Optimal timing for the first cystoscopic follow-up using time-to-treatment initiation analysis of oncologic outcomes in primary non-muscle invasive bladder cancer.

Various guidelines recommend the first follow-up cystoscopy at 3 months; however, no data exist on the optimal timing for initial follow-up cystoscopy. We tried to provide evidence on the timing of the first cystoscopy after the initial transurethral resection of bladder tumor (TUR-BT) for patients with non-muscle invasive bladder cancer (NMIBC) using big data. This was a retrospective National Health Insurance Service database analysis. The following outcomes were considered: recurrence, progression, cancer-specific mortality, and all-cause mortality. Exposure was the time-to-treatment initiation (TTI), a continuous variable representing the time to the first cystoscopy from the first TUR-BT within 1 year. Additionally, we categorized TTI (TTIc) into five levels: < 2, 2-4, 4-6, 6-8, and 8-12 months. A landmark time of 1 year after the initial TUR-BT was described to address immortal-time bias. We identified the optimal time for the first cystoscopy using Cox regression models with and without restricted cubic splines (RCS) for TTI and TTIc, respectively. Among 26,660 patients, 16,880 (63.3%) underwent cystoscopy within 2-4 months. A U-shaped trend of the lowest risks at TTI was observed in the 2-4 months group for progression, cancer-specific mortality, and all-cause mortality. TTI within 0-2 months had a higher risk of progression (aHR 1.36; 95% confidence intervals [CI] 1.15-1.60; p < 0.001) and cancer-specific mortality (aHR 1.29; 95% CI 1.05-1.58; p = 0.010). Similarly, TTI within 8-12 months had a higher risk of progression (aHR 2.09; 95% CI 1.67-2.63; p < 0.001) and cancer-specific mortality (aHR 1.96; 95% CI 1.48-2.60; p < 0.001). Based on the RCS models, the risks of progression, cancer-specific mortality, and all-cause mortality were lowest at TTI of 4 months. The timing of the first cystoscopy follow-up was associated with oncologic prognosis. In our model, undergoing cystoscopy at 4 months has shown the best outcomes in clinical course. Therefore, patients who do not receive cystoscopy at approximately 4 months for any reason need more careful follow-up to predict a poor clinical course.

Impact of amyloid and tau positivity on longitudinal brain atrophy in cognitively normal individuals.

BACKGROUND: Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods. METHODS: This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models. RESULTS: A total of 367 participants (48 A + T + , 86 A + T - , 63 A - T + , and 170 A - T - ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T - and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A - T - group (lateral ventricle: ß = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P < .001 for A + T - , and ß = 0.889 cm3/year [0.523 to 1.255], P < .001 for A + T + ; PACC: ß = - 0.19 /year [- 0.36 to - 0.02], P = .029 for A + T - , and ß = - 0.59 /year [- 0.80 to - 0.37], P < .001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (ß = - 2.782 cm3/year [- 4.060 to - 1.504], P < .001), hippocampus (ß = - 0.057 cm3/year [- 0.085 to - 0.029], P < .001), and AD-signature regions (ß = - 0.02 mm/year [- 0.03 to - 0.01], P < .001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A - T - group (adjusted hazard ratio = 3.35 [1.76 to 6.39]). CONCLUSIONS: In cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression.

Melanocortin-1 Receptor Expression as a Marker of Progression in Melanoma.

PURPOSE: Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in patients with melanoma, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. METHODS: Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. RESULTS: We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions and ulcerated lesions and was associated with shorter survival in primary and metastatic tumors. On multivariable analysis, Breslow thickness, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. CONCLUSION: Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.

Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression.

Gastrointestinal carcinomas are a group of cancers associated with the digestive system and its accessory organs. The most prevalent cancers related to the gastrointestinal tract are colorectal, gall bladder, gastric, hepatocellular, and esophageal cancers, respectively. Molecular aberrations in different signaling pathways, such as signal transduction systems or developmental pathways are the chief triggering mechanisms in different cancers Though a massive advancement in diagnostic and therapeutic interventions results in improved survival of patients with gastrointestinal cancer; the lower malignancy stages of these carcinomas are comparatively asymptomatic. Various gastrointestinal-related cancers are detected at advanced stages, leading to deplorable prognoses and increased rates of recurrence. Recent molecular studies have elucidated the imperative roles of several signaling pathways, namely Wnt, Hedgehog, and Notch signaling pathways, play in the progression, therapeutic responsiveness, and metastasis of gastrointestinal-related cancers. This book chapter gives an interesting update on recent findings on the involvement of developmental signaling pathways their mechanistic insight in gastrointestinalcancer. Subsequently, evidences supporting the exploration of gastrointestinal cancer related molecular mechanisms have also been discussed for developing novel therapeutic strategies against these debilitating carcinomas.

TMEM9 promotes lung adenocarcinoma progression via activating the MEK/ERK/STAT3 pathway to induce VEGF expression.

Abnormal Transmembrane protein 9 (TMEM9) expression has been identified in various human tumors. However, the prognostic potential and mechanistic role of TMEM9 in lung adenocarcinoma (LUAD) remain unclear. Here, we first found a significant upregulation of TMEM9 in LUAD tissues, and TMEM9 expression was positively correlated with microvessel density (MVD), T stage, and clinical stage. Survival analysis demonstrated TMEM9 was an independent indicator of poor prognosis in LUAD patients. In addition, downregulation of TMEM9 suppressed tumor growth and metastasis in vitro and in vivo models, and reduced HUVEC proliferation, migration, and tube formation in a cancer cell/HUVEC coculture model. Furthermore, TMEM9 upregulated VEGF expression, and VEGF-neutralizing antibodies reversed HUVEC angiogenesis and cancer cell migration ability caused by overexpression of TMEM9. In contrast, recombinant VEGF (rVEGF) abolished the inhibitory effect of TMEM9-knockdown LUAD cells on HUVEC angiogenesis and tumor cell migration. Moreover, we showed that TMEM9 upregulated VEGF expression by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase/STAT3 (MEK/ERK/STAT3) pathway. Together, our study provides mechanistic insights into the role of TMEM9 in LUAD and highlights the potential of targeting the TMEM9/MEK/ERK/STAT3/VEGF pathway as a novel therapy for preventing LUAD progression.

siRNA treatment targeting integrin α11 overexpressed via EZH2-driven axis inhibits drug-resistant breast cancer progression.

BACKGROUND: Breast cancer, the most prevalent cancer in women worldwide, faces treatment challenges due to drug resistance, posing a serious threat to patient survival. The present study aimed to identify the key molecules that drive drug resistance and aggressiveness in breast cancer cells and validate them as therapeutic targets. METHODS: Transcriptome microarray and analysis using PANTHER pathway and StemChecker were performed to identify the most significantly expressed genes in tamoxifen-resistant and adriamycin-resistant MCF-7 breast cancer cells. Clinical relevance of the key genes was determined using Kaplan-Meier survival analyses on The Cancer Genome Atlas dataset of breast cancer patients. Gene overexpression/knockdown, spheroid formation, flow cytometric analysis, chromatin immunoprecipitation, immunocytochemistry, wound healing/transwell migration assays, and cancer stem cell transcription factor activation profiling array were used to elucidate the regulatory mechanism of integrin α11 expression. Tumour-bearing xenograft models were used to demonstrate integrin α11 is a potential therapeutic target. RESULTS: Integrin α11 was consistently upregulated in drug-resistant breast cancer cells, and its silencing inhibited cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) while restoring sensitivity to anticancer drugs. HIF1α, GLI-1, and EZH2 contributed the most to the regulation of integrin α11 and EZH2 expression, with EZH2 being more necessary for EZH2 autoinduction than HIF1α and GLI-1. Additionally, unlike HIF1α or EZH2, GLI-1 was the sole transcription factor activated by integrin-linked focal adhesion kinase, indicating GLI-1 as a key driver of the EZH2-integrin α11 axis operating for cancer stem cell survival and EMT. Kaplan-Meier survival analysis using The Cancer Genome Atlas (TCGA) dataset also revealed both EZH2 and integrin α11 could be strong prognostic factors of relapse-free and overall survival in breast cancer patients. However, the superior efficacy of integrin α11 siRNA therapy over EZH2 siRNA treatment was demonstrated by enhanced inhibition of tumour growth and prolonged survival in murine models bearing tumours. CONCLUSION: Our findings elucidate that integrin α11 is upregulated by EZH2, forming a positive feedback circuit involving FAK-GLI-1 and contributing to drug resistance, cancer stem cell survival and EMT. Taken together, the results suggest integrin α11 as a promising prognostic marker and a powerful therapeutic target for drug-resistant breast cancer.

Epithelial-Mesenchymal Transformation Promotes the Progression of Hepatocellular Carcinoma through NF-κB/MMP9 Axis.

BACKGROUND: Primary liver cancer (PHC) stands as one of the most prevalent malignant diseases in clinical settings. Studies have indicated that transcatheter arterial chemoembolization (TACE) treatment exhibits superior clinical outcomes, potentially increasing the complete necrosis rate in patients with PHC. A correlation exists between the clinical outcomes of TACE surgery and the process of epithelial-mesenchymal transition (EMT), yet the underlying mechanism remains a mystery. Hence, it is crucial to investigate the impact and mechanism of EMT on hepatocellular carcinoma (HCC). METHODS: Retrospectively, patients with advanced liver cancer who underwent TACE were selected and categorized into two groups based on the assessment of clinical efficacy: the effective group and the ineffective group. The expression levels of nuclear factor-kappa B (NF-κB), matrix metalloproteinase 9 (MMP9), Ki-67, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), Vimentin, E-cadherin, and N-cadherin in tumor tissues were evaluated using reverse transcription-polymerase chain reaction (RT-PCR). In vitro, Huh7 cells were cultured, and lentivirus infections were utilized to inhibit the overexpression of NF-κB and MMP9. The determination of EMT and cell viability was conducted through Cell Counting Kit-8 (CCK-8) assays, RT-PCR, and Western blot. RESULTS: Sixty patients diagnosed with advanced liver cancer were selected for the study. Based on their clinical outcomes, 30 patients with advanced hepatocellular carcinoma were categorized into the effective group, while the remaining 30 patients were categorized into the ineffective group. The results of the Western blot analysis indicated that, in comparison to the effective group, the expression levels of NF-κB, MMP9, Ki-67, Bcl-2, Vimentin, and N-cadherin were significantly higher in the tumor tissues of the ineffective group. Conversely, the expression of Bax and E-cadherin was notably lower in the effective group. Following the individual knockdown of NF-κB and MMP9, the cell experiments revealed a remarkable decrease in the expression levels of Ki-67, Bcl-2, Vimentin, and N-cadherin, whereas the expression of Bax and E-cadherin showed significant elevation (p < 0.05). Furthermore, there was a significant increase in cell viability and a decrease in cell apoptosis after the knockdown of NF-κB and MMP9. CONCLUSIONS: The NF-κB/MMP9 signaling axis serves as a pivotal regulator that fosters proliferation and impedes apoptosis in Huh7 cells by modulating the process of EMT.

Neurological Deterioration in Wilson's Disease-Types, Etiology, Course, and Management.

Wilson's disease (WD) is an inherited disorder of copper metabolism in which pathological copper accumulation, mainly in the liver and the brain, leads to hepatic and/or neuropsychiatric signs and symptoms. Chelators and zinc salts can successfully induce negative copper balance in many patients; however, neurological deterioration may still be observed. This phenomenon can be divided into: (1) early 'paradoxical' neurological deterioration, which usually develops in the first 6 months of anti-copper treatment and may be commonly related to drug type, or (2) late neurological deterioration, which mostly occurs after 6 months of treatment and is often related either to non-compliance with treatment, overtreatment resulting in copper deficiency, or adverse drug reactions. Another explanation, especially for early neurological deterioration, is natural WD progression, which can be difficult to differentiate from drug-related deterioration, but usually leads to a worse outcome. There is still no consensus on how to define neurological deterioration in WD using scales or biomarkers, how to distinguish it from the natural disease progression, its risk factors, and optimal management. This narrative review, based on the current literature, aims to provide definitions, prevalence, pathological mechanisms and factors related to neurological deterioration, and also proposes schemes for diagnosis and treatment.

EZH2 Promotes Multiple Myeloma Progression via STAT3 Pathway Activation.

BACKGROUND: Multiple myeloma (MM) is a malignant disorder of plasma cells in the bone marrow. MM causes the clonal proliferation of terminally differentiated plasma cells and the accumulation of monoclonal plasma cells. The enhancer of zeste homolog 2 (EZH2) has been proven to play a significant role in disease development and could act on the signal transducers and activators of the transcription 3 (STAT3) signaling pathway. This pathway contributes to the pathogenesis and maintenance of malignancies. This study aimed to explore the effect of EZH2 on MM progression and the role of the STAT3 pathway in this process. The goal was to increase knowledge and provide further insights about the pathogenesis of MM and identify novel targets for potential therapies. METHODS: The abnormal expression of EZH2 in MM cell lines was tested through real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot analysis. Based on the MM cell line H929, transfection was used to modify EZH2 expression, followed by the subsequent evaluation of induced alteration in STAT3 activation. The STAT3 phosphorylation activator colivelin and inhibitor stattic were used for promoting and inhibiting the STAT3 activation, respectively. Colony-forming assay, transwell migration assay, and flow cytometry were used to explore cell proliferation, cell migration, and cell apoptosis, respectively. RESULTS: Both the EZH2 mRNA and protein were over-expressed in multiple MM cell lines including H929 (p < 0.001), U266 (p < 0.01), RPMI-8226 (p < 0.01) and MM.1S (p < 0.001). Increased EZH2 promoted cell proliferation (p < 0.001) and migration (p < 0.001) and simultaneously inhibited cell apoptosis (p < 0.001), which could be reversed by inhibited STAT3 activation (p < 0.001). In contrast, promoted STAT3 activation increased cell proliferation (p < 0.001) and migration (p < 0.001), while simultaneously inhibiting cell apoptosis (p < 0.001), despite decreased EZH2 expression. CONCLUSIONS: The effect of EZH2 and STAT3 pathways on MM regulation was revealed and verified. EZH2 promoted the progression of MM cells by activating the STAT3 pathway. The EZH2 and STAT3 pathways could be potential targets for effective MM treatment.

Local Tumor Progression Predictive Model Based on MRI for Colorectal Cancer Liver Metastases after Radiofrequency Ablation.

PURPOSE: To investigate the post-radiofrequency ablation (RFA) magnetic resonance imaging (MRI) characteristics in patients with liver metastases from colorectal cancer and to build a predictive model for local tumor progression based on these imaging markers. MATERIALS AND METHODS: A cohort of 73 patients with 110 colorectal cancer liver metastases (CRCLM) who underwent RFA and MRI one month post-ablation was included in image signs analysis and predictive model training. Using a newly developed MRI appearance scoring criteria, MR Image Appearance Scoring at One Month after RFA (MRIAS 1MO), the semi-quantitative analysis of MRI findings within the ablation zone were conducted independently by two radiologists. The intraclass correlation coefficient (ICC) was calculated to evaluate measurement reliability. Differences in MRIAS 1MO scores were compared using Mann-Whitney U test, focusing on local tumor response outcomes. Using local tumor progression (LTP) as the primary end point, MRIAS 1MO scores and other lesion morphological and clinical characteristics were included to establish predictive model. Predication accuracy was subsequently evaluated using calibration curve, time-dependent concordance index (C index) curve, and LTP-free survival (LTPFS) curve. Another cohort comprising 60 patients with 76 CRCLMs provided additional MRIAS 1MO scores and clinical data associated with LTP. We evaluated the performance of the established predictive model using calibration curve, time-dependent C index curve, and LTPFS curve. RESULTS: The MRIAS 1MO criteria exhibited strong measurement reliability. The ICC values of T1S (scores from T1WI), T2S (scores form T2WI) and NCES (scores by adding T1S to T2S) MRIS (the overall scores) were 0.825, 0.779, 0.826 and 0.873, respectively. Lesions with LTP showed significantly higher median values for the overall MRIAS 1MO score (MRIS) compared to lesions without LTP (16 vs. 12, p < 0.001). MRIS and lesion diameter were independent prognostic factors of LTP and were included in predictive model (hazard ratio: MRIS over 13.5:4.275, lesion diameter larger than 30 mm: 2.056). The predictive model demonstrated an overall C index of 0.721 and risk stratification using the predictive model resulted in significantly different LPTFS times. In the validation cohort, the C index were 0.825, 0.794 and 0.764 at six, twelve and twenty-four months, respectively. Patients classified as high-risk in the validation cohort had a median LTPFS time of 10.0 months, while the median LTPFS time was not reached in the low-risk group. CONCLUSIONS: The semi-quantitative MRIAS 1MO criteria, used for post-RFA MRI appearance analysis, exhibited strong measurement reliability. Prediction models established based on overall MRIAS 1MO score (MRIS) and lesion diameter had good predictive performance for LTP in patients undergoing RFA for CRCLM treatment.

[Treatments for multiple sclerosis: update]. / Traitements de la sclérose en plaques : mise à jour.

The management of multiple sclerosis (MS) has undergone a veritable revolution in recent years, with the arrival of highly effective treatments. In some cases, therapeutic discussions even precede the first clinical signs of the disease. The aim of this review is to present the therapeutic arsenal of progression-preventing treatments available in 2024 for MS, with anti-CD20 antibodies taking pride of place, also available for certain progressive forms of MS. The use of these immunosuppressants requires in-depth knowledge of their mechanisms of action, in order to understand their risks, such as the occurrence of opportunistic infections.

La prise en charge de la sclérose en plaques (SEP) a subi une véritable révolution ces dernières années avec l'arrivée de traitements à haute efficacité. La discussion thérapeutique précède même, dans certains cas, l'apparition des premiers signes cliniques de la maladie. Cet article a pour but de présenter l'arsenal des traitements de fond de la SEP disponibles en 2024. Parmi eux, les anticorps monoclonaux anti-lymphocytes B (anti-CD20) occupent une grande place. Ces derniers sont validés dans la forme poussée-rémission mais aussi pour les formes progressives de la SEP. L'utilisation de ces traitements nécessite une connaissance approfondie de leurs mécanismes d'actions afin de comprendre leurs risques tels que la survenue d'infections opportunistes.

[Discontinuing disease-modifying therapies in multiple sclerosis]. / Traitements de la sclérose en plaques : quand les arrêter ?

Aging in multiple sclerosis (MS) leads to altered clinical manifestations, where the pathophysiology shifts towards compartmentalized inflammation that drives clinical progression independent of relapse activity. Consequently, the effectiveness of disease-modifying therapies (DMTs) diminishes in older patients, coinciding with an elevated risk of adverse events. This raises the question of whether MS therapies should be discontinued after a certain age, which is often proposed for patients over 55 years. Studies on treatment discontinuation have shown a slight increase in disease activity, yet without significant disability progression. This suggests that the decision to stop DMTs should be discussed with older patients, considering existing comorbidities. Following the cessation of therapy, meticulous monitoring is essential.

L'avancée en âge modifie la présentation clinique de la sclérose en plaques (SEP). La physiopathologie évolue progressivement au profit d'une inflammation restreinte au système nerveux central entraînant une progression clinique indépendante des poussées. Cette évolution est associée à une baisse d'efficacité des traitements de la SEP, alors qu'en parallèle le risque de complications augmente. Se pose donc la question d'un arrêt des thérapies de la SEP après un certain âge, souvent proposé à 55 ans. Bien que les premières études suggèrent une légère reprise d'activité à l'arrêt des traitements, celle-ci n'est pas associée à une progression du handicap. L'arrêt du traitement chez les patients les plus âgés devrait donc être envisagé en prenant en compte les comorbidités. Par la suite, une surveillance méticuleuse est indispensable.

Predictors of chronic kidney disease survival in type 2 diabetes: a 12-year retrospective cohort study utilizing estimated glomerular filtration rate.

Predicting the course of kidney disease in individuals with both type 1 and type 2 diabetes mellitus (DM) is a significant clinical and policy challenge. In several regions, DM is now the leading cause of end-stage renal disease. The aim of this study to identify both modifiable and non-modifiable risk factors, along with clinical markers and coexisting conditions, that increase the likelihood of stage 3-5 chronic kidney disease (CKD) development in individuals with type 2 DM in the United Arab Emirates (UAE). This was a single-center retrospective cohort study based on data derived from electronic medical records of UAE patients with DM who were registered at outpatient clinics at Tawam Hospital in Al Ain, UAE, between January 2011 and December 2021. Type 2 DM patients aged ≥ 18 years who had serum HbA1c levels ≥ 6.5% were included in the study. Patients with type 1 DM, who had undergone permanent renal replacement therapy, who had under 1 year of follow-up, or who had missing or incomplete data were excluded from the study. Factors associated with diabetic patients developing stage 3-5 CKD were identified through Cox regression analysis and a fine and gray competing risk model to account for competing events that could potentially hinder the development of CKD. A total of 1003 patients were recruited for the study. The mean age of the study cohort at baseline was 70.6 ± 28.2 years. Several factors were found to increase the risk of developing stage 3-5 CKD: advancing age (HR 1.005, 95% CI 1.002-1.009, p = 0.026), a history of hypertension (HR 1.69, 95% CI 1.032-2.8, p = 0.037), a history of heart disease (HR 1.49, 95% CI 1.16-1.92, p = 0.002), elevated levels of serum creatinine (HR 1.006, 95% CI 1.002-1.010, p = 0.003), decreased levels of estimated glomerular filtration rate (eGFR) (HR 0.943, 95% CI, 0.938-0.947; p < 0.001), and the use of beta-blockers (HR 139, 95% CI 112-173, p = 0.003). Implementing preventative measures, initiating early interventions, and developing personalized care plans tailored to address specific risk factors are imperative for reducing the impact of CKD. Additionally, the unforeseen findings related to eGFR highlight the ongoing need for research to deepen our understanding of the complexities of kidney disease.

Circulating tumor cell-derived exosome-transmitted long non-coding RNA TTN-AS1 can promote the proliferation and migration of cholangiocarcinoma cells.

BACKGROUND: Exosomes assume a pivotal role as essential mediators of intercellular communication within tumor microenvironments. Within this context, long noncoding RNAs (LncRNAs) have been observed to be preferentially sorted into exosomes, thus exerting regulatory control over the initiation and progression of cancer through diverse mechanisms. RESULTS: Exosomes were successfully isolated from cholangiocarcinoma (CCA) CTCs organoid and healthy human serum. Notably, the LncRNA titin-antisense RNA1 (TTN-AS1) exhibited a conspicuous up-regulation within CCA CTCs organoid derived exosomes. Furthermore, a significant elevation of TTN-AS1 expression was observed in tumor tissues, as well as in blood and serum exosomes from patients afflicted with CCA. Importantly, this hightened TTN-AS1 expression in serum exosomes of CCA patients manifested a strong correlation with both lymph node metastasis and TNM staging. Remarkably, both CCA CTCs organoid-derived exosomes and CCA cells-derived exosomes featuring pronounced TTN-AS1 expression demonstrated the capability to the proliferation and migratory potential of CCA cells. Validation of these outcomes was conducted in vivo experiments. CONCLUSIONS: In conclusion, our study elucidating that CCA CTCs-derived exosomes possess the capacity to bolster the metastasis tendencies of CCA cells by transporting TTN-AS1. These observations underscore the potential of TTN-AS1 within CTCs-derived exosomes to serve as a promising biomarker for the diagnosis and therapeutic management of CCA.

Clinical and radiological features of intracranial ancient schwannomas: a single-institution, retrospective analysis.

Ancient schwannoma (AS) is a subtype of schwannoma characterized by slow progression despite degenerative changes in pathology. Although it is considered a benign tumor, most previous reports have focused on extracranial AS; therefore, the clinical characteristics of intracranial AS is not clear. We included 174 patients who underwent surgery for sporadic intracranial schwannoma, and 13 patients (7.5%) were diagnosed with AS. Cysts were significantly more common in patients with AS than conventional schwannomas (92.3% vs. 44.7%, p < 0.001), as was bleeding (38.5% vs. 6.9%, p = 0.003) and calcification (15.4% vs. 1.3%, p = 0.029). The maximum tumor diameter was also larger in patients with AS (35 mm vs. 29 mm, p = 0.017). The median duration from symptom onset to surgery (7.0 vs. 12.5 months, p = 0.740) did not significantly differ between groups, nor did the probability of postoperative recurrence (p = 0.949). Intracranial AS was strongly associated with cyst formation and exhibited a benign clinical course with a lower rate of recurrence and need for salvage treatment. Extracranial AS is reportedly characterized by a slow progression through a long-term clinical course, whereas intracranial AS did not progress slowly in our study and exhibited different clinical features to those reported for extracranial AS.

Whole-course management of chronic obstructive pulmonary disease in primary healthcare: an internet of things-enabled prospective cohort study in China.

BACKGROUND: Despite substantial progress in reducing the global burden of chronic obstructive pulmonary disease (COPD), traditional methods to promote understanding and management of COPD are insufficient. We developed an innovative model based on the internet of things (IoT) for screening and management of COPD in primary healthcare (PHC). METHODS: Electronic questionnaire and IoT-based spirometer were used to screen residents. We defined individuals with a questionnaire score of 16 or higher as high-risk population, COPD was diagnosed according to 2021 Global Initiative for COPD (Global Initiative for Chronic Obstructive Lung Disease) criteria. High-risk individuals and COPD identified through the screening were included in the COPD PHC cohort study, which is a prospective, longitudinal observational study. We provide an overall description of the study's design framework and baseline data of participants. RESULTS: Between November 2021 and March 2023, 162 263 individuals aged over 18 from 18 cities in China were screened, of those 43 279 high-risk individuals and 6902 patients with COPD were enrolled in the cohort study. In the high-risk population, the proportion of smokers was higher than that in the screened population (57.6% vs 31.4%), the proportion of males was higher than females (71.1% vs 28.9%) and in people underweight than normal weight (57.1% vs 32.0%). The number of high-risk individuals increased with age, particularly after 50 years old (χ2=37 239.9, p<0.001). Female patients are more common exposed to household biofuels (χ2=72.684, p<0.05). The majority of patients have severe respiratory symptoms, indicated by a CAT score of ≥10 (85.8%) or an Modified Medical Research Council Dyspnoea Scale score of ≥2 (65.5%). CONCLUSION: Strategy based on IoT model help improve the detection rate of COPD in PHC. This cohort study has established a large clinical database that encompasses a wide range of demographic and relevant data of COPD and will provide invaluable resources for future research.

Autoimmunity against melanoma differentiation-associated gene 5 induces interstitial lung disease mimicking dermatomyositis in mice.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) is characterized by amyopathic DM with interstitial lung disease (ILD). Patients with anti-MDA5 antibody-associated ILD frequently develop rapidly progression and present high mortality rate in the acute phase. Here, we established a murine model of ILD mediated by autoimmunity against MDA5. Mice immunized with recombinant murine MDA5 whole protein, accompanied with complete Freund's adjuvant once a week for four times, developed MDA5-reactive T cells and anti-MDA5 antibodies. After acute lung injury induced by intranasal administration of polyinosinic-polycytidylic acid [poly (I:C)] mimicking viral infection, the MDA5-immunized mice developed fibrotic ILD representing prolonged respiratory inflammation accompanied by fibrotic changes 2 wk after poly (I:C)-administration, while the control mice had quickly and completely recovered from the respiratory inflammation. Treatment with anti-CD4 depleting antibody, but not anti-CD8 depleting antibody, suppressed the severity of MDA5-induced fibrotic ILD. Upregulation of interleukin (IL)-6 mRNA, which was temporarily observed in poly (I:C)-treated mice, was prolonged in MDA5-immunized mice. Treatment with anti-IL-6 receptor antibody ameliorated the MDA5-induced fibrotic ILD. These results suggested that autoimmunity against MDA5 exacerbates toll-like receptor 3-mediated acute lung injury, and prolongs inflammation resulting in the development of fibrotic ILD. IL-6 may play a key role initiating ILD in this model.

Influence of Disease-Related Stigma on Patients' Decisions to Upload Medical Reports to the German Electronic Health Record: Randomized Controlled Trial.

BACKGROUND: The rollout of the electronic health record (EHR) represents a central component of the digital transformation of the German health care system. Although the EHR promises more effective, safer, and faster treatment of patients from a systems perspective, the successful implementation of the EHR largely depends on the patient. In a recent survey, 3 out of 4 Germans stated that they intend to use the EHR, whereas other studies show that the intention to use a technology is not a reliable and sufficient predictor of actual use. OBJECTIVE: Controlling for patients' intention to use the EHR, we investigated whether disease-specific risk perceptions related to the time course of the disease and disease-related stigma explain the additional variance in patients' decisions to upload medical reports to the EHR. METHODS: In an online user study, 241 German participants were asked to interact with a randomly assigned medical report that varied systematically in terms of disease-related stigma (high vs low) and disease time course (acute vs chronic) and to decide whether to upload it to the EHR. RESULTS: Disease-related stigma (odds ratio 0.154, P<.001) offset the generally positive relationship between intention to use and the upload decision (odds ratio 2.628, P<.001), whereas the disease time course showed no effect. CONCLUSIONS: Even if patients generally intend to use the EHR, risk perceptions such as those related to diseases associated with social stigma may deter people from uploading related medical reports to the EHR. To ensure the reliable use of this key technology in a digitalized health care system, transparent and easy-to-comprehend information about the safety standards of the EHR are warranted across the board, even for populations that are generally in favor of using the EHR.

Exacerbating effects of circadian rhythm disruption on the systemic lupus erythematosus.

OBJECTIVE: Circadian rhythm disruption (CRD) has been associated with inflammation and immune disorders, but its role in SLE progression is unclear. We aimed to investigate the impact of circadian rhythms on immune function and inflammation and their contribution to SLE progression to lupus nephritis (LN). METHODS: This study retrospectively analysed the clinical characteristics and transcriptional profiles of 373 samples using bioinformatics and machine-learning methods. A flare risk score (FRS) was established to predict overall disease progression for patients with lupus. Mendelian randomisation was used to analyse the causal relationship between CRD and SLE progression. RESULTS: Abnormalities in the circadian pathway were detected in patients with SLE, and lower enrichment levels suggested a disease state (normalised enrichment score=0.6714, p=0.0062). The disruption of circadian rhythms was found to be closely linked to lupus flares, with the FRS showing a strong ability to predict disease progression (area under the curve (AUC) of 5-year prediction: 0.76). The accuracy of disease prediction was improved by using a prognostic nomogram based on FRS (AUC=0.77). Additionally, Mendelian randomisation analysis revealed an inverse causal relationship between CRD and SLE (OR 0.6284 (95% CI 0.3630 to 1.0881), p=0.0485) and a positive causal relationship with glomerular disorders (OR 0.0337 (95% CI 1.634e-3 to 6.934e-1), p=0.0280). CONCLUSION: Our study reveals that genetic characteristics arising from CRD can serve as biomarkers for predicting the exacerbation of SLE. This highlights the crucial impact of CRD on the progression of lupus.

NXPH4 can be used as a biomarker for pan-cancer and promotes colon cancer progression.

NXPH4 promotes cancer proliferation and invasion. However, its specific role and mechanism in cancer remain unclear. Transcriptome and clinical data for pan-cancer were derived from the TCGA database. K-M survival curve and univariate Cox were used for prognostic analysis. CIBERSORT and TIMER algorithms were employed to calculate immune cell infiltration. Gene set enrichment analysis (GSEA) was employed for investigating the function of NXPH4. Western blot verified differential expression of NXPH4 in colon cancer. Functional assays (CCK-8, plate clonogenicity assay, wound healing assay, and Transwell assay) confirmed the impact of NXPH4 on proliferation, invasion, and migration of colon cancer cells. Dysregulation of NXPH4 in pan-cancer suggests its potential as a diagnostic and prognostic marker for certain cancers, including colon and liver cancer. High expression of NXPH4 in pan-cancer might be associated with the increase in copy number and hypomethylation. NXPH4 expression in pan-cancer is substantially linked to immune cell infiltration in the immune microenvironment. NXPH4 expression is associated with the susceptibility to immunotherapy and chemotherapy. Western blot further confirmed the higher expression of NXPH4 in colon cancer. Knockdown of NXPH4 significantly suppresses proliferation, invasion, and migration of colon cancer cell lines HT-29 and HCT116, as validated by functional assays.