Therapeutic phages are primarily chosen based on their in vitro bacteriolytic activity. Although anti-phage antibodies are known to inhibit phage infection, the influence of other immune system components is less well known. An important anti-bacterial and anti-viral innate immune system that may interact with phages is the complement system, a cascade of proteases that recognizes and targets invading microorganisms. In this study, we aimed to study the effects of serum components such as complement on the infectivity of different phages targeting Pseudomonas aeruginosa. We used a fluorescence-based assay to monitor the killing of P. aeruginosa by phages of different morphotypes in presence of human serum. Our results reveal that several myophages are inhibited by serum in a concentration-dependent way, while the activity of four podophages and one siphophage tested in this study is not affected by serum. By using specific nanobodies blocking different components of the complement cascade, we show that activation of the classical complement pathway is a driver of phage inhibition. To determine the mechanism of inhibition, we produced bioorthogonally labeled fluorescent phages to study their binding by means of microscopy and flow cytometry. We show that phage adsorption is hampered in presence of active complement. Our results indicate that interactions with complement may affect in vivo activity of therapeutically administered phages. A better understanding of this phenomenon is essential to optimize the design and application of therapeutic phage cocktails.

Rehabilitation after rotator cuff repair is crucial for functional recovery and for minimizing the risk of retear. There are two rehabilitation protocols (early and traditional) and the debate about which is the best is still open. This umbrella review aimed to compare the effect of these rehabilitation protocols in terms of reduction of pain, functional recovery and retear risk. We selected systematic reviews and meta-analyses published between 2012 to 2022 dealing with the aim. Nineteen systematic reviews were included. No significant differences were found between early and traditional protocols in terms of pain reduction. Early rehabilitation provided better short-term results regarding Range of Motion improvement, but long-term functional outcomes were similar. Retear risk remains a significant concern for the early protocol. We found major differences between the analyzed protocols. This review suggests that both protocols are useful to recover global shoulder function, but the standard protocol has a greater safety profile for larger tears. On the other hand, the early protocol may be preferable for smaller lesions, allowing a faster recovery and having less impact on medical costs. Further research is needed to identify optimal rehabilitation strategies tailored to the individual patient's needs and characteristics.

I. Introduction: Adherence to ART reduces morbidity and mortality among PLHIV by suppression of viral replication, restoration and preservation of immune function. However, poor adherence may lead to treatment failure and death. PLHIV have high probability of treatment interruptions due to lockdowns related to COVID-19 protocol. Mortality rate is higher among COVID-19 patients with HIV than those with COVID-19 only. This led to determination of the barriers to antiretroviral medication adherence in PLHIV at the time of COVID-19 pandemic and seek significant association between identified HIV treatment barriers and socio-demographic characteristics. II. Methods: A cross-sectional study using online survey questionnaire was distributed via social media. Sample size was computed using Open Epi software. Data was analyzed using Stata software. Categorical variables and quantitative data were summarized using frequencies and percentages, and mean and standard deviation respectively. Chi-square test or Fisher’s exact test, whichever is more appropriate, was used to determine association between socio-demographic characteristics and HIV treatment barriers. III. Results: There is a total of 116 respondents, 115 were males, homosexual (59.5%), with mean age of 30.25 years old (SD = 6.22) and majority (53.4%) were from NCR. The most common HIV treatment barriers reported by PLHIV in accessing treatment and care were unavailability of transportation and cost of courier services for ARV delivery (62.1%), location of treatment hubs (52.6%) and financial assistance (37.9%). IV. Conclusion: There is significant association between location of treatment hubs and respondents who finished college/graduate studies; checkpoints and crossing borders and: 1. respondents from Northern Luzon, 2. unemployment; financial assistance and: 1. Respondents 18 to 25 years old, 2. unemployment, 3. respondents who finished elementary/high school; psychosocial support and: 1. Respondents from NCR, 2. Respondents 26 to 30 years old;

Background: Spinal pain is highly prevalent and in Spain it produces a very high economic cost and the scientific evidence supporting treatments shows low to moderate evidence for exercise. Therefore, the aim of this study was to assess the effectiveness of a therapeutic group exercise protocol in reducing pain intensity and disability in patients with spinal pain in primary health care setting. Methods: A total sample of 149 patients who suffered from chronic non-specific spinal pain. Patients received a therapeutic exercise protocol, including exercises of auto-mobilization of the neck and lumbar regions, as well as core stabilization exercises. Pain intensity and disability were evaluated before and after the therapeutic exercise protocol. Results: Statistically significant differences (P<0.05) were shown for pain intensity and disability of patients with neck and low back pain with an effect size from moderate to large. Conclusions: A therapeutic exercise protocol may provide beneficial effects on disability and pain intensity in patients with chronic non-specific spinal pain, including neck and low back pain conditions. Clinicians should consider the use of self-administered exercise protocols, demonstrate great effectiveness, and be less costly.

Introduction: Type 2 Diabetes mellitus (T2DM) is a common disease burdened with significant morbidity and mortality. Despite the substantial number of new available drug treatments, adherence to therapy and adverse drug reactions (ADRs) are the major constrain in the management of this disease. We evaluated the use, the adherence and the dsaftey of antidiabetic drugs in patients with T2DM. Methods: we performed an observational, retrospective, multicenter study on medical records of outpatients referred to general practitioners. Drug adherence was measured in agreement to the European Society for Patient Adherence, Compliance and Persistence Medication Adherence Reporting Guideline. ADRs were evaluated using the Naranjo probability scale. Collected data were analyzed using the Statistical Package for the Social Sciences. Results: During the study we evaluated 12,170 medical records of 7 general practitioners. The most prescribed drug was metformin alone (28.4%) or with other oral antidiabetics (19.6%) and then insulin (n: 354; men 190, women 164). Enrolled patients were stratified as high (35%), medium (41%) and low (24%) adherence. Logistic regression showed an association between T2DM less than or equal to 5 years and low adherence (P = 0.023). During the study we recorded 26 ADRs that was correlated with sex (women) and insulin treatment. Conclusion: this real-life study shows that patients with T2DM have high adherence probably related dto a low number of ADRs

In this work, alkylammonium-functionalized hollow mesoporous silica as nonocarrier of drugs was synthesized to realize enhanced cancer therapy by pH stimuli for sustained drug release. First, functionalized hollow mesoporous silica nanoparticles (Hollow MSNs) were synthesized using dodecyl dimethyl(3-sulfopropyl)ammonium hydroxide (DDAPS), sodium dodecyl sulfate (SDS), and triethanolamine as structure-directing agents, and tetraethyl orthosilicate (TEOS) and N-trimethoxysilypropyl-N,N,N-trimethylammonium chloride (TMAPS) as silica sources under basic condition via the sol-gel process. The structure and morphology of the alkylammonium-functionalized hollow mesoporous silica nanoparticles (Hollow MSN-N+CH3) were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption-desorption analysis, and Fourier-transform infrared (FT-IR) spectroscopy. The functionalized hollow MSNs had a particle size of about 450 nm and a shell thickness of about 60 nm with uniform size. The nanoparticle had a surface area of 408 m2g-1, pore volume of 0.8 cm3g-1 and a uniform pore diameter of 45.9 Å. In the cancer cell viability test with MCF-7 cell, fludarabine-incorporated and alkylammonium-functionalized hollow mesoporous silica nanoparticles (Flu/Hollow MSN-N+CH3) showed excellent cancer cell death comparable with pure fludarabine drug with the controlled drug release by pH stimuli. It is considered that our current materials have the potential applicability as pH-responsive nanocarriers in the field of cancer therapy.

Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy, characterized by ventricular chamber dilatation and systolic dysfunction, in the absence of coronary artery disease, arterial hypertension, valvular or congenital diseases. DCM is a heterogeneous group of disorders of the myocardium caused by genetic factors, environmental factors, or a combination of both. DCM affects mainly men aged between 20 and 50 years, being considered one of the main causes of heart failure (HF) and the main indication for heart transplantation. Guideline-based HF treatment is the mainstay of management for patients with DCM. In recent years, gene therapy and induced pluripotent stem cells have become promising strategies. In this review, we summarize the relevant clinical issues, and current treatment of DCM patients, including the role of genetic evaluation.

Bilateral recurrent nerve damage following total thyroidectomy in thyroid surgery represents severe complications. These complications have almost low incidence thanks also by using the Nerve Intraoperative Monitoring. The aim of this observational retrospective study is to evaluate the inception mode and the recovery time for different clinical laryngeal pictures that arise from this surgery. We enrolled 25 patients with bilateral vocal folds mobility deficit between October 2017 and October 2022, diagnosed in ENT Unit of University of Campania “L. Vanvitelli”, out of a total of 1417 patients undergoing total thyroidectomy. The 25 patients (23F,2M) aged from 24 to 78 years old (average age 51.7) presented a bilateral vocal folds motility deficit (occurring in about 0.1% of cases). All patients underwent 9 months diagnostic/therapeutic process, which started approximately 30 days after thyroid surgery. There are several outcomes of these complications with functional laryngeal defects being mainly related to respiratory and phonatory activities. These clinical manifestations evolve in different ways within a context of a wide range of possibilities, from spontaneous bilateral or monolateral recovery to functional or surgical restoration. This study allowed the acquisition of useful information about prognostic indications and an adequate therapeutic process, based on the specific clinical characteristics.

Regulatory T cell master transcription factor, Forkhead box P3 (Foxp3) has been detected in cancer cells, but its role in breast tumor pathogenesis remains controversial. Here we assessed Foxp3 tumor intrinsic effects in experimental breast cancer using a Foxp3 binder peptide (P60) that impairs Foxp3 nuclear translocation. Cisplatin upregulated Foxp3 expression in HER2+ and triple negative breast cancer (TNBC) cells. Foxp3 inhibition with P60 enhanced chemosensitivity and reduced cell survival and migration in human and murine breast tumor cells. We also developed an adenoviral vector encoding P60 (Ad.P60) that efficiently transduced breast tumor cells, reduced cell viability and migration, and improved the cytotoxic response to cisplatin. Conditioned medium from transduced breast tumor cells contained lower levels of IL-10 and improved the activation of splenic lymphocytes. Intratumor administration of Ad.P60 in breast tumor-bearing mice significantly reduced tumor infiltration of Tregs, delayed tumor growth and inhibited the development of spontaneous lung metastases. Our results suggest that Foxp3 exerts protumoral intrinsic effects in breast cancer cells, and that gene therapy-mediated blockade of Foxp3 could constitute a therapeutic strategy to improve the response of these tumors to standard treatment.

Spinal cord injury is a traumatic injury that causes a catastrophic state in patients due to neuronal deficits, loss of motor and sensory function, and this is due to secondary deleterious events subsequent to mechanical damage that expands the death of neural cells beyond the initial trauma. One of the most important events is inflammation, which activates molecules like pro-inflammatory cytokines (IL-1beta, IFN-gamma, TNF-alpha) that provoke a toxic environment, inhibiting axonal growth and exacerbating CNS damage. As there is no effective treatment, one of the strategies developed is neuroprotection to preserve healthy neural tissue and reduce neuroinflammation. Some of the neuroprotective treatments that have been practiced are the use of cell therapy, the administration of peptides and molecules or supplements that have been shown to favor an anti-inflammatory environment, and help to preserve the cells and tissues surrounding the injured area, favoring axonal growth and improving locomotor function. In this review we will explain some of these strategies used in different animal models of spinal cord injury, their activity as modulators of the immune system and the benefits they have shown.

The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of tumor microenvironment, Nor-Adrenaline (NA) is poured-in by innervating nerves and tumor tissues itself. The receptors for nor-adrenaline are present on the surface of cancer and immune cells and are often involved in activation of pro-tumoral signaling pathways. β2-adrenergic receptor (β2-AR) is an emerging class of receptors that are capable of modulating the functioning of immune cells. β2-AR is reported to activate the regulatory immune cells and inhibit the effector immune cells. Blocking β2-AR increases activation, proliferation and cytokine release of T lymphocytes. Moreover β2-AR deficiency during metabolic reprograming of T cells increases mitochondrial membrane potential and biogenesis. In the view of available research data, immunosuppressive role of β2-AR in T cells presents it a targetable checkpoint in CAR-T cell therapies. In this review, we have abridged contemporary knowledge about adrenergic stress mediated β2-AR activation on T lymphocytes inside tumor milieu.

Current methodologies for developing patient-derived xenografts (PDX) in humanized mice in preclinical trials to test response to immune-based therapies are limited by graft versus host disease. Here we compared two approaches for establishing PDX tumors in humanized mice: 1) PDX are first established in immune-deficient mice; 2) PDX are initially established in humanized mice, before transplanting established PDX’s to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Pre-clinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with limited infiltration of CD8+ T cell into the tumor. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in the presence of human immune cells before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.

The 2019 COVID-19 pandemic caused by SARS-CoV-2 has resulted in many fatalities worldwide. Despite various types of supportive care, mortality rates for patients with comorbidities remain high. To explore alternative treatment options, interferons (IFNs) have emerged as promising therapeutic drugs for SARS-CoV-2. This review aims to investigate the potential of IFNs as a drug with details on their mechanisms of action, and available data on their use with ongoing clinical trials, results, potential limitations, and challenges. Recently published research articles, which were systematically searched through online databases, have been selected and found that IFNs have colossal potential in treating SARS-CoV-2 infection by modulating the host's immune response and inhibiting viral replication and decreasing the severity of disease and hospitalization (p = 0.03, ±0.05) and (p = 0.04, ±0.05) respectively. However, due to less available data, more controlled and randomized trials are needed to confirm the efficacy and safety of IFN therapy. The optimal dosing and duration of IFN therapy also remain to be determined. Although further research is needed the wait for ongoing clinical trial results under investigation is also important for a better understanding of IFN therapy.

Objectives: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by elevated platelet counts and an increased risk of thrombotic events, including ischemic strokes. Methods: We conducted a retrospective analysis of data from consecutive ischemic stroke patients with ET between March 2014 and February 2023. Results: This case series describes the clinical presentation, radiological features, and management of five patients with ET-associated ischemic strokes, all harboring the JAK2 mutation. The diverse radiological findings suggest that both large and small vessel diseases may be influenced by the prothrombotic state induced by ET. A significant elevation in platelet count was observed to correlate with the emergence of new acute infarctions in some cases. Conclusions: The study highlights combined use of antiplatelet and cytoreductive therapy in preventing secondary stroke events in patients with ET and JAK2 mutations. The heterogeneity of stroke patterns in this population necessitates a comprehensive understanding of the underlying pathophysiological mechanisms and tailored therapeutic approaches.

Chagas disease (CD), caused by Trypanosoma cruzi, is a neglected tropical disease prevalent in Latin America. The treatment of infected patients is aimed at eliminating the parasite, reducing the risk of cardiomyopathy, and interrupting the disease transmission cycle. At present, the World Health Organization only recognizes benznidazole (BZ) and nifurtimox as effective drugs for treating CD. However, both present low cure rates in the chronic phase and often have serious side effects. T. cruzi infection produces an intense inflammatory response in several tissues, critical for controlling parasite proliferation and CD evolution. Compounds that liberate nitric oxide (NO) (NO donors) have been used as therapeutic agents against T. cruzi. However, to date, there is no evidence about the related nitrogen oxide, nitroxyl (HNO) on the outcome of T. cruzi infection. In this study, we investigated the effect of the HNO donor Angeli's salt (AS) on C57BL/6 mice infected with T. cruzi (Y strain, 5 × 103 trypomastigotes, i.p.). The use of AS showed positive results, such as a decrease in the number of parasites present in the bloodstream and in nests within the heart, as well as improved the protective antioxidant capacity of erythrocytes in infected animals, leading to an overall decrease in the severity of the disease. Furthermore, in vitro experiments showed that AS treatment reduced parasite uptake and the release of trypomastigotes by macrophages. Taken together, these findings from both the mouse model and in vitro testing suggest that AS could be a promising therapy for CD.

Despite recent advances in optimizing reliever, controller and maintenance therapy in asthma, a large subgroup of asthmatic patients continues to suffer from severe asthma, affecting their psychosociological status, their quality of life and even their life expectancy. Identifying and recognizing the specific phenotypic and endotypic characteristics in asthma has provided the medical community to drive the development of targeted therapies that are proved to benefit patients in terms of symptom control, exacerbation rate, quality of life and lung function. Adopting a more tailored and targeted approach is proving to be the key factor in reforming severe asthma treatment, minimizing the patients’ burden, as well as the socioeconomical impact worldwide. In this review, we are going to describe the different phenotypes and endotypes of asthma, the currently approved targeted therapies in severe asthma as imprinted in Global Initiative for Asthma (GINA) 2023, as well as other potential pharmacological agents and strategies investigated or currently under investigation for the treatment of severe asthma.

Aim: to provide a comprehensive overview of the existing literature concerning the applications of positron emission tomography (PET)-radiomics in lung cancer patients candidates or undergoing immunotherapy. Materials and Methods: A systematic review was conducted on databases and web sources. English-language original articles were considered. The title and abstract were in-dependently reviewed to evaluate study inclusion. Papers duplicate, out-of-topic, review or edi-torials articles and letters to editors were excluded. For each study, the radiomics analysis was assessed based on the relies on radiomics quality score (RQS 2.0). The review was registered on the PROSPERO database with the number CRD42023402302. Results: 15 papers were included, 13 were qualified as conventional radiomics approaches, and two were as Deep Learning radiomics. The content of each study was different, indeed, 7 papers investigated the potential role of radiomics to predict PD-L1 expression and tumor microenvironment before starting immunotherapy. Moreo-ver, 2 were relative to the prediction of response and 4 investigated the utility of radiomics to predict the response to immunotherapy. Finally, 2 papers were relative to the prediction of adverse events due to the immunotherapy. Conclusions: radiomics is promising in the evaluation of TME and for the prediction of response to immunotherapy, but some limitations should be overpassed.

Urethral prolapse (UP) is a rare condition in which the distal urethral mucosa protrudes circularly from the external urethral meatus. Urethral prolapse is seen in two age groups: prepubertal girls and postmenopausal women. The fact that it is seen in older women shows that it may be acquired. Causes of acquired UP include weakening of smooth muscle layers secondary to estrogen deficiency, chronic cough, chronic constipation, trauma, recurrent urinary tract infections, pelvic radiotherapy, and sexual abuse. The priority in treatment is conservative management, such as manual reduction, sitz baths, topical estrogen creams, and antibiotics. The general consensus is to switch to surgical treatment in patients who do not benefit from a conservative approach. In this case report, we describe the surgical treatment of a 56-year-old postmenopausal female patient with necrotic UP who presented with urinary retention.

Rapid in vitro assessment of antimicrobial drug efficacy under clinically relevant pharmacokinetic conditions is an essential element of both drug development and clinical use. Here we present an overview of a novel integrated methodology for rapid assessment of such efficacy, particularly against emergence of resistant bacterial strains, as jointly researched by the authors in recent years. This methodology enables rapid in vitro assessment of antimicrobial efficacy of a single or multiple drugs in combination, following clinically relevant pharmacokinetics. The proposed methodology entails (a) automated collection of longitudinal time-kill data in an optical-density instrument; (b) processing of collected time-kill data with the aid of a mathematical model to de-termine optimal dosing regimens under clinically relevant pharmacokinetics for a single or mul-tiple drugs; and (c) in vitro validation of promising dosing regimens in a hollow fiber system. Proof-of-concept of this methodology through a number of in vitro studies is discussed. Future directions for refinement of optimal data collection and processing are discussed.

Variable during practice is widely accepted to be advantageous for motor learning and therefor a valuable strategy to effectively reduce high-risk landing mechanics and prevent primary anterior cruciate ligament (ACL) injury. Few attempts have examined the specific effects of variable train-ing in athletes who have undergone ACL reconstruction. Thereby it is still unclear to what extent the variations in different sensor areas lead to different effects. Accordingly, we compared the effects of versatile movement variations (DL) with variations of movements with emphasis on disrupting visual information (VMT) in athletes who had undergone ACL reconstruction. For-ty-five interceptive sports athletes after ACL reconstruction were randomly allocated to a DL group (n= 15), VT group (n= 15) or control group (n= 15). The primary outcome was functional performance (Triple Hop Test). The secondary outcomes included dynamic balance (Star Excur-sion Balance Test (SEBT)), biomechanics during single-leg drop-landing task hip flexion (HF), knee flexion (KF), ankle dorsiflexion (AD), knee valgus (KV), and vertical ground reaction force (VGRF), and kinesiophobia (Tampa Scale of Kinesiophobia (TSK)) assessed before and after the 8-weeks of interventions. Data were analyzed be means of 3×2 repeated measures ANOVA fol-lowed by post hoc comparison (Bonferroni) at the significance level of p≤0.05. Significant group × time interaction effects, main effect of time and main effect of group were found for triple hop test, all eight directions of SEBT, HF, KF, AD, KV, VGRF and TSK. There was no significant main ef-fect of group in HF and triple hop test. Also, significant differences in triple hop test, seven direc-tions of SEBT, HF, KF, KV, VGRF and TSK were found between control group with the DL and VMT groups. Between group differences in AD and medial direction of SEBT were not signifi-cant. Also, there was no significant differences between VMT and control groups in triple hop test and HF variables. Both motor learning (DL and VMT) programs improved outcomes in patients after ACL reconstruction. Findings suggest that DL and VMT training programs lead to compa-rable improvements in rehabilitation.

Laser therapy devices (LTDs) operating with near-infrared laser light are increasingly being used in sports medicine. For several reasons the users cannot evaluate whether or not such devices emit laser beams according to the specifications provided by the manufacturer and the settings of the device. In this study the laser beams from two different LTDs that can be used in sports medicine were thoroughly characterized by measuring the emitted power, pulse shapes and lengths, and spatial intensity distributions using professional, high-fidelity laser measurement technology. This was repeated for three units of each LDT independently to distinguish problems of individual units from potential intrinsic instrument design errors. The laser beams from the units of one LTD agreed with the settings at the device, with the measured average power for these units being within 3.3% of the set power. In contrast, the laser beams from the units of the other LTD showed large deviations between the settings and the actual emitted light. This device came with three laser diodes that could be used independently and simultaneously. The average power differed greatly between the units as well as between the laser diodes within each unit. Some laser diodes emitted essentially no light, which could lead to a lack of treatment of patients. Other laser diodes emitted much more power than set at the device (up to 230%) that could result in skin irritations or burnings of patients. These findings indicate a need for better standardization and consistency of therapeutic laser light sources.

New generation antibiotics are needed to combat the development of resistance to antimicrobials. One of the most promising new classes of antibiotics is cannabidiol (CBD). It is a non-toxic and low-resistance chemical that can be used to treat bacterial infections. The antibacterial activity of Cannabis sativa L. byproducts, specifically CBD, has been of growing interest in the field of novel therapeutics. As research continues to define and characterize the antibacterial activity that CBD possesses against a wide variety of bacterial species it is important to examine potential interaction between CBD and common therapeutics such as broad-spectrum antibiotics. Here, we show that CBD-antibiotic co-therapy can effectively fight S. typhimurium via membrane integrity disruption. This research serves to examine the potential synergy between CBD and three broad-spectrum antibiotics for potential antibiotic-CBD co-therapy. In this study, we reveal that Salmonella typhimurium (S. typhimurium) growth is inhibited at very low dosages of CBD-antibiotic. This interesting finding demonstrates that CBD and CBD-antibiotic co-therapies are viable novel alternatives to combating Salmonella typhimurium.

Dry eye disease (DED) most commonly caused by evaporative subtypes and mainly induced by meibomian gland dysfunction (MGD). Intense pulsed light (IPL) combined with meibomian gland expression (MGX) is noninvasive treatment for improvement of ocular discomfort symptoms and MGD. In this prospective study between November 2020 and May 2022, the patients met the criteria of both ocular surface disease index (OSDI) ≥13 scores and standardized patient evaluation of eye dryness (SPEED)≥ 8 scores were enrolled in Kaohsiung Veteran General Hospital. Three separate treatment sessions of IPL therapy combined with MGX administered to the lower lids with an interval of 28 days. Further tear film assessment included lipid layer thickness (LLT), tear meniscus height (TMH), non-invasive tear break-up time (NIBUT), meibomian gland loss (MGL) either beforeor after 1st and 3rd IPL therapy combined with MGX. Besides, lissamine green staining and pain scores were also recorded. We totally enrolled 37 patients of 74 eyes. Men accounted for 18.92% (7/37). The mean age was 54.51 ± 11.72 years. The mean OSDI scores were 58.12 ± 22, while the SPEED scores were 17.03 ± 5.98. The mean Schirmer’s test was 3.66 ± 2.43 mm. After three sessions IPL treatment with MGX, the OSDI, SPEED, LLT, TMH, MGL, MGXS and pain scores were significantly improved. For the MGX scores (MGXS) ≤20 group, MGL and lissamine green scores showed significant improvements. For the MGXS >20 group, TMH and dry spot rate revealed statistically improvement. Noninvasive IPL therapy with MGX statistically improved not only dry eye symptoms but also tear film assessments.

Patients with underlying health conditions are at risk for a poor outcome from Coronavirus disease 2019 (COVID-19). Using machine reasoning by the sci.AI system, we investigated the pathobiochemistry of this observation to generate therapeutic guidelines. Facts were extracted and linked from publications available in nlm.nih.gov and Europe PMC to form the dataset which was validated by medical experts. Previously we described how preexisting chronic inflammation renders the acute inflammatory response to Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) excessive translating the SARS-CoV-2 infection into the clinical COVID-19 syndrome. Herein we focus on therapeutic interventions that mitigate the immune response. In essence, from bench to bedside, as depicted in the Graphical Abstract, the clinical management of COVID-19 should aim at: A. Control of excessive oxidant production. B. Neutralization of excessive oxidants. C. Upregulation of nitric oxide (NO) production.

With rapid advances in gene editing and gene therapy technologies, the development of genetic, cell, or protein-based cures to disease are no longer the realm of science fiction but that of today’s practice. The impact of these technologies are rapidly bringing them to the veterinary market as both enhanced therapeutics and towards modeling their outcomes for translational application. Simply put, gene editing enables scientists to modify an organism’s DNA a priori through the use of site-specific DNA targeting tools like clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). Gene therapy is a broader definition that encompasses the addition of exogenous genetic materials into specific cells to correct a genetic defect. More precisely, the U.S Food and Drug Administration (FDA) defines gene therapy as “a technique that modifies a person’s genes to treat or cure disease” by either (i) replacing a disease-causing gene with a healthy copy of the gene; (ii) inactivating a disease-causing gene that was not functioning properly; or (iii) introducing a new or modified gene into the body to help treat a disease. In some instances, this can be accomplished through direct transfer of DNA or RNA into target cells of interest or more broadly through gene editing. While gene therapy is possible through the simple addition of genetic information into cells of interest, gene editing allows the genome to be reprogrammed intentionally through the deletion of diseased alleles, reconstitution of wild type sequence, or targeted integration of exogenous DNA to impart new function. Cells can be removed from the body, altered, and reinfused, or edited in vivo. Indeed, manufacturing and production efficiencies in gene editing and gene therapy in the 21^st century has brought the therapeutic potential of in vitro and in vivo reprogrammed cells, to the front lines of therapeutic intervention (Brooks et al., 2016). For example, CAR-T cell therapy is revolutionizing hematologic cancer care in humans and is being translated to canines by us and others, and gene therapy trials are ongoing for mitral valve disease in dogs.

Breast cancer (BC) is the most common cancer diagnosed in women worldwide. Approximately 70% of BC patients have the luminal subtype, which expresses hormone receptors (HR+). Adjuvant endocrine treatments are the standard of care for HR+/HER2- BC patients. Over time, approximately 30% of those patients develop endocrine resistance and metastatic disease. Cyclin-dependent kinase inhibitors (CDKi) in combination with an aromatase inhibitor or fulvestrant have demonstrated superior efficacies in increasing progression-free survival, with a safe toxicity profile, in HR+/HER2- metastatic BC patients. CDKi blocks kinases 4/6, preventing G1/S cell cycle transition. However, not all patients respond to CDKi, and those who do respond ultimately develop resistance to the combined therapy. Studies in tumour tissues and cell lines have tried to elucidate the mechanisms underlying this progression, but there are still no conclusive data. Over the last few years, liquid biopsy has contributed relevant information. Circulating tumour materials are potential prognostic markers for determining patient prognosis in metastatic luminal BC, for monitoring disease and for treatment selection. This review outlines the different studies performed using liquid biopsy in patients with HR+ metastatic BC treated with CDKi plus endocrine therapy. We focus mainly on those studies that describe possible resistance mechanisms in circulating tumour-derived material.

Focal vibration therapy can provide neurophysiological benefits. Unfortunately, standardized protocols are non-existent. Previous research presents a wide range of protocols with a wide range of effectiveness. This paper is part of a broader effort to identify effective, standardized protocols for focal vibration therapy. The vibration characteristics of four commercially available focal vibration devices that have been used for research and clinically were measured. An accelerometer was used for the measurements. Frequency and peak-to-peak amplitude were measured. Measurements were made when the devices were free and then again when they were strapped to the human body. Vibration frequency ranged from 120 to 225 Hz. Free vibration amplitude ranged from 2.0 to 7.9 g’s (peak-to-peak). When the devices were strapped to the body (constrained), vibration amplitude decreased by up to 65.7%. These results identify effective ranges of focal vibration frequency and amplitude. They illustrate the importance of identifying vibration environment, free or constrained, when quoting vibration characteristics. Finally, the inconsistency of multi-actuator devices is discussed. These results will guide protocol development for focal vibration and potentially better focal vibration devices.

Breast cancer is the most commonly diagnosed cancer in women worldwide. Approximately, 70 % of breast cancer patients express hormone receptors (HR) (Luminal subtype). Adjuvant endocrine treatments are the standard of care in HR+/HER2- breast cancer. Over time, about 50% of those patients develop endocrine resistance and metastatic breast cancer. Cyclin-dependent kinase inhibitors (CDKi) in combination with an aromatase inhibitor or fulvestrant have demonstrated superior efficacy increasing progression-free survival, with a safe toxicity profile, in HR+/HER2- metastatic breast cancer patients. CDKi blocks kinases 4/6 ATP-binding domain preventing G1/S cell cycle transition. Despite this, not all patients respond to CDKi and those who respond, finally develop resistance to combination therapy. Different studies, in tumour tissue or cell lines, have tried to elucidate the mechanisms underlying this progression, but there are still no conclusive data. In the last few years, liquid biopsy has contributed relevant information to this knowledge. Liquid biopsy can be performed in real-time, non-invasively and be repeated whenever needed. Circulating tumour material are potential prognostic markers in metastatic luminal breast cancer to determine patient prognosis, monitor disease and treatment selection. The objective of this review is to outline the different studies carried out in HR+ metastatic breast cancer patients treated with CDKi plus endocrine therapy using liquid biopsy approaches looking for possible resistance mechanisms.

BACKGROUND AND PURPOSE—Atherosclerotic plaque instability and rupture in patients with asymptomatic carotid artery stenosis (ACAS) is a leading cause of major adverse cardiac events (MACE). This could be mainly evidenced in patients with pre-diabetes. Indeed, the altered glucose homeostasis and insulin resistance could cause over-inflammation of atherosclerotic plaque, favoring its conversion to unstable phenotype with rupture and MACE. Notably, the metformin therapy reducing the metabolic distress and the inflammatory burden, could lead to reduction of MACE in ACAS patients with pre-diabetes. In this setting, microRNAs (miRs) could be used as molecular biomarkers of atherosclerosis progression, plaque rupture and worse prognosis in normoglycemics (NG) vs. pre-diabetics metformin users (PDMU) vs. pre-diabetics non metformin users (PDNMU). However, the aim of our study was to investigate a wide miRNA panel in peripheral blood exosomes from patients with ACAS divided in NG vs. PDMU vs. PDNMU, and to associate the circulating miRNA expression profiles with MACE at 2 years of follow-up after endarterectomy. METHODS—The study included 234 patients with ACAS divided in NG (n 125), PDNMU (n 73) and PDMU (n 36). The miRs’ expression profiles of circulating exosomes were determined at baseline and at 2 years of follow-up by Affymetrix microarrays from plasma samples of the patients from any study cohort. Then we collected and analyzed MACE at 2 years of follow-up in NG vs. PDMU vs. PDNMU. RESULTS—prediabetics vs. NG had over-inflammation (p<0.05) and over expressed miR 24 and miR 27 at baseline. At 2 years of follow-up PDNMU vs. NG, PDMU vs. NG and PDNMU vs. PDMU over-expressed inflammatory markers and miR 24, miR 27, miR 100, miR 126 and miR 133 (p<0.05). Finally, at follow-up end we observed a significant difference about MACE comparing PDNMU vs. NG (n 27 (36.9%) vs. n 8 (6.4%); p<0.05), PDNMU vs. PDMU (n 27 (36.9%) vs. n 6 (16.6%); p <0.05), and PDMU vs. NG (n 6 (16.6%) vs. n 8 (6.4%); p<0.05). Admission glucose values (HR 1.020, CI 95% [1.001-1.038], p 0.029), atheromatous carotid plaque (HR 5.373, CI 95% [1.251-11.079], p 0.024), and miR 24 (HR 3.842, CI 95% [1.768-19.222], p 0.011) predicted MACE at 2 years of follow-up. CONCLUSIONS—Specific circulating miRs could be over-expressed in pre-diabetics and specifically in PDNMU vs. PDMU after endarterectomy. MiR24, hyperglycemia and atheromatous plaque could predict MACE at 2 years of follow-up.

Exogenous miRNAs derived from dietary substances have been shown to be orally transferred to the mammalian system and proven to remain active to regulate host-gene expression. This way they have become an active area of research as functional food components and aspects for dietary supplementation. They are being studied as a new class of metabolically targeted therapeutics that work through diet manipulation and may hold promise for a therapeutic approach in reducing the risk of life-threatening diseases. However, a substantial amount of evidence also defies this dietary miRNA concept in terms of their absorption, bioavailability, cellular uptake and its physiological effects in the mammalian system. But recent advances in the identification of some unique sequence and structural characteristics of dietary miRNAs and a deeper understanding of their stability in host peripheral blood for its cellular uptake have strengthened the whole concept. The review comprehensively summarizes the mechanism for miRNA extracellular transport, absorption through the gastrointestinal tract (GI), stability in peripheral blood, and cellular uptake in mammalian cells. It recapitulates the shreds of evidence, related to the influence of dietary miRNAs on gene expression based on the source of the origin (plant vs animal), and compares their cross-kingdom behaviour in terms of their unique sequence and stem-loop structure properties that help them to get stabilized in the mammalian system. The review also summarizes the parameters required for maintaining the sustainable uptake and bioavailability of the dietary miRNAs with existing examples of successful in-vivo and in-vitro delivery of dietary miRNA for augmented therapy. Lastly, it provides an overview of the available and required databases, webserver, and tools that can be used for the successful identification of potential dietary miRNA candidates.

Trophoblast cell-surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is highly expressed in various cancer types with relatively low or no baseline expression in most of normal tissues. Its overexpression is associated with tumor growth and poor prognosis; Trop 2 is therefore, an ideal therapeutic target for epithelial cancers. Several Trop 2 targeted therapeutics have recently been developed for the treatment of cancers, such as anti-Trop 2 antibodies and antibody-drug conjugates (ADCs), as well as Trop 2-specific cell therapy. In particular, the safety and clinical benefit of Trop 2-based ADCs have been demonstrated in clinical trials across multiple tumor types, including those with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and heavily pretreated non-small cell lung cancer. In this review, we elaborate on recent advances in Trop 2 targeted modalities and provide an overview of novel insights for future developments in this field.

Although diet interventions are mostly related to metabolic disorders, nowadays they are used in wide variety of pathologies. From diabetes and obesity to cardiovascular diseases, through cancer or neurological disorders and stroke, nutritional recommendations applied to almost all diseases. Among those disorders, metabolic disturbances and brain function and/or diseases have recently been shown to be linked. Indeed, numerous neurological functions are often associated with perturbations of whole-body energy homeostasis. In this regard, specific diets are used in various neurological conditions such as epilepsy, stroke, or seizure recovery. In addition, Alzheimer’s disease or Autism Spectrum Disorders are also considered as putatively improved by diet intervention. Glycemic index diets are a novel developed indicator expected to anticipate the changes in blood glucose induced by specific foods, and how they can affect various physiological function. Several results provide indications of efficiency of low glycemic index diets in weight management, insulin sensitivity, but also cognitive function, epilepsy treatment, stroke, or neurodegenerative diseases. Overall, studies involving glycemic index could provide new insight in the relationship between energy homeostasis regulation and brain function or related disorders. Therefore, in this review we will summarize main evidences on glycemic index involvement in brain mechanisms of energy homeostasis regulation.

Objective: The study investigated the benefit of practicing the art of bonsai and the well-being of practitioners. The art promotes relaxation, focus and art therapy that can have personal and emotional value in a self-help setting. When the bonsai tree is used as a healing object, it may improve the ability of the bonsai practitioner to adapt to adverse and stressful life events, such as the present global COVID-19 pandemic. Method: International bonsai artists (n = 255) participated in a study that examined the effect their bonsai had on their mental well-being. Semi-structured interviews were conducted with bonsai artists answering the question: “How has bonsai helped you?”. Results: Most participants acknowledged that being able to take care of their bonsais affected their mood in a positive manner. Discussion: Although the participants did not report overall improved mental health, participants expressed an improvement in their mood when being able to work on a bonsai tree. Conclusion: These findings are significant in that it can be useful in as a preventative and restorative manner in the mental well-being of people who practice the art.

Three patients with severe life-threatening COVID-19 who failed to achieve substantial improvement on tocilizumab, received pulse therapy with corticosteroids (methylprednisolone, 1000 mg/day IV for three consecutive days) and intravenous immunoglobulin (20 g/day IV). This was associated with a prompt resolution of respiratory failure, elimination of cytokine release syndrome, and reversal of pulmonary CT changes. The treatment was generally safe and well tolerated. There was no evidence of protracted persistence of the virus in the patients who received pulse therapy. Randomized controlled trials are necessary to specify the efficacy and safety of high-dose methylprednisolone and intravenous immunoglobulin in the treatment of severe life-threatening COVID-19 separately or in combination.

Background: At present, the treatments for patients with advanced lung cancer focus on chemotherapy, targeted therapy, immunotherapy, or a combination of multiple treatments. Purpose: The main purpose of this study is to compare the various chemotherapy-based combination therapies and find the best one for patients with advanced lung cancer. Methods: Based on database (PubMed, EMBASE and Medline) for randomized controlled trials of advanced lung cancer with combination therapy from 2008 to 2020, we searched literatures with overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse as outcome indicators and established a Bayesian mesh meta-analysis for multiple treatment strategies. Then, we combined the results of four outcome indicators to find out the best chemotherapy-based combination therapy strategy for patients with advanced lung cancer, further, we tried to screen out the best drugs of which were commonly used now. Results: It contained a total of 51 studies, including five combination therapies: Chemotherapy/Chemotherapy plus placebo (CT), chemotherapy plus one targeted therapy drug (CT+T), chemotherapy plus two targeted therapy drugs (CT+T+T), chemotherapy combined with immunotherapy (CT+I) or chemotherapy combined with biotherapy (CT+B). In terms of four outcome indicators, CT+I showed the best therapeutic benefits. In the comparison of immunotherapy drugs, pembrolizumab showed the best effect. Conclusion: Our results showed that, among the multiple chemotherapy-based combination therapy strategies, chemotherapy combined with immunotherapy is the best choice for patients with advanced lung cancer, and pembrolizumab combined with chemotherapy has the best effect.

Nonpharmacological therapeutic interventions in elderly may lead to the reduction of cognitive and depressive symptoms. The aim of the study was to evaluate changes in cognitive functions and mood er or not. in older adults participating in therapy, conducted in the community day-care center (CD-CC). 46 elderly adults (21 M, 25 W) (SG) were examined. The control group (CG) included 45 adults (12 M, 33 W), who participated in the activities of the University of the Third Age (U3A). The following measuring tools were used: Mini-Mental State Examination (MMSE), Clock-Drawing Test (CDT), Verbal Fluency Test (VFT), Digit Span Test (DST), Stroop Color and Word Test (SCWT), Beck's Depression Inventory (BDI), and Hospital Anxiety and Depression Scale (HADS). The intervention consisted of CD-CC 6-month complex therapy. In the SG, compared to the CG, the scores on the: MMSE, CDT, VFT, DST, and SCWT were significantly lower (p<0,05), and BDI was significantly higher (p<0,05). After intervention, the SG and the CG, did not show substantial differences in their scores on the: MMSE, CDT, and BDI. In the SG, a significant improvement (p<0,05) was reported on the: VFT, BDI, and HADS scores. The CD-CC complex therapy can be helpful for the cognitive and emotional elderly functioning.

The experimental determination of the relative biological effectiveness of thermal neutron factors is fundamental in Boron Neutron Capture Therapy. Present values have been obtained using mixed beams consisting of both neutrons and photons of various energies. A common weighting factor has been used for both thermal and fast neutron doses, although such an approach has been questioned. At the nuclear reactor of the Institut Laue-Langevin a pure low-energy neutron beam has been used to determine thermal neutron relative biological effectiveness factors. Different tumor cell lines, corresponding to glioblastoma, melanoma, and head and neck squamous cell carcinoma, and non-tumor cell lines (lung fibroblast and embryonic kidney) have been irradiated using an experimental arrangement designed to minimise neutron-induced secondary gamma radiation. Additionally, the cells were irradiated with photons at a medical linear accelerator, providing reference data for comparison with that from neutron irradiation. Survival and proliferation were studied after irradiation, yielding the Relative Biological Effectiveness corresponding to the damage of thermal neutrons for the different tissue types.

Stem cells are currently being used in many clinical trials for regenerative purposes. These are promising results for stem cells in the treatment of several diseases, including cancer. Nevertheless, there are still many variables which should be addressed before the application of stem cells for cancer treatment. One approach should be to establish well-characterized therapeutic stem cell banks to minimize the variation in results from different clinical trials and facilitate their effective use in basic and translational research.

Neutrophils play an important role as the first line of innate immune defense. One function of neutrophils, called neutrophil extracellular traps (NETs), has been discovered recently. NETs are extensive fibrous structures released extracellularly from activated neutrophils in response to infection. They are composed of cytosolic protein assembled on a scaffold of released chromatin. These structures suppress the dissemination of micro-organisms in blood by trapping them mechanically, and by exploiting coagulant function to segregate them within the circulation. In addition, NET components (DNA, histone, and granule proteins) also contribute to the triggering of an inflammatory process. NET function, however, can be regarded as a double-edged sword. On one hand, NET formation is an efficient strategy for neutralizing invading micro-organisms. On the other hand, NET can be harmful to the host, as its exposed by-products that are toxic to endothelial cells and parenchymal tissue. We present here the analogous biological and physiological features of the harmful positive amplification loop between inflammation and tissue damage induced by NETosis dysregulation and Coronavirus Disease-2019 (COVID-19) pathogenesis. Considering the rapid evolution of this disease symptoms and its lethality, we hypothesize that COVID-19 progresses under an amplifier loop, leading to an massive, uncontrolled inflammation process. We also describe the correlations of COVID-19 symptoms and biological features with those consecutive to uncontrolled NET formation causing various sterile or infectious diseases. General clinical conditions, and numerous pathological and biological features, are analogous with NETs deleterious effects. We postulate that Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2) induces a disproportionate virus-induced NET release, and that this plays a key role in COVID-19 pathogenesis. While neutrophils are the principal starting point for extracellular and circulating DNA release, targeting NETs rather than neutrophils themselves may stand for an effective strategy. This paper offers an in-depth review of NET formation, function and pathogenic dysregulation, as well as of current and future therapies to control NET unbalance. As such, it enables us also to suggest new therapeutic strategies to fight COVID-19. In combination with or independent of the latest tested approaches, we propose that, in the short term, deoxyribonuclease I (DNase-1) treatment should be evaluated; we also advocate a significant increase in research on the development of toll-like receptors (TLR) and C-type Lectin like receptors (CLEC) inhibitors, and on anti-IL26 therapies.

Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.

Corneal ulcer (CU) is an ophthalmopathy characterized by depression of the corneal surface with at least one stromal loss. CU is common in canine and feline species and is usually caused, among others, by trauma, infections, toxic contamination and endocrine disorders. They usually result from an increased inflammatory response and are associated with some clinical signs such as blepharospasm, photophobia, epiphora, pain and loss of corneal transparency. Despite advances in conventional and pharmacological therapy, in many cases indolent and recurrent ulcer treatments still lead to loss of visual acuity of the animal. This paper aims to report the effect of topical application of canine adipose tissue-derived mesenchymal stem cell (cATMSCs) as treatment of recurrent CU in a Poodle dog breed that showed clear difficulty in the healing process associated with diabetes. The animal was submitted to two applications of cATMSCs and showed improvement in the blepharospasm, conjunctival hyperemia, mucopurulent ocular secretion, photophobia, corneal opacity, chemosis, pigmentation, neovascularization, and pain parameters. Besides, Fluorescein test, Schirmer test and ocular fundus exam also showed improvement in their values concomitantly with lesion resolution. Due this, we showed that cATMSC therapy contribute to the regeneration of corneal tissue in CU and may contribute to the treatment to others ophthalmopathies.

In the modern world, the problem of antibiotic therapy is acute. Despite the diversity of existing antibiotic drugs, their efficacy decreases as new, resistant forms of pathogenic microorganisms emerge. It is extremely difficult to control such processes and even more difficult to treat severe bacterial infections. In such situations, an individual approach to each patient is required and physicians need parameters to estimate the efficacy of antibiotic therapy. This review discusses the significance of monitoring the content of antibiotics in the blood for this purpose, in combination with the content of inflammatory markers, such as C-reactive protein and procalcitonin. The basic principles of antibiotic therapy, and factors in the resistance of microorganisms to antibiotics, are examined. Approaches to assess the efficacy of antibiotic therapy, as well as methods to detect antibiotics and inflammatory markers in the blood of patients, and comparative assessment of their capabilities and limitations, are described.

In western societies about one in six employees works in shifts. Shiftwork is associated with a number of poor somatic and psychological health outcomes, especially sleep issues. Higher rates of absenteeism and accidents in the workplace are possible consequences. Still, prevention programs and treatment options that are specifically tailored to shift workers’ needs are rare. We devised a 4-week online sleep intervention (n = 21) and compared treatment outcomes to our outpatient treatment for shift workers (n = 12). Measures included the WHO-5, ISI, and ESS scales as well as sleep diaries. Shift workers reported worse symptoms of insomnia than other participants. Results show significant average increases in sleep efficiency (+ 7%) and total sleep time (+ 25 min.), as well as significant improvements regarding insomnia symptoms and wellbeing in the online sample. Rates of improvement did not differ between the online and outpatient samples. Sleep disorders affect a relevant part of the working population, especially shift workers. Online approaches to treatment of these issues seem feasible and effective. Randomized controlled trials are needed.

With the rapid progress of genetic engineering and gene therapy, World Anti-Doping Agency has alerted to gene doping and prohibited its use in sports. However, there is no standard method available yet for detection of transgenes delivered by recombinant adenoviral (rAdV) vectors. Here we aimed to develop a detection method for transgenes delivered by rAdV vectors in a mouse model that mimics gene doping. rAdV vectors containing mCherry gene was delivered in mice through intravenous injection or local muscular injection. After five days, stool and whole blood samples were collected, and total DNA was extracted. As additional experiments, whole blood was also collected from mouse tail tip until 15 days from injection of the rAdv vector. Transgene fragments from different DNA samples were analyzed using semi-quantitative PCR (sqPCR), quantitative PCR (qPCR), and droplet digital PCR (ddPCR). In the results, transgene fragments could directly be detected from blood cell fraction-DNA, plasma-cell free DNA and stool-DNA by qPCR and ddPCR, depending on specimen type and injection methods. We observed that a combination of blood cell fraction-DNA and ddPCR was more sensitive than other combinations used in this model. These results could accelerate the development of detection methods for gene doping.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of a timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including an angiogenic switch, immune escape, cancer stem cells, extra cellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced-p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer, and discuss the implications of such approaches in cancer treatment.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of a timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including an angiogenic switch, immune escape, cancer stem cells, extra cellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced-p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer, and discuss the implications of such approaches in cancer treatment.

Owing to their unique physicochemical properties, nanoparticles are used in a variety of ways in the field of cancer treatment, including imaging, drug delivery, and photothermal and photodynamic therapies. The fascinating properties of nanoparticles are determined by their size, morphology, and constituent elements, and various synthetic methods and post-synthetic techniques have been applied to control these factors. Herein, we present examples of shape and composition control through galvanic replacement, a technique that exploits redox potential differences between elements to induce spontaneous ion-exchange and highlight its specific contributions to cancer treatment applications. The present article identifies the recent advances in nanoparticle formation techniques and discusses the future outlook of the field.

Photodynamic therapy (PDT) with a suitable photosensitizer molecule is a promising anticancer treatment. We evaluated two chlorin molecules as potential photosensitizers, methyl pyropheophorbide a (MPPa) and N-methoxyl purpurinimide (NMPi), against A549 human lung adenocarcinoma cells in vitro as well as in A549 tumor-bearing mice in vivo. Cell viability, microscopy, and FACS analyses were performed for the in vitro studies. MPPa and NMPi showed high phototoxicity in vitro, which was dependent on the concentration of the photosensitizers as well as the light irradiation time. In the animal study, tumor volume change, tumor surface alterations, and H&E and TUNEL staining analyses were performed and compared between small (tumor volume of <50 mm³) and large (tumor volume of >50 mm³) size of initial tumors. MPPa and NMPi showed high anticancer efficacy against small-size tumors, indicating that early treatment with PDT is effective. Especially, repeated two times PDT with NMPi allowed almost complete eradication against small-size tumors. However, MPPa and NMPi were not effective against large-size tumors. In conclusion, the two chlorin derivatives, MPPa and NMPi, show good anticancer efficacy as promising photosensitizers for PDT in vitro and in vivo. Moreover, their activity in vivo was significantly dependent on the initial tumor size in mice, which confirms the importance of early cancer treatment.

The shortage of physicians in rural communities contributes to increased mortality rates among Medicare beneficiaries. This increase in mortality risk is commonly due to diseases such as heart disease and cancer, including melanoma and non-melanoma skin cancer (NMSC). Mohs micrographic surgery (MMS) is considered the gold-standard treatment for NMSC tumors, however, due to a shortage of dermatologists and Mohs surgeons in rural areas, access to MMS is limited. In these areas, image guided superficial radiation therapy (IGSRT) serves as a viable option for the treatment of NMSC lesions, with fewer recurrences and 99% cure rates, which are comparable to MMS cure rates. IGSRT is performed in dermatology clinics with support from a multidisciplinary team, including radiation therapists, medical physicists, radiation oncologists, and dermatologists. As IGSRT is able to be performed by general dermatologists, Medicare beneficiaries in rural communities will have an increase in access to treatment options and a decrease in delayed skin cancer treatment.

Historically, the evaluation and assessment of the clinical response to treatment for canine back pain is subjective and relies on owner and clinician assessment of pain. This study evaluated the use of sequential infrared thermal images as a measure of the response of canine patients with back pain to a prescribed series of photobiomodulation therapy (PBMT) treatments. Qualifying participants had histories of pain and dysfunction associated with spinal osteoarthritis or intervertebral disk disease, or of non-specific uni- or bilateral back pain along the paravertebral epaxial muscles. Each patient was initially thermally imaged prior to PBMT treatment and then received multiple PBMT treatments delivered to the appropriate spinal area on days 1, 2, 3, and 4. Participants were reimaged on day 7. Thermal images provided an objective measure of superficial temperature changes over the area of PBMT treatment of each patient after the PBMT regimen. The temperature correlated with statistically significant changes in Colorado State University Canine Chronic Pain Scale scoring (CPS) and owner assessment using the Canine Brief Pain Inventory (CBPI), which includes a Pain Severity Score (PSS) and Pain Interference Score (PIS). The correlation of objective thermal imaging data with more subjective outcome measures suggests thermal imaging may be a valuable additional tool in monitoring therapy outcome.

Three patients with multi-year histories of relapsing and remitting Lyme disease and associated co-infections despite extended antibiotic therapy were each given double dose dapsone combination therapy (DDD CT) for a total of 7-8 weeks. At the completion of therapy, all three patients major Lyme symptoms remained in remission for a period of 25-30 months. In conclusion, Double dose dapsone therapy could represent a novel and effective anti-infective strategy in chronic Lyme disease/PTLDS, especially in those individuals who have failed regular dose dapsone combination therapy (DDS CT) or standard antibiotic protocols. A randomized, blinded, placebo-controlled trial is warranted to evaluate the efficacy of DDD CT in those individuals with chronic Lyme disease/PTLDS.

Arguably the most important parameter in treating cognitive decline associated with Alzheimer’s disease is the length of time in which improvement, if achieved at all, is sustained. However, monotherapies such as donepezil and memantine are associated with a more rapid decline than no treatment in patients over multi-year follow-ups {Kennedy, 2018 #535}. Furthermore, anti-amyloid antibody treatment, which at best simply slows decline, is associated with accelerated cerebral atrophy [2], resulting in earlier dementia-associated brain volumes for those treated at the MCI stage than untreated patients. In contrast, a precision medicine approach, in which the multiple potential drivers of cognitive decline are identified for each patient and then targeted with a personalized protocol (such as ReCODE), has led to documented improvement in patients with cognitive decline [3]; [4]; [5], but long-term follow-up (>5 years) has not been reported previously. Therefore, we report here sustained cognitive improvement, in some cases for over a decade, in patients treated with a precision medicine protocol—something that has not been reported in patients treated with anti-cholinesterase, glutamate receptor inhibitory, anti-amyloid, or other therapeutic methods. These case studies warrant long-term cohort studies to determine how frequently such sustained cognitive improvements occur in patients treated with precision medicine protocols.

Hydrogel wound dressings hold great potential in eliminating bacteria and accelerating the healing process. However, it remains a challenge to fabricate hydrogel wound dressings that simultaneously exhibit excellent mechanical and photothermal antibacterial properties. Here we report the development of polydopamine-functionalized graphene oxide/calcium alginate/Polypyrrole cotton fabric-reinforced hydrogels (abbreviated as rGO@PDA/CA/PPy FHs) for tackling bacterial infections. The mechanical properties of hydrogels were greatly enhanced by cotton fabric reinforcement and an interpenetrating structure, while excellent broad-spectrum photothermal antibacterial properties based on the photothermal effect were obtained by incorporating PPy and rGO@PDA. Results indicated that rGO@PDA/CA/PPy FHs exhibited superior tensile strength in both the warp (289±62.1N) and weft directions (142±23.0N) similar to cotton fabric. By incorporating PPy and rGO@PDA, the swelling ratio was significantly decreased from 673.5% to 236.6%, while photothermal conversion performance was significantly enhanced with a temperature elevated to 45.0 ℃. Due to the synergistic photothermal properties of rGO@PDA and PPy, rGO@PDA/CA/PPy FHs exhibited excellent bacteria-eliminating efficiency for S. aureus (0.57%) and E. coli (3.58%) after exposure to NIR for 20 min. We believe that the design of fabric-reinforced hydrogels could serve as a guideline for developing hydrogel wound dressings with improved mechanical properties and broad-spectrum photothermal antibacterial properties for infected wound treatment.

Abstract: Delayed initiation of effective antifibrotic therapy in patients with interstitial lung diseases (ILD) may influence the progression and outcome of the disease. This study analyzes the differences in the journey of patients with ILD in the Brazilian and Mexican health systems. An evaluative study was conducted in reference centers for interstitial lung diseases in Brazil and Mexico with a panel of four specialists. The patient's journey in both countries begins when the patient seeks medical care after observing a chronic respiratory symptom. In both countries, due to diagnostic complexity, these patients arrive at ILD referral centers at an advanced stage of the disease. Once diagnosis is established, the treatment onset differs between Mexico and Brazil. Antifibrotic drugs are not yet available by SUS in Brazil, and the purchase is unfeasible for most of the population, which forces specialists to only offer support to patients until the treatment can get the drug. In Mexico, antifibrotics have been available in health sectors since 2018. Brazil and Mexico have several similarities regarding the initial journey of the patient due to diagnosis difficulties, but the outcome tends to be different due to a difference in access to treatment with antifibrotics. For this reason, advancing health policies that ensure proper treatment for patients with ILD is crucial for the sustainability and reliability of the health system.

Alzheimer's Disease (AD) presents a significant challenge in the wake of its multifaceted nature, characterized by cognitive decline, memory impairment, and neuroinflammation. Despite extensive research, effective pharmacological interventions remain elusive, prompting exploration into non-pharmacological approaches. Microcurrent therapy (MC), utilizing imperceptible currents, has emerged as a potent clinical protocol. While previous studies have focused on its therapeutic effects, this study investigates its impact on neuronal damage and neuroinflammation in an AD mouse model, specifically addressing potential side effects. Utilizing 5xFAD transgenic mice, we examined the effects of MC therapy on neuronal integrity and inflammation. Our findings suggest that MC therapy attenuates memory impairment and reduces neurodegeneration, as evidenced by improved performance in memory tests and preservation of neuronal structure. Additionally, MC therapy significantly decreases amyloid-beta (Aβ) plaque deposition and inhibits apoptosis, indicating its potential to mitigate AD pathology. Our study discovered that MC therapy effectively reduces glial activation by inhibiting the TLR4-MyD88-NFκB pathway, consequently leading to decreased levels of inflammatory factors TNF-α, IL-1β, and IL-6, thus implicating TLR4 in neurodegenerative disease-related neuroinflammation. Furthermore, while our study did not observe significant adverse effects, further clinical trial into potential side effects and neuroinflammatory responses associated with MC therapy is warranted.

To explore the relevant factors that affect the efficacy of consciousness-regaining therapy (CRT)for prolonged disorder of consciousness(pDOC),a retrospective analysis was conducted on the case data of 114 patients with pDOC admitted to department of functional neurosurgery of Tianjin Huanhu Hospital from January 2019 to January 2022. Basic information on the cases,data on pDOC disease assessment, consciousness-regaining therapy methods, and efficacy evaluation were collected. A total of 114 patients were grouped and compared based on the efficacy at the end of treatment. Among them, there were 61 cases in the ineffective group and 53 cases in the effective group. There was no statistically significant difference (P&gt;0.05) between the two groups in terms of gender, age, etiology, acute cerebral herniation, emergency craniotomy surgery, emergency decompressive craniectomy, time from onset to start of consciousness-regaining therapy , and duration of consciousness-regaining therapy(P&gt;0.05). However, there were statistically significant differences (P&lt;0.05) in terms of secondary hydrocephalus, , consciousness-regaining therapy methods, CRS-R grading before treatment, and GOSE score at 6 months after treatment. Binary logistic regression analysis showed that the type of therapy (OR=0.169, 95% CI: 0.057-0.508) was a related factor affecting the efficacy of consciousness-regaining therapy (P&lt;0.05).Compared with non-invasive therapy, personalized awakening therapy using various invasive consciousness-regaining therapy methods can help improve the efficacy of therapy for pDOC.

To investigate the impact of electrode structure on Electrical Stimulation Therapy (EST) for chronic wound healing, this study designed three variants of flexible microelectrodes (FMs) with Ag-Cu coverings (ACCs), each exhibiting distinct geometrical configurations: hexagonal, cross-shaped, and serpentine. These were integrated with PPY@PDA/PANI (3/6) hydrogel dressings. Comprehensive animal studies, coupled with detailed electrical and mechanical modeling and simulations, were conducted to assess their performance. Results indicated that the serpentine-shaped FM outperformed its counterparts in terms of flexibility and safety, exhibiting minimal thermal effects and a reduced risk of burns. Notably, FMs with metal coverings under 3% demonstrated promising potential for optoelectronic self-powering capabilities. Additionally, simulation data highlighted the significant influence of hydrogel non-uniformity on the distribution of electrical properties across the skin surface, providing critical insights for optimizing EST protocols when employing hydrogel dressings.

Background: Diabetes mellitus (DM) and periodontitis are two chronic diseases that are interconnected. The coexistence of these conditions leads to increased severity of periodontitis and challenges in controlling blood glucose levels in diabetic patients. Objectives: The aim of this study was to evaluate both the influence of periodontal disease and its treatment in patients with DM in terms of a reduction in glycosylated hemoglobin levels at 3 and 6 months after treatment. Methods: A sequential, nonprobabilistic, controlled, prospective and longitudinal case−control study was carried out at the University Dental Clinic of the Morales Meseguer Hospital in Murcia, Spain. Thirty diabetic patients were divided into two groups: patients with periodontitis (test group) and patients without periodontitis (control group). The periodontal and endocrine-metabolic variables were measured at baseline and at 3 and 6 months after periodontal treatment for both groups. Results: Statistically significant differences were found at 3 and 6 months after periodontal treatment with respect to HbA1c levels in the group of periodontal patients. However, these differences were not observed in the control group. Conclusion: The presence of periodontal disease increased HbA1c levels in patients with DM. Nonsurgical periodontal treatment significantly decreased the degree of periodontal inflammation and the HbA1c level at 3 and 6 months after treatment.

Recently, I described a novel approach for cancer therapy in an article entitled “Promoting Oncolytic Vector Replication with Switches that Detect Ubiquitous Mutations”. However, there are a few more design details that should potentially be taken into consideration. Also, multiregion, multisample tumor sequencing may be simplified by analyzing cell-free DNA in the blood of patients.

This study aimed to investigate the effect of adding Mirror Visual Feedback Therapy (MFT) after Dry Needling (DDN) on sensitivity and motor performance in patients diagnosed with Post-Needling pain from Myofascial Trigger Points (MTrPs) in lateral elbow pain patients. A randomized, controlled, two-arm pilot trial following Consolidated Standards of Reporting Trials (CONSORT) was conducted at the European University of Madrid between February 1, 2023, and June 2, 2023. A total of 49 patients (F=23, M=26) were randomly assigned to the Experimental Group Deep Dry Needling, Ischemic Compression, Cold Spray, Stretching, and Mirror Therapy (n=25), and the others receiving the same interventions without Mirror Therapy (n=24). Pre- and post-treatment assessments encompassed Post-needling pain (VAS), pressure pain threshold (PPT), two-point discrimination threshold (TPDT), and maximum hand grip strength (MHGS). Post-needling pain intensity in the EG showed statistically significant reductions (MD = 0.400, SEM = 0.271, W = 137.00, p = 0.047) following the addition of MT to the DDN protocol. Similarly, PPT exhibited significant improvements (MD = 0.148 Kg/cm2, SEM = 0.271, W = 262.00, p < 0.001). However, TPDT and MHGS did not show significant differences between initial and post-treatment measurements. The addition of MFT to DDN for MTrPS in lateral elbow pain reduced Post-needling pain and influenced on sensory perception in lateral elbow pain patients with Myofascial Trigger Points. Despite observed clinical effects not reaching statistical significance, these findings offer valuable insights for future research considerations.

We developed an ovarian cancer-targeted drug delivery system based on a follicle-stimulating hormone receptor (FSHR) peptide. The lipophilic chemotherapeutic drug SN38 and the photosensitizer IR820 were loaded into the phospholipid bilayer of liposomes. Near-infrared laser irradiation stimulated the generation of reactive oxygen species, causing short-term reactive molecular species and spatial-temporal restricted photodamage to the biological targets. The reactive molecular species and spatial-temporal restricted photodamage enhanced the release and uptake of chemotherapy drugs and increased the sensitivity to chemotherapy drugs in ovarian cancer cells. FSH liposomes loaded with SN38 and IR820 (SN38/IR820-Lipo@FSH) were prepared using thin-film hydration-sonication. FSH peptide binding was analyzed using 1H NMR spectrum and Maldi-Tof. The average size and zeta potential of SN38/IR820-Lipo@FSH were 105.1 ± 1.15 nm (PDI: 0.204 ± 0.03) and −27.8 ± 0.42 mV, respectively. SN38/IR820-Lipo@FSH exhibited good drug-loading properties and the in vitro release was slow. FSH significantly increased the uptake of liposomes, inhibited cell proliferation, and induced apoptosis in A2780 cells. Moreover, SN38/IR820-Lipo@FSH exhibited good tumor-targeting ability and anti-ovarian cancer activity in vivo. The SN38/IR820-Lipo@FSH exhibited specific targeting to A2780 ovarian cancer cells. The combination of chemotherapy and photodynamic treatment based on an FSH peptide-targeted delivery system may be an effective approach to treating ovarian cancer.

we describe an atypical case of Whipple disease involving exclusively the spinal cord in an adolescent receiving immunosuppressive therapy for systemic lupus erythematosus. The diagnosis was particularly difficult since lupus and Whipple disease can present similar clinical features and the patient’s prolonged contact with sewage was initially not mentioned. A literature review of the clinical, imaging, diagnostic, and therapeutic challenges of Whipple disease is also performed.

Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood-brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor β (ERβ), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17β-estradiol (E2) and the selective ERβ agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative HER2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERβ as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications.

Foot pain related to the plantar fascia is common in adults regardless of athletic background. Many pathologies can lead to the diagnosis of plantar enthesopathy, but the most relevant to this case study is related to structural defects within the plantar fascia. Due to the variety and sometimes unclear etiology of plantar fasciosis, no single standard of care treatment protocol is recognized. Often, patients receive NSAIDs, night splints, taping, physical therapy, foot orthosis, and extracorporeal shock wave therapies. This study presents Wharton Jelly (WJ) tissue allografts as an additional intervention for patients who fail standard-care treatments. WJ allografts are applied to supplement connective tissue defects directly, unlike other therapies, which aim to reduce swelling and symptomatic pain. This retrospective study includes seven patients who have previously failed standard-of-care treatment. Each received extracorporeal pulse-activated therapy (EPAT), WJ, laser therapy, and an orthotic. Patient progress was tracked using a visual analog scale, 0-10 scoring, reported by the patient at the initial visit and approximately thirteen weeks following, reporting an average improvement of 50%. The study's limitations include a small cohort size and a non-blinded retrospective design. These promising results provide evidence for a more extensive, randomized study to define dosage protocols further and confirm safety and efficacy.

Here we explore the emerging role of NKG2D CAR-T cell therapy in the realm of solid tumor treatment. Unique capabilities of NKG2D CAR-T cells to recognize stress-induced ligands on cancer cells are discussed, highlighting the therapy's potential for targeted and precise antitumor responses. We also examine the challenges and opportunities associated with NKG2D CAR-T cell therapy, emphasizing the ongoing advancements and clinical trial progress shaping its future. Ultimately, the discussion underscores the transformative promise of NKG2D CAR-T cell therapy in revolutionizing the landscape of solid tumor treatment and enhancing the prospects for improved patient outcomes.

Diarrhea-related mortality remains an important public health concern, particularly in developing countries, and has become difficult to treat because of antibacterial resistance. The development of synergistic antimicrobial agents appears to be a promising alternative treatment against diar-rheal infections. In this study, the combined effect of tetracycline together with either nitroxoline, sanguinarine, or zinc pyrithione (representing various classes of alkaloid-related compounds) was evaluated in vitro against selected diarrheagenic bacteria (Enterococcus faecalis, Escherichia coli, Listeria monocytogenes, Shigella flexneri, Vibrio parahaemolyticus, and Yersinia enterocolitica). The chequerboard method in 96-well microtiter plates was used to determine the sum of the fractional inhibitory concentration indices (FICIs). Three independent experiments were performed per combination, each in triplicate. It was observed that the combinations of tetracycline with either nitroxoline, sanguinarine, or zinc pyrithione produced synergistic effects against most of the pathogenic bacteria tested, with FICI values ranging from 0.086 to 0.5. Tetracycline-nitroxoline combinations produced the greatest synergistic action against S. flexneri at a FICI value of 0.086. Combinations of the agents tested in this study can thus be used for the development of new anti-diarrheal medications. However, studies focusing on their in vivo anti-diarrheal activity and safety are required before any consideration for utilization in human medicine.

Auger-emitting radionuclides exemplified by Pd-103, exhibit considerable therapeutic potential in cancer treatment due to their heightened cytotoxicity and localized biological impact. Despite these advantages, the separation of such radionuclides presents a complicated challenge, requiring intricate and time-intensive "wet chemistry" methods attributed to the exceptional chemical inertness of the associated metals. This study proposes an innovative solution to this separation challenge through the design and implementation of a radionuclide separation equipment (RSE). The equipment employs a dry distillation approach, capitalizing on differences in partial vapor pressures between irradiated and resulting radioactive metals, with a diffusion-driven extraction method applied to separate Pd-103 radionuclides generated via proton irradiation of Rh-103 at the ATOMKI MGC-20 cyclotron. Optimization endeavors focused on determining the optimal temperature for effective metal separation, adjusting diffusion, evaporation, and deposition rates, as well as addressing chemical impurities. Calculations indicate 17 % ± 2 % separation efficiency with our RSE. Approximately 77% ± 2% and 49% ± 2% of the deposited Pd-103 were isolated on substrates of Nb foil and ZnO-covered W disk, respectively. The proposed innovative dry distillation method that has been experimentally tested, offers a promising alternative to conventional separation techniques, enabling enhanced purity and cost-efficient cancer treatment strategies.

Hyperbaric oxygen therapy (HBOT) is a well-established treatment for carbon monoxide (CO) poisoning. HBOT is performed in a hyperbaric chamber, which increases the atmosphere absolute (ATA) and oxygen concentration in the chamber. To ensure patient safety during HBOT, a gas monitoring system is used to monitor the oxygen levels, ATA, and other parameters. This study aims to perform the safety evaluation of the monoplace hyperbaric chamber compared to a gas monitoring system in the treatment of CO poisoning. In addition, it examined the clinical characteristics of the patients diagnosed with CO poisoning who performed HBOT. In the safety evaluation of the monoplace chamber, it was compared the values of oxygen (O2), carbon dioxide (CO2), humidity, and temperature were measured in the hyperbaric chamber and gas monitoring system when operating at 2.0 ATA and 3.0 ATA. Moreover, in the clinical characteristics of patients with CO poisoning who performed HBOT, 1,006 patients were analyzed by using the data registry. Under the condition at 3.0 ATA, the average CO2 was higher in the hyperbaric chamber than in the gas monitoring system (p&lt;0.001). Also, the average humidity was higher in the hyperbaric chamber than in the gas monitoring system (p=0.004). Under the condition at 2.0 ATA, the average humidity was higher in the hyperbaric chamber than in the gas monitoring system (p&lt;0.001). Also, the average temperature was lower in the hyperbaric chamber than in the gas monitoring system (p&lt;0.001). The mean age of the 1,006 CO poisoning patients who received HBOT was 44.93±19.78 years. According to the source of CO, 680 patients (67.6%) visited ER most commonly due to charcoal. The median maximal CO exposure time and time from rescue to ER were 4.0 hours and 3.09 hours, respectively. The median GCS score at the scene or ER was 15. According to the underlying comorbidities, psychiatric diseases (19.5%) were the most common, followed by hypertension (18.1%) and diabetes mellitus (11.5%). In the emergency room, some patients had appeared symptoms such as loss of consciousness (59.8%), shock (6.7%), or seizure (8.3%). The results of this study could be expected that HBOT can be effectively performed by monitoring the gas concentration change inside the hyperbaric chamber.

The Fas associated Death Domain (FADD) is an adaptor protein that predominantly transduces apoptosis signal from death receptor (DR) to activate caspases, leading to the initiation of apoptotic signaling and the coordinated removal of damaged, infected, or unwanted cells. In addition to its apoptotic functions, FADD is involved in signaling pathways related to autophagy, cell proliferation, necroptosis, and cellular senescence, indicating its versatile role in cell survival and proliferation. The subcellular localization and intracellular expression of FADD play a crucial role in determining its functional outcomes, thereby highlighting the importance of spatiotemporal mechanisms and regulation. Furthermore, FADD has emerged as a key regulator in inflammatory signaling, contributing to immune responses and cellular homeostasis. This review provides a comprehensive summary and analysis of cellular dynamics of FADD in regulating of programmed cell death and inflammation through distinct molecular mechanisms associated with various signaling pathways.

Stroke remains one of the leading causes of death and disability worldwide. Current reperfusion treatments for ischaemic stroke are limited due to their narrow therapeutic window in rescuing ischaemic penumbra. Stem cell therapy offers a promising alternative. As a regenerative medicine, stem cells offer a wider range of treatment strategies, including long-term intervention for chronic patients, through the reparation and replacement of injured cells via mechanisms of differentiation and proliferation. The purpose of this review is to evaluate the therapeutic role of stem cells for ischaemic stroke. The paper discusses the pathology during acute, subacute, and chronic phases of cerebral ischaemic injury, highlights the mechanisms involved in mesenchymal, endothelial, haematopoietic, and neural stem cell-mediated cerebrovascular regeneration and evaluates the pre-clinical and clinical data concerning the safety and efficacy of stem cell-based treatments. Treatment of stroke patients with different type of stem cells appears to be safe and efficacious even at relatively higher concentrations irrespective of the route and timing of administration. Priming or preconditioning of cells prior to administration appears to help augment their therapeutic impact. However, larger patient cohorts and later phase trials are required to consolidate these findings.

Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.

Monoclonal antibody (mAb) therapy has revolutionized the treatment of various diseases, including cancer and autoimmune disorders. However, the emergence of SARS-CoV-2 variants, as well as other pathogenic variants, poses challenges in maintaining the therapeutic efficacy of mAbs. In this mini review article, we aim to explore the strategies to overcome variants resistance in mAb therapy against viral infections. Firstly, we discuss the mechanisms through which variants can evade the neutralizing effects of mAbs. Understanding these mechanisms is crucial in developing targeted approaches to combat resistance. Next, we delve into the strategies being pursued to address variants resistance. These include developing new mAbs or antibody cocktails that target multiple epitopes, engineering mAbs with improved binding affinities or enhanced neutralizing capabilities, and exploring alternative therapeutic modalities such as bispecific antibodies or antibody-drug conjugates. Furthermore, we highlight the role of computational modeling and artificial intelligence in predicting variant escape mutations and aiding in the design of more effective mAbs. Additionally, we examine the importance of continuous surveillance and monitoring of emerging variants to inform treatment strategies. This article emphasizes the urgent need for proactive approaches to tackle variants resistance in mAb therapy. By combining innovative design strategies, computational modeling, and vigilant surveillance, we can maintain the therapeutic effectiveness of mAbs and stay ahead in the battle against evolving pathogens and viral infections.

Prostate cancer (PCa) used to be one of the most common nondermatologic cancers in men that can be treated only with surgery. However, a revolutionary breakthrough came in the 1980s with the introduction of long-acting luteinizing hormone-releasing hormone (LHRH) agonists for the cu-rative treatment of PCa. This paradigm shift contributed to the combined use of androgen depri-vation therapy (ADT), chemotherapy, and radiotherapy for the treatment. The latest data high-light the use of treatment intensification (TI), i.e., combined use of radiotherapy (RT) and hormo-nal or drug treatments, for localized or locally advanced PCa. Indeed, the results of combined modality treatments have shown a reduction in disease-specific mortality and improved overall survival. Although TI seems promising, more research studies are warranted to confirm its effi-cacy. This review summarizes the latest available outcome results of pivotal trials and clinical studies on the efficacy of TI.

Antimicrobial photodynamic therapy (aPDT) used to sterilize carious dentin may irritate the pulp tissues because of tissue-penetrating laser and singlet oxygen generation. This study aimed to assess the effects of aPDT on rat pulp tissues. A cavity formed in a rat maxillary first molar was treated with aPDT. The combined photosensitizer and laser irradiation conditions in the aPDT groups were as follows: methylene blue and 100 mW for 60 s, brilliant blue (BB) and 100 mW for 60 s, BB and 50 mW for 120 s, and BB and 200 mW for 30 s. Each cavity was treated with an all-in-one adhesive and filled with flowable resin. aPDT was not applied for the control. In each group, the rats were sacrificed on postoperative days 1 and 14, and thin sections of the treated teeth were prepared. Pulp tissue disorganization (PTD), inflammatory cell infiltration (ICI), and tertiary dentin formation (TDF) were evaluated. At 1 day evaluation, there were significant differences between the aPDT group and controls with respect to PTD and ICI. 14 days later, almost all specimens showed tertiary dentin formation. aPDT caused temporarily reversible injury to the rat dental pulp, which healed with tertiary dentin formation.

Current treatments in patients with pancreatic cancer offer limited benefits. In this report, we applied “alkalization therapy”, which was efficacious for other solid tumors at our clinic, to stage 4 pancreatic cancer patients, and investigated its effect on disease prognosis. Patients with metastatic pancreatic cancer who were treated at Karasuma Wada Clinic in Kyoto, Japan, between 2011 and 2022 were included in the study. All patients received alkalization therapy (combination of an alkaline diet, bicarbonate, and citric acid administration), alongside standard chemotherapy. Urine samples were collected to assess urine pH as a marker for whole-body alkalization. In the 98 patients analyzed, the median overall survival (OS) from the time of diagnosis was 13.2 months. Patients with a mean urine pH of 7.5 or greater had a median OS of 29.9 months, compared with 15.2 months for those with a mean urine pH of 6.5 to 7.5, and 8.0 months for those with a mean urine pH of less than 6.5, which suggests a trend of a longer OS in patients with a higher urine pH. Conclusions: Alkalization therapy may offer a viable approach to enhance the survival of stage 4 pancreatic cancer patients, who typically have an unfavorable prognosis.

The aim of this study is to prepare redox-sensitive nanophotosensitizers for targeted delivery of chlorin e6 (Ce6) against cervical cancer. For this purpose, Ce6 was conjugated with β-cyclodextrin (bCD) via disulfide bond creating nanophotosensitizers that were fabricated for redox-sensitive delivery of Ce6 against cancer cells. bCD was treated with succinic anhydride to synthesize suc-cinylated bCD (bCDsu). After that, cystamine was attached to the carboxylic end of bCDsu (bCDsu-ss) and the amine end group of bCDsu-ss was conjugated with Ce6 (bCDsu-ss-Ce6). Chemical composition of bCDsu-ss-Ce6 was confirmed with 1H and 13C NMR spectra. bCDsu-ss-Ce6 nanophotosensitizers were fabricated by dialysis procedure. They formed small particles with an average particle size of 152.0±23.2 nm and they showed improved singlet oxygen (SO) generation in the aqueous solution under light irradiation and was significantly higher than that of Ce6 alone. Ce6 release rate from bCDsu-ss-Ce6 nanophotosensitizers was accelerated by addition of glutathione (GSH), indicating that bCDsu-ss-Ce6 nanophotosensitizers have re-dox-sensitive photosensitizer delivery capacity. bCDsu-ss-Ce6 nanophotosensitizers have low in-trinsic cytotoxicity against CCD986Sk human skin fibroblast cells as well as Ce6 alone. However, bCDsu-ss-Ce6 nanophotosensitizers showed improved Ce6 uptake ratio, higher reactive oxygen species (ROS) production and phototoxicity compared to those of Ce6 alone. GSH addition resulted in higher Ce6 uptake ratio, ROS generation and phototoxicity than those of Ce6 alone, indicating that bCDsu-ss-Ce6 nanophotosensitizers have redox-sensitive biological activity in vitro against HeLa human cervical cancer cells. At tumor xenograft model using HeLa cells, bCDsu-ss-Ce6 nanophotosensitizers efficiently accumulated in the tumor rather than normal organs, i.e. fluores-cence intensity in tumor tissues was significantly higher than those of other organs while Ce6 alone did not specifically target tumor tissue. These results indicated higher anticancer activity of bCDsu-ss-Ce6 nanophotosensitizers, by efficiently inhibiting growth of tumor in in vivo animal tumor xenograft study.

This review provides information on acne transcriptomics allowing deeper insights into acne pathogenesis and isotretinoin´s mode of action. Puberty-induced insulin-like growth factor 1 (IGF-1), insulin and androgen signaling activate the kinase AKT and mechanistic target of rapamycin complex 1 (mTORC1). Western diet (hyperglycemic carbohydrates, milk/dairy products) as well co-stimulate AKT/mTORC1 signaling. AKT-mediated phosphorylation of nuclear FoxO1 and FoxO3 results in their extrusion into the cytoplasm, a critical switch, which enhances the transactivation of lipogenic and proinflammatory transcription factors including androgen receptor (AR), sterol regulatory element-binding transcription factor 1 (SREBF1), peroxisome proliferator-activated receptor γ (PPARγ), and signal transducer and activator of transcription 3 (STAT3) but reduces FoxO1-dependent expression of GATA binding protein 6 (GATA6), the key transcription factor of infundibular keratinocyte homeostasis. AKT-mediated phosphorylation of the p53-binding protein MDM2 promotes the degradation of p53. In contrast, isotretinoin enhances the expression of p53, FoxO1 and FoxO3 in sebaceous glands of acne patients. Overexpression of these proapoptotic transcription factors explains isotretinoin´s desired sebum-suppressive effect via induction of sebocyte apoptosis but also its adverse effects including teratogenicity (neural crest cell apoptosis), reduced ovarian reserve (granulosa cell apoptosis), risk of depression (apoptosis of hypothalamic neurons), VLDL hyperlipidemia, intracranial hypertension and dry skin.

Damaged connective tissues between the bone and tendons or ligaments are common among adults regardless of activity level. Achilles tendinosis is one of the most common tissue defects and enthesopathies. The patient in this study is a 54-year-old female with chronic Achilles tendinosis from chronic enthesopathy at the Achilles tendon insertion with a retrocalcaneal exostosis for three years who has failed standard-of-care practices for over two years. The patient received extracorporeal pulsed-activated therapy (EPAT) before applying 2ml of CryoText, a Wharton’s jelly tissue allograft. The patient then received class IV laser therapy treatments twice weekly for three weeks. The patient started with a 10/10 VAS at the initial visit. At five weeks post-application, the patient’s score had improved by 80% at 2/10 VAS. By week 13, the patient rated her pain as 0/10 VAS. The improvement in patient-reported pain and functionality reported in this study after the application of Wharton’s Jelly, EPAT, and class IV laser therapy warrants future research studying the safety and efficacy of these patient care modalities together.

Research has shown the role of growth factors in lung cancer angiogenesis. Angiogenesis promotes lung cancer progression by stimulating tumor growth, enhancing tumor invasion, contributing to metastasis, and modifying immune system responses within the tumor microenvironment. As a result, new treatment techniques based on the anti-angiogenic characteristics of compounds have been developed. These compounds selectively block the growth factors themselves, their receptors, or the downstream signaling pathways activated by these growth factors. The EGF and VEGF families are the primary targets in this approach, and several studies are being conducted to propose anti-angiogenic drugs that are increasingly suitable for the treatment of lung cancer, either as monotherapy or as combined therapy. The efficacy results are encouraging, but a caution must be placed on the higher risk of toxicity, outlining the importance of personalized follow-up in the management of these patients.

The concept of targeted drug delivery can be described in terms of the drug’s ability to mimic the other biological objects’ property to localize to target cells or tissues. For example, drug delivery systems based on red blood cells or mimicking some of their useful features, such as long circulation in stealth mode, have been known for decades. On the contrary, therapeutic strategies based on macrophages have gained very limited attention until recently. Here we review two biomimetic strategies associated with macrophages, that can be used to develop new therapeutic modalities: First, the mimicry of certain types of macrophages (i.e., the use of macrophages, including tumor-associated, or macrophage-like particles as a carrier for targeted delivery of therapeutic agents); and Second, the mimicry of ligands, naturally absorbed by macrophages (i.e., the use of therapeutic agents specifically targeted at macrophages). We discuss potential applications of biomimetic systems involving macrophages for the new advancements in treatment of infections, inflammatory diseases, and cancer.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and biologically heterogeneous disease. Approximately 40% of patients with DLBCL will experience disease relapse or will be refractory to first line chemoimmunotherapy. In recent years there have been several new therapeutic agents approved for the treatment of relapsed/refractory (R/R) DLBCL. These agents include anti-CD19 chimeric antigen receptor T-cell therapies (CAR T-cells) and monoclonal antibodies as polatuzumab and tafasitamab. Nevertheless, despite the high efficacy of all these new therapies, there are still patients who do not respond or relapse, representing an unmet clinical need. This review describes new promising therapies that are under investigation to treat R/R DLBCL.

(1) Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that poses unique management challenges. This review aims to synthesize the current literature on IBC, focusing on diagnosis, treatment, and prognosis, while highlighting recent advances and ongoing issues in patient management.; (2) Methods: We outline the typical clinical presentation and diagnostic criteria of IBC. Additionally, we detail the main therapeutic strategies, including neoadjuvant chemotherapy, surgery, radiation therapy, targeted therapies, hormonal therapies, and emerging treatments such as immunotherapy. The review is based on a comprehensive analysis of the existing literature.; (3) Results: Despite advancements in systemic therapy and a better understanding of IBC biology, the prognosis for patients with IBC remains poor. The overall survival rate has shown only marginal improvement over the past few decades. Future research directions, including the identification of novel biomarkers for early detection and personalized medicine strategies, are identified. The need for more high-quality clinical trials to address the challenges in IBC management is emphasized.; (4) Conclusions: Managing IBC is a complex task that necessitates multidisciplinary care and patient-centered communication. This review provides clinicians and researchers with a comprehensive overview of the current challenges and future directions in IBC management. The goal is to guide treatment decisions and inform further research, ultimately improving patient outcomes and prognosis.

Pancreas transplantation is a high-risk operation that requires significant skill and expertise from the surgeons and the postoperative care team. Prior to candidate qualification, all contraindications to this procedure must be excluded. The use of screening tools and nutritional assessment aims to emphasize the importance of accurately diagnosing nutritional status in order to implement early nutritional interventions and reduce complications associated with malnutrition. This plays a crucial role in improving postoperative outcomes for patients undergoing pancreas and/or kidney transplantation. Objective: The aim of this study was to analyze the parameters of nutritional status in patients eligible for kidney transplantation and kidney with pancreas transplantation. Methods: The study analyzed the database of hospitalized patients in our Center from 2020 to 2023 to identify preoperative parameters of nutritional status in patients eligible for kidney transplantation (Ktx) and kidney with pancreas transplantation (SPKTx). Participants: A total of 59 patients participated in the study, who were candidates for kidney transplantation (23, including 11 females and 12 males) or kidney with pancreas transplantation (36, including 24 females and 12 males). Parameters examined included: Onoder's Prognostic Nutritional Index (PNIO), Nutrition Risk Index (NRI), ideal body weight (IBW) calculated using the Lorenz formula, and the neutrophil-to-lymphocyte ratio (NLR). All patients admitted to the clinic underwent the NRS-2002 clinical assessment scale for nutritional status. Results: Upon analyzing the obtained results, it was found that BMI was not a good differentiating parameter for the studied groups. The PNIO index also insufficiently differentiated the studied groups, and similarly, the NRI index was a weak differentiating parameter. The NRS-2002 index and albumin level were the best indicators of differences between the groups. In the group of transplantation candidates, several parameters indicated that patients in the Ktx group (kidney transplantation candidates) had better nutritional status than SPKtx candidates (kidney with pancreas transplantation candidates), despite the former group being older patients. Conclusion: It seems that more effort should be made to start a proper nutrition plan for SPKTx (and especially peritoneal dialysis) patients. Regular assessment of nutrition status should be performed. SPKtx patients in the perioperative period should receive parenteral nutrition and, as soon as their general condition allows it, enteral nutrition, taking into account the caloric and protein needs

Coronary no-reflow (CNR) is a frequent phenomenon that develops in patients with ST-segment elevation myocardial infarction (STEMI) following reperfusion therapy. CNR is highly dynamic and develops gradually (over hours) and persists for days to weeks after reperfusion. Microvascular obstruction (MVO) developing as a consequence of myocardial ischemia, distal embolization and reperfusion-related injury is the main pathophysiological mechanism of CNR. The frequency of CNR or MVO after primary PCI differs widely depending on the sensitivity of the tools used for diagnosis and timing of examination. Coronary angiography is readily available and most convenient to diagnose CNR but it is highly conservative and underestimates the true frequency of CNR. Cardiac magnetic resonance (CMR) imaging is the most sensitive method to diagnose MVO and CNR that provides information on the presence, localization and extent of MVO. CMR imaging detects intramyocardial hemorrhage and accurately estimates the infract size. MVO and CNR markedly negate the benefits of reperfusion therapy and contribute to poor clinical outcomes including adverse remodeling of left ventricle, worsening or new congestive heart failure and reduced survival. Despite extensive research and the use of therapies that target almost all known pathophysiological mechanisms of CNR, no therapy has been found that prevents or reverses CNR and provides consistent clinical benefit in patients with STEMI undergoing reperfusion. Currently the prevention or alleviation of MVO and CNR remain unmet goals in the therapy of STEMI that continue to be under intense research.

Patient value is an important factor in clinical decision-making, but conventionally, it is not incorporated in the decision processes. In this paper, a value-based therapy recommendation comprehensive model is proposed. A literature analysis is conducted to collect value-based evidence. Categorized values and candidate therapies are used in combination as filtering keywords to build this evidence. Then a formalism model is put forward to integrate the value-based evidence with clinical evidence. The relative importance of two evidence can be adjusted dynamically by decision-makers during the decision-making processes. A prototype system was implemented using a case study for breast cancer and validated for feasibility and effectiveness.

Duchenne muscular dystrophy (DMD) is a yet incurable rare genetic disease that affects the skeletal and cardiac muscles, leading to progressive muscle wasting and premature death. DMD is caused by the lack of dystrophin, a muscle protein essential for the biochemical support and integrity of muscle fibers. Gene replacement strategies for Duchenne muscular dystrophy (DMD) employing the adeno-associated virus (AAV) face the challenge imposed by the limited packaging capacity of AAV, only allowing the accommodation of a short version of dystrophin (µDys) that is still far removed from correcting human disease. The need to develop strategies leading to the expression of a best performing dystrophin variant led to only few studies reporting on the use of dual vectors, but none reported on a method to assess in vivo transgene reconstitution efficiency, the degree of which directly affects the use of safe AAV dosing. We report here on the generation of a dual AAV vector approach for the expression of a larger dystrophin version (quasidystrophin) based on homologous recombination, and the development of a methodology employing a strategic droplet digital PCR design, to determine the recombination efficiency as well as the occurrence of unwanted concatemerization events or aberrant expression from the single vectors. We demonstrated that, upon systemic delivery in the dystrophic DBA2mdx mice, our dual AAV approach led to high transgene reconstitution efficiency and negligible ITR-dependent concatemerization, with consequent remarkable protein restoration in muscles and improvement of muscle pathology. This evidence supports the suitability of our system for gene therapy application and the potential of this methodology to assess and improve the feasibility for therapeutic translation of multiple vector approaches

Background: Boron Neutron Capture Therapy (BNCT) is an emerging radiotherapy. There are ongoing efforts to develop a Canadian accelerator-based BNCT center. However, it remains unclear how Canadian radiation oncologists (RO), medical physicists (MP), and their trainees perceive BNCT and its impact on radiation oncology as a discipline. Methods: A survey was created to explore knowledge of BNCT, its clinical role, and support for Canadian research. It was distributed through the Canadian Association of Radiation Oncology (CARO) and Canadian Organization of Medical Physicists (COMP). Results: We received 118 valid responses from all 10 provinces, from 70 RO (59.3%) and 48 MP (40.7%), including 9 residents. Most knew of BNCT and its indications (60.2%). Although many were unaware of reasons behind early failures (44.1%), common reasons were lack of clinical trials and inaccessibility of neutron sources (42.4%) and reactor unsuitability (34.7%). Additionally, 90.6% showed definite (66.9%) or possible (23.7%) support for Canadian BNCT research, while 89% indicated definite (56.8%) or possible (32.2%) willingness for BNCT referrals. Conclusions: Most RO and MP supported Canadian BNCT research and would refer patients. However, limited awareness and lack of experiences remain a challenge. Educational sessions are needed to realize this innovative cancer treatment in Canada.

Long non-coding RNAs (LncRNAs) are mRNA-like molecules that do not encode for proteins and that are longer than 200 nucleotides. LncRNAs play important biological roles in normal cell physiology and organism development. Therefore, deregulation of their activities is involved in disease processes such as cancer. Lung cancer is the leading cause of cancer-related deaths due to late stage at diagnosis, distant metastasis, and high rates of therapeutic failure. LncRNAs are emerging as important molecules in lung cancer for their oncogenic or tumor suppressive functions. LncRNAs are highly stable in circulation, presenting an opportunity for use as non-invasive and early-stage cancer diagnostic tools. Here, we summarize latest works providing in vivo evidence available for LncRNAs role in cancer development, therapy-induced resistance, and their potential as biomarkers for diagnosis and prognosis, with a focus on lung cancer. Additionally, we discuss current therapeutic approaches to target LncRNAs. The evidence discussed here strongly suggests that investigation of LncRNAs in lung cancer in addition to protein-coding genes will provide a holistic view of molecular mechanisms of cancer initiation, development, and progression, and could open a new avenue for cancer treatment.

Gene therapy has seen major progress in recent years. Viral vectors have made a significant contribution through efficient engineering for improved delivery and safety. A large variety of indications such as cancer, cardiovascular, metabolic, hematological, neurological, muscular, ophthalmological, infectious diseases, and immunodeficiency have been targeted. Viral vectors based on adenoviruses, adeno-associated viruses, herpes simplex viruses, retroviruses including lentiviruses, alphaviruses, flaviviruses, measles viruses, rhabdoviruses, Newcastle disease virus, poxviruses, picornaviruses, reoviruses, and polyomaviruses have been used. Proof-of-concept has been demonstrated for different indications in animal models. Therapeutic efficacy has also been achieved in clinical trials. Several viral vector-based drugs have been approved for the treatment of cancer, and hematological, metabolic, and neurological diseases. Moreover, viral vector-based vaccines have been approved against COVID-19 and Ebola virus disease.

Background and Objectives: Light therapy (LT) is used as an adjunctive treatment for sleep problems. This study evaluates the impact of LT on sleep quality and sleep-related parameters in patients with sleep disorders. Materials and Methods: We performed a pilot randomized, open-label clinical trial. Fourteen patients aged 20–60 years with sleep disorders for more than three months were randomized into the control and LT groups (1:1 ratio). The LT group was instructed to use a device that provides bright LT (6000 K, 380 lux, wavelength 480 nm) for at least 25 minutes before 09:00 am for two weeks. A self-reported questionnaire was used to evaluate circadian preference, mood, and sleep-related parameters. We analyzed serum cortisol levels and clock genes expression. Results: The Epworth Sleepiness Scale (ESS), insomnia severity index, and Pittsburgh Sleep Quality index were significantly improved within the LT group only after the two-week period. When comparing the two groups, only the change in ESS significant was significant (mean difference; control: -0.14 vs LT: -1.43, p=0.021) after adjusting for baseline characteristics. There were no significant differences in serum cortisol or clock genes expression. Conclusions: LT can improve daytime sleepiness in patients with sleep disorders; however, further well-designed studies are warranted to confirm its efficacy.

Lipofuscin is indigestible garbage that accumulates in the autophagic vesicles and cytosol of post-mitotic cells with age. Drs. Brunk and Terman postulated that lipofuscin accumulation is the main or at least a major driving factor in aging. They even posited that the evolution of memory is the reason why we get lipofuscin at all, as stable synaptic connections must be maintained over time, meaning that the somas of neurons must also remain in the same locale. In other words, they cannot dilute out their garbage over time through cell division. Mechanistically, their position certainly makes sense given that rendering a large percentage of a post-mitotic cell’s lysosomes useless must almost certainly negatively affect that cell and the surrounding microenvironment. Here, I explore the possibility that the accumulation of lipofuscin to some extent underlies all other categories of age-related damage as defined by Dr. Aubrey de Grey. I do not think that lipofuscin removal will reverse/prevent all forms of aging, just the major component facing us currently. In this piece, I will review what is known about lipofuscin accumulation from evolutionary and mechanistic standpoints and discuss ways of removing it from non-dividing (or slowly-dividing) cells.

Due to its built-up chemoresistance after prolonged usage, the demand for replacing platinum in metal-based drugs (MBD) is rising. The first MBD approved by the FDA for cancer therapy was cisplatin in 1978. Even after nearly four and a half decades of trials, there has been no significant improvement in osteosarcoma (OS) therapy. In fact, many MBD have been developed, but the chemoresistance problem raised by platinum remains unresolved. This motivates us to elucidate the possibilities of the copper and zinc (CuZn) combination to replace platinum in MBD. Thus, the anti-chemoresistance properties of CuZn and their physiological functions for OS therapy are highlighted. Herein, we summarise their chelators, main organic solvents, and ligand functions in their structures that are involved in anti-chemoresistance properties. Through this review, it is rational to discuss their ligands’ roles as biosensors in drug delivery systems. Hereafter, an in-depth understanding of their redox and photoactive function relationships is provided. The disadvantage is that the other functions of biosensors cannot be elaborated on here. As a result, this review is being developed, which is expected to intensify OS drugs with higher cure rates. Nonetheless, this advancement intends to solve the major chemoresistance obstacle towards clinical efficacy.

Introduction: Individuals with gout are at higher risk of developing chronic conditions, such as diabetes, chronic kidney disease (CKD), and cardiovascular diseases. In this study, the association between urate-lowering therapy (ULT) use and the prevalence of these conditions was evaluated. Methods: This observational, cross-sectional pharmacoepidemiologic study used the 2013-2018 biannual cycles of the National Health and Nutrition Examination Survey. The inclusion criteria were adults 30 years of age and older with a diagnosis of gout. The association between ULT treatment status and dyslipidemia, coronary heart disease, heart failure, hypertension, and chronic kidney disease was evaluated, as well as associations with select clinical laboratory biomarkers. Results: Use of ULT was 28.9% (95%CI 24.3%-33.9%). There was no significant association between ULT use and the prevalence of heart failure, coronary heart disease, hypertension, or dyslipidemia (p>0.05). Those on ULT had a lower mean eGFR compared to those not on treatment (68.03 versus 74.74 mL/min/1.73m², p=0.014). LDL- and HDL- and total cholesterol were significantly lower among those receiving ULT treatment (p<0.05). Conclusion: ULT use continues to be low among those with gout. Those on ULT were more likely to be diagnosed with CKD, college graduates and above, older males, and obese. Clinical guidelines conditionally recommend ULTs in co-morbid kidney disease; while our results may reflect guidelines recommendation for ULT use in CKD patients, worsening kidney function while taking ULT is unlikely. Further research is necessary to determine the long-term impact of ULTs on kidney function and cardiovascular biomarkers.

Bright morning light (BML) entrains the body clock, modulates circadian rhythm, and improves sleep-wake disturbances. However, its impact on the autonomic nervous system (ANS) at night remains unclear. Hence, we investigated the effects of BML exposure on activities of the parasympathetic nervous system (PSNS) and sympathetic nervous system (SNS) at night. This non-randomized controlled pilot study included participants ≥60 years, diagnosed with a type of dementia or cognitive disorder. We excluded participants with pacemakers. The treatment group received 2500 lx BML, whereas the control group received approximately 200 lx of general lighting. We measured the heart rate variability to quantify ANS activity. The treatment group displayed significantly increased high-frequency (HF) power (Roy's largest root=2.44; P<.01) and insignificantly decreased normalized low-frequency (LF%) power. The corresponding low-frequency/high-frequency ratio (LF/HF), insignificant decrease, and cognitive function were correlated with PSNS activity (Roy's largest root=3.92; P<.01), which is effective for moderate dementia. BML exposure reduced SNS activity and enhanced PSNS activity at night, which consequently affected cognitive function. Furthermore, the light washout intervention markedly increased SNS activity at night. BML therapy may be a useful clinical tool for alleviating the deterioration of cognitive function.

A Pacific brittle star Ophiura sarsii has previously been shown to produce a chlorin (3S,4S)-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (ETPA) (1) with potent phototoxic activities making it applicable to photodynamic therapy. Using extensive LC-MS metabolite profiling, molecular network analysis and targeted isolation with de novo NMR structure elucidation, we here identify five additional chlorin compounds from O. sarsii and its deep-sea relative O. ooplax: 10S-Hydroxypheophorbide a (2), Pheophorbide a (3), Pyropheophorbide a (4), (3S,4S,21R)-14-Ethyl-9-(hydroxymethyl)-21-(methoxycarbonyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (5), and (3S,4S,21R)-14-Ethyl-21-hydroxy-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (6). Chlorins 5 and 6 have not been previously reported in natural sources. Interestingly, low amounts of chlorins 1-4 and 6 could also be identified in a distant species, the basket star Gorgonocephalus cf. eucnemis, demonstrating that chlorins are produced by a wide spectrum of marine invertebrates of the class Ophiuroidea. Following purification of these major Ophiura chlorin metabolites, we discovered the high singlet oxygen quantum yield upon their photoinduction and their strong phototoxicity against a panel of cancer cell lines. These studies identify an arsenal of brittle star chlorins as powerful natural photosensitizers with potential photodynamic therapy applications.

There is increasing interest in the application of near-infrared (NIR) laser light for the treatment of various musculoskeletal disorders. The present study thoroughly examined the physical characteristics of laser beams from two different laser therapy devices that are commercially available for the treatment of musculoskeletal disorders. Then, these laser beams were used to measure the penetration depth in various biological tissues from different animal species. The key result of the present study was the finding that for all investigated tissues, most of the initial light energy was lost in the first one to two millimeters, more than 90% of the light energy was absorbed within the first ten millimeters, and there was hardly any light energy left after 15 – 20 mm of tissue. Furthermore, the investigated laser therapy devices fundamentally differed in several laser beam parameters that can have an influence on how light is transmitted through tissue. Overall, the present study showed that a laser therapy device that is supposed to reach deep layers of tissue for treatments of musculoskeletal disorders should operate with a wavelength between 800 nm and 905 nm, a top-hat beam profile, and it should emit very short pulses with a large peak power.

The discovery of first ATP-binding cassette (ABC) transporter, whose overexpression in cancer cells is responsible for exporting anticancer drugs out of tumor cells, initiated enormous efforts to overcome tumor cell multidrug resistance (MDR) by inhibition of ABC-transporter. Because of its many physiological functions, diverse studies have been conducted on the mechanism, function and regulation of this important group of transmembrane transport proteins. In this review, we will focus on the structural aspects of this transporter superfamily. Since the resolution revolution of electron microscope, experimentally solved structures increased rapidly. A summary of the structures available and an overview of recent structure-based studies are provided. More specifically, the artificial intelligence (AI)-based predictions from AlphaFold 2 will be discussed.

Human Adenovirus (HAdV) infection occurs in 14-16% of patients in the early months after pediatric hematopoietic cell transplantation (HCT) and this correlates with a higher risk to develop HAdV disease and overall 6-month mortality. The main risk factors for HAdV infection are T-cell depletion of the graft by ex vivo CD34+ selection or in vivo use of alemtuzumab or anti-thymocyte serum, the development of grade III-IV graft versus host disease (GVHD), the type of donor (unrelated donor, cord blood, haploidentical or HLA mismatched parent) and severe lymphopenia (< 0.2 x 109/L). The prevention of HAdV disease is based on early intervention with antivirals in the asymptomatic patient when the permitted viral load threshold on blood (> 102-3 copies/ml) and/or on the stool (109 copies/g stool) is exceeded. Cidofovir, a monophosphate nucleotide analog of cytosine, is the primary drug for preemptive therapy, used at 5 mg/kg/week for 2 weeks followed by 3-5 mg/kg every 2 weeks. The alternative schedule is 1 mg/kg every other day (three times/week). Enhancing virus-specific T-cell immunity in the first months post-HCT by donor-derived or third-party-derived virus-specific T cells represents an innovative and promising way of intervention applicable both in prevention and therapeutic setting.

The introduction of tenofovir-derived prodrugs has revolutionised the prevention and management of HIV, which has coincided with 23% reduction in new HIV incidences globally. To date, there are two formulations of tenofovir-derived nucleoside reverse transcriptase inhibitor (NRTI): tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and tenofovir alafenamide fumarate/emtricitabine (TAF/FTC). Although these prodrugs have shown favourable safety profile, their effects on cardiovascular health are differ from one another: TDF/FTC exhibits potential lipid-lowering effect, TAF/FTC demonstrates potential lipid-inducing effect, which is a major risk factor for cardiovascular diseases. However, this issue has not been previously elucidated, especially among the marginalised populations [lesbian, gay, bisexual and transgender (LGBT) and men who have sex with men (MSM)] who are likely be the main users of these prodrugs. This is of clinically significance as the cardiovascular health in these populations is often overlooked, in addition to a lack of appropriate cardiovascular risk prediction algorithm. Therefore, this review aims to (1) highlight the cardiovascular risks of tenofovir-derived prodrugs in the marginalized populations, and also to (2) establish the importance of having a cardiovascular risk prediction model that is specific to this particular populations so that their health management could be more comprehensive.

Chronic myeloid leukaemia (CML) is a haematological neoplasm driven by the BCR/ABL fusion oncogene. The monogenic aspect of the disease and the feasibility of ex vivo therapies in haematological disorders make CML an excellent candidate for gene therapy strategies. The ability to abolish any coding sequence by CRISPR-Cas9 nucleases offers a powerful therapeutic opportunity to CML patients. However, a definitive cure can only be achieved when only CRISPR-edited cells are selected. A gene-trapping approach combined with CRISPR technology would be an ideal approach to ensure this. Here, we have developed a CRISPR-Trap strategy that efficiently inserts a donor gene trap (SA-CMV-Venus) cassette into the BCR-ABL1-specific fusion point in the CML K562 human cell line. The trapping cassette interrupts the on-cogene coding sequence and expresses a reporter gene that enables the selection of edited cells. Quantitative expression analyses showed significantly higher level of expression of the BCR-Venus allele coupled with a drastically lower level of BCR/ABL expression in Venus+ cell fractions. Functional in vitro experiments showed cell proliferation arrest and apoptosis in selected Venus+ cells. Finally, xenograft experiments with the selected Venus+ cells showed a large reduction in tumour growth, thereby demonstrating a therapeutic benefit in vivo. This study is a proof of concept for the therapeutic potential of a CRISPR-Trap system as a novel strategy for gene elimination in haematological neoplasms.