Mitoquinone mesylate as post-exposure prophylaxis against SARS-CoV-2 infection in humans: an exploratory single center pragmatic open label non-randomized pilot clinical trial with matched controls.

BACKGROUND: An ongoing important need exists to rapidly develop novel therapeutics for COVID-19 that will retain antiviral efficacy in the setting of rapidly evolving SARS-CoV-2 variants and potential future development of resistance of SARS-COV-2 to remdesivir and protease inhibitors. To date, there is no FDA-approved treatment for post-exposure prophylaxis against SAR-CoV-2. We have shown that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has antiviral activity against SARS-CoV-2 in vitro and in SARS-CoV-2 infected K18-hACE2 mice. METHODS: In this exploratory, pragmatic open label clinical trial (ClinicalTrials.gov identifier NCT05381454), we studied whether Mito-MES is an effective post-exposure prophylaxis treatment in people who had high-grade unmasked exposures to SARS-CoV-2 within 5 days prior to study entry. Participants were enrolled in real-world setting in Los Angeles, United States between May 1 and December 1, 2022 and were assigned to either mito-MES 20 mg daily for 14 days (n = 40) or no mito-MES (controls) (n = 40). The primary endpoint was development of SARS-CoV-2 infection based on 4 COVID-19 diagnostic tests [rapid antigen tests (RATs) or PCR] performed during the study period (14 days post exposure). FINDINGS: Out of 40 (23 females; 57.5%) study participants who took Mito-MES, 12 (30%) developed SARS-CoV-2 infection compared to 30 of the 40 controls (75%) (difference -45.0%, 95% confidence intervals (CI): -64.5%, -25.5%). Out of 40 (19 females; 47.5%) study participants in the control group, 30 (75.0%) had at least one positive COVID-19 diagnostic test and 23 (57.5%) were symptomatic. With regards to key secondary outcomes, among symptomatic SARS-CoV-2 infections, the median duration of viral symptoms was lower in the Mito-MES group (median 3.0, 95% CI 2.75, 3.25) compared to the control group (median 5.0, 95% CI 4.0, 7.0). None of the study participants was hospitalized or required oxygen therapy. Mito-MES was well tolerated and no serious side effect was reported in any study participant. INTERPRETATION: This work describes antiviral activity of mito-MES in humans. Mito-MES was well tolerated in our study population and attenuated transmission of SARS-CoV-2 infection. Given established safety of Mito-MES in humans, our results suggest that randomized control clinical trials of Mito-MES as post-exposure prophylaxis against SARS-CoV-2 infection are warranted. FUNDING: This work was supported in part by National Institutes of Health grant R01AG059501 (TK), National Institutes of Health grant R01AG059502 04S1 (TK), NIH/National Center for Advancing Translational Sciences (NCATS) UCLA CTSI Grant Number UL1TR001881 and California HIV/AIDS Research Program grant OS17-LA-002 (TK).

Strategies to enhance treatment fidelity and music-based intervention reporting in dementia research.

Creative solutions are needed to address the well-being of the growing number of individuals living with dementia. Music-based interventions (MBIs) are promising and can be cost-effective; however, empirical evidence for MBIs is limited and published findings have not been widely translated into practice. Here, we describe how we implemented strategies to enhance rigor in a randomized clinical trial of an MBI for persons with dementia. We examined the impact of a singing-based MBI on feelings, emotions, and social engagement, relative to a non-music treatment (verbal discussion), delivered in small group format (25 minutes, 3 times/week for 2 weeks). We implemented National Institutes of Health Behavior Change Consortium strategies regarding: (i) design, (ii) interventionist training, (iii) treatment delivery, (iv) treatment receipt, and (v) treatment skills enactment. We applied the MBI Reporting Criteria including: (i) theoretical framework, (ii) musical content, (iii) dosage, (iv) interventionist, (v) treatment fidelity, (vi) setting, and (vii) delivery unit. We analyzed data with a separate linear mixed model for each dependent variable. 32 older adults with dementia (65-97 years) participated. The MBI yielded significant positive effects on all measured outcomes (all p's < .05). Application of established guidelines enhanced methodological rigor and MBI reproducibility. To support translation of research into practice, clinicians should understand how to implement an MBI reported in research. Our study illustrates practical steps to address the need for improved MBI research in persons with dementia and can provide a model for others to enhance evidence-based practice with this population.

Music-based interventions (MBIs) can be very effective in improving the psychosocial well-being of persons with dementia. Nonetheless, scientific evidence to support the use and appropriate application of MBIs for this population is very limited and often not applied in care settings. Here, we describe how we used established guidelines to conduct a rigorous experiment of an MBI for persons with dementia in nursing homes. Specifically, we examined the impact of a live singing-based MBI on feelings, emotions, and social engagement, relative to a non-music treatment (verbal discussion). We implemented National Institutes of Health Behavior Change Consortium strategies regarding study design and implementation and the MBI Reporting Criteria to thoroughly describe implementation principles and components of the MBI. We learned that the MBI resulted in significant, positive effects on all measured outcomes. Application of established guidelines helped ensure that our study was rigorous and the MBI could be reproduced in practice. Clinicians should understand how to implement an MBI reported in research. Our study illustrates practical steps to appropriately describe an MBI and addresses the need for improved MBI research in persons with dementia. Our work provides a model for how such an approach could be used in other similar work.

Intra- and Interpatient Drug Response Heterogeneity Exist in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Nongynecologic Cancers.

BACKGROUND: Select patients with peritoneal metastases are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We assayed for intra- and interpatient drug response heterogeneity through testing of patient-derived tumor organoids (PDTOs). METHODS: PDTOs were generated from CRS/HIPEC patients from December 2021 to September 2022 and subjected to an in vitro HIPEC drug screen. Drug response was assessed with a cell viability assay and cleaved caspase-3 staining. RESULTS: A total of 31 patients were consented for tissue collection. Viable tissue was harvested from 23, and PDTO generation was successful in 13 (56%). PDTOs were analyzed from six appendiceal, three colorectal, two small bowel, one gastric, and one adrenal tumor. Drug screen results were generated in as few as 7 days (62%), with an average time of 12 days. Most patients received mitomycin-C (MMC) intraoperatively (n = 9); however, in only three cases was this agent considered the optimal choice in vitro. Three sets of PDTOs were resistant (defined as > 50% PDTO viability) to all agents tested and two were pan-sensitive (defined as 3 or more agents with < 50% PDTO viability). In three patients, organoids were generated from multiple metastatic sites and intrapatient drug response heterogeneity was observed. CONCLUSIONS: Both intra- and interpatient drug response heterogeneity exist in patients undergoing CRS/HIPEC for nongynecologic abdominal cancers. Caution must be used when interpreting patient response to chemotherapeutic agents based on a single site of testing in those with metastatic disease.

Anticancer activity and other biomedical properties of ß-sitosterol: Bridging phytochemistry and current pharmacological evidence for future translational approaches.

Sterols, including ß-sitosterol, are essential components of cellular membranes in both plant and animal cells. Despite being a major phytosterol in various plant materials, comprehensive scientific knowledge regarding the properties of ß-sitosterol and its potential applications is essential for scholarly pursuits and utilization purposes. ß-sitosterol shares similar chemical characteristics with cholesterol and exhibits several pharmacological activities without major toxicity. This study aims to bridge the gap between phytochemistry and current pharmacological evidence of ß-sitosterol, focusing on its anticancer activity and other biomedical properties. The goal is to provide a comprehensive understanding of ß-sitosterol's potential for future translational approaches. A thorough examination of the literature was conducted to gather relevant information on the biological properties of ß-sitosterol, particularly its anticancer therapeutic potential. Various databases were searched, including PubMed/MedLine, Scopus, Google Scholar, and Web of Science using appropriate keywords. Studies investigating the effects of ß-sitosterol on different types of cancer were analyzed, focusing on mechanisms of action, pharmacological screening, and chemosensitizing properties. Modern pharmacological screening studies have revealed the potential anticancer therapeutic properties of ß-sitosterol against various types of cancer, including leukemia, lung, stomach, breast, colon, ovarian, and prostate cancer. ß-sitosterol has demonstrated chemosensitizing effects on cancer cells, interfering with multiple cell signaling pathways involved in proliferation, cell cycle arrest, apoptosis, survival, metastasis invasion, angiogenesis, and inflammation. Structural derivatives of ß-sitosterol have also shown anti-cancer effects. However, research in the field of drug delivery and the detailed mode of action of ß-sitosterol-mediated anticancer activities remains limited. ß-sitosterol, as a non-toxic compound with significant pharmacological potential, exhibits promising anticancer effects against various cancer types. Despite being relatively less potent than conventional cancer chemotherapeutics, ß-sitosterol holds potential as a safe and effective nutraceutical against cancer. Further comprehensive studies are recommended to explore the biological properties of ß-sitosterol, including its mode of action, and develop novel formulations for its potential use in cancer treatment. This review provides a foundation for future investigations and highlights the need for further research on ß-sitosterol as a potent superfood in combating cancer.

Current situation and trend of translational research of acupuncture-moxibustion in treatment of aphasia based on knowledge graph analysis. / åŸºäºŽçŸ¥è¯†å›¾è°±æŠ€æœ¯åˆ†æžé’ˆç¸æ²»ç–—å¤±è¯­ç—‡è½¬åŒ–ç ”ç©¶çš„çŽ°çŠ¶ä¸Žè¶‹åŠ¿.

OBJECTIVES: To investigate the hot topics in acupuncture-moxibustion research for treatment of aphasia and explore the current situation and trend of technology transformation in this field through analyzing the relevant Chinese literatures in recent 30 years by means of knowledge graph technology. METHODS: CiteSpace 6.1.R 2 and VOSviewer V1.6.16 software were used to collate the data, draw knowledge graphs and conduct visual analysis of the literatures related to acupuncture-moxibustion treatment of aphasia, searched from CNKI, WanFang and VIP databases.The time line view and strongest bursts of keywords were formed in the field of acupuncture-moxibustion treatment for aphasia. The treatment-based keyword networks were visualized. RESULTS: A total of 773 Chinese articles were included. Through visual analysis of the co-occurrence networks, the top 10 high-frequency overall keywords and the top 10 clusters of overall keywords were listed. The top 5 high-frequency aphasia categories were Broca aphasia, hysterical aphasia, transcortical motor aphasia, nominal aphasia and sensory aphasia. Regarding the keywords of the techniques of acupuncture-moxibustion, the occurrence frequencies of scalp acupuncture, tongue acupuncture, body acupuncture and electroacupuncture were ≥ 10 times.The occurrence frequencies of 16 acupoints were ≥25 times. After collation and cluster analysis of acupoints and techniques of acupuncture-moxibustion, 7 keyword clusters of "acupuncture techniques-acupoints" were obtained. The time line view showed that the strongest burst of keywords were transcranial magnatic stimulation, language rehabilitation training, acupuncture-medicine therapy and stroke, etc. in the recent 5 years. CONCLUSIONS: Acupuncture-moxibustion displays its unique advantage in treatment of aphasia. With the deepening of modern research, the hot topics for aphasia treated with acupuncture-moxibustion are present and the achievements enriched. In future, these therapeutic methods should be further investigated to explore a model of translational medicine for aphasia in line with the characteristics of acupuncture-moxibustion.

Building strong health and career trajectories through translational research.

Translational research (TR) is the movement of fundamental scientific discoveries into healthcare settings and population health policy, and parallels the goals of DOHaD research. Unfortunately, there is little guidance on how to become a translational researcher. To understand the opinions of DOHaD trainees towards TR, we conducted a workshop at the DOHaD World Congress 2022. We found that trainees were enthusiastic for their work to have translational impact, and that they feel that holistic, multidisciplinary solutions may lead to more generalisable research. However, there lacks support for TR career pathways, which may stall the execution of the long-term vision of the DOHaD agenda. We put forward recommendations for trainees to clarify their purpose in pursuing TR and for seeking relevant people and patronages to support their training paths. For mentors, training institutions, and scientific societies, we recommend developing TR-specific programmes, and implementing training opportunities, networking events, and funding to support these endeavours.

Therapeutic Lymphangiogenesis Is a Promising Strategy for Secondary Lymphedema.

Secondary lymphedema is caused by lymphatic insufficiency (lymphatic drainage failure) following lymph node dissection during the surgical treatment or radiation therapy of breast or pelvic cancer. The clinical problems associated with lymphedema are reduced quality of life in terms of appearance and function, as well as the development of skin ulcers, recurrent pain, and infection. Currently, countermeasures against lymphedema are mainly physical therapy such as lymphatic massage, elastic stockings, and skin care, and there is no effective and fundamental treatment with a highly recommended grade. Therefore, there is a need for the development of a fundamental novel treatment for intractable lymphedema. Therapeutic lymphangiogenesis, which has been attracting attention in recent years, is a treatment concept that reconstructs the fragmented lymphatic network to recover lymphatic vessel function and is revolutionary to be a fundamental cure. This review focuses on the translational research of therapeutic lymphangiogenesis for lymphedema and outlines the current status and prospects in the development of therapeutic applications.

Novel concepts of treating vascular inflammation underlying neonatal lung diseases.

Bronchopulmonary dysplasia (BPD) is the most common sequela of prematurity. Although multifactorial in etiology, there is increasing evidence that fetal growth restriction (FGR) and antenatal exposure of the fetus to inflammation play important roles in the postnatal pathophysiology of BPD. Recent studies have focused on disrupted angiogenesis and its influence on alveolarization. Although there are multiple mechanistic links, inflammation is known to be a key driver of this disruption, affecting pulmonary arterial circulation. Although postnatal corticosteroids are commonly used in extremely premature infants to treat inflammation, aimed at obviating the need for intubation and mechanical ventilation or to facilitate extubation, the use of dexamethasone has not reduced the incidence of BPD. Here, we summarize current knowledge on alternative anti-inflammatory treatment options, which have shown promising outcomes either preclinically or clinically. These include supplementation with vitamins C and E (antioxidants), ω-3 polyunsaturated fatty acids, pentoxifylline, anti-inflammatory cytokines of the IL (interleukin)-1 family, namely IL-1 receptor antagonist and IL-37, and the beneficial properties of breast milk. Evaluating these alternative treatments, either individually or as combination therapies in randomized controlled trials stands to immensely benefit the clinical outlook, particularly regarding BPD, for extremely premature infants.

[Challenges and choices: translational acupuncture research spectrum-a proposal].

For more than half a century，the modern bioresearch in acupuncture has made remarkable advancements, proving scientific basis underlying the traditional, intuitive treatment, as well as leading to some new discoveries with the potential to enhance the effectiveness of acupuncture as we know it. Meanwhile, the clinical researches have started to shift its paradigm from traditional individual observation to modern evidence-based medicine. However, there is little interaction between basic and clinic researches, which are like two separate worlds, not benefiting each other. Also the education and training of acupuncture are still traditional style, little combining with modern studies. To bridging the large gap, we need translational science involving in. In this article, with a critical reviews of the limitations of the traditional methods of acupuncture, the challenges faced by clinic practices and placebo-control studies, and the advantages and disadvantages of basic research, we propose a methodological paradigm of the translational research, Translational Acupuncture Research Spectrum, that meets the current situation of acupuncture researches, hoping to give insights into this field and to promote modern acupuncture to move towards a new stage.

Simvastatin therapy in higher dosages deteriorates bone quality: Consistent evidence from population-wide patient data and interventional mouse studies.

BACKGROUND: Combining mouse experiments with big data analysis of the Austrian population, we investigated the association between high-dose statin treatment and bone quality. METHODS: The bone microarchitecture of the femur and vertebral body L4 was measured in male and ovariectomized female mice on a high-fat diet containing simvastatin (1.2 g/kg). A sex-specific matched big data analysis of Austrian health insurance claims using multiple logistic regression models was conducted (simvastatin 60-80 mg/day vs. controls; males: n = 138,666; females: n = 155,055). RESULTS: High-dose simvastatin impaired bone quality in male and ovariectomized mice. In the trabecular femur, simvastatin reduced bone volume (µm3: ♂, 213 ± 15 vs. 131 ± 7, p < 0.0001; ♀, 66 ± 7 vs. 44 ± 5, p = 0.02) and trabecular number (1/mm: ♂, 1.88 ± 0.09 vs. 1.27 ± 0.06, p < 0.0001; ♀, 0.60 ± 0.05 vs. 0.43 ± 0.04, p = 0.01). In the cortical femur, bone volume (mm3: ♂, 1.44 ± 0.03 vs. 1.34 ± 0.03, p = 0.009; ♀, 1.33 ± 0.03 vs. 1.12 ± 0.03, p = 0.0002) and cortical thickness were impaired (µm: ♂, 211 ± 4 vs. 189 ± 4, p = 0.0004; ♀, 193 ± 3 vs. 169 ± 3, p < 0.0001). Similar impairments were found in vertebral body L4. Simvastatin-induced changes in weight or glucose metabolism were excluded as mediators of deteriorations in bone quality. Results from mice were supported by a matched cohort analysis showing an association between high-dose simvastatin and increased risk of osteoporosis in patients (♂, OR: 5.91, CI: 3.17-10.99, p < 0.001; ♀, OR: 4.16, CI: 2.92-5.92, p < 0.001). CONCLUSION: High-dose simvastatin dramatically reduces bone quality in obese male and ovariectomized female mice, suggesting that direct drug action accounts for the association between high dosage and increased risk of osteoporosis as observed in comparable human cohorts. The underlying pathophysiological mechanisms behind this relationship are presently unknown and require further investigation.

Exposure to statins post localized prostate cancer diagnosis and risk of metastasis among men who did not receive curative prostate cancer treatment.

BACKGROUND: Few studies have evaluated the effect of statin exposure on metastasis risk among prostate cancer patients not receiving curative treatment. METHODS: We included men diagnosed with localized prostate cancer at an integrated health care system between 1997 and 2006 who did not receive curative treatment within 6 months of diagnosis. We followed these men until a metastatic event, disenrollment, death, or 12/31/2016. We collected all data from electronic health records supplemented by chart review. We used Cox regressions to examine the association between post-diagnostic statin exposure and metastasis, controlling for clinical characteristics and pre-diagnostic statin exposure. RESULTS: There were 4245 men included. Mean age of diagnosis was 68.02 years. 46.6% of men used statins after prostate cancer diagnosis. During follow-up, 192 men developed metastasis (cumulative incidence rate: 14.5%). In the adjusted Cox model, statin use post-prostate cancer diagnosis was not significantly associated with a metastatic event (HR = 0.97, 95% CI = 0.69, 1.36). Pre-diagnostic statin use was also not associated with development of metastasis (HR = 0.76, 95% CI = 0.53, 1.10). We did not observe a dose-response for the proportion of person-time at-risk post-prostate cancer diagnosis on statins (HR = 0.98 per 10% increase in person-time exposed [95% CI = 0.93, 1.03]). CONCLUSIONS: We did not find an inverse association between post-diagnosis statin exposure and metastasis development in localized prostate cancer patients who did not receive active treatment. Our results did not offer support to the chemopreventive potential of post-diagnostic statin use among men on active surveillance.

Cardiac radiotherapy transiently alters left ventricular electrical properties and induces cardiomyocyte-specific ventricular substrate changes in heart failure.

AIMS: Ongoing clinical trials investigate the therapeutic value of stereotactic cardiac radioablation (cRA) in heart failure patients with ventricular tachycardia. Animal data indicate an effect on local cardiac conduction properties. However, the exact mechanism of cRA in patients remains elusive. Aim of the current study was to investigate in vivo and in vitro myocardial properties in heart failure and ventricular tachycardia upon cRA. METHODS AND RESULTS: High-density 3D electroanatomic mapping in sinus rhythm was performed in a patient with a left ventricular assist device and repeated ventricular tachycardia episodes upon several catheter-based endocardial radio-frequency ablation attempts. Subsequent to electroanatomic mapping and cRA of the left ventricular septum, two additional high-density electroanatomic maps were obtained at 2- and 4-month post-cRA. Myocardial tissue samples were collected from the left ventricular septum during 4-month post-cRA from the irradiated and borderzone regions. In addition, we performed molecular biology and mitochondrial density measurements of tissue and isolated cardiomyocytes. Local voltage was altered in the irradiated region of the left ventricular septum during follow-up. No change of local voltage was observed in the control (i.e. borderzone) region upon irradiation. Interestingly, local activation time was significantly shortened upon irradiation (2-month post-cRA), a process that was reversible (4-month post-cRA). Molecular biology unveiled an increased expression of voltage-dependent sodium channels in the irradiated region as compared with the borderzone, while Connexin43 and transforming growth factor beta were unchanged (4-month post-cRA). Moreover, mitochondrial density was decreased in the irradiated region as compared with the borderzone. CONCLUSION: Our study supports the notion of transiently altered cardiac conduction potentially related to structural and functional cellular changes as an underlying mechanism of cRA in patients with ventricular tachycardia.

Taurine as a biomarker for aging: A new avenue for translational research.

The physiologic and irreversible process of ageing is accompanied by a wide range of structural and functional shifts at multiple different levels. It is also suggested that variations in the blood concentrations of metabolites, hormones, and micronutrients may play a role in the ageing process. Recently, Singh et al. 1,2 investigated a study on Taurine shortage as a driver and biomarker of ageing and its impact on a healthy lifespan.2 They further proposed that functional abnormalities in numerous organs associated with age-related illnesses have been linked to early-life Taurine insufficiency. Taurine deficiency in the elderly and the possible benefits of Taurine supplements One of the reasons for decreasing Taurine concentration is the loss of endogenous synthesis, which may contribute to the decrease in Taurine levels seen in the elderly. While it was previously believed that the liver was responsible for most Taurine synthesis in humans, new research suggests that other organs or common intermediates may play a larger role. The authors experimented with and analysed a life-span examination of various organisms, for example, mice to assess the impacts of Taurine supplementation. They also analysed after the administration of oral Taurine supplementation in conjunction with other interventions using multi-omics data sets (RNA sequencing, metabolomics etc.) across different species.

Cutting-edge strategies and critical advancements in characterization and quantification of metabolites concerning translational metabolomics.

Despite remarkable progress in drug discovery strategies, significant challenges are still remaining in translating new insights into clinical applications. Scientists are devising creative approaches to bridge the gap between scientific and translational research. Metabolomics is a unique field among other omics techniques for identifying novel metabolites and biomarkers. Fortunately, characterization and quantification of metabolites are becoming faster due to the progress in the field of orthogonal analytical techniques. This review detailed the advancement in the progress of sample preparation, and data processing techniques including data mining tools, database, and their quality control (QC). Advances in data processing tools make it easier to acquire unbiased data that includes a diverse set of metabolites. In addition, novel breakthroughs including, miniaturization as well as their integration with other devices, metabolite array technology, and crystalline sponge-based method have led to faster, more efficient, cost-effective, and holistic metabolomic analysis. The use of cutting-edge techniques to identify the human metabolite, including biomarkers has proven to be advantageous in terms of early disease identification, tracking the progression of illness, and possibility of personalized treatments. This review addressed the constraints of current metabolomics research, which are impeding the facilitation of translation of research from bench to bedside. Nevertheless, the possible way out from such constraints and future direction of translational metabolomics has been conferred.

Stem Cell Theory of Cancer: Implications for Translational Research from Bedside to Bench.

A stem cell theory of cancer considers genetic makeup in the proper cellular context. It is a unified theory of cancer that unites the genome with the epigenome, links the intracellular with the extracellular, and connects the cellular constituents and compartments with the microenvironment. Although it allies with genomic medicine, it is better aligned with integrated medicine. In this perspective, we focus on translational research in cancer care. We expose some intrinsic fallacies in translational research when it relates to the basic principles of the scientific method in the care of patients with genomic medicine versus integrated medicine. We postulate that genomic medicine may be at the root of many failed efforts in drug development and data reproducibility. We propose an alternate heuristic approach that may expedite the development of safe and effective treatments and minimize the generation of unproductive pharmaceutical products and nonreproducible experimental results. Importantly, a heuristic approach emphasizes the role of a pertinent scientific theory and distinguishes therapy development from drug development, such that we discover not only useful drugs but also better ways to use them in order to optimize patient care and maximize clinical outcomes.

Microtumor Models as a Preclinical Investigational Platform for Photodynamic Therapy.

Classic preclinical investigations on the mechanisms and effects of photodynamic therapy (PDT) are typically performed in two-dimensional cell cultures that have some, albeit limited, relevance to cancer biology. Bioengineered three-dimensional (3D) culture models of cancer are gaining traction in translational oncology as microtumors recapitulate the tumor architectures and cellular heterogeneity more faithfully than conventional 2D cultures. These 3D models bridge a gap between highly relevant but low-throughput in vivo animal models and high-throughput two-dimensional cultures with low clinical relevance, and thus hold promise as preclinical testing platforms in PDT research. Here, we discuss the potential applications of organotypic cancer models for PDT research and provide two well-established methodologies for generating 3D cultures of cancer: a liquid-suspended spheroid model and an adherent microtumor culture model grown on extracellular matrix scaffolds. Particular emphasis is given to harvesting the cultures for the purpose of immunoblotting and flow cytometry.

Selenium, TGF-Beta and Infectious Endemic Cardiopathy: Lessons from Benchwork to Clinical Application in Chagas Disease.

For over 60 years, selenium (Se) has been known as an essential microelement to many biological functions, including cardiovascular homeostasis. This review presents a compilation of studies conducted in the past 20 years related to chronic Chagas disease cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, a neglected disease that represents a global burden, especially in Latin America. Experimental and clinical data indicate that Se may be used as a complementary therapy to prevent heart failure and improve heart function. Starting from the main questions "Is Se deficiency related to heart inflammation and arrhythmogenesis in CCC?" and "Could Se be recommended as a therapeutic strategy for CCC?", we show evidence implicating the complex and multidetermined CCC physiopathology, discussing its possible interplays with the multifunctional cytokine TGF-ß as regulators of immune response and fibrosis. We present two new proposals to face this global public health challenge in vulnerable populations affected by this parasitic disease: fibrosis modulation mediated by TGF-ß pathways and the possible use of selenoproteins as antioxidants regulating the increased reactive oxygen stress present in CCC inflammatory environments. We assess the opportunity to consider the beneficial effects of Se in preventing heart failure as a concept to be applied for CCC patients.

Pathogenesis and Treatment of Refractory Disease Courses in Systemic Juvenile Idiopathic Arthritis: Refractory Arthritis, Recurrent Macrophage Activation Syndrome and Chronic Lung Disease.

Systemic juvenile idiopathic arthritis is a distinct and heterogeneous disease presently classified under the umbrella of juvenile idiopathic arthritis, with some patients following a monophasic remitting course, whereas others have persistent disease with chronic organ- and life-threatening complications. Although biologic therapies have revolutionized treatment, recent follow-up studies report significant numbers of children with persistently active disease on long term follow-up. This review focuses on refractory disease courses, specifically refractory arthritis, systemic juvenile idiopathic arthritis with recurrent, or longstanding signs of macrophage activation syndrome, and systemic juvenile idiopathic arthritis associated with suspected, probable, or definite lung disease.

Mechanisms of Stem Cell Therapy in Spinal Cord Injuries.

Every year, 0.93 million people worldwide suffer from spinal cord injury (SCI) with irretrievable sequelae. Rehabilitation, currently the only available treatment, does not restore damaged tissues; therefore, the functional recovery of patients remains limited. The pathophysiology of spinal cord injuries is heterogeneous, implying that potential therapeutic targets differ depending on the time of injury onset, the degree of injury, or the spinal level of injury. In recent years, despite a significant number of clinical trials based on various types of stem cells, these aspects of injury have not been effectively considered, resulting in difficult outcomes of trials. In a specialty such as cancerology, precision medicine based on a patient's characteristics has brought indisputable therapeutic advances. The objective of the present review is to promote the development of precision medicine in the field of SCI. Here, we first describe the multifaceted pathophysiology of SCI, with the temporal changes after injury, the characteristics of the chronic phase, and the subtypes of complete injury. We then detail the appropriate targets and related mechanisms of the different types of stem cell therapy for each pathological condition. Finally, we highlight the great potential of stem cell therapy in cervical SCI.

Induction of specific brain oscillations may restore neural circuits and be used for the treatment of Alzheimer's disease.

Brain oscillations underlie the function of our brains, dictating how we both think and react to the world around us. The synchronous activity of neurons generates these rhythms, which allow different parts of the brain to communicate and orchestrate responses to internal and external stimuli. Perturbations of cognitive rhythms and the underlying oscillator neurons that synchronize different parts of the brain contribute to the pathophysiology of diseases including Alzheimer's disease, (AD), Parkinson's disease (PD), epilepsy and other diseases of rhythm that have been studied extensively by Gyorgy Buzsaki. In this review, we discuss how neurologists manipulate brain oscillations with neuromodulation to treat diseases and how this can be leveraged to improve cognition and pathology underlying AD. While multiple modalities of neuromodulation are currently clinically indicated for some disorders, nothing is yet approved for improving memory in AD. Recent investigations into novel methods of neuromodulation show potential for improving cognition in memory disorders. Here, we demonstrate that neuronal stimulation using audiovisual sensory stimulation that generated 40-HZ gamma waves reduced AD-specific pathology and improved performance in behavioural tests in mouse models of AD, making this new mode of neuromodulation a promising new avenue for developing a new therapeutic intervention for the treatment of dementia.