Disease Progression Research Articles

Autoantibodies as putative biomarkers and triggers of cell dysfunctions in systemic sclerosis.

Antinuclear autoantibodies represent a serological hallmark of systemic sclerosis (SSc), with anticentromere, antitopoisomerase-I, and anti-RNA polymerase III antibodies routinely assessed for diagnosis, clinical subset classification, and prognosis. In addition, an increasing number of autoantibodies have been demonstrated to play a pathogenic role by mediating different SSc manifestations. This review aims to give an overview on autoantibodies as putative biomarkers in SSc and discuss their possible pathogenic role as triggers of cell dysfunctions. Over the years, different autoantibodies have been proposed as biomarkers aiding in diagnosis, disease subtype classification, disease progression prediction, organ involvement, as well as in understanding treatment response. Increasing literature also indicates functional autoantibodies as direct contributors to SSc pathogenesis by exerting agonistic or antagonistic activities on their specific cognate targets. In SSc, search and validation of novel autoantibodies with higher diagnostic specificity and more accurate predictive values are increasingly needed for early diagnosis and specific follow-up, and to define the best therapeutic option according to different disease subsets. Moreover, since autoantibodies are also emerging as functional pathogenic players, a better unraveling of their possible pathomechanisms becomes essential to identify new targets and develop promising therapeutic agents able to neutralize their effects.

Anatomy-specific Progression Classification in Chest Radiographs via Weakly Supervised Learning.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To develop a machine learning approach for classifying disease progression in chest radiographs using weak labels automatically derived from radiology reports. Materials and Methods In this retrospective study, a twin neural network was developed to classify anatomy-specific disease progression into four categories: improved, unchanged, worsened, and new. A two-step weakly-supervised learning approach was employed, pretraining the model on 243,008 frontal chest radiographs from 63,877 MIMIC-CXR patients (mean age 51.7 years; female 34,813), and fine-tuning it on the subset with progression labels derived from consecutive studies. Model performance was evaluated for six pathologic observations on test datasets of unseen MIMIC-CXR patients. Area under the receiver operating characteristic (AUC) analysis was used to evaluate classification performance. The algorithm is also capable of generating bounding-box predictions to localize areas of new progression. Recall, precision, and mean average precision (mAP) were used to evaluate the new progression localization. One-tailed paired t tests were used to assess statistical significance. Results The model outperformed most baselines in progression classification, achieving macro AUC scores of 0.72 ± 0.004 for atelectasis, 0.75 ± 0.007 for consolidation, 0.76 ± 0.017 for edema, 0.81 ± 0.006 for effusion, 0.7 ± 0.032 for pneumonia, and 0.69 ± 0.01 for pneumothorax. For new observation localization, the model achieved mAP scores of 0.25 ± 0.03 for atelectasis, 0.34 ± 0.03 for consolidation, 0.33 ± 0.03 for edema, and 0.31 ± 0.03 for pneumothorax. Conclusion Disease progression classification models were developed on a large chest radiograph dataset, which can be used to monitor interval changes and detect new pathologies on chest radiographs. ©RSNA, 2024.

Programmed cell death 1 inhibitor sintilimab plus concurrent chemoradiotherapy for locally advanced pancreatic adenocarcinoma

BACKGROUND Pancreatic adenocarcinoma, a malignancy that arises in the cells of the pancreas, is a devastating disease with unclear etiology and often poor prognosis. Locally advanced pancreatic cancer, a stage where the tumor has grown significantly but has not yet spread to distant organs, presents unique challenges in treatment. This article aims to discuss the current strategies, challenges, and future directions in the management of locally advanced pancreatic adenocarcinoma (LAPC). AIM To investigate the feasibility and efficacy of programmed cell death 1 (PD-1) inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC. METHODS Eligible patients had LAPC, an Eastern cooperative oncology group performance status of 0 or 1, adequate organ and marrow functions, and no prior anticancer therapy. In the observation group, participants received intravenous sintilimab 200 mg once every 3 wk, and received concurrent chemoradiotherapy (concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-1 40 mg/m2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression, death, or unacceptable toxicity). In the control group, participants only received concurrent chemoradiotherapy. From April 2020 to November 2021, 64 participants were finally enrolled with 34 in the observation group and 30 in the control group. RESULTS Thirty-four patients completed the scheduled course of chemoradiotherapy, while 32 (94.1%) received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group. Thirty patients completed the scheduled course of chemoradiotherapy in the control group. Based on the Response Evaluation Criteria in Solid Tumors guidelines, the analysis of the observation group revealed that a partial response was observed in 11 patients (32.4%), stable disease was evident in 19 patients (55.9%), and 4 patients (11.8%) experienced progressive disease; a partial response was observed in 6 (20.0%) patients, stable disease in 18 (60%), and progressive disease in 6 (20%) in the control group. The major toxic effects were leukopenia and nausea. The incidence of severe adverse events (AEs) (grade 3 or 4) was 26.5% (9/34) in the observation group and 23.3% (7/30) in the control group. There were no treatment-related deaths. The observation group demonstrated a significantly longer median overall survival (22.1 mo compared to 15.8 mo) (P < 0.05) and progression-free survival (12.2 mo vs 10.1 mo) (P < 0.05) in comparison to the control group. The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group (P > 0.05). CONCLUSION Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients, and warrants further investigation.

Characterizing Clinical Progression in Cognitively Unimpaired Older Individuals with Brain Amyloid: Results from the A4 Study

BackgroundClinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials.ObjectivesWe sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer’s Disease (A4) secondary prevention study.DesignAll participants entered the study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment/problem solving) and function (community affairs and home/hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits.SettingThe A4 study took place at 67 sites in Australia, Canada, Japan and the United States.Participants1,147 individuals, ages 65–85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks.MeasurementsGeneralized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment.ResultsThere were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the trial. Changes in judgment/problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression.ConclusionsThe findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.

Increased basal fibronectin is sufficient to promote excess endothelial cell matrix assembly causing localized barrier dysfunction.

Endothelial cell behavior is regulated by subendothelial extracellular matrix (ECM). The ECM protein fibronectin (FN) is rare in healthy blood vessels but accumulates in disease accompanied by endothelial dysfunctions. Here, we report that excess assembly of FN disrupts key endothelial functions. We mimicked increased FN expression as in diseased stroma by providing exogenous FN basally in a Transwell insert and found dose-dependent upregulation of subendothelial FN matrix assembly. Taking advantage of discontinuous matrix assembly by endothelial cells, we show correlations between regional increases in FN matrix and disruptions in endothelial cell morphology, VE-cadherin junctions, and the cell cycle, all of which were not changed in FN-deficient regions of the monolayer. These changes affected endothelial barrier function with increased monolayer permeability exposing basal regions of high FN matrix and permitting FN-dependent adhesion of MDA-MB-231 tumor cells from the apical side of the monolayer. FN matrix accumulation was quick and increases in FN matrix preceded all other changes in the endothelium. Therefore, subendothelial accumulation of FN matrix is a cause, not an effect, of endothelial monolayer disorganization and leakiness. Regulating FN accumulation in the subendothelial space could be an important target for controlling progression of fibrosis and related diseases.

Cost-effectiveness of dapagliflozin plus standard treatment compared to standard therapy for the management of chronic kidney disease in Colombia.

The DAPA-CKD study showed that dapagliflozin added to standard treatment reduced the risk of chronic kidney disease progression, and death from renal or cardiovascular causes compared to placebo. Assess the cost-effectiveness of dapagliflozin and standard treatment versus standard treatment alone for chronic kidney disease within the Colombian health system. We employed a Markov model based on the DAPA-CKD study, tailored to the Colombian scenario. The model forecasted hospitalizations for heart failure, overall and cardiovascular mortality, and chronic kidney disease progression over a 10-year horizon with a 5% discount rate. Dapagliflozin combined with standard treatment is a cost-effective intervention in treating stage 2-4 CKD. In the base case, the ICER was US $5,366, below 1 GDP (US $6.558) per capita. This was consistent in the sensitivity analyses. Our study showed that dapagliflozin, when combined with standard treatment, is cost-effective against standard treatment alone, aligning with Colombia's willingness-to-pay threshold.

AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice

BackgroundAmyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS.MethodsWe used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice.ResultsSOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice.ConclusionsAAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.

Neural circuit mechanisms underlying aberrantly prolonged functional hyperemia in young Alzheimer's disease mice.

Neurovascular defects are one of the most common alterations in Alzheimer's disease (AD) pathogenesis, but whether these deficits develop before the onset of amyloid beta (Aβ) accumulation remains to be determined. Using in vivo optical imaging in freely moving mice, we explored activity-induced hippocampal microvascular blood flow dynamics in AppSAA knock-in and J20 mouse models of AD at early stages of disease progression. We found that prior to the onset of Aβ accumulation, there was a pathologically elevated blood flow response to context exploration, termed functional hyperemia. After the onset of Aβ accumulation, this context exploration-induced hyperemia declined rapidly relative to that in control mice. Using in vivo electrophysiology recordings to explore the neural circuit mechanism underlying this blood flow alteration, we found that hippocampal interneurons before the onset of Aβ accumulation were hyperactive during context exploration. Chemogenetic tests suggest that hyperactive activation of inhibitory neurons accounted for the elevated functional hyperemia. The suppression of nitric oxide (NO) produced from hippocampal interneurons in young AD mice decreased the accumulation of Aβ. Together, these findings reveal that neurovascular coupling is aberrantly elevated before Aβ deposition, and this hyperactive functional hyperemia declines rapidly upon Aβ accumulation.

Disease modification in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is a debilitating, inflammatory skin condition characterized by infiltrating immune cells. Available treatments are limited to improving the signs and symptoms. There is an unmet need to develop therapies that target disease-driving pathways upstream of mast cell activation to inhibit or delay the progression of CSU and associated comorbidities. Here, we aim to define disease modification due to a treatment intervention and criteria that disease-modifying treatments (DMTs) must meet in CSU. We have defined disease modification in CSU as a favorable treatment-induced change in the underlying pathophysiology and, therefore, the disease course, which is clinically beneficial and enduring. A DMT must fulfil the following criteria: (1) prevents or delays the progression of CSU, (2) induces long-term, therapy-free clinical remission, which is the sustained absence of CSU signs and symptoms without the need for treatment, and (3) affects the underlying mechanism of CSU, as demonstrated by an effect on disease-driving signals and/or a biomarker. DMTs in CSU should slow disease progression, achieve long-lasting disease remission, target disease-driving mechanisms, reduce mast cell-activating IgE autoantibodies, target cytokine profile polarization, and normalize the gut microbiome and barrier. Treating CSU at the immune system level could provide valuable alternatives to pharmacotherapy in CSU management. Specific DMTs in CSU are yet to be developed, but some show potential benefits, such as inhibitors of Bruton's Tyrosine Kinase, IL-4 and IL-13. Future therapies could prevent CSU signs and symptoms, achieve long-term clinical benefits after discontinuing treatment, and prevent associated concomitant disorders.

Structural and Molecular Imaging-based Characterization of Soft Tissue and Vascular Calcification in Hyperphosphatemic Familial Tumoral Calcinosis.

Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) is a rare disorder caused by deficient FGF23 signaling and resultant ectopic calcification. In this study, we systematically characterized and quantified macro- and micro-calcification in an HFTC cohort using computed tomography (CT) and 18F-sodium fluoride positron emission tomography/CT (18F-NaF PET/CT). Fourier-transform infrared (FTIR) spectroscopy was performed on four phenotypically different calcifications from a patient with HFTC, showing the dominant component to be hydroxyapatite. Eleven patients with HFTC were studied with CT and/or 18F-NaF PET/CT. Qualitative review was done to describe the spectrum of imaging findings on both modalities. CT-based measures of volume (e.g., total calcific burden and lesion volume) and density (Hounsfield units) were quantified and compared to PET-based measures of metabolic activity (e.g., mean standardized uptake values). Microcalcification scores (mCSs) were calculated for the vasculature of six patients using 18F-NaF PET/CT and visualized on a standardized vascular atlas. Ectopic calcifications were present in 82% of patients, predominantly near joints and the distal extremities. Considerable heterogeneity was observed in total calcific burden per patient (823.0 ± 670.1cm3, n = 9) and lesion volume (282.5 ± 414.8cm3, n = 27). The largest lesions were found at the hips and shoulders. 18F-NaF PET offered the ability to differentiate active vs. quiescent calcifications. Calcifications were also noted in multiple anatomic locations, including brain parenchyma (50%). Vascular calcification was seen in the distal aorta, carotid, and coronaries in 50%, 70%, 73%, and 50%, respectively. 18F-NaF-avid, but CT-negative calcification was seen in a 17-year-old patient, implicating early onset vascular calcification. This first systematic assessment of calcifications in a cohort of patients with HFTC has identified the early onset, prevalence, and extent of macro- and micro-calcification. It supports 18F-NaF PET/CT as a clinical tool for distinguishing between active and inactive calcification, informing disease progression, and quantification of ectopic and vascular disease burden.

Superior detection of low-allele burden Janus kinase 2 V617F mutation and monitoring clonal evolution in myeloproliferative neoplasms using chip-based digital PCR.

The JAK2 V617F is a prevalent driver mutation in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs), significantly affecting disease progression, immunophenotype, and patient outcomes. The World Health Organization (WHO) guidelines highlight the JAK2 V617F mutation as one of the key diagnostic criterions for Ph-MPNs. In this study, we analyzed 283 MPN samples with the JAK2 V617F mutation to assess the effectiveness of three detection technologies: chip-based digital PCR (cdPCR), real-time quantitative PCR (qPCR), and next-generation sequencing (NGS). Additionally, we investigated the relationship between JAK2 V617F mutant allele burden (% JAK2 V617F) and various laboratory characteristics to elucidate potential implications in MPN diagnosis. Our findings demonstrated high conformance of cdPCR with qPCR/NGS for detecting % JAK2 V617F, but the mutant allele burdens detected by qPCR/NGS were lower than those detected by cdPCR. Moreover, the cdPCR exhibited high sensitivity with a limit of detection (LoD) of 0.08% and a limit of quantification (LoQ) of 0.2% for detecting % JAK2 V617F in MPNs. Clinical implications were explored by correlating % JAK2 V617F with various laboratory characteristics in MPN patients, revealing significant associations with white blood cell counts, lactate dehydrogenase levels, and particularly β2-microglobulin (β2-MG) levels. Finally, a case report illustrated the application of cdPCR in detecting low-allele burdens in a de novo chronic myeloid leukemia (CML) patient with a hidden JAK2 V617F subclone, which expanded during tyrosine kinase inhibitor (TKI) treatment. Our findings underscore the superior sensitivity and accuracy of cdPCR, making it a valuable tool for early diagnosis and monitoring clonal evolution.

Characterize molecular signatures and establish a prognostic signature of gastric cancer by integrating single-cell RNA sequencing and bulk RNA sequencing

Gastric cancer is a significant global health concern with complex molecular underpinnings influencing disease progression and patient outcomes. Various molecular drivers were reported, and these studies offered potential avenues for targeted therapies, biomarker discovery, and the development of precision medicine strategies. However, it was posed that the heterogeneity of the disease and the complexity of the molecular interactions are still challenging. By seamlessly integrating data from single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq), we embarked on characterizing molecular signatures and establishing a prognostic signature for this complex malignancy. We offered a holistic view of gene expression landscapes in gastric cancer, identified 226 candidate marker genes from 3 different dimensions, and unraveled key players’ risk stratification and treatment decision-making. The convergence of molecular insights in gastric cancer progression occurs at multiple biological scales simultaneously. The focal point of this study lies in developing a prognostic model, and we amalgamated four molecular signatures (COL4A1, FKBP10, RNASE1, SNCG) and three clinical parameters using advanced machine-learning techniques. The model showed high predictive accuracy, with the potential to revolutionize patient care by using clinical variables. This will strengthen the reliability of the model and enable personalized therapeutic strategies based on each patient’s unique molecular profile. In summary, our research sheds light on the molecular underpinnings of gastric cancer, culminating in a powerful prognostic tool for gastric cancer. With a firm foundation in biological insights and clinical implications, our study paves the way for future validations and underscores the potential of integrated molecular analysis in advancing precision oncology.

Clinical impact of a dose-escalation strategy for lenvatinib in differentiated thyroid cancer.

Treatment options for patients with differentiated thyroid cancer (DTC) who experience disease progression on lenvatinib treatment are limited. Although dose escalation of treatment with tyrosine kinase inhibitors at disease progression has been reported across cancer types, clinical significance in patients with DTC has not been investigated. We retrospectively reviewed patients with DTC who experienced disease progression on lenvatinib treatment from September 2011 to June 2022. We compared subjects who received dose-escalation treatment with standard treatment of termination at the time of initial disease progression. The escalated dose was decided by referencing to the previous effective and tolerated dose. Thirty-three patients were identified, 15 with dose escalation and 18 with lenvatinib termination. In both groups, the starting dose of lenvatinib was 24mg/day, and the median dose at initial disease progression was 10mg/day. In the former, the median dose escalation was 6mg/day (range: 4-12). Objective response rate, clinical benefit rate by escalation, and median treatment duration of the dose-escalation phase were 13.3%, 73.3%, and 9.9months (95% confidence interval [CI] 5.71-27.6), respectively. Median overall survival from initial disease progression was significantly longer in the dose-escalation group (median OS: 20.4months [95% CI 7.0-NA] vs. 3.9months [95% CI 1.7-7.9], log-rank p-value; 0.0004, hazard ratio; 0.22 [95% CI 0.09-0.55]). There were no grade 5 adverse events, and one patient discontinued due to a grade 3 lung abscess. The dose-escalation strategy appears to be a safe and effective treatment option after disease progression in patients treated with lenvatinib for DTC.

Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.

Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival. Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate. Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029). We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.

Computational Exploration of Ganoderma lucidum Metabolites as Potential Anti-Atherosclerotic Agents: Insights from Molecular Docking and Dynamics Simulations

Ganoderma lucidum is a unique form of fungus utilized in Chinese medicine for various therapies as it exhibits a wide range of pharmacological activity. In this study, the purpose is to evaluate the possible drug-like qualities of the metabolites of G. lucidium as well as the impact that these metabolites have on the pathways involved in atherosclerosis. Throughout our research, a total of 17 compounds were chosen based on their drug-like properties. These compounds were then utilized in the subsequent networking and docking simulations. According to the findings, the compound ganodone has a maximum binding energy of -7.243 Kcal/mol. In terms of the binding energy, it has been discovered that the compound cianidanol has the lowest value. Based on the findings of the molecular docking investigations, it was determined that TNF, AKT1, SRC, and STAT3 exhibited a higher affinity for the complex. To determine this, molecular dynamics simulation was performed for about 100 nanoseconds. Following the completion of the GO functional analysis, it was discovered that the target genes were involved in the processes of protein binding, ATP binding, enzyme binding, and protein tyrosine kinase activity. Overall, the study results provide a view of possible metabolites that may have an impact on disease progression.

Clinicopathological analysis of gastric adenocarcinoma with elevated serum alpha-fetoprotein and enteroblastic differentiation

Objective: To investigate the immunophenotypic and molecular biological characteristics of patients with elevated serum alpha-fetoprotein (AFP) and enteroblastic differentiated gastric adenocarcinoma (GAED). Methods: The clinicopathological data of 13 patients with elevated serum AFP and GAED admitted to Shanxi Cancer Hospital from 2018 to 2020 were collected. Immunohistochemistry (IHC) and next-generation sequencing (NGS) were used to analyze the immune markers and molecular biological characteristics of the pathological tissues of the patients. Kaplan-Meier method and log rank test were used for survival analysis. Results: Among the 13 patients with GAED, 12 were male and 1 was female, aged 41-70 years, with a median age of 64 years. The lesions were mainly located in the gastric antrum (5 cases) and gastric body (4 cases). IHC results showed that the tumor embryonic protein (AFP, SALL4, GPC3), intestinal epithelial differentiation protein (CDX-2, CD10), and some original intestinal epithelial phenotype markers (OCT3/4, Claudin6) were expressed in the tumor tissues. Combined application of multiple markers can reduce the rate of missed diagnosis. Among the 13 patients, 12 had at least one mutation (1 mutation: 1 case, 2-5 mutations: 3 cases, 6-15 mutations: 8 cases), and 1 case was not detected. The gene with the highest mutation frequency was TP53 (10 cases), and other mutant genes included EPHB1 (3 cases), ATRX (2 cases), EPHA5 (2 cases), GATA3 (2 cases), LRP1B (2 cases) and MAP2K4 (2 cases) were also detected. Three of the 13 patients had structural variations, which were C14orf177-GNAS, AIM1-FGFR3, and EPHA6-ROS1 gene rearrangements. All 13 patients had copy number variation, and 11 patients had copy number variation of more than 2 genes. The common amplification genes were IRS2 (5 cases), PTEN (5 cases), GNAS (4 cases), CCNE1 (3 cases), CEBPA (3 cases), PCK1 (3 cases) and ERBB2 (2 cases). The common deletion genes were SOX2 (5 cases) and MYC (5 cases). Among the 13 patients, 4 died, and 2 of the dead patients had liver metastasis. There were 4 patients with disease-free survival and 5 patients with disease progression, including 3 cases of abdominal metastasis and 2 cases of liver metastasis. The 3-year survival rate of patients was 65.9 %, and the 3-year progression-free survival rate was 30.7 %. Gene LRP1B point mutation was associated with poor prognosis (P＜0.001). There was no significant improvement in the prognosis of patients treated with immunotherapy compared with those treated with chemotherapy alone (P=0.595), but the prognosis of patients treated with postoperative chemotherapy or postoperative chemotherapy plus immunotherapy was better than that of patients treated with surgery alone (P＜0.05). Conclusions: Elevated serum AFP with GAED is a highly invasive tumor with unique molecular characteristics, often accompanied by multiple molecular events. TP53 mutation is the most common type of gene mutation. In addition, some cases are accompanied by HER2 amplification and gene rearrangement.

Multicenter Real-World Analysis of Combined MET and EGFR Inhibition in Patients with Non-Small Cell Lung Cancer and Acquired MET Amplification or Polysomy after EGFR Inhibition

Purpose: MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification. Methods: This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥2) or polysomy (gene copy number ≥5, MET-CEP7 <2). Results: A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54). Conclusion: In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response. Micro Abstract: MET amplification is a common resistance mechanism to EGFR inhibition in NSCLC. However, the term MET amplification has been used inconsistently and frequently included polysomy. In this retrospective study, patients with true MET amplification rather than polysomy derived clinical benefit from combined MET and EGFR inhibition compared to SoC.

Preventable fraction in the context of disease progression.

The relevance of the epidemiologic concept of preventable fraction to the study of the population-level impact of preventive exposures is unequivocal. Here, we discuss how the preventable fraction can be usefully understood for the class of outcomes that relate to disease progression (e.g., clinical severity given diagnosis), and, under the principal stratification framework, derive an expression for this quantity for this type of outcome. In particular, we show that, in the context of disease progression, the preventable fraction is a function of the effect on the post-diagnosis outcome in the principal stratum in the unexposed group who would have disease regardless of exposure status. This work will facilitate understanding of the contribution of principal effects to the impact of preventive exposures at the population level.

Expression of miR-34a, RASSF1A and E-cadherin in relation to PRB in endometrioid carcinoma and its precursor.

The current study aims to evaluate the levels of miR-34a, RASSF1A, and E-cadherin in relation to the levels of isoform B of progesterone receptor (PRB) in endometrioid carcinoma (EC) and atypical hyperplasia (AEH) and their association with clinicopathological parameters. 105 cases (35 EC, 35 AEH, and 35 control) were involved in this study. Cases of AEH received treatment, and other samples were obtained after 6 months to assess the response. E-cadherin and PRB were assessed by immunohistochemistry (IHC), RASSFA methylation by MSP-PCR, and its serum level by ELISA and miR-34a via quantitative PCR. The expressions of miR-34a, RASSF1A, E-cadherin, and PRB differ among the studied groups; all were higher in normal compared with AEH and EC, with a statistically significant difference. The higher PRB expression and decreased miR-34a and RASSF1A expression were associated with resistance to hormonal therapy in AEH. High PRB in EC is associated with lower RASSFA1, E-cadherin, and miR-34a. Decreased expressions of RASSF1A, miR-34a, and E-cadherin had a significant connection to advanced stages. Expression of PRB and miR-34a and serum levels of RASSF1A predict response to treatment in cases of AEH. High PRB and low E-cadherin expression are associated with progressive disease in EC.

The efficacy and safety of anlotinib combined with niraparib in treating patients with platinum-resistant recurrent ovarian cancer

Objectives: To investigate the efficacy and safety of anlotinib combined with niraparib in treating patients with platinum-resistant ovarian cancer. Methods: Thirty-five patients with pathological confirmed platinum-resistant ovarian cancer who experienced progression after receiving at least two lines of standard treatment were eligible. All of them were treated with anlotinib combined with niraparib between September 2019 and October 2021. The primary endpoint was progression-free survival (PFS). The second endpoints included overall survival, objective response rate (ORR), disease control rate (DCR) and safety. Survival analysis was performed using the Kaplan-Meier method and Log-rank test, and influence factor analysis was performed using Cox proportional risk regression models. Results: The best overall response showed that partial response was observed in 14 patients, stable disease was noted within 13 patients, and progressive disease was found in 8 patients. Therefore, the ORR and DCR of these 35 patients were 40.0% (95% CI:22.9%-57.1%) and 77.1% (95% CI:62.9%-91.4%), respectively. The median follow-up duration was 18.9 months (6.9-32.2). The median PFS was 6.5 months (95% CI:5.35-7.66). Multivariate Cox regression analysis for PFS indicated that age, Eastern Cooperative Oncology Group performance status (ECOG PS) score, International Federation of Gynecology and Obstetrics (FIGO) stage, and BRCA mutation status were independent factors influencing PFS (P＜0.05). Additionally, the PFS in patients with BRCA mutation who have never received PARP inhibitor treatment was significantly longer than that in patients without BRCA mutation who have been exposed to prior PARPi treatment (15.0 vs 6.0 month, P=0.029). The most common treatment-related adverse reactions were fatigue (85.7%), hematologic toxic (85.7%) and hypertension (74.3%). There were no treatment-related deaths. Conclusion: Anlotinib combined with niraparib shows a promising efficacy and tolerable safety in platinum-resistant ROC patients.