Progression Of Lesions Research Articles

Methylation of SOX1 and PAX1 Are Risk Factors and Potential Biomarkers for Cervical Lesions.

The correlation between methylation of paired box gene 1 (PAX1) and sex determining region Y-box 1 (SOX1) with human papillomavirus (HPV) infection and the progression of cervical lesions is not well understood. This study aims to explore the potential value of PAX1 and SOX1 as diagnostic biomarkers for cervical diseases. A total of 139 cervical biopsy tissue samples were obtained from the Department of Pathology, the Seventh Medical Center, Chinese PLA General Hospital from 2021 to 2023. The samples include 32 cases of chronic cervicitis (inflammation group), 30 cases of low-grade squamous intraepithelial lesions (LSIL group), 50 cases of high-grade squamous intraepithelial lesions (HSIL group), and 27 cases of cervical squamous cell carcinoma (CSCC group). DNA was extracted from paraffin-embedded tissues, and the levels of HPV infection and methylation of PAX1 and SOX1 were detected. The methylation index (M-index) of PAX1 and SOX1 in the HSIL and CSCC groups is significantly higher than in the inflammation group (both P < 0.0001), with no significant difference between the LSIL and inflammation groups. There is no significant difference in the positive PAX1 and SOX1 methylation rate with HPV infection and age. The positive rates of PAX1 methylation in the inflammation, LSIL, HSIL, and CSCC groups were 3.13%, 10.00%, 44.00%, and 88.89%, respectively. The positive rates of SOX1 methylation were 3.13%, 10.00%, 40.00%, and 77.78%, respectively, and increasing with the progression of cervical lesions (R2 = 0.9189/R2 = 0.9279, P < 0.0001/P < 0.0001). Comparing LSIL, HSIL, and CSCC with the inflammation group and using cervical biopsy pathology diagnosis as the gold standard, methylation of PAX1 and SOX1 is a risk factor for HSIL and CSCC, with odds ratio (OR) values significantly increasing as lesions progress. The sensitivity of PAX1 and SOX1 methylation to cervical lesions increases with the progression of the lesions. Methylation of SOX1 and PAX1 is not associated with HPV infection. The positive rate of methylation for SOX1 and PAX1 is positively correlated with cervical lesions, which can serve as potential biomarkers for HSIL and CSCC. They are risk factors and potential screening indicators for HSIL and above cervical lesions.

Bone marrow-derived NGFR-positive dendritic cells regulate arterial remodeling.

It has been proposed that bone marrow contributes to the pathogenesis of arteriosclerosis. Nerve growth factor receptor (NGFR) is expressed in bone marrow stromal cells; it is also present in peripheral blood and ischemic coronary arteries. We hypothesized that bone marrow-derived NGFR-positive (NGFR+) cells regulate arterial remodeling. We found that human NGFR+ mononuclear cells (MNCs) in peripheral blood expressed markers for plasmacytoid dendritic cells (DCs) and were susceptible to apoptosis in response to proNGF secreted by activated arterial smooth muscle cells (SMCs). Bone marrow-specific depletion of NGFR+ cells increased neointimal formation following arterial ligation in mice. Bone marrow-derived NGFR+ cells accumulated in the neointima and underwent apoptosis. In contrast, in a bone marrow-specific NGFR-knockout model, SMCs occupied the neointima with augmented proliferation. NGFR+ cells in the neointima promoted mannose receptor C-type 1-positive anti-inflammatory macrophage accumulation and secreted anti-inflammatory IL-10, thereby inhibiting SMC proliferation in the neointima. In patients with acute coronary syndrome (ACS), NGFR+ peripheral MNCs increased after ACS onset. Multiple linear regression analysis showed that an insufficient increase in NGFR+ peripheral MNCs in ACS was an adjusted independent risk factor for 9-mo intimal progression of a nontargeted lesion. Taken together, these observations imply that bone marrow-derived NGFR+ DCs are suppressors of arteriosclerosis.NEW & NOTEWORTHY We propose a new concept of arterial remodeling after injury in which bone marrow-derived NGFR+ dendritic cells inhibit neointimal progression mediated by apoptosis. NGFR+ dendritic cells promote anti-inflammatory MRC1+ M2 macrophage accumulation and production of interleukin-10, inhibiting smooth muscle cell proliferation within the neointima. In a clinical study, insufficient mobilization of NGFR+ peripheral mononuclear cells in acute coronary syndrome was an independent risk factor for 9-mo nontargeted coronary intimal progression.

An organogold compound impairs Leishmania amazonensis amastigotes survival and delays lesion progression in murine cutaneous leishmaniasis: Mechanistic insights.

Leishmaniasis is one of the most important neglected diseases, classically characterized by three clinical forms that if left untreated can lead to skin lesions, lifelong scarring, or death depending on the parasite species. Unfortunately, treatment is unsatisfactory and the search for an improved therapy has been a priority. Gold compounds have emerged as promising candidates and among them, Au(I)bis-N-heterocyclic carbene (Au(BzTMX)2) has stood out. We have shown that it alters the plasma membrane permeability of Leishmania amazonensis and L. braziliensis, with superior activity for L. amazonensis. Herein, we moved a step forward towards the elucidation of its mechanism of action in L. amazonensis axenic amastigotes in vitro and in vivo. After 24 h incubation, Au(BzTMX)2 induced changes in safranin O uptake, reflecting the ultrastructural changes observed in mitochondria, especially cristae swelling, and oxygen consumption rates. Besides mitochondrial alterations, plasma membrane blebbing and the formation of multilamellar structures were also observed suggesting an autophagy-like process induction. In vivo, Au(BzTMX)2 was capable of delaying lesion progression, decreasing the total ulcerated area and leading to a marked reduction in the parasite burden of infected BALB/c mice. Taking all into consideration, our results give support to the current knowledge of the importance of gold compounds in therapeutics and open new possibilities for leishmaniasis treatment.

Lesion Formation in Cardiac Pulsed-Field Ablation: Acute to Chronic Cellular Level Changes.

As pulsed-field ablation (PFA) emerges as a promising therapy for atrial arrhythmias, an understanding of the cellular injury to cardiac tissue is critical to evaluating and interpreting results for each PFA system. This review aims to detail the mechanism of cell death for PFA, compare the cell death mechanism to thermal ablation modalities, clarify common histology markers, detail the progression of PFA lesions from the acute, to subacute, to chronic maturation states, and discuss clinical indicators of PFA lesions.

Abstract B019: Mathematical modeling-based optimization of gamma knife surgery after checkpoint blockade in melanoma brain metastases

Abstract Gamma knife radiotherapy (RT) treatment is often used as a salvage therapy after progression of melanoma brain metastasis (MBM) lesions under immune checkpoint inhibitor (ICI) blockade therapy; however, waiting until progression of nonresponsive lesions can result in significant symptomatic progression, and the toxicity of RT is greater for larger lesions as it is directly proportional to lesion volume. Robust and reliable standards for consistently maximizing the benefit of combination ICI + RT therapy remain elusive, likely in part due to the complexity of mechanistic interactions between each therapy. Addressing this clinical need will require optimizing the effects of their reported synergistic interactions such as tumor microenvironment modulation and immune activation while mitigating inhibitory effects such as immunosuppressive radiation effects. The ability to identify lesions unlikely to respond to ICI shortly after start of treatment would offer immediate clinical benefit by enabling earlier RT delivery, reduce the volume-dependent toxicities of RT, and reduce symptoms from lesion progression. To address the unmet clinical need for methods to optimize outcomes of combination ICI and RT therapy, we have developed a mechanistic mathematical model based on the biological and physical underpinnings of these complex therapies, and their interactions, which is able to describe and quantify interactions between ICI and RT and their interactions on the tumor. This builds upon our previous ICI modeling work by expanding the model based on the assumption that therapeutic outcome is not only a result of direct interaction between the treatment and disease, but is also a result of complex interplay between heterogeneous tumor populations that may be sensitive or resistant to treatment and their unique interactions with the immune system that serve to maintain or disrupt the tumor-immune equilibrium. RT further modulates this tumor-immune dynamic both by killing T cells in the tumor interior and by stimulating release of T cell activating antigens which can alter T cell activation exterior to the tumor, thereby affecting T cell recruitment into the tumor. By capturing how the complex time-dependent dynamics of tumor-immune interaction and recruitment influences – and is influenced by – transient shifts in treatment sensitive and resistant populations, our model aims to describe and quantify long-term tumor dynamics after ICI + RT therapy. This platform provides a consistent framework for systematically evaluating various proposed mechanisms underlying treatment interactions and how these may determine treatment failure or success. By applying the model to a retrospective, in-house generated melanoma brain metastasis data set, we are examining and refining our model structure with a goal of capturing a wide range of observed tumor dynamics using only clinically available data. This may lead to robust, quantitative methods to maximize treatment outcomes based on the unique characteristics of individual tumors. Citation Format: Alexander R. J. Silalahi, Caroline Chung, James W. Welsh, Zhihui Wang, Joseph D. Butner. Mathematical modeling-based optimization of gamma knife surgery after checkpoint blockade in melanoma brain metastases. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B019.

Lysosome Functions in Atherosclerosis: A Potential Therapeutic Target

Lysosomes in mammalian cells are recognized as key digestive organelles, containing a variety of hydrolytic enzymes that enable the processing of both endogenous and exogenous substrates. These organelles digest various macromolecules and recycle them through the autophagy–lysosomal system. Recent research has expanded our understanding of lysosomes, identifying them not only as centers of degradation but also as crucial regulators of nutrient sensing, immunity, secretion, and other vital cellular functions. The lysosomal pathway plays a significant role in vascular regulation and is implicated in diseases such as atherosclerosis. During atherosclerotic plaque formation, macrophages initially engulf large quantities of lipoproteins, triggering pathogenic responses that include lysosomal dysfunction, foam cell formation, and subsequent atherosclerosis development. Lysosomal dysfunction, along with the inefficient degradation of apoptotic cells and the accumulation of modified low-density lipoproteins, negatively impacts atherosclerotic lesion progression. Recent studies have highlighted that lysosomal dysfunction contributes critically to atherosclerosis in a cell- and stage-specific manner. In this review, we discuss the mechanisms of lysosomal biogenesis and its regulatory role in atherosclerotic lesions. Based on these lysosomal functions, we propose that targeting lysosomes could offer a novel therapeutic approach for atherosclerosis, shedding light on the connection between lysosomal dysfunction and disease progression while offering new insights into potential anti-atherosclerotic strategies.

A deep learning approach for early prediction of breast cancer neoadjuvant chemotherapy response on multistage bimodal ultrasound images

Neoadjuvant chemotherapy (NAC) is a systemic and systematic chemotherapy regimen for breast cancer patients before surgery. However, NAC is not effective for everyone, and the process is excruciating. Therefore, accurate early prediction of the efficacy of NAC is essential for the clinical diagnosis and treatment of patients. In this study, a novel convolutional neural network model with bimodal layer-wise feature fusion module (BLFFM) and temporal hybrid attention module (THAM) is proposed, which uses multistage bimodal ultrasound images as input for early prediction of the efficacy of neoadjuvant chemotherapy in locally advanced breast cancer (LABC) patients. The BLFFM can effectively mine the highly complex correlation and complementary feature information between gray-scale ultrasound (GUS) and color Doppler blood flow imaging (CDFI). The THAM is able to focus on key features of lesion progression before and after one cycle of NAC. The GUS and CDFI videos of 101 patients collected from cooperative medical institutions were preprocessed to obtain 3000 sets of multistage bimodal ultrasound image combinations for experiments. The experimental results show that the proposed model is effective and outperforms the compared models. The code will be published on the https://github.com/jinzhuwei/BLTA-CNN.

Relationship between stress hyperglycemia ratio and progression of non target coronary lesions: a retrospective cohort study

BackgroundStress hyperglycemia ratio is a novel indicator of acute coronary synthesis (ACS), which is closely related to the severity and complications of ACS and other cardiovascular diseases. However, its relationship with the progression of non target coronary lesions remains unclear. The purpose of this paper is to explore the relationship between stress hyperglycemia ratio and the progression of non target coronary lesions.MethodsThis study retrospectively enrolled patients diagnosed with acute coronary syndrome who underwent stent implantation and follow-up evaluations by coronary angiography at Zhongda Hospital between January 2019 and January 2024. Patients were classified into progression and non progression groups based on follow-up angiography findings. Logistic regression models, restricted cubic spline analysis, and machine learning algorithms (LightGBM, decision tree, and XGBoost) were utilized to analyse the relationship of stress hyperglycemia ratio and non target lesion progression.ResultsA total of 1,234 ACS patients were included; 29.1% experienced non target lesions progression. Logistic regression analysis showed that stress hyperglycemia ratio (SHR) was a risk factor for non target disease progression (P < 0.001), and after adjusting for other variables, SHR was still independently associated with non target disease progression (OR = 2.12, 95% CI: 1.30–3.44, p = 0.003). RCS analysis revealed a near-linear relationship between SHR and nontarget lesions progression (P = 0.14). With the increase of SHR, the risk of non target lesions progression continued to increase, and the risk was significant when the SHR was greater than 0.96, but tended to be stable when the SHR was greater than 1.36 (p = 0.0047). A hybrid model combining logistic regression and XGBoost yielded the best predictive performance, with an AUC of 0.78 (95% CI: 0.72–0.85), incorporating SHR, number and stenosis severity of non target lesions (NTLs), hypertension and high-density lipoprotein cholesterol (HDL-c). Subgroup analysis showed that elevated SHR was a stronger predictor of NTL progression in non-diabetic patients (OR = 3.76, p = 0.007) compared with diabetic patients (OR = 1.69, p = 0.083).ConclusionStress hyperglycemia ratio is closely related to the progression of non target lesions. This study provides a novel insight for optimizing the long-term management of non target lesions after PCI.

Baseline PSMA PET/CT parameters predict overall survival and treatment response in metastatic castration-resistant prostate cancer patients.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with varying survival outcomes. This study investigated whether baseline PSMA PET/CT parameters are associated with survival and treatment response. Sixty mCRPC patients underwent [18F]PSMA-1007 PET/CT before treatment with androgen receptor-targeted agents (ARTAs) or chemotherapy. Intensity-based parameters, volumetric parameters, metastatic sites and DmaxVox (distance between the two outermost voxels) from baseline PSMA PET/CT were collected, as well as age, Gleason score and laboratory parameters. Cox regression analysis evaluated their prognostic value for overall survival (OS). Additionally, a preliminary lesion-level analysis was done (n = 241 lesions) with lesion location and twelve radiomic features selected from previous literature. Logistic regression evaluated their association with PSMA PET/CT-based lesion progression after 3-4 months of treatment. Total tumour volume (PSMA-TV) (HR = 1.41 per doubling [1.17-1.70]), total lesion uptake (TL-PSMA) (HR = 1.40 per doubling [1.16-1.69]) and DmaxVox (HR = 1.31 per 10 cm increase [1.07-1.62]) were prognostic for OS, each independent of baseline PSA level (HR = 0.82 per doubling [0.68-0.98]), haemoglobin level (HR = 0.68 per mmol/L increase [0.49-0.95]) and line of treatment. On lesion-level, location (prostate vs bone OR = 0.23 [0.06-0.83]) and SUVmean (OR = 1.72 per doubling [1.08-2.75]) were independent prognostic markers for lesion progression, morphological and texture-based radiomic features were not. Baseline PSMA PET/CT scans have prognostic value in mCRPC patients and can potentially aid in treatment decision-making. DmaxVox can serve as a simpler alternative to PSMA-TV when automated segmentation software is not available. When combined with PSMA-TV, lower PSA levels indicated worse OS, which may be a marker of tumour dedifferentiation. Further research is needed to validate these models in larger patient cohorts. Question mCRPC is a highly heterogeneous disease, requiring good prognostic markers. Findings PSMA-TV was the best independent prognostic marker for OS; maximum distance between lesions (DmaxVox) can be used as a simpler alternative. Clinical relevance Baseline PSMA PET/CT parameters representing tumour burden were independently associated with OS in mCRPC patients, providing prognosticinsights for clinical decision-making. Although PSMA-TV was the best prognostic marker, DmaxVox can serve as an easier to obtain alternative.

Survival Outcomes Associated With Radiological Progressive Disease Subtypes in Patients With Atezolizumab and Bevacizumab-Treated HCC.

To assess the relationship between survival outcomes and subtypes of radiological progressive disease (PD) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Atezo/Bev). A total of 462 patients with Atezo/Bev-treated HCC diagnosed with radiological PD during follow-up were enrolled. PD was classified into three categories: progression or emergence of intrahepatic lesions (PD-IH), macroscopic vascular invasion (PD-MVI), and extrahepatic spread lesions (PD-EHS). We defined PD-multiple as the presence of two or more PD categories. Subsequent analysis was categorized into the "PD-IH or PD-EHS" and "PD-MVI or PD-multiple" groups. The median progression-free survival (PFS) durations for patients with PD-IH, PD-MVI, PD-EHS, and PD-multiple were 5.3, 3.2, 3.9, and 3.5 months (p = 0.003). Patients with "PD-IH or PD-EHS" and "PD-MVI or PD-multiple" had median PFS of 5.2 and 3.5 months (p < 0.001). Median overall survival (OS) for PD-IH, PD-MVI, PD-EHS, and PD-multiple was 22.3, 15.1, 19.4, and 14.2 months (p = 0.002). The OS for patients with "PD-IH or PD-EHS" and "PD-MVI or PD-multiple" was 21.4 and 14.5 months (p < 0.001). Multivariate analysis demonstrated that ECOG-PS ≥ 1 (hazard ratio (HR), 1.508), α-fetoprotein levels ≥ 100 ng/mL (HR, 1.293), albumin-bilirubin grade ≥ 2 (HR, 1.573), liver cirrhosis (HR, 1.361), and PD subtypes PD-MVI or PD-multiple (HR, 1.735) were independently associated with OS. Patients with HCC undergoing Atezo/Bev treatment, diagnosed with PD-multiple (not solely based on IH or EHS) or PD-MVI, experienced poor prognosis, specifically in terms of OS.

The impact of stony coral tissue loss disease and amoxicillin treatments on coral gametogenesis

The unprecedented mortality of stony corals on Florida’s Coral Reef from stony coral tissue loss disease (SCTLD) was mitigated on some priority sites and corals through the use of a topical amoxicillin paste to halt disease lesion progression. One management concern about the use of antibiotics on these corals was the impact it may have on gametogenesis. We used histology to assess gametogenesis within Orbicella faveolata and Montastraea cavernosa samples from six sites and across three treatment groups. The sites covered the geographic regions of the Florida Keys, including both inshore and offshore habitats. The treatment groups were: healthy corals, samples adjacent to active SCTLD lesions, and samples adjacent to previous SCTLD lesions that were halted by topical amoxicillin. Across both species, colonies from all sites and treatment groups were producing normal oocytes and spermaries. For M. cavernosa, gametogenesis metrics did not differ among treatment groups. Among O. faveolata colonies, healthy corals exhibited higher fecundity and higher oocyte presence than treated corals and larger oocytes than diseased corals. However, of the treated corals, those which had been treated more frequently had higher fecundity than those that were treated less frequently, suggesting that diminished fecundity throughout the group may have been the result of disease occurring earlier in gametogenesis rather than the treatment itself. Fecundity of O. faveolata colonies in the diseased group was highly dependent on whether the corals were from nearshore or offshore environments. The relationship between disease, treatment, and habitat warrants further examination, but we show that amoxicillin treatments do not prevent gametogenesis in corals.

Analysis of clinical features and prognostic factors of focal cerebral arteriopathy in children

Objective: To summarize the clinical characteristics of focal cerebral arteriopathy (FCA) in children, and to analyze its influencing factor of prognosis. Methods: A retrospective cohort study was conducted. Clinical data from 40 children with FCA who were hospitalized at the Department of Neurology, Beijing Children's Hospital, Capital Medical University, from September 2015 to August 2024 were collected. A centralized follow-up was conducted in October 2024 via outpatient clinics or the internet. The pediatric stroke outcome measure (PSOM) was used to evaluate their outcomes. Based on the PSOM, the children were further divided into a group with normal neurological function and another group with abnormal neurological function. Differences between groups were analyzed using the Mann-Whitney U test and Fisher exact test. Univariate Logistic regression analysis was performed to identify the influencing factors for neurological outcomes in children with FCA. Results: A total of 40 children were included, with 20 males and 20 females, and the onset age of 9.2 (6.8, 12.5) years. Among them, 12 cases (30%) had a history of varicella within 1 year before onset. There were 23 cases (58%) presenting with transient ischemic attack (TIA) or recurrent fluctuating symptoms of onset, while 3 cases (8%) developed progressive stroke within the first month of onset. The M1 segment of the middle cerebral artery was the most commonly affected vascular site, with a total of 16 cases (40%). Arterial occlusion occurred in 8 cases (20%). Lumbar puncture was completed in 36 children, and white blood cell counts in cerebrospinal fluid was increased in 6 cases. All 23 patients who completed magnetic resonance vessel wall imaging (VWI) showed circular enhancement of the arterial wall. A total of 28 patients (70%) received antiplatelet or anticoagulation therapy, and 16 patients (40%) received hormone therapy. At admission, the pediatric National Institute of Health Stroke Scale (PedNIHSS) score was 6.0 (2.0, 8.8) points, which decreased to 0.5 (0, 3.0) points at discharge. The follow-up duration was 1.6 (0.8, 4.9) years, with 1 case lost to follow-up. There was 1 case presenting with recurrence course manifesting as TIA. Among the 39 cases who completed the follow-up, 23 cases (59%) were assessed as neurologically normal by PSOM, while 16 cases (41%) were assessed as neurologically abnormal. Among the 29 cases who completed the imaging review, magnetic resonance angiography (MRA) review in 23 cases indicated stability or improvement in the original arterial stenosis, with 6 cases experiencing transient worsening of arterial stenosis early in the disease course (within 2 months), which later improved. Arterial stenosis progression occurred in 6 cases at the final review of 29 cases who completed the imaging review, with 1 case developing progressive cerebral arteriopathy. The proportion of patients with headache, altered consciousness, and aphasia in the abnormal neurological function group, as well as the PedNISS scores at admission and discharge, were all higher than those in the normal neurological function group (all P<0.05). Univariate Logistic regression analysis revealed that only a PedNISS score>6 points at onset was an influencing factor for abnormal neurological function (OR=20.58, 95%CI 3.93-107.70, P<0.001). Conclusions: Childhood FCA often presents with fluctuating onset, and the proximal segment of the middle cerebral artery is frequently affected. Progression of arterial stenosis is common within 2 months of the disease course, but clinical progression and new ischemic lesions are uncommon. Most patients have a favorable long-term prognosis. PedNIHSS score>6 points at admission is related to abnormal neurological function outcomes.

Next generation sequencing (NGS)-based molecular panel analysis for metastatic prostate cancer: how often can we detect druggable mutations? : NGS for metastatic adenocarcinoma of the prostate

Prostate cancer guidelines recommend molecular analysis of biomaterial following resistance to first-line systemic therapy in order to identify druggable mutations. We report on our results of molecular analysis of tissue specimens via next generation sequencing (NGS) in men with metastatic castration resistant prostate cancer (mCRPC). In all, 311 mCRPC patients underwent NGS analysis from biopsy samples of progressive metastatic lesions or archival radical prostatectomy specimens. NGS analysis was either performed using a panel of 18 prostate cancer-specific amplicons or via the TS0500 panel. Of the 311 biopsies, 299 (96%) revealed sufficient DNA content for NGS analysis independent on the specimen origin. Biopsies were taken from prostate (31%), lymph nodes (26%), visceral (17%) or osseous (18%) metastases. In 223 (75%) and 76 (25%) patients activating/inhibiting and no mutations were identified, respectively. Most frequently, mutations of HRD genes including a positive HRD score and p53 were identified in 22% of patients each. About 50% of HRD gene mutations were pathogenic and treatment with PARP inhibitors was initiated. Although the majority of p53 alterations were inactivating mutations, 3 patients demonstrated gain-of-function mutations resulting in an inactivation of ATM. Activating androgen receptor mutations and inactivating PTEN mutations were identified in 42 (14%) and 24 (8%) patients, respectively. Specific AR mutations resulted in a switch of hormonal therapy. Mutations of mismatch repair deficiency genes/MSI high were identified in 5 patients resulting in the administration of pembrolizumab. Addition of the TSO 500 panel identified additional mutations in 4.5% of patients and only 2% of the total cohort would have benefitted from this large panel with the identification of druggable mutations. Druggable mutations were identified in one third of mCRPC patients using an 18 amplicon-panel analyzed via NGS. Based on our data, molecular analysis of AR mutations or mutations of the HRD genes should be performed following progression after first-line hormonal therapy. A more extensive molecular analysis seems to be useful following progression to the standard sequential hormonal, cytotoxicand radioligand therapies. Use of the expensive TSO 500 panel seems to be of additional therapeutic value in only a minority of patients.

Clinical Experience with TNF Inhibition and Longitudinal Image Monitoring in Osseous Sarcoidosis.

In this case series, we present longitudinal imaging surveillance of 6 cases of osseous sarcoidosis, each of which was effectively treated with tumor necrosis factor (TNF) inhibition. We identified 6 patients from Brooke Army Medical Center with osseous sarcoidosis, who were treated with TNF inhibition and followed with longitudinal imaging studies. Cases of osseous sarcoidosis were defined as having pathologic evidence of noncaseating granulomas on bone biopsy and evidence of osseous lesions on imaging attributable to sarcoidosis by the radiologist, treating clinician, and reviewer. Clinical data were obtained through review of the military electronic medical record. Longitudinal imaging with positron emission tomography/computed tomography, magnetic resonance imaging, and bone scintigraphy assisted in the identification of active disease and clinical remission. Imaging progression of asymptomatic lesions was associated with the eventual development of bone pain 1 to 3 years later. Clinical remission was achieved in all six cases of osseous sarcoidosis and effective doses for TNF inhibition were adalimumab 40 mg subcutaneously every 1 to 2 weeks and infliximab 5 mg/kg every 6 to 8 weeks. Time to complete imaging response ranged from 3 to 8 months. Longitudinal imaging with bone scintigraphy, positron emission tomography/computed tomography, and magnetic resonance imaging demonstrated several benefits including evaluation for occult disease, surveillance of asymptomatic lesions, and evaluation of treatment response. TNF inhibition with adalimumab or infliximab was successful in all cases, and complete resolution of osseous lesions was demonstrated in 5 of 6 patients. Discontinuation of TNF inhibition led to disease recurrence in 2 cases, which prompted the use of long-term immunosuppressive therapy in all treated patients.

Short-term efficacy and safety of upadacitinib combined with 308 excimer light versus upadacitinib alone and 308 excimer light alone in patients with progressing facial vitiligo.

Patients with progressing facial vitiligo who had been treated with upadacitinib, 308nm excimer light and upadacitinib combined with 308nm excimer light were selected for retrospective analysis and comparison of their efficacy and safety. Efficacy was evaluated using the Vitiligo Area Severity Index (VASI) and Dermatology Life Quality Index (DLQI) at baseline, after 8weeks, and after 20weeks. The progression of skin lesions was monitored through reflectance confocal microscopy (RCM), while adverse reactions were documented. In the combination treatment group, the average VASI at baseline was 0.875 ± 0.4111, which decreased to 0.56 ± 0.32 at week 8 and 0.23 ± 0.218 at week 20 of follow-up (F = 9.918, p = 0.001). RCM analysis indicated that cases achieving VASI100 showed restoration to normalcy regarding loss of integrity within the pigment ring in lesion areas. Although one patient experienced exacerbation of acne, this condition was manageable with topical medication. In contrast, the average VASI score in the 308nm excimer light group prior to treatment was recorded at 0.908 ± 0.334; by week twenty, it further declined to an average of 0.495 ± 0.4196. The differences observed were statistically significant (F = 28.644, p < 0.001). For patients in the upadacitinib group, the initial average VASI score was noted as being 0.825 ± 0.34; by twenty weeks it averaged approximately 0.53 ± 0.33; however, these differences did not reach statistical significance (F = 2.87, p = 0.14). The efficacy of the combined treatment group was significantly superior compared to both other groups (F = 3.927, p = 0.026). In conclusion, upadacitinib combined with308nm excimer light represents an effective therapeutic option for progressive facial vitiligo and is associated with fewer adverse reactions as well as improved quality of life for patients.

Detrimental effects of chronic sugar-sweetened carbonated soft drink consumption on inflammatory response and the size of apical periodontitis: An animal-based study.

This study aimed to evaluate the effects of chronic consumption of two sugar-sweetened carbonated soft drinks - one containing caffeine (Coca-Cola®) and one without (Sprite®) - on the progression of periapical lesions and the levels of pro-inflammatory cytokines in rats. Twelve Wistar rats were divided into three groups (n = 4): Control group, Coca-Cola group and Sprite group. The rats in Coca-Cola and Sprite groups were given ad libitum access to their respective soft drinks for 3 months, while the Control group received filtered water. After 2 months of consumption, the pulps of the lower left first molars were exposed for 28 days to induce periapical lesions. Following euthanasia, the jaws were removed, and the periapical lesions were assessed using micro-computed tomography imaging. Blood samples were collected to analyse the pro-inflammatory cytokines IL-1β, IL-6, IL-2, IL-17 and TNF-α via Luminex assay. Non-parametric data were analysed using the Kruskal-Wallis test followed by Dunn's test, while parametric data were analysed using one-way ANOVA followed by Tukey's test (p < 0.05). Both the Coca-Cola and Sprite groups exhibited periapical lesions with significantly greater volume and diameter compared to the Control group (p < 0.05). Additionally, both soft drink groups had significantly higher levels of IL-1β, IL-6 and IL-2 compared to the Control group (p < 0.05). The Sprite group displayed significantly higher levels of IL-1β than the Coca-Cola group (p < 0.05), while the Coca-Cola group showed significantly elevated TNF-α levels compared to both the Control and Sprite groups (p < 0.05). No significant differences in IL-17 levels were observed among the groups (p > 0.05). The chronic consumption of sugar-sweetened carbonated soft drinks, regardless of caffeine content, has detrimental effects on the inflammatory response and progression of apical periodontitis in rats.

Identification of critical endoplasmic reticulum stress-related genes in advanced atherosclerotic plaque

Atherosclerosis (AS) is the principal pathological cause of atherosclerotic cardiovascular diseases. Chronic endoplasmic reticulum stress (ERS) has been implicated in AS aetiopathogenesis, but the underlying molecular interactions remain unclear. This study aims to identify the molecular mechanisms of ERS in AS pathogenesis to inform innovative diagnostic approaches and therapeutic targets for managing AS. GSE28829 and GSE43292—human early and advanced carotid atherosclerotic tissue samples—were obtained from the Gene Expression Omnibus database. Endoplasmic reticulum stress-related genes (ERSRGs) were obtained from GeneCards. Differential gene expression and weighted gene co-expression network analyses were conducted to identify genes associated with atherosclerosis, and intersection with ER-related genes revealed three ERSRGs (i.e. CTSB, LYN, and CYBB) associated with advanced atherosclerotic plaque. These three ERSRGs exhibited associations with various immune cells. Additionally, the three ERSRGs were upregulated in human atherosclerotic tissues, mouse models of progressive atherosclerotic lesions, and in vitro macrophage models. In conclusion, this study identified CTSB, LYN, and CYBB as potentially critical ERSRGs associated with advanced atherosclerotic plaque, demonstrating their good diagnostic utility and offering novel insights into the potential pathobiology of AS progression, paving the way for exploring innovative therapeutic targets.

Application of Principal Component Analysis as a Prediction Model for Feline Sporotrichosis.

Sporotrichosis is a worldwide zoonotic disease that is spreading and causing epidemics in large urban centers. Cats are the most susceptible species to develop the disease, which could cause significant systemic lesions. The aim was to investigate and to identify predictive indicators of disease progression by correlations between the blood profile (hematological and biochemical analytes) and cutaneous lesion patterns of 70 cats diagnosed with Sporothrix brasiliensis. The higher occurrence in male cats in this study could be related to being non-neutered and having access to open spaces. Principal component analysis (PCA) with two principal components, followed by binary logistic regression, and binary logistic regression analysis, with independent variables and backward elimination modeling, were performed to evaluate hematological (n = 56) and biochemical (n = 34) analytes, including red blood cells, hemoglobin, hematocrit, leukocytes, segmented neutrophils, band neutrophils, eosinophils, lymphocytes, monocytes, total plasma protein, albumin, urea, creatinine, and alanine aminotransferase. Two logistic regression models (PCA and independent variables) were employed to search for a predicted model to correlate fixed (isolated) and disseminated cutaneous lesion patterns. Total plasma protein concentration may be assessed during screening diagnosis as it has been recognized as an independent predictor for the dissemination of cutaneous lesion patterns, with the capability of serving as a predictive biomarker to identify the progression of cutaneous lesions induced by S. brasiliensis infections in cats.

Antimelanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis: clinical features and outcomes in a racially diverse patient cohort

BackgroundThe anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis is known for its association with rapidly progressive interstitial lung disease (RP-ILD) and ulcerative skin lesions, often presenting with or without muscle involvement. The aim of this study was to identify distinct clinical and laboratory features that could be used to evaluate disease progression in an ethnically diverse cohort of anti-MDA5 dermatomyositis patients at a U.S. academic center.MethodsA retrospective chart review was conducted on dermatomyositis patients hospitalized at our institution between January 2014 and June 2023. The data were analyzed via Fischer’s exact test and a t test.ResultsAmong the 195 dermatomyositis patients reviewed, 22 tested positive for the MDA5 antibody, comprising of thirteen adults and nine pediatric patients. Myositis was significantly more common in pediatric patients than in adult patients (p = 0.002). RP-ILD was more frequently observed in adult patients of African ancestry (including both Black Hispanic and Black non-Hispanic individuals) (p = 0.04). There was a significant association noted between Raynaud’s phenomenon and ILD (p = 0.02). The overall mortality rate of 13.6% was more favorable than the previously reported rates of 40–60%.ConclusionThis study enhances our understanding of the disease by emphasizing potential racial and demographic variations, as well as delineating the similarities and differences between adult and pediatric populations.

Cardiac Biomarkers, Subclinical Brain Vascular Changes, and Cognitive Decline: Post Hoc Analysis of the SPRINT Trial.

The association between subclinical cardiovascular disease (CVD) and cognitive decline in hypertensive adults and the underlying brain pathologies remain unclear. It is also undetermined whether intensifying blood pressure (BP) treatment slows down cognitive decline associated with subclinical CVD. We conducted a post hoc analysis of the Systolic Blood Pressure Intervention Trial. Subclinical CVD at baseline was identified by elevated levels of high-sensitivity cardiac troponin T (hs-cTnT≥14ng/L) and N-terminal pro-B-type natriuretic peptide (NT-proBNP≥125 pg/mL). Global cognitive function and domain-specific measures (memory, processing speed, language, and executive function) were assessed at baseline and follow-up (years 2, 4, and 6) in 2733 participants. White matter lesions, cerebral blood flow, and brain tissue volume were assessed by MRI at baseline and years 4 in a subset of 639 participants. Both elevated hs-cTnT and NT-proBNP levels at baseline were associated with accelerated cognitive decline across all domains after adjusting for potential confounding factors. The group with elevated levels of both cardiac biomarkers showed the fastest decline, with a larger annual decline rate of 0.033 (95% CI: 0.024-0.041) in the z-score of global cognitive function compared to the group with normal levels. Elevated levels of both biomarkers were also associated with a faster progression in white matter lesions, but not with changes in total brain tissue volume or cerebral blood flow. Intensive BP treatment did not attenuate these associations compared to standard treatment. Subclinical CVD may contribute to faster white matter lesion progression and accelerated cognitive decline in patients with hypertension, regardless of intensive BP treatment.