Exosomal microRNAs in hepatocellular carcinoma, expanding research field.

In this editorial we comment on the review by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023. Small extracellular vesicles (exosomes) play important roles in the tumor microenvironment. In this review, the authors introduce the following points: (1) The composition and function of exosomal microRNAs (miRNAs) of different cell origins in hepatocellular carcinoma (HCC); (2) the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC; and (3) the potential applicability of exosomal miRNAs derived from mesen-chymal stem cells in the treatment of HCC. In addition, the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced. In this review, the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC, which provides a deeper understanding of exosomal miRNAs to the readers.

Heatstroke Comorbid with SARS-CoV-2 Infection: A Case Report and Literature Review.

Background: Hyperthermia and multiple organ dysfunction syndrome (MODS) are the main characteristics of heatstroke and COVID-19. Differentiating between these illnesses is crucial during a summer COVID-19 pandemic, but cases of heatstroke comorbid with COVID-19 are rarely reported. Case description: We report the first case of heatstroke comorbid with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in a 52-year-old male. After receiving intravenous antibiotics, organ protection measures, and treatment for coagulation disorders, his fever and coma resolved. However, he developed dyspnea and cerebral hemorrhage after several days. This patient experienced a multi-pathogen pulmonary infection and an intractable coagulopathy that ultimately resulted in MODS and death. Conclusion: The combination of heatstroke and SARS-CoV-2 infection exacerbated inflammation, immune abnormalities, and coagulation disorders. The interaction between inflammation and coagulation disturbances contributed to the underlying mechanism in this case, highlighting the importance of early anti-infection, treatment for coagulopathy, immune regulation, and organ protection as crucial interventions.

Neurotoxic effects of triclosan in adolescent mice: Pyruvate kinase M2 dimer regulated Signal transducer and activator of transcription 3 phosphorylation mediated microglia activation and neuroinflammation.

Triclosan (TCS), a commonly used antibacterial agent, is associated with various harmful effects on mammalian neurodevelopment, particularly when exposed prenatally. This study investigated the impact of long-term exposure to TCS on the prefrontal cortex development in adolescent mice. We evaluated the motor ability, motor coordination, and anxiety behavior of mice using open field tests (OFT) and elevated cross maze tests (EPM). An increase in movement distance, number of passes through the central area, and open arm retention time was observed in mice treated with TCS. Hematoxylin eosin staining and Nissl staining also showed significant adverse reactions in the brain tissue of TCS-exposed group. TCS induced microglia activation and increased inflammatory factors expression in the prefrontal cortex. TCS also increased the expression of pyruvate kinase M2 (PKM2), thereby elevating the levels of PKM2 dimer, which entered the nucleus. Treatment with TEPP46 (PKM2 dimer nuclear translocation inhibitor) blocked the expression of inflammatory factors induced by TCS. TCS induced the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3) in vivo and in vitro, upregulating the levels of inflammatory cytokines. The results also demonstrated the binding of PKM2 to STAT3, which promoted STAT3 phosphorylation at the Tyr705 site, thereby regulating the expression of inflammatory factors. These findings highlight the role of PKM2-regulated STAT3 phosphorylation in TCS-induced behavioral disorders in adolescents and propose a reliable treatment target for TCS.

Multi-instance learning based artificial intelligence model to assist vocal fold leukoplakia diagnosis: A multicentre diagnostic study.

OBJECTIVE: To develop a multi-instance learning (MIL) based artificial intelligence (AI)-assisted diagnosis models by using laryngoscopic images to differentiate benign and malignant vocal fold leukoplakia (VFL). METHODS: The AI system was developed, trained and validated on 5362 images of 551 patients from three hospitals. Automated regions of interest (ROI) segmentation algorithm was utilized to construct image-level features. MIL was used to fusion image level results to patient level features, then the extracted features were modeled by seven machine learning algorithms. Finally, we evaluated the image level and patient level results. Additionally, 50 videos of VFL were prospectively gathered to assess the system's real-time diagnostic capabilities. A human-machine comparison database was also constructed to compare the diagnostic performance of otolaryngologists with and without AI assistance. RESULTS: In internal and external validation sets, the maximum area under the curve (AUC) for image level segmentation models was 0.775 (95 % CI 0.740-0.811) and 0.720 (95 % CI 0.684-0.756), respectively. Utilizing a MIL-based fusion strategy, the AUC at the patient level increased to 0.869 (95 % CI 0.798-0.940) and 0.851 (95 % CI 0.756-0.945). For real-time video diagnosis, the maximum AUC at the patient level reached 0.850 (95 % CI, 0.743-0.957). With AI assistance, the AUC improved from 0.720 (95 % CI 0.682-0.755) to 0.808 (95 % CI 0.775-0.839) for senior otolaryngologists and from 0.647 (95 % CI 0.608-0.686) to 0.807 (95 % CI 0.773-0.837) for junior otolaryngologists. CONCLUSIONS: The MIL based AI-assisted diagnosis system can significantly improve the diagnostic performance of otolaryngologists for VFL and help to make proper clinical decisions.

Revealing molecular and cellular heterogeneity in hypopharyngeal carcinogenesis through single-cell RNA and TCR/BCR sequencing.

Introduction: Hypopharyngeal squamous cell carcinoma (HSCC) is one of the malignant tumors with the worst prognosis in head and neck cancers. The transformation from normal tissue through low-grade and high-grade intraepithelial neoplasia to cancerous tissue in HSCC is typically viewed as a progressive pathological sequence typical of tumorigenesis. Nonetheless, the alterations in diverse cell clusters within the tissue microenvironment (TME) throughout tumorigenesis and their impact on the development of HSCC are yet to be fully understood. Methods: We employed single-cell RNA sequencing and TCR/BCR sequencing to sequence 60,854 cells from nine tissue samples representing different stages during the progression of HSCC. This allowed us to construct dynamic transcriptomic maps of cells in diverse TME across various disease stages, and experimentally validated the key molecules within it. Results: We delineated the heterogeneity among tumor cells, immune cells (including T cells, B cells, and myeloid cells), and stromal cells (such as fibroblasts and endothelial cells) during the tumorigenesis of HSCC. We uncovered the alterations in function and state of distinct cell clusters at different stages of tumor development and identified specific clusters closely associated with the tumorigenesis of HSCC. Consequently, we discovered molecules like MAGEA3 and MMP3, pivotal for the diagnosis and treatment of HSCC. Discussion: Our research sheds light on the dynamic alterations within the TME during the tumorigenesis of HSCC, which will help to understand its mechanism of canceration, identify early diagnostic markers, and discover new therapeutic targets.

Multi-Instance Learning for Vocal Fold Leukoplakia Diagnosis Using White Light and Narrow-Band Imaging: A Multicenter Study.

OBJECTIVES: Vocal fold leukoplakia (VFL) is a precancerous lesion of laryngeal cancer, and its endoscopic diagnosis poses challenges. We aim to develop an artificial intelligence (AI) model using white light imaging (WLI) and narrow-band imaging (NBI) to distinguish benign from malignant VFL. METHODS: A total of 7057 images from 426 patients were used for model development and internal validation. Additionally, 1617 images from two other hospitals were used for model external validation. Modeling learning based on WLI and NBI modalities was conducted using deep learning combined with a multi-instance learning approach (MIL). Furthermore, 50 prospectively collected videos were used to evaluate real-time model performance. A human-machine comparison involving 100 patients and 12 laryngologists assessed the real-world effectiveness of the model. RESULTS: The model achieved the highest area under the receiver operating characteristic curve (AUC) values of 0.868 and 0.884 in the internal and external validation sets, respectively. AUC in the video validation set was 0.825 (95% CI: 0.704-0.946). In the human-machine comparison, AI significantly improved AUC and accuracy for all laryngologists (p < 0.05). With the assistance of AI, the diagnostic abilities and consistency of all laryngologists improved. CONCLUSIONS: Our multicenter study developed an effective AI model using MIL and fusion of WLI and NBI images for VFL diagnosis, particularly aiding junior laryngologists. However, further optimization and validation are necessary to fully assess its potential impact in clinical settings. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Narrow band imaging-based radiogenomics for predicting radiosensitivity in nasopharyngeal carcinoma.

Objectives: This study aims to assess the efficacy of narrow band imaging (NBI) endoscopy in utilizing radiomics for predicting radiosensitivity in nasopharyngeal carcinoma (NPC), and to explore the associated molecular mechanisms. Materials: The study included 57 NPC patients who were pathologically diagnosed and underwent RNA sequencing. They were categorized into complete response (CR) and partial response (PR) groups after receiving radical concurrent chemoradiotherapy. We analyzed 267 NBI images using ResNet50 for feature extraction, obtaining 2048 radiomic features per image. Using Python for deep learning and least absolute shrinkage and selection operator for feature selection, we identified differentially expressed genes associated with radiomic features. Subsequently, we conducted enrichment analysis on these genes and validated their roles in the tumor immune microenvironment through single-cell RNA sequencing. Results: After feature selection, 54 radiomic features were obtained. The machine learning algorithm constructed from these features showed that the random forest algorithm had the highest average accuracy rate of 0.909 and an area under the curve of 0.961. Correlation analysis identified 30 differential genes most closely associated with the radiomic features. Enrichment and immune infiltration analysis indicated that tumor-associated macrophages are closely related to treatment responses. Three key NBI differentially expressed immune genes (NBI-DEIGs), namely CCL8, SLC11A1, and PTGS2, were identified as regulators influencing treatment responses through macrophages. Conclusion: NBI-based radiomics models introduce a novel and effective method for predicting radiosensitivity in NPC. The molecular mechanisms may involve the functional states of macrophages, as reflected by key regulatory genes.

[Effects of Controlled-release Blended Fertilizer on Crop Yield and Greenhouse Gas Emissions in Wheat-maize Rotation System].

The increasing use of nitrogen fertilizers exerts extreme pressure on the environment (e.g., greenhouse gas emissions, GHGs) for winter wheat-summer maize rotation systems in the North China Plain. The application of controlled-release fertilizers is considered as an effective measure to improve crop yield and nitrogen fertilizer utilization efficiency. To explore the impact of one-time fertilization of controlled-release blended fertilizer on crop yield and GHGs of a wheat-maize rotation system, field experiments were carried out in Dezhou Modern Agricultural Science and Technology Park from 2020 to 2022. Five treatments were established for both winter wheat and summer maize, including no nitrogen control (CK), farmers' conventional nitrogen application (FFP), optimized nitrogen application (OPT), CRU1 (the blending ratio of coated urea and traditional urea on winter wheat and summer maize was 5:5 and 3:7, respectively), and CRU2 (the blending ratio of coated urea and traditional urea on winter wheat and summer maize was 7:3 and 5:5, respectively). The differences in yield, nitrogen fertilizer utilization efficiency, fertilization economic benefits, and GHGs among different treatments were compared and analyzed. The results showed that nitrogen application significantly increased the single season and annual crop yields of the wheat-maize rotation system (P < 0.05). Compared with those of FFP, the CRU1 and CRU2 treatments increased the yields of summer maize by 0.4% to 5.6%, winter wheat by -5.4% to 4.1%, and annual yields by -1.1% to 3.9% (P > 0.05). N recovery efficiency (NRE), N agronomic efficiency (NAE), and N partial factor productivity (NPFP) were increased by -8.6%-43.4%, 2.05-6.24 kg·kg-1, and 4.24-10.13 kg·kg-1, respectively. Annual net income increased by 0.2% to 6.3%. Nitrogen application significantly increased the annual emissions of soil N2O and CO2 in the rotation system (P < 0.05) but had no effect on the annual emissions of CH4 (except for in the FFP treatment in the first year). The annual total N2O emissions under the CRU1 and CRU2 treatments were significantly reduced by 23.4% to 30.2% compared to those under the FFP treatment (P < 0.05). Additionally, nitrogen application significantly increased the annual global warming potential (GWP) of the rotation system (P < 0.05), but the intensity of greenhouse gas emissions was reduced due to the increase in crop yields. Compared with that under FFP, the annual GWP under the CRU1 and CRU2 treatments decreased by 9.6% to 11.5% (P < 0.05), and the annual GHGs decreased by 11.2% to 13.8% (P > 0.05). In summary, the one-time application of controlled-release blended fertilizer had a positive role in improving crop yield and economic benefits, reducing nitrogen fertilizer input and labor costs, and GHGs, which is an effective nitrogen fertilizer management measure to promote cleaner production of food crops in the North China Plain.

The discovery of three-dimensional Van Hove singularity.

Arising from the extreme/saddle point in electronic bands, Van Hove singularity (VHS) manifests divergent density of states (DOS) and induces various new states of matter such as unconventional superconductivity. VHS is believed to exist in one and two dimensions, but rarely found in three dimension (3D). Here, we report the discovery of 3D VHS in a topological magnet EuCd2As2 by magneto-infrared spectroscopy. External magnetic fields effectively control the exchange interaction in EuCd2As2, and shift 3D Weyl bands continuously, leading to the modification of Fermi velocity and energy dispersion. Above the critical field, the 3D VHS forms and is evidenced by the abrupt emergence of inter-band transitions, which can be quantitatively described by the minimal model of Weyl semimetals. Three additional optical transitions are further predicted theoretically and verified in magneto-near-infrared spectra. Our results pave the way to exploring VHS in 3D systems and uncovering the coordination between electronic correlation and the topological phase.

Effect of hyperbaric oxygen treatment on patients with heatstroke complicated by multiple organ dysfunction:A retrospective study.

Background: The benefits of hyperbaric oxygen (HBO) in treating animals with heat stroke (HS) have been established. This study aims to retrospectively analyze the effect of HBO on multiple organ dysfunction following HS in humans. Methods: Retrospective data were collected from patients with HS admitted to our hospital in the past 7 years. Patients were categorized into groups based on whether they received HBO therapy. The study compared various factors, including sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation-Ⅱ (APACHE-Ⅱ) scores, mortality rates, neurological function scores, serum myocardial enzyme levels, liver, kidney, and coagulation function indicators, blood routine results, electrolyte levels, and modified Barthel index (MBI) score for standard daily living ability before treatment and after 2 and 4 weeks of treatment. Results: The mortality rates in the HBO and control group were 0% and 8.49%, respectively. Upon admission, the HBO group had higher SOFA and APACHE-Ⅱ scores and lower neurological, coagulation, and liver functions than those of the control group. HBO treatment significantly improved SOFA, APACHE-Ⅱ, and neurological scores while relieving levels of alanine aminotransferase, aspartate aminotransferase, creatinine, and myocardial enzymes. Additionally, it mitigating lymphocyte and platelet count decline caused by HS. The MBI score was significantly enhanced after treatment in the HBO group. Conclusions: Clinical practice advocates administering HBO therapy to patients with severe illness, organ damage, and nerve impairment. Compared with conventional treatment, combined HBO therapy demonstrated superior efficacy in alleviating multiple organ dysfunction and improving daily living ability in patients with HS.

Effects of an explain-simulate-practice-communicate-support intervention on quality of life for patients with chronic heart failure: A randomized control trial.

Background: Patients with New York Heart Association (NYHA) grade III chronic heart failure (CHF) present with low capacity for daily activities, severe self-perceived burden, and poor quality of life. Effective nursing interventions may reduce patients' self-perceived burden and improve their quality of life. Objectives: To explore the effects of an explain-simulate-practice-communicate-support intervention on the self-perceived burden, cardiac function, and activities of daily living (ADL) ability in patients with New York Heart Association grade III chronic heart failure. Methods: Of the 100 patients with New York Heart Association grade III chronic heart failure who were electronically randomized and equally divided into control and intervention groups, data from 88 patients who completed our study were analyzed. The primary outcome was quality of life; secondary outcomes were self-perceived burden, 6-min walking test distances, serum N-terminal pro-brain natriuretic peptide levels, New York Heart Association cardiac function classification, and ability to perform activities of daily living. Results: After 12 weeks' intervention, the intervention group had significantly lower self-perceived burden, Minnesota Living with Heart Failure Questionnaire scores, N-terminal pro-brain natriuretic peptide levels, and New York Heart Association grades compared with the control group, while 6-min walking test distances, left ventricular ejection fraction, and modified Barthel Index scale scores were significantly higher than those in the control group (P > 0.05). Conclusions: The explain-simulate-practice-communicate-support intervention improved patients' quality of life through reducing the level of self-perceived burden, and improving cardiac function and activities of daily living ability. This intervention was found to be effective for patients with New York Heart Association grade III chronic heart failure.

Nourishing Yin traditional Chinese medicine: potential role in the prevention and treatment of type 2 diabetes.

Type 2 diabetes mellitus (T2DM), a common and frequently occurring disease in contemporary society, has become a global health threat. However, current mainstream methods of prevention and treatment, mainly including oral hypoglycemic drugs and insulin injections, do not fundamentally block the progression of T2DM. Therefore, it is imperative to find new ways to prevent and treat diabetes. Traditional Chinese medicine is characterized by multiple components, pathways, and targets with mild and long-lasting effects. Pharmacological studies have shown that nourishing yin traditional Chinese medicine (NYTCM) can play a positive role in the treatment of T2DM by regulating pathways such as the phosphatidylinositol 3-kinase/serine-threonine kinase, mitogen-activated protein kinase, nuclear factor-kappa B, and other pathways to stimulate insulin secretion, protect and repair pancreatic ß cells, alleviate insulin resistance, ameliorate disordered glucose and lipid metabolism, mitigate oxidative stress, inhibit inflammatory responses, and regulate the intestinal flora. The pharmacologic activity, mechanisms, safety, and toxicity of NYTCM in the treatment of T2DM are also reviewed in this manuscript.

Triclosan induces liver injury in long-life exposed mice via activation of TLR4/NF-κB/NLRP3 pathway.

Triclosan (TCS) is a widely used synthetic, with broad-spectrum antibacterial properties found in both pharmaceuticals and personal care products. More specifically, it is hepatotoxic in rodents and exhibits differential effects in mice and humans. However, the mechanisms underlying TCS-induced liver toxicity have not been elucidated. This study examined the role of the toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB)/ nod-like receptor protein 3 (NLRP3) pathway in TCS-exposed liver toxicity by established a long-life TCS-exposed mice liver injury model. The 24 C57BL/6 pregnant mice exposed to TCS (0, 50 and 100 mg/kg) every day during the gestation and nursing period. After weaning, the male mice were left to continue administrate with TCS until 8 weeks of age. Then, mice in each group were sacrificed for investigation. Long-life exposure to TCS resulted in a reduction of body weight in growth mice. TCS exposure caused the increase of serum ALT, AST and ALP. The situation of inflammatory cell infiltration, macrophage recruitment and collagen fiber deposition in TCS-exposed mice liver tissues were performed by histological analysis including hematoxylin-eosin, Masson, Sirius red, and immunohistochemistry staining. Protein expression levels in TLR4/NF-κB/NLRP3 pathway was measured through Western blot, and the NLRP3 inflammasome activation was measured using real-time quantitative PCR (RT-qPCR). The results showed that exposure to TCS elevated TLR4, myeloid differentiation factor 88 (Myd88), TNF receptor associated factor 6 (TRAF6), enhanced NF-κB activation, and affected NLRP3 inflammasome activation in mice liver. Collectively, these findings indicate that long-life exposure to TCS-induced mice by upregulating the TLR4-Myd88-TRAF6 pathway, activating the NF-κB signaling cascade, initiating the NLRP3 inflammasome pathway, and ultimately leading to liver injury, including inflammation, hepatocyte pyroptosis and hepatofibrosis. Henceforth, the TLR4/NF-κB/NLRP3 pathway may now provide a theoretical basis and valuable therapeutic targets for overcoming TCS-induced liver toxicity.

Current progression in application of extracellular vesicles in central nervous system diseases.

Early diagnosis and pharmacological treatment of central nervous system (CNS) diseases has been a long-standing challenge for clinical research due to the presence of the blood-brain barrier. Specific proteins and RNAs in brain-derived extracellular vesicles (EVs) usually reflect the corresponding state of brain disease, and therefore, EVs can be used as diagnostic biomarkers for CNS diseases. In addition, EVs can be engineered and fused to target cells for delivery of cargo, demonstrating the great potential of EVs as a nanocarrier platform. We review the progress of EVs as markers and drug carriers in the diagnosis and treatment of neurological diseases. The main areas include visual imaging, biomarker diagnosis and drug loading therapy for different types of CNS diseases. It is hoped that increased knowledge of EVs will facilitate their clinical translation in CNS diseases.

The Detection of Nasopharyngeal Carcinomas Using a Neural Network Based on Nasopharyngoscopic Images.

OBJECTIVE: To construct and validate a deep convolutional neural network (DCNN)-based artificial intelligence (AI) system for the detection of nasopharyngeal carcinoma (NPC) using archived nasopharyngoscopic images. METHODS: We retrospectively collected 14107 nasopharyngoscopic images (7108 NPCs and 6999 noncancers) to construct a DCNN model and prepared a validation dataset containing 3501 images (1744 NPCs and 1757 noncancers) from a single center between January 2009 and December 2020. The DCNN model was established using the You Only Look Once (YOLOv5) architecture. Four otolaryngologists were asked to review the images of the validation set to benchmark the DCNN model performance. RESULTS: The DCNN model analyzed the 3501 images in 69.35 s. For the validation dataset, the precision, recall, accuracy, and F1 score of the DCNN model in the detection of NPCs on white light imaging (WLI) and narrow band imaging (NBI) were 0.845 ± 0.038, 0.942 ± 0.021, 0.920 ± 0.024, and 0.890 ± 0.045, and 0.895 ± 0.045, 0.941 ± 0.018, and 0.975 ± 0.013, 0.918 ± 0.036, respectively. The diagnostic outcome of the DCNN model on WLI and NBI images was significantly higher than that of two junior otolaryngologists (p < 0.05). CONCLUSION: The DCNN model showed better diagnostic outcomes for NPCs than those of junior otolaryngologists. Therefore, it could assist them in improving their diagnostic level and reducing missed diagnoses. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:127-135, 2024.

Laryngoscopy-based scoring system for the diagnosis of vocal fold leukoplakia.

OBJECTIVE: To propose a scoring system based on laryngoscopic characteristics for the differential diagnosis of benign and malignant vocal fold leukoplakia. METHODS: Laryngoscopic images from 200 vocal fold leukoplakia cases were retrospectively analysed. The laryngoscopic signs of benign and malignant vocal fold leukoplakia were compared, and statistically significant features were assigned and accumulated to establish the leukoplakia finding score. RESULTS: A total of five indicators associated with malignant vocal fold leukoplakia were included to construct the leukoplakia finding score, with a possible range of 0-10 points. A score of 6 points or more was indicative of a diagnosis of malignant vocal fold leukoplakia. The sensitivity, specificity and accuracy values of the leukoplakia finding score were 93.8 per cent, 83.6 per cent and 86.0 per cent, respectively. The consistency in the leukoplakia finding score obtained by different laryngologists was strong (kappa = 0.809). CONCLUSION: This scoring system based on laryngoscopic characteristics has high diagnostic value for distinguishing benign and malignant vocal fold leukoplakia.

Tislelizumab and radiation therapy in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type: a phase II study protocol.

Low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type has a favorable outcome with radiation therapy alone, and the addition of chemotherapy shows no survival benefit. Nonetheless, a proportion of patients will relapse or progress, with a dismal outcome, highlighting the need for a novel therapeutic strategy. Promising preliminary findings indicate the efficacy of PD-1/PD-L1 inhibitors in extranodal natural killer/T-cell lymphoma, nasal type, with good toxicity profiles. Here we describe the design of a phase II study (CLCG-NKT-2101), which is evaluating the safety and efficacy of adding anti-PD-1 antibody to the current radiation therapy regimen in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type patients. Tislelizumab will be added in an inductive and concurrent way to radiation therapy. The primary end point will be the complete response rate after induction immunotherapy. Clinical trial registration: ClinicalTrials.gov (NCT05149170).

New JAK3-INSL3 Fusion Transcript-An Oncogenic Event in Cutaneous T-Cell Lymphoma.

Constitutively activated tyrosine kinase JAK3 is implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCL). The mechanisms of constitutive JAK3 activation are unknown although a JAK3 mutation was reported in a small portion of CTCL patients. In this study, we assessed the oncogenic roles of a newly identified JAK3-INSL3 fusion transcript in CTCL. Total RNA from malignant T-cells in 33 patients with Sézary syndrome (SS), a leukemic form of CTCL, was examined for the new JAK3-INSL3 fusion transcript by RT-PCR followed by Sanger sequencing. The expression levels were assessed by qPCR and correlated with patient survivals. Knockdown and/or knockout assays were conducted in two CTCL cell lines (MJ cells and HH cells) by RNA interference and/or CRISPR/Cas9 gene editing. SS patients expressed heterogeneous levels of a new JAK3-INSL3 fusion transcript. Patients with high-level expression of JAK3-INSL3 showed poorer 5-year survival (n = 19, 42.1%) than patients with low-level expression (n = 14, 78.6%). CTCL cells transduced with specific shRNAs or sgRNAs had decreased new JAK3-INSL3 fusion transcript expression, reduced cell proliferation, and decreased colony formation. In NSG xenograft mice, smaller tumor sizes were observed in MJ cells transduced with specific shRNAs than cells transduced with controls. Our results suggest that the newly identified JAK3-INSL3 fusion transcript confers an oncogenic event in CTCL.

Retinal Dystrophy Associated With RLBP1 Retinitis Pigmentosa: A Five-Year Prospective Natural History Study.

Purpose: To assess the progression in functional and structural measures over a five-year period in patients with retinal dystrophy caused by RLBP1 gene mutation. Methods: This prospective, noninterventional study included patients with biallelic RLBP1 mutations from two clinical sites in Sweden and Canada. Key assessments included ocular examinations, visual functional measures (best-corrected visual acuity [BCVA], contrast sensitivity [CS], dark-adaptation [DA] kinetics up to six hours for two wavelengths [450 and 632 nm], Humphrey visual fields [HVF], full-field flicker electroretinograms), and structural ocular assessments. Results: Of the 45 patients enrolled, 38 completed the full five years of follow-up. At baseline, patients had BCVA ranging from -0.2 to 1.3 logMAR, poor CS, HVF defects, and prominent thinning in central foveal thickness. All patients had extremely prolonged DA rod recovery of approximately six hours at both wavelengths. The test-retest repeatability was high across all anatomic and functional endpoints. Cross-sectionally, poorer VA was associated with older age (right eye, correlation coefficient [CC]: 0.606; left eye, CC: -0.578; P < 0.001) and HVF MD values decreased with age (right eye, CC: -0.672, left eye, CC: -0.654; P < 0.001). However, no major changes in functional or structural measures were noted longitudinally over the five-year period. Conclusions: This natural history study, which is the first study to monitor patients with RLBP1 RD for five years, showed that severely delayed DA sensitivity recovery, a characteristic feature of this disease, was observed in all patients across all age groups (17-69 years), making it a potentially suitable efficacy assessment for gene therapy treatment in this patient population.