecutive PCR-positive cases identified through mass screening of the entire city's 14 million residents. 45.3% of the cases were male, and the median age was 37 (range 0.3-90). 389 (93%) cases had complete data for analysing the correlation between clinical features and the timing of viral clearance. MAIN OUTCOME AND MEASURE: Time to viral clearance. RESULTS: Tianjin initiated the 'dynamic zero-COVID' policy very early, that is, when daily new case number was ≈0.4 cases per 1 000 000 residents. Daily new cases dropped to <5 after 3 February, and the number of affected residential subdivisions dropped to ≤2 after 13 February. 64% (267/417) of the cases had no or mild symptoms. The median interval from hospital admission to viral clearance was 10 days (range 3-28). An exploratory analysis identified a feature cluster associated with earlier viral clearance, with HRs of 3.56 (95% CI 1.66 to 7.63) and 3.15 (95% CI 1.68 to 5.91) in the training and validation sets, respectively. CONCLUSIONS: The 'dynamic zero-COVID' policy can suppress an omicron wave within a month. It might be possible to predict in advance which cases will require shorter periods of isolation based on their clinical features.

The role of human antigen R (HuR) in modulating proliferation, senescence and radiosensitivity of skin cells.

The skin is the largest outermost organ of the human body. It is vulnerable to various damages, such as ionizing radiation. Exploration of proliferation, senescence and radiosensitivity of skin cells contributes to the development of medical and cosmetic countermeasures against skin aging and toward injury protection. Human antigen R (HuR) is one of the most widely studied RNA-binding proteins and serves an important role in stabilization of mRNA and regulation of the expression of the target genes. To investigate the role of HuR in modulating proliferation, senescence and radiosensitivity of skin cells, the present study performed an in vitro study using lentivirus-mediated overexpression or silencing of HuR in human keratinocyte HaCaT cells and human skin fibroblast WS1 cells. The results indicated that overexpression of HuR promoted proliferation, whereas downregulation of HuR inhibited proliferation of HaCaT and WS1 cells. Overexpression of HuR reduced apoptosis and senescence in skin cells. RNA-Seq of skin cells with HuR overexpression or knockdown identified 77 mRNAs positively or negatively correlated with HuR expression levels. In addition, silencing of HuR induced a significant increase in radiogenic reactive oxygen species after irradiation. Overexpression of HuR increased radiotolerance of HaCaT and WS1 cells. RNA immunoprecipitation coupled with RNA-Seq identified 14 mRNAs interacting with HuR upon radiation exposure. Overall, the findings of the present study illustrated the key role of HuR in modulating proliferation, senescence and radiosensitivity of skin cells providing a new therapeutic strategy for cosmetic treatments and to combat skin injury.

Regulating Acidosis and Relieving Hypoxia by Platelet Membrane-Coated Nanoparticle for Enhancing Tumor Chemotherapy.

Acidosis and hypoxia of tumor remain a great challenge for cancer therapy. Herein, we developed Hb-LOX-DOX-ZIF8@platelet membrane nanoparticles (H-L-D-Z@PM NPs) to address this problem. Lactate oxidase (LOX) could deplete intratumoral lactate adequately and amplify oxidative stress efficiently. In the meantime, hemoglobin (Hb) was intended to deliver oxygen, relieve hypoxia, and boost the catalytic activity of LOX. The coated PM bestowed active tumor-targeting ability and good biocompatibility to these nanoparticles. Moreover, the encapsulation of zeolitic imidazolate framework-8 (ZIF8) offered the acid response capacity to nanoparticles. With the synergism of chemotherapy drug doxorubicin (DOX), these H-L-D-Z@PM NPs appeared to have excellent antitumor competence. Collectively, this study offered a new strategy for enhancing tumor chemotherapy by regulating acidosis and relieving hypoxia.

Transcriptome Profiling Unveils a Critical Role of IL-17 Signaling-Mediated Inflammation in Radiation-Induced Esophageal Injury in Rats.

Elucidation of the molecular mechanisms involving the initiation and progression of radiation-induced esophageal injury (RIEI) is important for prevention and treatment. Despite ongoing advances, the underlying mechanisms controlling RIEI remain largely unknown. In the present study, RNA-seq was performed to characterize mRNA profiles of the irradiated rat esophagus exposed to 0, 25, or 35 Gy irradiation. Bioinformatics analyses including dose-dependent differentially expressed genes (DEGs), Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG) pathway, protein-protein interaction (PPI) network, and immune infiltration were performed. 134 DEGs were screened out with a dose-dependent manner (35 Gy > 25 Gy > control, or 35 Gy < 25 Gy < control). GO and KEGG analyses showed that the most significant mechanism was IL-17 signaling-mediated inflammatory response. 5 hub genes, Ccl11, Cxcl3, Il17a, S100a8, and S100a9, were identified through the intersection of the DEGs involved in inflammatory response, IL-17 pathway, and PPI network. Additionally, immune infiltration analysis showed the activation of macrophages, monocytes, T cells, NKT cells, and neutrophils, among which macrophages, monocytes, and neutrophils might be the main sources of S100a8 and S100a9. Thus, these findings further our understanding on the molecular biology of RIEI and may help develop more effective therapeutic strategies.

Deletion of Non-histidine Domains of Histidine Kinase CHK1 Diminishes the Infectivity of Candida albicans in an Oral Mucosal Model.

Objectives: The histidine kinase (HK) CHK1 and other protein kinases in Candida albicans are key players in the development of hyphae. This study is designed to determine the functional roles of the S_Tkc domain (protein kinase) and the GAF domain of C. albicans CHK1 in hyphal formation and mucosal invasion. Methods: The domain mutants CHK25 (ΔS_Tkc CHK1/Δchk1) and CHK26 (ΔS_TkcΔgaf CHK1/Δchk1) were first constructed by the his1-URA3-his1 method and confirmed by sequencing and Southern blots. A mouse tongue infection model was used to evaluate the hyphal invasion and fungal loads in each domain mutant, full-gene deletion mutant CHK21 (chk1Δ/chk1Δ), re-constituted strain CHK23 (chk1Δ/CHK1), and wild type (WT) from day 1 to day 5. The degree of invasion and damage to the oral mucosa of mice in each strain-infected group was evaluated in vivo and compared with germ tube rate and hyphal formation in vitro. Result: When compared with severe mucosal damage and massive hyphal formation in WT- or CHK23-infected mouse tongues, the deletion of S_Tkc domain (CHK25) caused mild mucosal damage, and fungal invasion was eliminated as we observed in full-gene mutant CHK21. However, the deletion of S_Tkc and GAF (CHK26) partially restored the hyphal invasion and mucosal tissue damage that were exhibited in WT and CHK23. Regardless of the in vivo results, the decreased hyphal formation and germ tube in vitro were less apparent and quite similar between CHK25 and CHK26, especially at the late stage of the log phase where CHK26 was closer to WT and CHK23. However, growth defect and hyphal impairment of both domain mutants were similar to CHK21 in the early stages. Conclusion: Our data suggest that both protein kinase (S_Tkc) and GAF domains in C. albicans CHK1 are required for hyphal invasiveness in mucosal tissue. The appropriate initiation of cell growth and hyphal formation at the lag phase is likely mediated by these two functional domains of CHK1 to maintain in vivo infectivity of C. albicans.

Case Report and Literature Review of Impetigo-Like Tinea Faciei.

Impetigo, commonly caused by bacteria, is characterized by lesions of pustules, bullae or golden yellow crusts; it is seldom caused by fungi. Here, we report one case of a 17-year-old female patient with a 1-month history of erythematous pustules on her left cheek. She was clinically diagnosed with "impetigo", but did not respond to 1 week of treatment with topical mupirocin cream (antibacterial agent). We then saw that a fungal colony grew on the culture, which was identified as T. mentagrophytes based on the morphological and molecular characteristics. The patient was then diagnosed with tinea faciei and was topically treated with 0.2% ketoconazole cream twice per day for 7 days. Through a literature review, we found another 18 cases of impetigo-like tinea faciei with similar clinical manifestations and pathogenic characteristics. Among these, the most common causative agent was T. mentagrophytes complex, which frequently occurs in children and adolescents and exhibits no gender preferences. Systemic and topical antifungals such as terbinafine or itraconazole are effective for impetigo-like tinea faciei caused by T. mentagrophytes complex. However, prolonged course of impetigo in more than 50% cases highlights the importance of mycological examination when dealing with apparent antibiotic-resistant impetigo cases in clinical settings.