Future Interventions Research Articles

Serum proteomic profiling reveals potential inflammatory biomarkers in long-COVID patients: a comparative analysis with healthy controls

Abstract Background Long-COVID (also known as post-acute sequelae of SARS-CoV-2 infection, PASC), is defined as the persistence, or the new onset, of symptoms after recovery from the acute phase of COVID-19. It consists of a multiorgan syndrome expressing itself with a wide variety of cardiovascular and non-cardiovascular symptoms such us chest pain, fatigue, shortness of breath, autonomic dysfunction, cognitive impairment and sleep disorders even in the absence of a clear evidence of organ dysfunction. Some previous studies have suggested the potential role of an abnormal inflammatory response after SARS-CoV-2 infection, however the specific underlying mechanisms remain unclear. In this study we performed a proteomic analysis of the serum of 80 long-COVID patients to identify potential biomarkers that may act as indicators or therapeutic targets for long COVID. Methods and results We compared the levels of the proteins in both long-COVID group and a control group using multivariate and univariate analysis. Both PLS-DA and PCA analysis showed a clear distinction between the two groups; clustering analysis also clearly separated control from long-COVID patients. Proteins were then filtered based on (a) statistical analysis, considering proteins with a VIP>1 (PLSDA) and p<0.05 (t-test); (b) coefficient of variation (CV), where only proteins with CV<10 were considered; (c) and fold change (FC), for which proteins with FC<0.67 or FC>1.5 were selected for further analysis. The selected proteins were then subjected to a ROC curve analysis to identify antithrombin as a potential biomarker with an area under the curve (AUC) near 1. Other proteins, displaying an AUC > 0.98, were also identified as potential biomarkers (Sirtuin 1, NatriureticPeptide B, Hemopexin Arachidonate 5-Lipoxygenase). In addition, a multivariate ROC method, using linear SVM as classification method, identified that a combination of ten proteins would also result in an AUC near 1. Finally, a correlation analysis between the proteins of interest and the clinical manifestations was performed. A positive correlation (above 0.5) was found between dyspnea and Glucocorticoid Receptor and between memory deficit and Antithrombin. Arachidonate 5-Lipoxygenase was negatively correlated (below -0.5) with tremors and hair loss, MannoseBinding Lectin 2 was found to be positively linked to asthenia, Antithrombin with concentration deficit and Endothelin-2 with muscles aches. Conclusions The identified biomarkers are associated with inflammatory processes, corroborating literature evidence that long-COVID patients develop an inflammatory state that damages many tissues. Further studies are needed to validate this data in larger cohorts to identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular and non-cardiovascular sequelae.

Distal versus conventional transradial access for coronary angiography: a pooled analysis from the randomized RAPID trial

Abstract Background Transradial access (TRA) is the recommended approach for coronary procedures considering safety benefits over femoral access with radial artery occlusion (RAO) being the most frequent complication. Although usually not clinically significant, the presence of RAO affects potential future procedures and medical treatments. Distal TRA (dTRA) has been suggested to reduce the risk of postprocedural RAO compared to conventional TRA (cTRA) with, however, inconsistent results in clinical trials. Purpose This study aimed to compare the efficacy and safety of dTRA versus cTRA in patients undergoing diagnostic coronary angiography. Methods The RAPID trial is a single-center, open-label, 2x2 factorial, randomized study of patients undergoing coronary angiography through a 6-F radial access. The trial was stopped early by the data and safety monitoring board after the second pre-planned interim analysis and inclusion of 600 participants. Patients were randomized to dTRA or cTRA with further stratification according to periprocedural heparin use and preexisting oral anticoagulation. The primary endpoints were the incidence of RAO assessed by vascular ultrasound and puncture-site related bleedings. Results The final study population consisted of 298 patients randomized to dTRA and 302 patients to cTRA. Periprocedural heparin was administered in 382 patients (63.7%) and percutaneous coronary intervention was performed in 161 cases (26.8%) without differences between the study groups (p=0.700 and p=0.465; respectively). Distal TRA was associated with a significantly increased number of puncture attempts (2.4 ± 2.0 versus 1.5 ± 1.2; p<0.001) and failed punctures leading to access site crossover (11.7% versus 5.0%; p=0.003). Consequently, the total procedure time was longer in the dTRA group (30 min versus 25 min; p=0.004) without increasing fluoroscopy time (p=0.320), dose area product (p=0.245), or contrast volume (p=0.884). Patent hemostasis was achieved in 91.7% of patients with cTRA. The rates of RAO (16.1% versus 15.6%, p=0.855) and puncture-site related bleedings (6.7% versus 8.3%; p=0.466) were similar in both groups. Conclusions According to this study, dTRA does not reduce the risk of RAO or bleeding events compared to cTRA.

Pituitary neuroendocrine tumors treated with stereotactic radiosurgery.

Pituitary neuroendocrine tumors (pitNETs) are benign tumors that may recur after surgical resection or persist following medical management. The objective of this study was to evaluate outcomes and toxicities of patients with pitNETs treated with stereotactic radiosurgery (SRS) at a single institution. We completed a retrospective, single-institution study of patients with pitNETs treated with frame-based, single-fraction, cobalt-60 SRS between September 2005 and June 2023. The primary endpoint was local tumor control. Secondary endpoints included endocrine control (for functional tumors), overall survival, and toxicities. A total of 88 lesions in 83 patients were treated with SRS. Most lesions (70%) were non-functional tumors. Of the 26 functioning tumors, 6 patients achieved endocrine remission with SRS alone (23%), and the remainder achieved remission with combined medical management. With a median patient follow-up of 4.7 years, no local tumor recurrences were observed with an estimated local control probability of 100%. Two- and five-year overall survival estimates were 97% (95% confidence interval [CI] 89-99) and 95% (95% CI 84-98), respectively. Causes of death were unrelated to PitNET or SRS. Twelve patients (14%) developed hypopituitarism after SRS. Despite the 34 lesions that were ≤ 3mm from optic structures, no patients developed any optic neuropathy or visual decline post SRS. SRS is a highly effective modality for recurrent or residual pitNETs. This study observed a local control of 100% with no cases of optic toxicities after a median follow-up of 4.7 years. These observed findings suggest that dose de-escalation may be possible for future treatment of pitNETs.

High prevalence of cardiotropic viruses in endomyocardial biopsies from patients with inflammatory cardiomyopathy demonstrated by a novel targeted NGS approach

Abstract Background Viral infection of the heart muscle is a common cause of myocarditis and viral persistence can lead to chronic inflammatory cardiomyopathies (DCMi). A number of viruses including parvovirus B19 (B19V), adenovirus (AdV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes virus 6 (HHV-6) and enteroviruses (EV) are known to infect the myocardium, but their prevalence and role in persisting DCMi are not well understood. Virological etiologies can only be determined via endomyocardial biopsy (EMB), but the low tissue amount limits the number of conventional viral nucleic acid tests (virus-specific PCR) that can be performed in parallel. This study aimed to detect known and novel cardiotropic viruses in EMB of DCMi patients using a targeted next generation sequencing (NGS) approach. Methods A cohort of 33 patients with inflammatory cardiomyopathy (DCMi) (LVEF=29±12%) were retrospectively analyzed and compared to previous results of virus-specific PCR. DNA and RNA extracted from EMB were used for sequencing library preparation, and viral nucleic acids were enriched via a custom myBaits hybridization capture approach. Enriched libraries were sequenced on an Illumina MiSeq-platform in paired-end mode (500.000 reads/sample), and reads were taxonomically classified via Kraken2 and mapped against viral reference genomes using BWA-MEM2 or HiSat2, and subsequently deduplicated. Viral reads detected via both Kraken2 and mapping were classified as valid. Results Targeted NGS confirmed 19 out of 22 (86%) of the previous PCR-based viral detections. However, NGS was able to detect B19V DNA and RNA in an additional 11 and 15 patient samples respectively; CMV DNA/RNA in additional 5 and 4 samples respectively; EBV DNA/RNA in additional 5 and 1 samples respectively; and HHV-6 DNA/RNA in additional 3 and 1 samples respectively. Furthermore, viral reads of adenovirus type 2, adenovirus-associated virus type 2 (AAV-2), herpes viruses 7 and 8, and human parvovirus 4 were also found among the cohort. Thus, targeted NGS was able to identify 82 viral infections in a cohort of 33 DCMi patients, while only 22 were found using routine PCR tests. For routinely tested B19V, the use of the new NGS diagnostic approach improved sensitivity by 42% and specificity by 72%. Conclusions The presented NGS method represents a powerful new tool for the diagnosis of viral and inflammatory heart disease. The sensitivity is significantly higher than with conventional PCR approaches and the taxonomic classification is more specific. This enables the detection of previously false-negative routine viruses as well as potentially new cardiotropic pathogens from limited bioptic patient material – thus significantly increasing the diagnostic yield of EMB. In addition, our study demonstrates a high prevalence of non-enteroviral cardiotropic viruses in DCMi patients, shedding new light on the etiology of this heterogenous diseases and paving the way for more specific future treatments.

Sacituzumab Govitecan in Triple Negative Breast Cancer: A Systematic Review of Clinical Trials

Background/Objectives: Triple-negative breast cancer is difficult to treat due to the absence of hormone receptors and Her2neu. Sacituzumab govitecan is a new therapeutic approach that uses an antibody directed against the Trop-2 antigen present in solid epithelial tumors, linked to the active metabolite SN-38, similar to irinotecan, to specifically target cancer cells while minimizing damage to healthy cells. The objective of the present review was to evaluate the efficacy and safety of sacituzumab govitecan as a single treatment in patients with triple-negative breast cancer and to compare its results with the standard conventional chemotherapy regimen currently used in this disease. Methods: A systematic review of randomized clinical trials of sacituzumab govitecan was performed. The search was performed in Medline (PubMed), Web of Science, and Cochrane from September 2022 to January 2024. Results: Thirty-eight articles are included and evaluated according to inclusion and exclusion criteria corresponding to the two most relevant clinical trials, including specific analyses of cohorts and subgroup study arms within these trials. Data from more recent clinical trials are also reviewed. Conclusions: The efficacy results showed a significantly greater clinical benefit with sacituzumab govitecan compared to standard chemotherapy in patients with triple-negative breast cancer. This drug will become a treatment of substantial impact in future treatment guidelines for this type of cancer.

Responsive Hydrogel-Based Drug Delivery Platform for Osteoarthritis Treatment

Osteoarthritis (OA) is the most prevalent chronic joint disorder and is a major cause of disability among the elderly population. The degeneration and damage of articular cartilage associated with OA can result in a diminished range of motion in joints, subsequently impacting fundamental activities such as ambulation, standing, and grasping objects. In severe cases, it may culminate in disability. Traditional pharmacological treatments are often accompanied by various side effects, while invasive surgical procedures increase the risk of infection and thrombosis. Consequently, identifying alternative new methods for OA treatment remains a formidable challenge. With advancements in responsive hydrogel drug delivery platforms, an increasing number of strategies have emerged to enhance OA treatment protocols. Injectable response hydrogel drug delivery platforms show many advantages in treating OA, including improved biocompatibility, prolonged drug release duration, elevated drug loading capacity and enhanced sensitivity. This article reviews the recent progress of injectable responsive hydrogel drug delivery platform for OA treatment over the past few years. These innovative methodologies present new strategies and directions for future OA treatment while summarizing a series of challenges faced during the clinical transformation of injectable response hydrogel drug delivery platforms. Overall, injectable responsive hydrogel drug delivery platforms show great potential in treating OA, especially regarding improving drug retention time and stimulus-responsive release at the lesion sites. These innovative methods provide new hope for future OA treatment and point the way for clinical applications.

The diagnostic challenge of differentiating Tumefactive Multiple Sclerosis (TMS) from other brain lesions: a case report and literature review on a rare subtype of MS

Introduction and Importance: This case report is a clinical diagnosis walk through of a rare subtype of Multiple sclerosis (MS). It gives an overview of how Tumefactive multiple sclerosis (TMS) is systematically narrowed down as the definitive diagnosis. Case Presentation: Our 29 year old male patient presented to the emergency department. He collapsed after experiencing pain over his right frontotemporal region followed by a seizure witnessed by his family. Magnetic Resonance Imaging of the brain displayed a diffuse enlargement and abnormal T2 weighted and FLAIR hyperintense signals in the diagnostic impressions described by the radiologist of the right temporoparietal region. Clinical Discussion: Liquefactive Multiple Sclerosis, also known as tumefactive multiple sclerosis or Marburg-type multiple sclerosis, is a rare subtype of the neurological disorder that can be difficult to diagnose. Unlike the traditional form of Multiple sclerosis (MS), Tumefactive multiple sclerosis (TMS) can present as a brain tumor and must be diagnosed with a biopsy rather than via magnetic resonance imaging (MRI) and clinical findings alone. Patients can typically present with headache, cognitive abnormalities, mental confusion, aphasia, apraxia, seizures, and weakness. Here, we discuss the presentation, disease diagnosis process and patient management. Conclusion: The patient was stabilized and discharged with a referral to the neurosurgery and neurology departments for outpatient consultation for future clinical management and treatment of their condition.

Drugs That Induce Gingival Overgrowth Drive the Pro-Inflammatory Polarization of Macrophages In Vitro

Several attempts have been made to elucidate the pathogenesis of drug-induced gingival overgrowth (DIGO), which is triggered by the chronic use of certain drugs that fall into three main categories: anticonvulsants, immunosuppressants, and calcium channel blockers. Previous research suggests that cytokines and impaired cellular functions play a role in DIGO. Of particular interest are macrophages, immune cells that can switch between M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes in response to exogenous signals and stimuli. An imbalance between M1 and M2 macrophage populations may underlie DIGO. M1 may contribute to the initial tissue damage in DIGO, while M2 may then attempt to repair the damage with anti-inflammatory mechanisms. To test the hypothesis that drugs associated with DIGO could influence macrophage polarization, human monocytes (precursors of macrophages) were induced to differentiate into M0-naïve macrophages and then exposed to drugs: diphenylhydantoin, gabapentin, mycophenolate, and amlodipine. Quantitative real-time PCR amplification was used to measure the expression of specific genes associated with macrophage polarization. All of the drugs tested induced M0 macrophages to overexpress genes typical of the M1 phenotype, such as CCL5, CXCL10, and IDO1. This investigation provides the first evidence of a link between drugs that cause DIGO and M1 pro-inflammatory macrophage polarization. The knowledge gained from this research could be valuable for future DIGO treatment strategies.

Optimal algae species inoculation strategy for algal-bacterial granular sludge: Sludge characteristics, performance and microbial community

The algal-bacterial granular sludge (ABGS) system is emerging as a promising technology for future wastewater treatment. This study assessed the impact of different algae species inoculation on granulation, performance, and microbial communities within ABGS systems. The experimental setup included single-species inoculations (Chlorella sp. (R1), Scenedesmus sp. (R2), and Desmodesmus sp. (R3)) and a mixed-species inoculation strategy (R4). Results revealed that R4 achieved the fastest completed granulation process (15 days) with the largest average granule diameter (772.93 μm) and highest physical strength (2.24 ± 0.26%) in the end of the experiment. The relative abundance of extracellular polymeric substances secreting bacteria of R4 maintained high level in whole operation time. Algae assimilation capacity and the abundance of functional bacteria can also influence removal performance. In mature stage, only the average effluent total nitrogen (3.15 ± 2.87 mg/L), total phosphorus (0.37 ± 0.27 mg/L), chemical oxygen demand (25.25 ± 2.98 mg/L) concentration in R4 was lower than that of Grade I discharge standard of municipal wastewater treatment plants in China. The best inorganic carbon utilization and lipid production ability were observed in R4 and R3, respectively. The choice of inoculated algae species was identified as a key factor for bacterial community dynamics. Overall, above results demonstrated that mixed algae species inoculation can be selected as the optimal algae inoculation strategy due to its excellent granulation, performance, and acceptable carbon utilization and lipid production.

Predicting optimal treatment allocation for cognitive analytic-guided self-help versus cognitive behavioural-guided self-help.

Given the ubiquity in routine services of low-intensity guided self-help (GSH) psychological interventions, better patient selection for these brief interventions would be organizationally efficient. This study therefore sought to define who would respond best to two different types of GSH for anxiety to enable better future treatment matching. The study used outcome data from a patient preference trial (N = 209) comparing cognitive analytic therapy-guided self-help (CAT-GSH) with cognitive behavioural therapy-guided self-help (CBT-GSH). Elastic Net regularization and Boruta random forest variable selection methods were applied. Regression models calculated the patient advantage index (PAI) to designate which GSH was likely the most effective for each patient. Outcomes were compared for those receiving their PAI-indicated optimal and non-optimal GSH. Lower baseline depression and anxiety severity predicted better outcomes for both types of GSH. Patient preference status was not associated with outcome during either GSH. Sixty-three % received their model indicating optimal GSH and these had significantly higher rates of reliable and clinically significant reductions in anxiety at both post-treatment (35.9% vs. 16.6%) and follow-up (36.6% vs. 19.2%). No single patient with a large PAI had a reliable and clinically significant reduction in anxiety at post-treatment or follow-up when they did not receive their optimal GSH. Treatment matching algorithms have the potential to support evidenced-based treatment selection for GSH. Treatment selection and supporting patient choice needs to be integrated. Future research needs to investigate the use of the PAI for GSH treatment matching, but with larger and more balanced samples.

Lung enteric-type adenocarcinoma with gastric metastasis: a rare case report and literature review

Lung enteric-type adenocarcinoma (ETAC) is a rare subtype of non-small cell lung cancer (NSCLC), comprising approximately 0.6% of all primary lung adenocarcinomas. It is characterized by a tendency for early metastasis and a prognosis comparable to that of common lung adenocarcinoma. This case report described a patient with lung-ETAC who developed gastric metastasis. The patient underwent treatment with chemotherapy and a PD-1 inhibitor, resulting in disease remission with a progression-free survival (PFS) of 8 months. The follow-up time was 13 months. This case report was aimed to enhance understanding of the biological behavior of this rare tumor and provide insights into potential future treatment strategies.

A case of successful conversion surgery for unresectable gallbladder cancer treated with durvalumab in combination with gemcitabine plus cisplatin.

We report a rare case of a patient with initially unresectable gallbladder cancer who underwent conversion surgery with durvalumab in combination with gemcitabine plus cisplatin and achieved an R0 resection. A 68year-old woman was found to have gallbladder cancer and multiple enlarged lymph nodes around the suprapancreatic rim and hepatic hilum invading the proper hepatic artery on computed tomography. The diagnosis was cT3cN2cM0, cStage IVB. After eight cycles of durvalumab in combination with gemcitabine plus cisplatin, all tumor markers became negative, and lymph node invasion of the hepatic artery disappeared. The patient underwent conversion surgery with gallbladder bed resection and regional lymph node dissection. There was no need for hepatic artery reconstruction. Pathology revealed ypT2aypN0ycM0, ypStage IIA, and radical resection was considered. Immunostaining of tissue collected at the time of endoscopic ultrasound-guided tissue acquisition revealed less than 1% programmed death ligand-1 expression. The patient continued adjuvant chemotherapy with single-agent durvalumab every 4weeks and maintained a relapse-free survival of 8months postoperatively. The utility of durvalumab in combination with gemcitabine plus cisplatin in unresectable gallbladder cancer independent of programmed death ligand-1 expression has been confirmed and may be an important option in future multimodal treatment, including conversion surgery.

Prior cocaine use diminishes encoding of latent information by orbitofrontal, but not medial, prefrontal ensembles.

Maladaptive decision-making is a hallmark of substance use disorders (SUDs), though how drugs of abuse alter neural representations supporting adaptive behavior remains poorly understood. Past studies show that the orbitofrontal (OFC) and prelimbic (PL) cortices are important for decision-making, tracking both task-relevant and latent information. However, previous studies have focused on how drugs of abuse impact the firing rates of individual units. More work at the ensemble level is necessary to accurately characterize potential drug-induced changes. Using single-unit recordings in rats during a multidimensional decision-making task and then applying population- and ensemble-level analyses, we show that prior use of cocaine altered the strength and structure of task-relevant and latent representations in the OFC, changes relatable to suboptimal decision-making in this and perhaps other settings. These data expand our understanding of the neuropathological underpinnings of maladaptive decision-making in SUDs, potentially enabling enhanced future treatment strategies.

Mesenchymal Stem Cell Therapy Mitigates Acute and Chronic Lung Damages of Sulfur Mustard Analog Exposure

Sulfur mustard (SM) is an established chemical weapon that can result in severe damage to parts of the body. Currently, there are no effective treatments available for SM-caused damage. We aimed to investigate the therapeutic potential of adipose-derived mesenchymal stromal cells (AD-MSCs) and conditioned medium (CM-MSCs) in acute and chronic pulmonary mouse models caused by 2-chloroethyl ethyl sulfide (CEES), an SM analog. The mice were divided into 4 experimental groups:(1) CEES+AD-MSCs, (2) CEES+CM-MSCs, (3) CEES, and (4) control. The model observation time was divided into 7 days for the short and 6 months for the long term. AD-MSCs were injected into mice via intraperitoneal injection 24 hours after CEES exposure. The therapeutic effects of AD-MSCs on pulmonary tissue damage were assessed using a histopathologic assay, measuring the neutrophil count, and bronchial alveolar lavage fluid (BALF) protein level. The levels of inflammatory and anti-inflammatory cytokines were evaluated using the enzyme-linked immunosorbent assay as the outcomes of interest. Lung damage progression was reduced by AD-MSC treatment in mice after CEES injection into the peritoneum. The proportion of CD11b+F4/80+ macrophages in the peritoneum was significantly lowered by AD-MSC treatment following CEES exposure. AD-MSC administration also reduced the level of pro-inflammatory cytokines, BALF protein, and nitric oxide levels in the peritoneal cavity. By reducing inflammation and enhancing tissue healing, AD-MSCs and CM-MSC help prevent acute lung damage caused by CEES. The current study supports the use of a mouse model as a solid experimental foundation and indicates potential use for future cell treatment.

Metabolomic signature of sperm in men with obesity-associated asthenozoospermia.

Obese men have a significantly increased risk of developing asthenozoospermia. Sperm motility is directly related to cellular energy supply and metabolic status. Sperm metabolomics research based on Gas chromatography-mass spectrometry (GC-MS) technology can provide useful information for the pathological mechanism, diagnosis, and treatment of obesity-associated asthenozoospermia. Sperm samples were obtained from a healthy control group (n = 49) and patients with obesity-associated asthenozoospermia (n = 40). After the analysis of sperm samples using GC-MS, various multivariate statistical methods such as principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and orthogonal partial least squares-discriminant analysis (OPLS-DA) were conducted. A total of 56 metabolites were identified in the sperm samples. Among them, 19 differential metabolites were found between the two groups. Metabolites such as glutamic acid, fumaric acid, and cysteine were significantly downregulated in the sperm of patients with obesity-associated asthenozoospermia, while metabolites like palmitic acid, stearic acid, and alanine were significantly upregulated. The differential metabolites were enriched in D-glutamine and D-glutamate metabolism; proline, aspartate, and glutamate metabolism; glutathione metabolism and the other metabolic pathways. Obesity may influence the composition of metabolic products in sperm, and metabolomic analysis proves beneficial for the future diagnosis and treatment of obesity-associated asthenozoospermia.

3D Coaxial Printing of Small‐Diameter Artificial Arteries

As a treatment for the widely spread cardiovascular diseases (CVD), bypass vascular grafts have room for improvement in terms of mechanical property match with native arteries. A 3D‐printed nozzle is presented, featuring unique internal structures, to extrude artificial vascular grafts with a flower‐mimicking geometry. The multilayer‐structured graft wall allows the inner and outer layers to interfere sequentially during lateral expansion, replicating the nonlinear elasticity of native vessels. Both experiment and simulation results verify the necessity and benefit of the flower‐mimicking structure in obtaining the self‐toughening behavior. The gelation study of natural polymers and the utilization of sacrificial phase enables the smooth extrusion of the multiphase conduit, where computer‐assisted image analysis is employed to quantify manufacturing fidelity. The cell viability tests demonstrate the cytocompatibility of the gelatin methacryloyl (GelMA)/sodium alginate grafts, suggesting potential for further clinical research with further developments. This study presents a feasible approach for fabricating bypass vascular grafts and inspires future treatments for CVD.

Exploring the Gene Expression and Plasma Protein Levels of HSP90, HSP60, and GDNF in Multiple Sclerosis Patients and Healthy Controls.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by immune-mediated inflammation and neurodegeneration in the central nervous system (CNS). In this study; we aimed to investigate the gene expression and plasma protein levels of three neuroprotective genes-heat shock proteins (HSP90 and HSP60) and glial cell line-derived neurotrophic factor (GDNF)-in MS patients compared to healthy controls. Forty patients with relapsing-remitting MS and 40 healthy volunteers participated in this study. Gene expression was measured using reverse transcription quantitative real-time PCR, and protein levels were assessed via ELISA. The results showed a significant increase in HSP90 (1.7-fold) and HSP60 (2-fold) gene expression in MS patients compared to controls, along with corresponding increases in protein levels (1.5-fold for both HSP90 and HSP60). In contrast, GDNF gene expression and protein levels were significantly reduced in MS patients, with a 7-fold decrease in gene expression and a 1.6-fold reduction in protein levels. Notably, a non-linear relationship between GDNF gene expression and protein concentration was observed in MS patients, suggesting complex regulatory mechanisms influencing GDNF in the disease. The upregulation of HSP90 and HSP60 in MS highlights their roles in immune regulation and stress responses, while the reduction in GDNF indicates impaired neuroprotection. These findings suggest that HSP90, HSP60, and GDNF could serve as biomarkers for disease progression and as potential therapeutic targets in MS, offering promising avenues for future research and treatment development.

Auranofin as a Novel Anticancer Drug for Anaplastic Thyroid Cancer.

Background/Objectives: Anaplastic thyroid cancer (ATC) is an aggressive and rare cancer with a poor prognosis, and traditional therapies have limited efficacy. This study investigates drug repositioning, focusing on auranofin, a gold-based drug originally used for rheumatoid arthritis, as a potential treatment for ATC. Methods: Auranofin was identified from an FDA-approved drug library and tested on two thyroid cancer cell lines, 8505C and FRO. Antitumor efficacy was evaluated through gene and protein expression analysis using Western blot, FACS, and mRNA sequencing. In vivo experiments were conducted using subcutaneous injections in nude mice to confirm the anticancer effects of auranofin. Results: Auranofin induced reactive oxygen species (ROS) production and apoptosis, leading to a dose-dependent reduction in cell viability, G1/S phase cell cycle arrest, and altered expression of regulatory proteins. It also inhibited cancer stem cell activity and suppressed epithelial-mesenchymal transition. mRNA sequencing revealed significant changes in the extracellular matrix-receptor interaction pathway, supported by Western blot results. In vivo xenograft models demonstrated strong antitumor activity. Conclusions: Auranofin shows promise as a repurposed therapeutic agent for ATC, effectively inhibiting cell proliferation, reducing metastasis, and promoting apoptosis. These findings suggest that auranofin could play a key role in future ATC treatment strategies.

Early minimally invasive image-guided endoscopic evacuation of intracerebral hemorrhage (EMINENT-ICH): a randomized controlled trial

BackgroundSpontaneous supratentorial intracerebral hemorrhage is the deadliest form of stroke with mortality rates over 50%. Currently, no sufficiently effective treatment to improve both mortality and functional outcome rates exists. However, it seems that minimally invasive surgery, especially endoscopic surgery, might be beneficial in improving survival and functional outcome rates, yet large confirmatory studies thereof are lacking. The aim of this trial is to compare whether early minimally invasive endoscopic surgery leads to improved functional outcome rates compared to the best medical treatment.MethodsThis is a prospective, parallel-arm, outcome assessor blinded multicenter trial across Switzerland. Endoscopic surgery will be compared to the best medical treatment in a 1:1 randomization over a total time of 12 months. The primary outcome is defined as improved functional outcome (mRS < 3) after 6 months; secondary outcomes include mortality and morbidity rates as well as patient reported outcomes and the temporal evolution of serum biomarkers for brain damage.DiscussionCurrently, large, randomized trials assessing the role and potential effect of early endoscopic surgery in intracerebral hemorrhage are lacking. Potential practical and methodological issues faced in this trial are patient enrollment, adherence to the hematoma evacuation technique used, potential patient cross-over, and the adaptive Bayesian statistical design. Nonetheless, this trial would be among the first to research the effects of early minimally invasive endoscopic surgery for SSICH and can provide class I evidence for future treatment options in intracerebral hemorrhage.Trial registrationClinicalTrials.gov NCT05681988. Registered on January 3, 2023.

Activation of Nrf2 and FXR via Natural Compounds in Liver Inflammatory Disease.

Liver inflammation is frequently linked to oxidative stress and dysregulation of bile acid and fatty acid metabolism. This review focuses on the farnesoid X receptor (FXR), a critical regulator of bile acid homeostasis, and its interaction with the nuclear factor erythroid 2-related factor 2 (Nrf2), a key modulator of cellular defense against oxidative stress. The review explores the interplay between FXR and Nrf2 in liver inflammatory diseases, highlighting the potential therapeutic effects of natural FXR agonists. Specifically, compounds such as auraptene, cafestol, curcumin, fargesone A, hesperidin, lycopene, oleanolic acid, resveratrol, rutin, ursolic acid, and withaferin A are reviewed for their ability to modulate both the FXR and Nrf2 pathways. This article discusses their potential to alleviate liver inflammation, oxidative stress, and damage in diseases such as metabolic-associated fatty liver disease (MAFLD), cholestatic liver injury, and viral hepatitis. In addition, we address the molecular mechanisms driving liver inflammation, including oxidative stress, immune responses, and bile acid accumulation, while also summarizing relevant experimental models. This review emphasizes the promising therapeutic potential of targeting both the Nrf2 and FXR pathways using natural compounds, paving the way for future treatments for liver diseases. Finally, the limitations of the clinical application were indicated, and further research directions were proposed.