Disease Progression Research Articles

The past 25 years in paediatric rheumatology: insights from monogenic diseases.

The past 25 years have seen major novel developments in the field of paediatric rheumatology. The concept of autoinflammation was introduced to this field, and medicine more broadly, with studies of familial Mediterranean fever, the most common autoinflammatory disease globally. New data on the positive evolutionary selection of familial Mediterranean fever-associated genetic variants might be pertinent to mild gain-of-function variants reported in other disease-associated genes. Genetic studies have unveiled the complexity of human heritability to inflammation and flourishing data from rare monogenic disorders have contributed to a better understanding of general disease mechanisms in paediatric rheumatic conditions. Beyond genomics, the application of other 'omics' technologies, including transcriptomics, proteomics and metabolomics, has generated an enormous dataset that can be applied to the development of new therapies and in the practice of precision medicine. Novel biomarkers for monitoring disease activity and progression have also emerged. A surge in the development of targeted biologic therapies has led to durable remission and improved prognosis for many diseases that in the past caused major complications. Last but not least, the COVID-19 pandemic has affected paediatric rheumatology practice and has sparked new investigations into the link between viral infections and unregulated inflammatory responses in children.

Contrastive machine learning reveals Parkinson’s disease specific features associated with disease severity and progression

Parkinson’s disease (PD) exhibits heterogeneity in terms of symptoms and prognosis, likely due to diverse neuroanatomical alterations. This study employs a contrastive deep learning approach to analyze Magnetic Resonance Imaging (MRI) data from 932 PD patients and 366 controls, aiming to disentangle PD-specific neuroanatomical alterations. The results reveal that these neuroanatomical alterations in PD are correlated with individual differences in dopamine transporter binding deficit, neurodegeneration biomarkers, and clinical severity and progression. The correlation with clinical severity is verified in an external cohort. Notably, certain proteins in the cerebrospinal fluid are strongly associated with PD-specific features, particularly those involved in the immune function. The most notable neuroanatomical alterations are observed in both subcortical and temporal regions. Our findings provide deeper insights into the patterns of brain atrophy in PD and potential underlying molecular mechanisms, paving the way for earlier patient stratification and the development of treatments to slow down neurodegeneration.

Emerging multisystem biomarkers in hereditary transthyretin amyloidosis: a pilot study

Hereditary transthyretin (ATTRv) amyloidosis is a rare, adult-onset, progressive, multisystemic condition caused by TTR pathogenic variants. Reliable biomarkers are needed to allow early diagnosis and to monitor disease severity and progression. We measured serum concentrations of growth differentiation factor-15 (GDF-15) and uromodulin (Umod) in ATTRv patients to evaluate correlations with standard markers of disease severity (FAP stage and PND score). Blood samples were collected from 16 patients diagnosed with ATTRv amyloidosis and a verified TTR variant and from 26 healthy controls. ATTRv patients were stratified by clinical phenotype (neurologic vs. mixed), genotype (V30M vs. non-V30M), and disease severity. We found significantly higher levels of serum GDF-15 in ATTRv patients compared with controls. Mean serum Umod levels were significantly lower in patients with ATTRv than controls. A positive correlation was found between serum Umod and estimated glomerular filtration rate (eGFR), while an inverse correlation was found with cystatin C levels. Conversely, GDF-15 showed a negative correlation with eGFR, and a direct correlation with cystatin C levels. No correlation was demonstrated between GDF-15 or Umod levels and traditional cardiac biomarkers. The results identify alteration of serum levels of GDF-15 and Umod in ATTRv amyloidosis.

Ethnic Differences in Atypical Parkinsonism-is South Asian PSP Different?

Progressive supranuclear palsy (PSP) is a progressive atypical parkinsonian condition that results in severe disability. There are few studies of PSP in patients of non-white European ancestry. We aim to perform deep phenotyping in a South Asian PSP cohort to uncover possible ethnic differences in disease characteristics. Consecutive PSP patients had their clinical records reviewed for clinical features operationalized in the Movement Disorder Society (MDS)-PSP diagnostic criteria and relevant investigations, including imaging and genetic tests. Clinical variables were summarized by descriptive statistics and Kaplan-Meier curves were generated for survival analysis. Twenty-seven patients, comprising Indians (78%), Pakistanis (11%) and Sri Lankans (11%) were included. Mean age of symptom onset was 63.8 ± 7.0 years and 22% of patients had an early age of onset (<60 years). The most common presenting symptom was parkinsonism (56%), followed by cognitive dysfunction (37%), falls (33%) and dysarthria (26%). The predominance types at final review were distributed across PSP-RS (67%), PSP-PGF (15%), PSP-P (15%) and PSP-F (4%). Atypical clinical features like cerebellar signs (33%), REM-sleep behavior disorder (RBD) (55%), visual hallucinations (22%), and a family history of parkinsonism (20%) were evident in a proportion of patients. We present a South Asian cohort of PSP patients with a higher than previously reported percentages of early-onset disease, family history and atypical clinical manifestations. These patients do not fit easily into the PSP phenotypes defined by the current MDS criteria. Dedicated clinicopathological and genetic tests are needed in this population to dissect the pathogenesis of clinically-defined PSP.

Comparison of Different Doses of Oral and Ocular Propranolol for Retinopathy of Prematurity: A Network Meta-Analysis.

The efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints. Fourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose-response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI). Bayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2-3; S23) of ROP progression compared with its administration at earlier stages (stages 0-1; S01). OR values for oral propranolol 1.5 and 2mg/kg/day given at S23 were 0.13 (95% CrI 0.04-0.37) and 0.16 (95% CrI 0.04-0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02-2.96) and 0.78 (95% CrI 0.14-4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09-1.00) versus an S01 OR of 0.64 (95% CrI 0.21-2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5-2mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose-response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02-0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05-0.93) and laser (OR 0.16; 95% CrI 0.02-1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5-1.0mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5mg/kg/day and the highest risk difference for oral propranolol 2.0mg/kg/day (0.06; 95% CI -0.01 to 0.13). A diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies.

Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.

The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.

Clinical and pathological significance of Orai1 channel expression in human diabetic nephropathy.

Targeted therapies for diabetic nephropathy (DN) are lacking, partly due to their irreversible nature. The role of Orai1, a store-operated Ca2+ channel, in DN remains debated, with conflicting evidence on its effect on proteinuria in animal models. We aimed to elucidate the functional relevance of Orai1 expression for clinicopathological parameters in patients with DN. In this study, we included 93 patients diagnosed with DN between 2009 and 2019. Immunohistochemical staining for Orai1 was performed on paraffin-embedded kidney sections. The significance of Orai1 expression in human DN was assessed by examining its correlation with DN's pathological and clinical parameters using Pearson's correlation coefficient and univariate logistic regression. Orai1 was significantly overexpressed in DN patients compared to control. A strong correlation was observed between increased Orai1 expression and higher Renal Pathology Society DN classification, enhanced interstitial fibrosis and tubular atrophy scores. Positive correlations with serum creatinine levels and prognosis of chronic kidney disease (CKD) by glomerular filtration rate (GFR) and albuminuria category were noted but the estimated GFR was inversely related to Orai1 expression. Orai1's association with advanced CKD stages persisted even after adjusting for confounding variables in multivariate logistic regression analysis. Orai1 expression is closely associated with histological and clinical severities of DN, suggesting its potential as a predictive biomarker for disease progression and prognosis. These findings provide new perspectives on therapeutic interventions targeting Orai1 in DN.

Assessment of HBV variants and novel viral and immune biomarkers in chronic hepatitis B patients with metabolic dysfunction associated steatotic liver disease.

Co-existing chronic hepatitis B virus (CHB) infection and metabolic dysfunction associated steatotic liver disease (MASLD) can exert complex effects on hepatic metabolism, requiring mechanistic study. CHB participants were assessed for MASLD and the impact of hepatic steatosis/metabolic syndrome (MetS) on novel viral and immunological markers. In this prospective, cohort study, untreated CHB subjects were assessed for liver disease by non-invasive tests (i.e. FibroScan, controlled attenuation parameter, CAP). Subjects were tested for cytokines and IFN-γ ELISPOT assay to HBV Surface (S) and Core (C) proteins. Standard HBV serological, exploratory biomarkers and deep sequencing of HBV S and C genes were performed. In 53 subjects (median age 45 years [SD = 10.6], 35% F, 56% Asian, 20% Black, 3% White), 94% (50) HBeAg negative, 63% genotype B/C, mean HBV DNA 3.2 log10 IU/mL (SD = 1.8), quantitative HBsAg 2.9 log10 IU/mL (SD = 1.2) and HBV pgRNA 2.1 log10 copies/mL (SD = 1.3). In enrolled subjects, the mean ALT was 41.9 U/L (SD = 24.0), FibroScan was 5.7 kPa (SD = 1.9) and CAP was 306.4 dB/m (SD = 49.0). The mean BMI was 28.2 kg/m2 (SD = 4.2), 20% (11/53) had diabetes, 35% (19/53) dyslipidaemia and 24% (13/53) hypertension. Subjects with MetS and steatosis showed lower HBV markers (p < .01), higher HBV S diversity (p = .02) and greater frequency of HBV variants associated with host-anti-viral immune escape. Pro-inflammatory cytokine levels and HBV-specific cellular responses were higher in participants with hepatic steatosis. In CHB, MASLD/hepatic steatosis was associated with HBV variants and systemic immune responses potentially impacting liver disease progression despite low-level viraemia.

Microglia through MFG-E8 signaling decrease the density of degenerating neurons and protect the brain from the development of cortical infarction after stroke.

Neuronal loss is a hallmark of stroke and other neurodegenerative diseases, and as such, neuronal loss caused by microglia has been thought to be a contributing factor to disease progression. Here, we show that microglia indeed contribute significantly to neuronal loss in a mouse model of stroke, but this microglial-dependent process of neuronal clearance specifically targets stressed and degenerating neurons in the ischemic cortical region and not healthy non-ischemic neurons. Nonspecific stimulation of microglia decreased the density of neurons in the ischemic cortical region, whereas specific inhibition of MFG-E8 signaling, which is required for microglial phagocytosis of neurons, had the opposite effect. In both scenarios, the effects were microglia specific, as the same treatments had no effect in mice whose microglia were depleted prior to stroke. Finally, even though the inhibition of MFG-E8 signaling increased neuronal density in the ischemic brain region, it substantially exacerbated the development of cortical infarction. In conclusion, microglia through MFG-E8 signaling contribute to the loss of ischemic neurons and, in doing so, minimize the development of cortical infarction after stroke.

The Application of a Serious Game Framework to Design and Develop an Exergame for Patients With Heart Failure.

Reducing inactivity in patients with chronic disease is vital since it can decrease the risk of disease progression and mortality. Exergames are an innovative approach to becoming more physically active and positively affecting physical health outcomes. Serious games are designed for purposes beyond entertainment and exergames are serious games for physical activity. However, current commercial exergames might not optimally meet the needs of patients with special needs. Developing tailored exergames is challenging and requires an appropriate process. The primary goal of this viewpoint is to describe significant lessons learned from designing and developing an exergame for patients with chronic heart failure using the player-centered, iterative, interdisciplinary, and integrated (P-III) framework for serious games. Four of the framework's pillars were used in the design and development of a mobile exergame: player-centered design, iterative development of the game, interdisciplinary teamwork, and integration of play and serious content. The mobile exergame was developed iteratively in 7 iterations by an interdisciplinary team involving users and stakeholders in all iterations. Stakeholders played various roles during the development process, making the team stay focused on the needs of the patients and creating an exergame that catered to these needs. Evaluations were conducted during each iteration by both the team and users or patients according to the player-centered design pillar. Since the exergame was created for a smartphone, the assessments were conducted both on the development computer and on the intended platforms. This required continuous deployment of the exergame to the platforms and smartphones that support augmented reality. Our findings show that the serious game P-III framework needs to be modified in order to be used for the design and development of exergames. In this viewpoint, we propose an updated version of the P-III framework for exergame development including (1) a separate and thorough design of the physical activity and physical interaction, and (2) early and continuous deployment of the exergame on the intended platform to enable evaluations and everyday life testing.

Histopathological Patterns of Otosclerosis Progression: Exploring Otic Capsule and Round Window Involvement.

Obliteration of the round window (RW) in cases of otosclerosis presents a significant clinical challenge due to its association with more severe hearing loss and a poorer prognosis for functional recovery after stapes surgery. The objective is to assess and characterize the occurrence of RW involvement in otosclerosis cases and to identify patterns of disease progression that may indicate a potential for RW obliteration. We selected archival temporal bones from donors with otosclerosis. We evaluated the degree of RW obliteration using a semi-quantitative scale and the location of the foci within the temporal bone, and whether the foci were continuous or isolated. Most of the foci were located anteriorly to the oval window (89.2%), while RW area involvement was seen in 26.9% of the ears. In cases with fenestral foci, 68.1% directly involved and/or fixed the footplate. Among donors with bilateral otosclerosis, foci affected both ears in a similar pattern in 64.2%. Among donors with RW involvement, ones with continuous, large lesions that extended from the oval window associated with complete RW obliteration, while ones with smaller degrees of obliteration had solitary foci scattered within the otic capsule. Our results demonstrate a high rate of RW involvement in cases of otosclerosis. Ears with continuous lesions extending from the oval window region to the RW area were more likely to present with complete RW obliteration. These results provide insights that could lead to better prognostic assessment of patients with otosclerosis in the future. N/A Laryngoscope, 2024.

Concomitant targeting of FLT3 and SPHK1 exerts synergistic cytotoxicity in FLT3-ITD+ acute myeloid leukemia by inhibiting β-catenin activity via the PP2A-GSK3β axis

BackgroundApproximately 25–30% of patients with acute myeloid leukemia (AML) have FMS-like receptor tyrosine kinase-3 (FLT3) mutations that contribute to disease progression and poor prognosis. Prolonged exposure to FLT3 tyrosine kinase inhibitors (TKIs) often results in limited clinical responses due to diverse compensatory survival signals. Therefore, there is an urgent need to elucidate the mechanisms underlying FLT3 TKI resistance. Dysregulated sphingolipid metabolism frequently contributes to cancer progression and a poor therapeutic response. However, its relationship with TKI sensitivity in FLT3-mutated AML remains unknown. Thus, we aimed to assess mechanisms of FLT3 TKI resistance in AML.MethodsWe performed lipidomics profiling, RNA-seq, qRT-PCR, and enzyme-linked immunosorbent assays to determine potential drivers of sorafenib resistance. FLT3 signaling was inhibited by sorafenib or quizartinib, and SPHK1 was inhibited by using an antagonist or via knockdown. Cell growth and apoptosis were assessed in FLT3-mutated and wild-type AML cell lines via Cell counting kit-8, PI staining, and Annexin-V/7AAD assays. Western blotting and immunofluorescence assays were employed to explore the underlying molecular mechanisms through rescue experiments using SPHK1 overexpression and exogenous S1P, as well as inhibitors of S1P2, β-catenin, PP2A, and GSK3β. Xenograft murine model, patient samples, and publicly available data were analyzed to corroborate our in vitro results.ResultsWe demonstrate that long-term sorafenib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates β-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit β-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3β (GSK3β) pathway.ConclusionsThese findings establish the sphingolipid metabolic enzyme SPHK1 as a regulator of TKI sensitivity and suggest that combining SPHK1 inhibition with TKIs could be an effective approach for treating FLT3-mutated AML.

Case–Control and Cohort Studies in Homeopathy: Part 4 of the Research Method Series

AbstractCase–control and cohort studies are fundamental epidemiological research designs utilized to investigate the relationship between exposures and outcomes in medical research. This paper provides a comparative analysis of these two study designs, focusing on their respective strengths, applications, and implications for understanding disease etiology, progression, and intervention effectiveness. Case–control studies offer a retrospective lens, enabling researchers to assess the impact of exposures on disease development by comparing individuals with a particular outcome (cases) to those without (controls). Through meticulous selection and analysis, case–control studies unveil potential risk factors and causal relationships, particularly beneficial for investigating rare diseases or long latency periods. Conversely, cohort studies adopt a prospective approach, following a group of individuals over time to evaluate the incidence of outcomes in relation to exposures. This design facilitates the assessment of cumulative exposure effects, disease progression, and intervention efficacy, providing valuable insights into the natural history of diseases. In the context of homeopathy, both the study designs may be utilized for the evaluation of long-term treatment effects, disease progression, and patient satisfaction, shedding light on the holistic nature of homeopathic care. By embracing rigorous methodologies and leveraging the strengths of both study designs, researchers in homeopathy can advance evidence-based practice, enhancing our understanding of homeopathic principles and their practical implications in clinical settings.

Pembrolizumab in Patients with Advanced Urothelial Carcinoma with ECOG Performance Status 2: A Real-World Study from the ARON-2 Project.

The benefit of immune checkpoint inhibitors (ICIs) for poor performance status patients with advanced urothelial carcinoma (UC) remains unknown. In the present sub-analysis of the ARON-2 study, we investigated the role of pembrolizumab for advanced UC patients with ECOG (Eastern Cooperative Oncology Group) performance status (ECOG-PS) 2. Patients aged ≥18 years with a cytologically and/or histologically confirmed diagnosis of advanced UC progressing or recurring after platinum-based therapy and treated with pembrolizumab between 1 January 2016 to 1 April 2024 were included. In this sub-analysis we focused on patients with ECOG-PS 2. We included 1,040 patients from the ARON-2 dataset; of these, 167 patients (16%) presented an ECOG-PS 2. The median overall survival (OS) was 14.8 months (95% confidence interval (CI) 12.5-16.1) in the overall study population, 18.2 months (95% CI 15.8-22.2) in patients with ECOG-PS 0-1, and 3.7 months (95% CI 3.2-5.2) in subjects with ECOG-PS 2 (p<0.001). The median progression-free survival (PFS) in the overall study population was 5.3 months (95% CI 4.3-97.1), 6.2 months (95% CI 5.5-97.1) in patients with ECOG-PS 0-1, and 2.8 months (95% CI 2.1-3.4) in patients with ECOG-PS 2. Among the latter, liver metastases and progressive disease during first-line therapy were significant predictors of OS at both univariate and multivariate analyses. For PFS, univariate and multivariate analyses showed a prognostic role for lung metastases, liver metastases, and progressive disease during first-line therapy. This large real-world evidence study suggests the effectiveness of second-line pembrolizumab for mUC patients with poor performance status. The presence of liver metastases and progressive disease during first-line therapy is associated with worse clinical outcomes and, thus, should be taken into account when making treatment decisions in clinical practice.

Case report: A case of widespread soft tissue infection and multiple abscesses secondary to hidradenitis suppurativa inducing septic shock caused by Lawsonella clevelandensis in China

Lawsonella clevelandensis is rare to associated with human infection, which may cause abscesses in abdominal cavity, liver, breast, and spine. Lawsonella clevelandensis is very difficult to be cultivated in regular manner; detection of 16S rRNA sequence is the main evidence for L. clevelandensis infection. The clinical manifestations of L. clevelandensis infection resemble other agents of Nocardia, Tuberculosis and non-tuberculous Mycobacterium (NTM) due to their morphologic similarities. Hidradenitis suppurativa (HS) is a chronic inflammatory disorder, which affects the intertriginous skin and is associated with numerous systemic comorbidities. HS eventually leads to severe pain, multiple abscesses, pus discharge, and irreversible tissue destruction. Lawsonella clevelandensis has not been reported to cause HS and systemic comorbidities. We presented the case of a 33-year-old male with widespread soft tissue infection and multiple abscesses secondary to HS (Hurley stage III) inducing septic shock caused by L. clevelandensis in China. He was diagnosed as HS and treated with intravenous antibiotic empirically. He developed multiple abscesses including lung and scrota. Bacterial and fungal cultures on blood and secretions from multiple skin lesions were all negative. Due to the misdiagnosis and progression of disease, the patient was transferred to intensive care unit, and he underwent drainage of the chest and right hemothorax removal under thoracoscopic. During the hospitalization, the patient developed septic shock and received mechanical ventilation. Computerized tomography (CT) scans revealed mediastinal emphysema, multiple subcutaneous emphysema, and severe pneumonia. Gene analysis of samples of incision and drainage of pus at the skin showed the rare infection of L. clevelandensis. Finally, the patients with recurrent soft tissue infections and multiple abscesses with negative microbiological culture results recovered after effective abscess drainage and antibiotic therapy. We suggested that NGS is a crucial supplementary diagnostic tool in individuals with recurrent skin infections and multiple abscesses, especially when conventional diagnostic methods are inconclusive.

A Retrospective Evaluation of the Treatment Effects of Rituximab in Patients with Progressive and Symptomatic Fibrosing Mediastinitis.

Fibrosing mediastinitis is an uncommon fibro-inflammatory condition without established or effective medical therapies. Infiltrating B-lymphocytes are commonly present, and progressive fibrosis compromises mediastinal structures including blood vessels and airways resulting in significant morbidity and mortality. To evaluate the benefits and side effects of Rituximab in patients with progressive and symptomatic fibrosing mediastinitis. We treated 22 patients (median age 35 years, range: 15-68 years, 45% female) with metabolically active, progressive fibrosing mediastinitis with off-label rituximab. Additionally, patients were put on pneumocystis and antifungal prophylaxis when immunosuppressed with rituximab. Modeling of longitudinal treatment response based on changes in relative lesion volume from baseline was performed retrospectively using functional data analysis; time-to-event modeling was performed to estimate treatment response rates based on a >30% reduction in pre-treatment volume. The primary end points were lack of disease progression and change in mediastinal lesion volume by CT (evaluated retrospectively). No patient experienced disease progression after rituximab therapy. Median clinical follow-up was 42 months (range: 7 to 94) and imaging follow-up 21 months (range: 7 to 62). 82% of patients had confirmed histoplasmosis-associated fibrosing mediastinitis. After rituximab treatment a 49.6% (95% CI = [17.5%, 64.4%]) mean estimated decrease in pre-treatment lesion volume was observed at 24 months. The estimated objective treatment response rate was 47.9% (95% CI = [26.7%, 70.3%]). This observational study suggests that Rituximab is well tolerated and potentially effective therapy in a cohort of patients with symptomatic and progressive FM.

Ferroptosis-related gene transferrin receptor protein 1 expression correlates with the prognosis and tumor immune microenvironment in cervical cancer

Background Ferroptosis is a non-apoptotic iron-dependent form of cell death implicated in various cancer pathologies. However, its precise role in tumor growth and progression of cervical cancer (CC) remains unclear. Transferrin receptor protein 1 (TFRC), a key molecule associated with ferroptosis, has been identified as influencing a broad range of pathological processes in different cancers. However, the prognostic significance of TFRC in CC remains unclear. The present study utilized bioinformatics to explore the significance of the ferroptosis-related gene TFRC in the progression and prognosis of CC. Methods We obtained RNA sequencing data and corresponding clinical information on patients with CC from The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx) and Gene Expression Omnibus (GEO) databases. Using least absolute shrinkage and selection operator (LASSO) Cox regression, we then generated a multigene signature of five ferroptosis-related genes (FRGs) for the prognostic prediction of CC. We investigated the relationship between TFRC gene expression and immune cell infiltration by employing single-sample GSEA (ssGSEA) analysis. The potential functional role of the TFRC gene was evaluated through gene set enrichment analysis (GSEA). Immunohistochemistry and qPCR was employed to assess TFRC mRNA and protein expression in 33 cases of cervical cancer. Furthermore, the relationship between TFRC mRNA expression and overall survival (OS) was investigated in patients. Results CC samples had significantly higher TFRC gene expression levels than normal tissue samples. Higher TFRC gene expression levels were strongly associated with higher cancer T stages and OS events. The findings of multivariate analyses illustrated that the OS in CC patients with high TFRC expression is shorter than in patients with low TFRC expression. Significant increases were observed in the levels of TFRC mRNA and protein expression in patients diagnosed with CC. Conclusion Increased TFRC expression in CC was associated with disease progression, an unfavorable prognosis, and dysregulated immune cell infiltration. In addition, it highlights ferroptosis as a promising therapeutic target for CC.

Adiponectin suppresses stiffness-dependent, pro-fibrotic activation of lung fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible respiratory disease with limited therapeutic options. A hallmark of IPF is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We performed an unbiased, next generation sequencing (NGS) screen to identify signaling pathways involved in stiffness-dependent lung fibroblast activation. Adipocytokine signaling was downregulated in primary lung fibroblasts (PFs) cultured on stiff matrices. Re-activating adipocytokine signaling with adiponectin suppressed stiffness-dependent activation of human PFs. Adiponectin signaling depended on CDH13 expression and p38 mitogen-activated protein kinase gamma (p38MAPKγ) activation. CDH13 expression and p38MAPKγ activation were strongly reduced in lungs from IPF donors. Our data suggest that adiponectin-signaling via CDH13 and p38MAPKγ activation suppresses pro-fibrotic activation of fibroblasts in the lung. Targeting of the adiponectin signaling cascade may provide therapeutic benefits in IPF.

Inhibition of Tumoral VISTA to Overcome TKI Resistance via Downregulation of the AKT/mTOR and JAK2/STAT5 Pathways in CML.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCR::ABL1-dependent and BCR::ABL1-independent pathways. The mechanisms underlying BCR::ABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCR::ABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/ mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCR::ABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCR::ABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.

Y90 Radiation Segmentectomy versus Microwave Ablation for Hepatocellular Carcinoma in Locations Suboptimal for Percutaneous Ablation

Abstract Purpose The purpose of our study was to evaluate outcomes following percutaneous microwave ablation (MWA) versus yttrium-90 (Y90) radiation segmentectomy (RS) for tumors in suboptimal locations for ablation. Materials and Methods Retrospective review (January 2014–July 2019) was performed on patients who underwent Y90-RS or MWA (with or without prior transarterial chemoembolization [TACE]) with curative intent for early-stage hepatocellular carcinoma (HCC) lesions in suboptimal locations for percutaneous ablation, defined as locations in which needle placement is within 5 mm of critical structures (liver dome, liver capsule, gallbladder, and hilum). The primary endpoints were treatment response as per the modified Response Evaluation Criteria in Solid Tumors criteria and complications. Statistical Analysis Fischer's exact test was performed for categorical variables, and Student's t-tests for nominal variables. Results Twenty-three lesions in 20 patients (13 male, 67 ± 8.8 years) and 30 lesions in 30 patients (18 male, 62.5 ± 10.6 years) were treated with Y90-RS and MWA (19 with prior TACE), respectively. There were no differences in demographics (p &gt; 0.05). Mean tumor diameter was 2.9 ± 1.0 in those treated with Y90-RS and 2.3 ± 0.9 for MWA (p &lt; 0.05). Lesions were located adjacent to the following structures: dome (n = 22), capsule (n = 16), hilum (n = 9), and gallbladder (n = 6). All patients were Eastern Cooperative Oncology Group performance status 0 to 1. Of the MWA cohort, 19 were Child-Pugh class A, 5 were B, and 6 were C and the mean pretreatment laboratory values were as follows: Model for End-stage Liver Disease sodium (MELD-Na) 12.7 ± 4.6, alpha-fetoprotein (AFP) 848 ± 3168.0, aspartate aminotransferase (AST) 71.9 ± 49.1, alanine aminotransferase (ALT) 48.0 ± 32.4, and total bilirubin 2.4 ± 2.7. Of the Y90-RS cohort, 15 were Child-Pugh class A, 4 were B, and 1 was C and pretreatment laboratory values were as follows: MELD-Na 10.5 ± 3.3 (Y90-RS), AFP 762.2 ± 1793.8 (Y90), AST 50.3 ± 30.5 (Y90), ALT 30.1 ± 16.9 (Y90), and total bilirubin 1.6 ± 1.1 (Y90). Complete response rate following Y90 was 96 versus 76% for MWA, with no disease progression after Y90-RS within the follow-up period. Three (13%) lesions demonstrated progression of disease (time to progression 6.3 months) after MWA. No grade &gt; 2 toxicities or procedure-related complications were noted following Y90-RS. There were 7 major (arterioportal fistula with hemoperitoneum, pneumothorax, liver infarction, and capsular burn) and 3 minor complications following MWA. Conclusion Y90-RS is a valuable alternative to percutaneous MWA as a first-line therapy for early-stage HCC for tumors in suboptimal locations for ablation, offering a favorable treatment response and safety profile.