Therapeutic Options Research Articles

Role of Culinary Indian Spices in the Regulation of TGF-β Signaling Pathway in Inflammation-Induced Liver Cancer.

Hepatocellular carcinoma (HCC) results from various etiologies, such as Hepatitis B and C, Alcoholic and Non-alcoholic fatty liver disorders, fibrosis, and cirrhosis. About 80 to 90% of HCC cases possess cirrhosis, which is brought on by persistent liver inflammation. TGF-β is a multifunctional polypeptide molecule that acts as a pro-fibrogenic marker, inflammatory cytokine, immunosuppressive agent, and pro-carcinogenic growth factor during the progression of HCC. The preclinical and clinical evidence illustrates that TGF-β can induce epithelial-to-mesenchymal transition, promoting progression and hepatocyte immune evasion. Therefore, targeting the TGF-β pathway can be a promising therapeutic option against HCC. We carry out a systemic analysis of eight potentially selected culinary Indian spices: Turmeric, Black pepper, Ginger, Garlic, Fenugreek, Red pepper, Clove, Cinnamon, and their bioactives in regulation of the TGF-β pathway against liver cancer. Turmeric and its active constituent, curcumin, possess the highest therapeutic potential in treating inflammation-induced HCC and they also have the maximum number of ongoing in-vivo and in-vitro studies.

Sinonasal mucosal melanoma in The Netherlands between 2001 and 2021: a clinical and epidemiological overview of 320 cases.

Sinonasal mucosal melanoma (SNMM) is a rare malignancy, characterised by high (local) recurrence rates and poor survival. Comprehensive understanding of tumour etiology is currently lacking, which complicates adequate tumour treatment. Besides examining trends in incidence, this study aims to assess the association between clinical characteristics, treatment practices and patient outcomes, with the objective of establishing a baseline from which SNMM management can be enhanced. All newly diagnosed SNMM cases in The Netherlands between 2001 and 2021 were included using data from The Netherlands Cancer Registry (NCR). A total of 320 patients were included. The annual incidence rate for the overall population was stable over the inclusion period with an annual percentage change (APC) of only - 0.01%. The 5-year overall survival (OS) and relative survival (RS) were 24.5 and 32.4%, respectively. Relative survival did not increase over time. The addition of adjuvant radiotherapy to surgery was not associated with a higher OS and RS compared to surgery alone. Sinonasal mucosal melanoma is a rare disease with stable incidence rates in the Netherlands between 2001 and 2021. There has been no improvement in survival over the course of the inclusion period. The study reaffirms that adjuvant radiotherapy does not seem to improve patient outcomes. Given the generally poor outcomes for SNMM patients, novel therapeutic options ought to be considered in order to improve care.

The value of virtual molecular tumor boards for informed clinical decision-making.

Genomic profiling and other new technologies have increased the volume and complexity of information available for guiding clinical decision-making in precision oncology. Consequently, there is a need for multidisciplinary expert teams, in the form of molecular tumor boards (MTBs), who can translate this information into a therapeutic plan, including matching patients to suitable clinical trials. Virtual MTBs (vMTBs) can help to overcome many of the challenges associated with in-person MTBs, such as limited time availability, access to appropriate experts or datasets, or interactions between institutions. However, real-world experience from vMTBs is lacking. Here, we describe oncologists' vMTB experiences and the value of working with multicenter and/or multinational vMTBs. We also address knowledge gaps and barriers that could affect the implementation of vMTBs in routine clinical practice. Case studies from Argentina, Turkey, and Portugal illustrate the value of informed clinical decision-making by vMTBs, including expansion of therapeutic options for patients, faster time to treatment, and the resulting improvement in patient outcomes or impact of vMTB discussions on patients. With the uptake of comprehensive genomic profiling and the evolution of some cancers now being conceptualized as a collection of rare diseases with small patient populations based on molecular profiling, the importance of MTBs has increased in modern cancer management. However, an adjustment in clinical decision-making by healthcare professionals is required and evidence of the added value of vMTBs is lacking. Existing vMTBs and recommendations from participating oncologists could point toward a structured evaluation and analysis of this new platform.

Matrix Metalloproteinase- and pH-Sensitive Nanoparticle System Enhances Drug Retention and Penetration in Glioblastoma.

Glioblastoma (GBM) is a primary malignant brain tumor with limited therapeutic options. One promising approach is local drug delivery, but the efficacy is hindered by limited diffusion and retention. To address this, we synthesized and developed a dual-sensitive nanoparticle (Dual-NP) system, formed between a dendrimer and dextran NPs, bound by a dual-sensitive [matrix metalloproteinase (MMP) and pH] linker designed to disassemble rapidly in the tumor microenvironment. The disassembly prompts the in situ formation of nanogels via a Schiff base reaction, prolonging Dual-NP retention and releasing small doxorubicin (Dox)-conjugated dendrimer NPs over time. The Dual-NPs were able to penetrate deep into 3D spheroid models and detected at the tumor site up to 6 days after a single intratumoral injection in an orthotopic mouse model of GBM. The prolonged presence of Dual-NPs in the tumor tissue resulted in a significant delay in tumor growth and an overall increase in survival compared to untreated or Dox-conjugated dendrimer NPs alone. This Dual-NP system has the potential to deliver a range of therapeutics for efficiently treating GBM and other solid tumors.

HER3 (ERBB3) amplification in liposarcoma - a putative new therapeutic target?

Liposarcomas are among the most common mesenchymal malignancies. However, the therapeutic options are still very limited and so far, targeted therapies had not yet been established. Immunotherapy, which has been a breakthrough in other oncological entities, seems to have no efficacy in liposarcoma. Complicating matters further, classification remains difficult due to the diversity of morphologies and nonspecific or absent markers in immunohistochemistry, leaving molecular pathology using FISH or sequencing as best options. Many liposarcomas harbor MDM2 gene amplifications. In close relation to the gene locus of MDM2, HER3 (ERBB3) gene is present and co-amplification could occur. Since the group of HER/EGFR receptor tyrosine kinases and its inhibitors/antibodies play a role in a broad spectrum of oncological diseases and treatments, and some HER3 inhibitors/antibodies are already under clinical investigation, we hypothesized that in case of HER3 co-amplifications a tumor might bear a further potential therapeutic target. We performed FISH analysis (MDM2, DDIT3, HER3) in 56 archived cases and subsequently performed reclassification to confirm the diagnosis of liposarcoma. Next to 16 out of 56 cases needed to be re-classified, in 20 out of 54 cases, a cluster-amplification of HER3 could be detected, significantly correlating with MDM2 amplification. Our study shows that the entity of liposarcomas show specific molecular characteristics leading to reclassify archived cases by modern, established methodologies. Additionally, in 57.1% of these cases, HER3 was cluster-amplified profusely, presenting a putative therapeutic target for targeted therapy. Our study serves as the initial basis for further investigation of the HER3 gene as a putative therapeutic target in liposarcoma.

Renal disease in pediatric rheumatology.

This review will provide updates in the outcomes in the common rheumatologic diseases with kidney involvement. Covered are also advances in therapeutics for the use of pediatric rheumatologic diseases with kidney involvement, as well as the potential kidney complications from other rheumatologic diseases and their medications. Two of the more common rheumatologic diseases with kidney involvement, lupus and vasculitis, continue to show inadequate response to initial therapy of renal disease and practice continues to be driven by results of adult studies. There is a continued need for pediatric specific studies in rheumatologic diseases with kidney involvement as outcomes continue to be inadequate. Despite recently approved treatments for adults with rheumatic diseases and kidney involvement, therapeutic options in pediatrics remain limited, contributing to the overall morbidity and mortality.

Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study.

Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

Semaglutide in Heart Failure With Preserved Ejection Fraction: Exploring Recent Evidence in Therapeutic Potential for the Obese Population.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent condition, particularly among the aging population in the United States, and is associated with significant challenges due to its complex pathophysiology and limited therapeutic options. Historically, few pharmacological therapies have successfully mitigated HFpEF, making the emergence of effective treatments particularly significant. This review evaluates recent evidence on the therapeutic potential of semaglutide for managing HFpEF, especially in the obese population. Results from the STEP-HFpEF and STEP-HFpEF DM trials demonstrate that semaglutide, a glucagon-like peptide-1 receptor agonist originally developed for type 2 diabetes but now also approved for obesity treatment, significantly improves clinical outcomes such as symptom scores, body weight, exercise capacity, and inflammation markers in the obese population suffering from HFpEF. These improvements are attributed to both the weight loss induced by semaglutide and its direct effects on the congestive pathophysiology of HFpEF. The efficacy of semaglutide offers new hope for addressing a condition that has long lacked effective pharmacological interventions.

Exploiting sweet relief for preeclampsia by targeting autophagy-lysosomal machinery and proteinopathy.

The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta. Targeting of these pathological pathways may be a novel therapeutic strategy for PE. Stimulation of autophagy with the natural disaccharide trehalose and its lacto analog lactotrehalose in hypoxia-exposed primary human trophoblasts restored autophagy, inhibited the accumulation of toxic protein aggregates, and restored the ultrastructural features of autophagosomes and autolysosomes. Importantly, trehalose and lactotrehalose inhibited the onset of PE-like features in a humanized mouse model by normalizing autophagy and inhibiting protein aggregation in the placenta. These disaccharides restored the autophagy-lysosomal biogenesis machinery by increasing nuclear translocation of the master transcriptional regulator TFEB. RNA-seq analysis of the placentas of mice with PE indicated the normalization of the PE-associated transcriptome profile in response to trehalose and lactotrehalose. In summary, our results provide a novel molecular rationale for impaired autophagy and proteinopathy in patients with PE and identify treatment with trehalose and its lacto analog as promising therapeutic options for this severe pregnancy complication.

ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia-2024 update.

In chronic lymphocytic leukemia (CLL), analysis of TP53 aberrations (deletion and/or mutation) is a crucial part of treatment decision-making algorithms. Technological and treatment advances have resulted in the need for an update of the last recommendations for TP53 analysis in CLL, published by ERIC, the European Research Initiative on CLL, in 2018. Based on the current knowledge of the relevance of low-burden TP53-mutated clones, a specific variant allele frequency (VAF) cut-off for reporting TP53 mutations is no longer recommended, but instead, the need for thorough method validation by the reporting laboratory is emphasized. The result of TP53 analyses should always be interpreted within the context of available laboratory and clinical information, treatment indication, and therapeutic options. Methodological aspects of introducing next-generation sequencing (NGS) in routine practice are discussed with a focus on reliable detection of low-burden clones. Furthermore, potential interpretation challenges are presented, and a simplified algorithm for the classification of TP53 variants in CLL is provided, representing a consensus based on previously published guidelines. Finally, the reporting requirements are highlighted, including a template for clinical reports of TP53 aberrations. These recommendations are intended to assist diagnosticians in the correct assessment of TP53 mutation status, but also physicians in the appropriate understanding of the lab reports, thus decreasing the risk of misinterpretation and incorrect management of patients in routine practice whilst also leading to improved stratification of patients with CLL in clinical trials.

KinomeMETA: a web platform for kinome-wide polypharmacology profiling with meta-learning.

Kinase-targeted inhibitors hold promise for new therapeutic options, with multi-target inhibitors offering the potential for broader efficacy while minimizing polypharmacology risks. However, comprehensive experimental profiling of kinome-wide activity is expensive, and existing computational approaches often lack scalability or accuracy for understudied kinases. We introduce KinomeMETA, an artificial intelligence (AI)-powered web platform that significantly expands the predictive range with scalability for predicting the polypharmacological effects of small molecules across the kinome. By leveraging a novel meta-learning algorithm, KinomeMETA efficiently utilizes sparse activity data, enabling rapid generalization to new kinase tasks even with limited information. This significantly expands the repertoire of accurately predictable kinases to 661 wild-type and clinically-relevant mutant kinases, far exceeding existing methods. Additionally, KinomeMETA empowers users to customize models with their proprietary data for specific research needs. Case studies demonstrate its ability to discover new active compounds by quickly adapting to small dataset. Overall, KinomeMETA offers enhanced kinome virtual profiling capabilities and is positioned as a powerful tool for developing new kinase inhibitors and advancing kinase research. The KinomeMETA server is freely accessible without registration at https://kinomemeta.alphama.com.cn/.

DNA methylation and type 2 diabetes: a systematic review.

DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid early detection and/or therapeutic treatment options for diabetics. A systematic literature search for associations between T2DM and DNA methylation was performed. Prospero registration ID: CRD42020140436. PubMed and ScienceDirect databases were searched (till October 19, 2023). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and New Castle Ottawa scale were used for reporting the selection and quality of the studies, respectively. Thirty-two articles were selected. Four of 130 differentially methylated genes in blood, adipose, liver or pancreatic islets (TXNIP, ABCG1, PPARGC1A, PTPRN2) were reported in > 1 study. TXNIP was hypomethylated in diabetic blood across ethnicities. Gene enrichment analysis of the differentially methylated genes highlighted relevant disease pathways (T2DM, type 1 diabetes and adipocytokine signaling). Three prospective studies reported association of methylation in IGFBP2, MSI2, FTO, TXNIP, SREBF1, PHOSPHO1, SOCS3 and ABCG1 in blood at baseline with incident T2DM/hyperglycemia. Sex-specific differential methylation was reported only for HOOK2 in visceral adipose tissue (female diabetics: hypermethylated, male diabetics: hypomethylated). Gene expression was inversely associated with methylation status in 8 studies, in genes including ABCG1 (blood), S100A4 (adipose tissue), PER2 (pancreatic islets), PDGFA (liver) and PPARGC1A (skeletal muscle). This review summarizes available evidence for using DNA methylation patterns to unravel T2DM pathophysiology. Further validation studies in diverse populations will set the stage for utilizing this knowledge for identifying early diagnostic markers and novel druggable pathways.

MiR-1976/NCAPH/P65 axis inhibits the malignant phenotypes of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a malignancy with an abysmal survival rate. High metastasis is the leading cause of the low survival rate of LUAD. NCAPH, an oncogene, is involved in the carcinogenesis of LUAD. However, the regulation of NCAPH in LUAD remains controversial. In this work, we identified an up-regulation of NCAPH in LUAD tissues. Patients who expressed more NCAPH had shorter overall survival (OS). Furthermore, NCAPH overexpression promoted LUAD cell migration while inhibiting apoptosis. MiR-1976 and miR-133b were predicted to target NCAPH expression by searching TargetScan and linkedomics databases. Following that, we confirmed that miR-1976 suppressed NCAPH by directly targeting a 7-bp region of NCAPH 3' untranslated regions (UTR). In addition, increased expression of miR-1976 decreased the proliferation & migration and promoted apoptosis of LUAD cells, and the re-introduction of NCAPH reversed these influences. Furthermore, the xenograft and metastasis mouse models also confirmed that miR-1976 inhibited tumor growth and metastasis in vivo by targeting NCAPH. Finally, we found that MiR-1976 targeting NCAPH blocked the activation of NF-κB. In conclusion, miR-1976 inhibits NCAPH activity in LUAD and acts as a tumor suppressor. The miR-1976/NCAPH/NF-κB axis may, in the future, represent crucial diagnostic and prognostic biomarkers and promising therapeutic options.

Comparison of different promoters to improve AAV vector-mediated gene therapy for neuronopathic Gaucher disease.

Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, is characterised by devastating neuropathology and death during infancy. In this study, we investigated the therapeutic benefit of systemically delivered AAV9 vectors expressing the human GBA1 gene at two different doses comparing a neuronal-selective promoter with ubiquitous promoters. Our results highlight the importance of a careful evaluation of the promoter sequence used in gene delivery vectors, suggesting a neuron-targeted therapy leading to high levels of enzymatic activity in the brain but lower GCase expression in the viscera, might be the optimal therapeutic strategy for nGD.

Curcumin and its Analogues in Oral Squamous Cell Carcinoma: State-of-the-art and Therapeutic Potential.

Oral Squamous Cell Carcinoma (OSCC) is the most common cancer arising from squamous epithelium in the oral cavity and is characterized by high aggressiveness and metastatic potential, which together with a late diagnosis results in a 5-year survival rate of only 50% of patients. The therapeutic options for OSCC management are limited and largely influenced by the cancer stage. While radical surgery can be curative in early stage of disease, most cases require adjuvant therapies, including chemotherapy and radiotherapy which, however, often achieve poor curative rates and are associated with important negative effects. Therefore, there is an urgent need to discover new alternative treatment strategies to improve patients' outcomes. Several medicinal herbs are being studied for their preventive or therapeutic effect in several diseases, including cancer. In particular, the Indian spice curcumin, largely used in oriental countries, has been studied as a chemopreventive or adjuvant agent for different malignancies. Indeed, curcumin is characterized by important biological properties, including antioxidant, anti-inflammatory, and anticancer effects, which could also be exploited in OSCC. However, due to its limited bioavailability and poor aqueous solubility, this review is focused on studies designing new synthetic analogues and developing novel types of curcumin delivery systems to improve its pharmacokinetic and biological properties. Thus, this review analyses the potential therapeutic role of curcumin in OSCC by providing an overview of current in vitro and in vivo studies demonstrating the beneficial effects of curcumin and its analogues in OSCC.

Can Stem Cell Therapy be an Effective Therapeutic Option for Complex and Neurological Conditions?

Can Stem Cell Therapy be an Effective Therapeutic Option for Complex and Neurological Conditions?

Hypertension and left ventricular hypertrophy.

In the initial stage, left ventricular hypertrophy (LVH) is adaptive, but in time, it transforms to maladaptive LVH which is specific for the development of various phenotypes that cause heart failure, initially with preserved, but later with reduced left ventricular ejection fraction. Pathophysiological mechanisms, which are characteristic for remodeling procedure, are numerous and extremely complex, and should be subjected to further research with the aim of making a comprehensive overview of hypertensive heart disease (HHD) and discovering new options for preventing and treating HHD. The contemporary methods, such as cardiac magnetic resonance (CMR) and computed tomography (CT) provide very accurate morphological and functional information on HHD. The objective of this review article is to summarize the available scientific information in terms of prevalence, pathophysiology, diagnostics, prevention, contemporary therapeutic options, as well as to present potential therapeutic solutions based on the research of pathological mechanisms which are at the core of HHD.

The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells

ObjectivePancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant ‘stem-like’ cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending...

Brief apnea with hypoventilation reduces seizure duration and shifts seizure location for several hours in a model of severe traumatic brain injury.

Seizures can be difficult to control in infants and toddlers. Seizures with periods of apnea and hypoventilation are common following severe traumatic brain injury (TBI). We previously observed that brief apnea with hypoventilation (A&H) in our severe TBI model acutely interrupted seizures. The current study is designed to determine the effect of A&H on subsequent seizures and whether A&H has potential therapeutic implications. Piglets (1 week or 1 month old) received multifactorial injuries: cortical impact, mass effect, subdural hematoma, subarachnoid hemorrhage, and seizures induced with kainic acid. A&H (1 min apnea, 10 min hypoventilation) was induced either before or after seizure induction, or control piglets received subdural/subarachnoid hematoma and seizure without A&H. In an intensive care unit, piglets were sedated, intubated, and mechanically ventilated, and epidural electroencephalogram was recorded for an average of 18 h after seizure induction. In our severe TBI model, A&H after seizure reduced ipsilateral seizure burden by 80% compared to the same injuries without A&H. In the A&H before seizure induction group, more piglets had exclusively contralateral seizures, although most piglets in all groups had seizures that shifted location throughout the several hours of seizure. After 8-10 h, seizures transitioned to interictal epileptiform discharges regardless of A&H or timing of A&H. Even brief A&H may alter traumatic seizures. In our preclinical model, we will address the possibility of hypercapnia with normoxia, with controlled intracranial pressure, as a therapeutic option for children with status epilepticus after hemorrhagic TBI.

Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance.

Osteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements. Time-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed. GoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level. This prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option.