Search Results (15,381)

Richter’s syndrome (RS) or transformation of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma (e.g., diffuse large B cell lymphoma, DLBCL) is a distinct disease that portends an overall poor prognosis and remains a challenge for clinicians to identify and treat effectively. This review of the current literature focuses on the pathology, diagnosis, and management of Richter’s syndrome. Clonally related RS has been found to have a worse prognosis than unrelated disease and the genomic profile of DLBCL-RS differs from that of de novo DLBCL. The standard of care therapy for RS has historically been chemoimmunotherapy; consolidative stem cell transplants have a role in improving durability of disease response. Given generally poor response rates to chemotherapy, there have been recent investigations into combination treatments with immune checkpoint inhibitors and small molecule targeted therapies, which have had mixed results. Additional studies are evaluating the use of bispecific antibodies, chimeric antigen receptor T cell therapy, and antibody drug conjugates. RS remains difficult to manage; however, advancements in the understanding of the underlying pathology of transformation and continued investigations into new therapies demonstrate promise for the future. Full article

Background: The therapeutic blockade of the PD1/PD-L1 axis with monoclonal antibodies has led to a breakthrough in cancer treatment, as it plays a key role in the immune evasion of tumors. Nevertheless, treating patients with cancer with vaccines that stimulate a targeted immune response is another attractive approach for which few side effects have been observed in combination immunotherapy clinical trials. In this sense, our group has recently developed a therapeutic cancer vaccine candidate called PKPD-L1^Vac which contains as an antigen the extracellular domain of human PD-L1 fused to a 47 amino-terminal, part of the LpdA gene of N. meningitides, which is produced in E. coli. The investigation of potential toxicities associated with PD-L1 blockade by a new therapy in preclinical studies is critical to optimizing the efficacy and safety of that new therapy. Methods: Here, we describe immunogenicity and preliminary safety studies in mice, rats, rabbits, and non-human primates that make use of a 200 μg dose of PKPD-L1 in combination with VSSPs or alum phosphate to contribute to the assessment of potential adverse events that are relevant to the future clinical development program of this novel candidate. Results: The administration of PKPD-L1^Vac to the four species at the doses studied was immunogenic and did not result in behavioral, clinical, hematological, or serum biochemical changes. Conclusions: Therefore, PKPD-L1^Vac could be considered suitable for further complex toxicological studies and the way for its clinical evaluation in humans has been opened. Full article

Background/Objective: Ovarian clear cell carcinomas (OCCCs) are a rare histological subtype of epithelial ovarian cancer characterized by resistance to platinum-based therapy. CDK8/19, a component of the regulatory CDK module associated with Mediator complex, has been implicated in transcriptional reprogramming and drug resistance in various solid tumors. Our study aimed to investigate the therapeutic potential of CDK8/19 kinase inhibition using selective inhibitors SNX631 and SNX631-6 in OCCC treatment, both as monotherapy and in combination with standard chemotherapeutics. Methods: CDK8 and Ki67 levels were evaluated via immunohistochemistry in benign, primary, and metastatic ovarian cancer tissues. The efficacy of SNX631 alone and in combination with cisplatin or paclitaxel was assessed in OCCC cell lines (ES-2, TOV-21-G, RMG-1). In vivo evaluation utilized xenograft models with subcutaneous and intraperitoneal delivery of the OCCC ES2 cells and oral delivery of SNX631-6, with the monitoring of tumor growth, metastatic spread, and survival. Results: CDK8 protein levels were elevated in OC tissues, particularly in OCCC primary and metastatic lesions compared to benign tissue. While CDK8/19 inhibition showed limited effects on in vitro cell proliferation, SNX631-6 demonstrated significant antitumor and anti-metastatic activity in vivo. Notably, SNX631-6 enhanced the efficacy of cisplatin, substantially inhibiting tumor growth and extending overall survival. Conclusions: Therapeutically achievable doses of CDK8/19 inhibitors may provide clinical benefit for OCCC patients by inhibiting tumor growth and reversing platinum resistance, potentially addressing a critical treatment challenge in this rare ovarian cancer subtype. Full article

Acute ischemic stroke (AIS) remains a critical concern in clinical practice, with significant implications for patient outcomes and healthcare costs. This review highlights the role of clot composition in AIS, emphasizing the clinical relevance of radiological characterization. Variations in thrombus composition, such as red blood cell (RBC)-rich and white blood cell (WBC)-dominant clots, influence the success of thrombolytic therapies and mechanical thrombectomy. Advanced radiological techniques, including non-contrast CT, CT angiography, and MRI, are essential for pre-interventional clot characterization, guiding optimal treatment decisions. Integrating artificial intelligence (AI) in radiology can enhance the precision of clot composition assessment, facilitating personalized treatment approaches and improving predictive accuracy. By combining histopathological insights with imaging and AI technologies, this review underscores the importance of comprehensive radiological evaluation in the management of AIS, ultimately aiming to enhance clinical outcomes and reduce the burden on healthcare systems. Full article

Cyclodextrin (CD)-based drug delivery systems have emerged as a promising strategy to overcome limitations commonly encountered in antidepressant therapy, including low bioavailability, poor solubility, and suboptimal penetration of the blood–brain barrier. This review synthesizes current evidence demonstrating that complexing various classes of antidepressants—such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and atypical antidepressants—with β-CD or its derivatives significantly enhances drug solubility and stability. In addition, encapsulation with CDs can diminish systemic toxicity and improve pharmacokinetics, thereby helping to optimize dosage regimens and reduce adverse effects. Analysis of published in vitro and in vivo studies indicates that CD formulations not only boost therapeutic efficacy but also enable sustained or targeted release, which is critical for drugs requiring precise plasma and tissue concentrations. When compared to other carriers (e.g., liposomes, polymeric nanoparticles, dendrimers), CD-based systems often stand out for their ease of formulation, biocompatibility, and cost-effectiveness, although limited drug-loading capacity can be a drawback. We recommend expanding in vivo trials to substantiate the clinical benefits of CD–antidepressant complexes, particularly for treatment-resistant cases or specific subpopulations (e.g., elderly and pediatric patients). Additional investigations should also explore hybrid systems—combining CDs with advanced nano- or macroparticles—to amplify their advantages and address any limitations. Ultimately, integrating CDs into antidepressant regimens holds substantial potential to refine therapy outcomes, reduce adverse events, and pave the way for more personalized, effective interventions for depression. Full article

Metabolic reprogramming is a hallmark of cancer, with cancer cells acquiring many unique metabolic traits to support malignant growth, and extensive intra- and inter-tumour metabolic heterogeneity. Understanding these metabolic characteristics presents opportunities in precision medicine for both diagnosis and therapy. However, despite its potential, metabolic phenotyping has lagged behind genetic, transcriptomic, and immunohistochemical profiling in clinical applications. This is partly due to the lack of a single experimental technique capable of profiling the entire metabolome, necessitating the use of multiple technologies and approaches to capture the full range of cancer metabolic plasticity. This review examines the repertoire of tools available for profiling cancer metabolism, demonstrating their applications in preclinical and clinical settings. It also presents case studies illustrating how metabolomic profiling has been integrated with other omics technologies to gain insights into tumour biology and guide treatment strategies. This information aims to assist researchers in selecting the most effective tools for their studies and highlights the importance of combining different metabolic profiling techniques to comprehensively understand tumour metabolism. Full article

Background/Objectives: Bipolar disorder (BD) is a chronic, severe mental health condition characterized by episodes of mood instability, including manic and depressive episodes. While pharmacological interventions remain foundational in BD treatment, psychotherapy offers significant benefits by addressing the psychological and behavioral components that contribute to mood episodes and overall functioning. The primary objective of this short communication is to propose new directions in psychotherapy for treating bipolar disorder, focusing on integrative models that combine evidence-based therapies such as Cognitive Behavioral Therapy (CBT), Interpersonal and Social Rhythm Therapy (IPSRT), Family-Focused Therapy (FFT), and mindfulness-based approaches. By integrating these therapies, clinicians can target both cognitive distortions and emotional dysregulation while simultaneously stabilizing sleep–wake cycles and improving interpersonal functioning. The secondary objective emphasizes the importance of better understanding and psychoeducation in family therapy, which can promote a better understanding of BD among family members and ensure more effective management of the disorder in daily life. Methods: We explore the potential of Cognitive Behavioral Therapy (CBT), Interpersonal and Social Rhythm Therapy (IPSRT), Family-Focused Therapy (FFT), and mindfulness-based interventions in enhancing symptom management and preventing relapse. Results: We identified psychoeducation and family therapy as critical components in supporting patients and improving treatment adherence. These therapeutic interventions play a pivotal role in enhancing patient engagement, improving coping strategies, and facilitating better overall treatment outcomes. Conclusions: We propose a multidisciplinary approach, integrating psychotherapy with pharmacotherapy, to optimize long-term outcomes and improve the overall quality of life for individuals with bipolar disorder. Full article

The extracellular matrix (ECM) is the common denominator of more than 50 chronic diseases. Some of these chronic pathologies lead to enhanced tissue formation and deposition, whereas others are associated with increased tissue degradation, and some exhibit a combination of both, leading to severe tissue alterations. To develop effective therapies for diseases affecting the lung, liver, kidney, skin, intestine, musculoskeletal system, heart, and solid tumors, we need to modulate the ECM’s composition to restore its organization and function. Across diverse organ diseases, there are common denominators and distinguishing factors in this fibroinflammatory axis, which may be used to foster new insights into drug development across disease indications. The 2nd Extracellular Matrix Pharmacology Congress took place in Copenhagen, Denmark, from 17 to 19 June 2024 and was hosted by the International Society of Extracellular Matrix Pharmacology. The event was attended by 450 participants from 35 countries, among whom were prominent scientists who brought together state-of-the-art research on organ diseases and asked important questions to facilitate drug development. We highlight key aspects of the ECM in the liver, kidney, skin, intestine, musculoskeletal system, lungs, and solid tumors to advance our understanding of the ECM and its central targets in drug development. We also highlight key advances in the tools and technology that enable this drug development, thereby supporting the ECM. Full article

Treatment-resistant schizophrenia (TRS) poses significant therapeutic challenges due to persistent symptoms, poor adherence, and high relapse rates. Long-acting injectable (LAI) antipsychotics offer a promising approach, yet limited evidence exists regarding the combination of two LAI formulations. We report the case of a 62-year-old woman with TRS, characterized by recurrent hospitalizations and inadequate responses to oral and monotherapy treatments. During her latest hospitalization, she received alternating intramuscular administrations of haloperidol decanoate (100 mg/28 days) and aripiprazole (400 mg/28 days). The dual LAI strategy resulted in a marked improvement in psychotic symptoms, functional recovery, and treatment adherence, with no reported side effects. This case highlights the potential benefits of dual LAI therapy in managing TRS, particularly in patients with non-adherence to oral medications or limited response to standard treatments. Additional studies are required to evaluate the long-term effectiveness and safety of this innovative therapeutic approach. Full article

In pancreatic cancer (PC), vascular endothelial growth factor (VEGF) and its primary receptor, vascular endothelial growth factor receptor (VEGFR)-2, are central drivers of angiogenesis and metastasis, with their overexpression strongly associated with poor prognosis. In some PC patients, VEGF levels correlate with disease stage, tumor burden, and survival outcomes. However, therapies targeting VEGF and VEGFR-2, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have demonstrated limited efficacy, partly due to the emergence of resistance mechanisms. Resistance appears to stem from the activation of alternative vascularization pathways. This review explores the multifaceted roles of VEGFRs in pancreatic cancer, including VEGFR-1 and VEGFR-3. Potential strategies to improve VEGFR-targeting therapies, such as combination treatments, the development of more selective inhibitors, and the use of biomarkers, are discussed as promising approaches to enhance treatment efficacy and outcomes. Full article

Background: Microbeam radiation therapy (MRT) is an advanced preclinical approach in radiotherapy that utilizes spatially fractionated dose distributions by collimating x-rays into micrometer-wide, planar beams. While the benefits of temporal fractionation are well established and widely incorporated into conventional radiotherapy protocols, the interplay between MRT and temporal dose fractionation remains largely unexplored. In this study, we investigate the effects of combining temporal and spatial dose fractionation by assessing clonogenic cell survival following temporally fractionated MRT with varying irradiation angles, compared to conventional broad-beam (BB) irradiation. Methods: A lung tumor cell line (A549) and a normal lung cell line (MRC-5) were irradiated with a total number of four fractions with a 24 h interval between each fraction. We compared a temporally fractionated BB regime to two temporally fractionated MRT schemes with either overlapping MRT fields or MRT fields with a 45° rotation per fraction. Subsequently, the clonogenic cell survival assay was used by analyzing the corresponding survival fractions (SFs). Results: The clonogenic survival of A549 tumor cells differed significantly between microbeam radiation therapy with rotation (MRT + R) and overlapping MRT. However, neither MRT + R nor overlapping MRT showed statistically significant differences compared to the broad-beam (BB) irradiation for A549. In contrast, the normal tissue cell line MRC-5 exhibited significantly higher clonogenic survival following both MRT + R and overlapping MRT compared to BB. Conclusions: This study demonstrates that combining temporal and spatial fractionation enhances normal tissue cell survival while maintaining equivalent tumor cell kill, potentially increasing the therapeutic index. Our findings support the feasibility of delivering temporally fractionated doses using different MRT modalities and provide clear evidence of the therapeutic benefits of temporally fractionated MRT. Full article

Background/Objectives: Cystoid macular edema (CMO) is a common complication that follows cataract surgery, presenting management challenges due to the lack of standardized treatment guidelines and the potential for spontaneous resolution. This study aimed to evaluate various treatment modalities for post-operative CMO, including topical non-steroidal anti-inflammatory drugs (NSAIDs), periocular steroids, and intravitreal injections. Methods: A systematic review of the literature was conducted to assess the efficacy of different treatment approaches for post-operative CMO. Studies evaluating topical NSAIDs, periocular steroids, intravitreal triamcinolone acetonide (TCA), dexamethasone implants (Ozurdex), and intravitreal bevacizumab were included. The main outcomes assessed included improvements in vision, resolution of CMO, recurrence rates, and safety profile. Results: Topical NSAIDs, particularly ketorolac and diclofenac, showed effectiveness in acute CMO, while their efficacy in chronic cases was variable. Periocular steroids, including retrobulbar TCA and sub-Tenon injections, demonstrated significant improvements in vision and the resolution of CMO, especially in cases resistant to topical therapy. Intravitreal TCA and dexamethasone implants exhibited variable effects on CMO resolution and recurrence rates, with some studies reporting sustained improvements over 12 months. The role of intravitreal bevacizumab as initial therapy remains unclear, although it may be considered in cases unresponsive to steroids. Conclusions: Topical NSAIDs, often combined with periocular steroids, serve as first-line therapy, with periocular steroids offering additional efficacy in resistant cases. Further research is needed to establish optimal treatment algorithms and improve outcomes for patients with post-operative CMO Full article

Background: Epilepsy is one of the most common and devastating neurological disorders, manifesting with seizures and affecting approximately 1–2% of the world’s population. The criticality of seizure occurrence and associated risks, combined with the overwhelming need for more precise and innovative treatment methods, has led to the development of invasive neurostimulation devices programmed to detect and apply electrical stimulation therapy to suppress seizures and reduce the seizure burden. Tiny Machine Learning (TinyML) is a rapidly growing branch of machine learning. One of its key characteristics is the ability to run machine learning algorithms without the need for high computational complexity and powerful hardware resources. The featured work utilizes TinyML technology to implement an algorithm that can be integrated into the microprocessor of an implantable closed-loop brain neurostimulation system to accurately detect seizures in real-time by analyzing intracranial EEG (iEEG) signals. Methods: A dataset containing iEEG signal values from both non-epileptic and epileptic individuals was utilized for the implementation of the proposed algorithm. Appropriate data preprocessing was performed, and two training datasets with 1000 records of non-epileptic and epileptic iEEG signals were created. A test dataset with an independent dataset of 500 records was also created. The web-based platform Edge Impulse was used for model generation and visualization, and different model architectures were explored and tested. Finally, metrics of accuracy, confusion matrices, and ROC curves were used to evaluate the performance of the model. Results: Our model demonstrated high performance, achieving 98% and 99% accuracy on the validation and test EEG datasets, respectively. Our results support the use of TinyML technology in closed-loop neurostimulation devices for epilepsy, as it contributes significantly to the speed and accuracy of seizure detection. Conclusions: The proposed TinyML model demonstrated reliable seizure detection in real-time by analyzing EEG signals and distinguishing epileptic activity from normal brain electrical activity. These findings highlight the potential of TinyML in closed-loop neurostimulation systems for epilepsy, enhancing both speed and accuracy in seizure detection. Full article

Background: The discovery of novel antibody–drug conjugates for low-expression human epidermal growth factor receptor 2 (HER2-low) breast cancer highlights the inadequacy of the conventional binary classification of HER2 status as either negative or positive. Identification of HER2-low breast cancer is crucial for selecting patients who may benefit from targeted therapies. This study aims to determine whether qualitative and quantitative magnetic resonance imaging (MRI) features can effectively reflect low-HER2-expression breast cancer. Methods: Pre-treatment breast MRI images from 232 patients with pathologically confirmed breast cancer were retrospectively analyzed. Both clinicopathologic and MRI features were recorded. Qualitative MRI features included Breast Imaging Reporting and Data System (BI-RADS) descriptors from dynamic contrast-enhanced MRI (DCE-MRI), as well as intratumoral T2 hyperintensity and peritumoral edema observed in T2-weighted imaging (T2WI). Quantitative features were derived from diffusion kurtosis imaging (DKI) using multiple b-values and included statistics such as mean, median, 5th and 95th percentiles, skewness, kurtosis, and entropy from apparent diffusion coefficient (ADC), D_app, and K_app histograms. Differences in clinicopathologic, qualitative, and quantitative MRI features were compared across groups, with multivariable logistic regression used to identify significant independent predictors of HER2-low breast cancer. The discriminative power of MRI features was assessed using receiver operating characteristic (ROC) curves. Results: HER2 status was categorized as HER2-zero (n = 60), HER2-low (n = 91), and HER2-overexpressed (n = 81). Clinically, estrogen receptor (ER), progesterone receptor (PR), hormone receptor (HR), and Ki-67 levels significantly differed between the HER2-low group and others (all p < 0.001). In MRI analyses, intratumoral T2 hyperintensity was more prevalent in HER2-low cases (p = 0.009, p = 0.008). Mass lesions were more common in the HER2-zero group than in the HER2-low group (p = 0.038), and mass shape (p < 0.001) and margin (p < 0.001) significantly varied between the HER2 groups, with mass shape emerging as an independent predictive factor (HER2-low vs. HER2-zero: p = 0.010, HER2-low vs. HER2-over: p = 0.012). Qualitative MRI features demonstrated an area under the curve (AUC) of 0.763 (95% confidence interval [CI]: 0.667–0.859) for distinguishing HER2-low from HER2-zero status. Quantitative features showed distinct differences between HER2-low and HER2-overexpression groups, particularly in non-mass enhancement (NME) lesions. Combined variables achieved the highest predictive accuracy for HER2-low status, with an AUC of 0.802 (95% CI: 0.701–0.903). Conclusions: Qualitative and quantitative MRI features offer valuable insights into low-HER2-expression breast cancer. While qualitative features are more effective for mass lesions, quantitative features are more suitable for NME lesions. These findings provide a more accessible and cost-effective approach to noninvasively identifying patients who may benefit from targeted therapy. Full article

Background: The majority of gliomas are astrocytic in nature. Gliomas have the lowest survival rate among all tumors of the central nervous system (CNS), characterized by high aggressiveness and poor response to treatment. The tumor microenvironment is a source of cytokines such as IL-6, IFN-γ, VEGF, and PDGF-BB, secreted mainly by tumor and immune cells. These cytokines play a significant role in angiogenesis, invasion, and metastasis formation. In vitro and in vivo studies have shown that Brazilian green propolis, derived from Baccharis dracunculifolia DC and rich in artepillin C, exhibits anti-inflammatory, antimicrobial, chemopreventive, and anticancer activities. Additionally, it can penetrate the blood–brain barrier, demonstrating neuroprotective effects. The aim of the present study was to determine the concentration of selected cytokines produced by astrocytes of the CCF-STTG1 cell line, isolated from the brain of a patient with stage IV glioma (astrocytoma). Methods: The cytotoxicity of the EEP-B was evaluated using the MTT assay. Astrocytes were stimulated with LPS at a final concentration of 200 ng/mL and/or IFN-α at 100 U/mL, followed by incubation with EEP-B (25–50 µg/mL) and artepillin C (25–50 µg/mL) under 2-h hypoxia and normoxia conditions. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine kit. Results: The absence of cytotoxic effects of EEP-B and artepillin C on human astrocytes of the CCF-STTG1 lineage was demonstrated. Stimulation with LPS, IFN-α, and their combination (LPS + IFN-α) significantly increased the secretion of the tested cytokines compared to the control cell line. The most pronounced and statistically significant reduction in cytokine levels, particularly IL-6 and VEGF, was observed following EEP-B treatment at both tested concentrations under both hypoxic and normoxic conditions. Conclusions: Brazilian green propolis may serve as a potential immunomodulator in combination therapies for gliomas of varying malignancy grades. Full article