Groundbreaking Treatment Research Articles

Deep brain stimulation: a promising approach to revolutionize the treatment of pediatric epilepsy.

A variety of treatment modalities currently exist for epilepsy, a debilitating disorder. With the emergence of drug-resistant epilepsy, however, new options are being explored. Deep brain stimulation is a neuromodulation technique that can prove to be a ground-breaking treatment option for pediatric epilepsy. It employs a neurosurgical method in which electrodes are implanted within the brain that send impulses to control abnormal brain activity. Significant gaps exist in literature, thereby emphasizing the importance of further research in this promising approach.

Nanotechnology in Advancing Chimeric Antigen Receptor T Cell Therapy for Cancer Treatment.

Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking treatment for hematological cancers, yet it faces significant hurdles, particularly regarding its efficacy in solid tumors and concerning associated adverse effects. This review provides a comprehensive analysis of the advancements and ongoing challenges in CAR-T therapy. We highlight the transformative potential of nanotechnology in enhancing CAR-T therapy by improving targeting precision, modulating the immune-suppressive tumor microenvironment, and overcoming physical barriers. Nanotechnology facilitates efficient CAR gene delivery into T cells, boosting transfection efficiency and potentially reducing therapy costs. Moreover, nanotechnology offers innovative solutions to mitigate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cutting-edge nanotechnology platforms for real-time monitoring of CAR-T cell activity and cytokine release are also discussed. By integrating these advancements, we aim to provide valuable insights and pave the way for the next generation of CAR-T cell therapies to overcome current limitations and enhance therapeutic outcomes.

Mind Unveiled: Cutting-Edge Neuroscience and Precision Brain Mapping

Neuroscience, a dynamic field at the forefront of scientific exploration, is unravelling the complexities of the human brain. By merging biology, psychology, physics, and computer science, researchers are gaining profound insights into cognition, behaviour, and the neurological underpinnings of diseases. Brain mapping is a key component of recent advancements. Techniques like fMRI, PET, and DTI offer unprecedented views of brain structure and function. The Human Connectome Project and similar initiatives have produced detailed maps of brain connections, revealing how different regions interact to support cognition and behaviour. These maps are crucial for identifying disease biomarkers, predicting treatment responses, and developing targeted therapies. Molecular biology and genetics are also driving progress. Researchers are uncovering the genetic basis of neurological disorders, providing clues about disease susceptibility and progression. Molecular imaging techniques visualise neurotransmitter systems and cellular processes, shedding light on disease mechanisms. The integration of neuroscience with computer modelling and AI is revolutionising research. AI algorithms analyse vast datasets, simulate neural networks, and even decode neural signals for brain-machine interfaces. This has the potential for personalised medicine and ground-breaking treatments. The future holds immense promise. Techniques like optogenetics and single-cell imaging will offer even greater precision in studying brain circuits. However, we must address ethical considerations around data privacy, cognitive enhancement, and brain-altering interventions. Neuroscience is not just about understanding the brain; it's about improving lives. Researchers are striving to conquer neurological disorders and maximize human potential by pushing the boundaries of knowledge and technology while upholding ethical principles.

IMMUnity Unveiled: A Translational NETwork for tackling PARKinson's Disease – IMMUPARKNET

Parkinson’s disease (PD) affects more than one million people in the EU. It currently has no definitive cure, meaning that patients rely only on symptomatic treatments, which themselves are burdened by side effects. The need for advancements in both knowledge and available treatments is thus strongly felt by patients, caregivers, and health operators. This unmet need sparked the idea of orchestrating a collaborative effort via a common network – IMMUPARKNET (The role of IMMUnity in tackling PARKinson’s disease through a Translational NETwork). The IMMUPARKNET COST Action focuses on challenges in PD and its related crosstalk with immune response. Although widely recognized, the role of immunity in the onset and development of PD is still unclear. The main goal of IMMUPARKNET is to fill this knowledge gap by establishing an innovative, interdisciplinary research network and fostering exchanges of expertise among specialists from different countries and institutions. As we gather scientists and clinicians who study immunity in PD and related fields, IMMUPARKNET will establish the first nucleus of a multidisciplinary ecosystem that aims to harmonize efforts and approaches, both in research and clinical practice, to boost the development of ground-breaking treatments for PD. Through meetings, training schools, webinars, position papers, and review manuscripts, IMMUPARKNET will lead fruitful exchanges of know-how among experts in the field. The IMMUPARKNET structure revolves around 5 working groups, with a total of 157 active members from 34 different countries. Of these active members, 58.5% are young researchers, while 67.5% come from Inclusiveness Target Countries (ITC - less research-intensive COST Members; https://www.cost.eu/about/members/). IMMUPARKNET output will facilitate the improved sharing and development of research resources, straightening the road to novel treatments and identifying where existing ones can be repurposed, all, ultimately and hopefully, finding a cure for PD.

Revitalizing oral cancer research: Crispr-Cas9 technology the promise of genetic editing.

This review presents an in-depth analysis of the immense potential of CRISPR-Cas9 technology in revolutionizing oral cancer research. It underscores the inherent limitations of conventional treatments while emphasizing the pressing need for groundbreaking approaches. The unparalleled capability of CRISPR-Cas9 to precisely target and modify specific genes involved in cancer progression heralds a new era in therapeutic intervention. Employing genome-wide CRISPR screens, vulnerabilities in oral cancer cells can be identified, thereby unravelling promising targets for therapeutic interventions. In the realm of oral cancer, the disruptive power of CRISPR-Cas9 manifests through its capacity to perturb genes that are intricately associated with drug resistance, consequently augmenting the efficacy of chemotherapy. To address the challenges that arise, this review diligently examines pertinent issues such as off-target effects, efficient delivery mechanisms, and the ethical considerations surrounding germline editing. Through precise gene editing, facilitated by CRISPR/Cas9, it becomes possible to overcome drug resistance by rectifying mutations, thereby enhancing the efficacy of personalized treatment strategies. This review delves into the prospects of CRISPR-Cas9, illuminating its potential applications in the domains of medicine, agriculture, and biotechnology. It is paramount to emphasize the necessity of ongoing research endeavors and the imperative to develop targeted therapies tailored specifically for oral cancer. By embracing this comprehensive overview, we can pave the way for ground-breaking treatments that instill renewed hope for enhanced outcomes in individuals afflicted by oral cancer.

Tumor Treating Fields for Treatment of Spinal Metastasis

INTRODUCTION: Tumor treating fields(TTF) has never been described for treatment of spinal metastasis. We investigate the anti-mitotic effect of TTF to inhibit the growth of human cancer using cells in vitro and in vivo models of spinal metastasis. METHODS: In-vitro: human derived osteosarcoma (Krib-Luc-1) and lund adenocarcinoma (A549-Luc) cells were seeded in 5x5mm human demineralized bone grafts kept in culture while treated with 0 KHz (control) or 150 KHz of TTF for 14 days. Bioluminescence images (BLI) were obtained at baseline and 14 days. In-vivo: Krib-Luc-1 cells were surgically implanted via trasperitoneal approach to the L3 vertebra in nude mice. Animals were treated with 0 KHz or 150 KHz of TTF for 30 days or until paralysis. BLI were obtained at day 0 and every 7 days. MRI was obtained at day 22. Histological analysis was performed at the end of the experiment. Control and TTF treated groups were compared with two-tailed t-tests. RESULTS: In vitro: BLI of the control grafts demonstrated a median value of 1×10^10 photons/sec at 14 days, significantly higher than 1×10^8 photons/sec observed in the 150 KHz group (p < 0.0001). In Vivo: median time to paralysis in control animals was 25 days, all animals treated with TTF at 150 KHz reached the 30 day mark without deficits. BLI of the control group was 3.5×10^9 photons/sec significantly higher than 1×10^9 photons/sec in the 150 KHz TTF group (p = 0.0212). MRI and histological analysis confirmed significant smaller tumors in the treated group when compared to controls. CONCLUSIONS: Application of TTF 150 KHz reduced cellular proliferation in both in vitro and in vivo models of spinal metastasis. We believe TTF could become a groundbreaking treatment for spinal metastasis.

Franz Alfred (1880-1962) and Georg Frederich (1921-2010) Kantorowicz.

George Kantorowicz was a senior lecturer/consultant in conservative dentistry at the Royal Dental Hospital who provided ground-breaking treatment for cleft palate children at Great Ormond Street Hospital. His father, Alfred, was a Jewish professor, dean at Bonn Dental School and a world-famous advocate of mobile dental surgeries and prevention for children's dental health, until the Nazis put him in a concentration camp. After important interventions, he became director of Istanbul Dental Institute.

Characteristics and use of patient-reported outcomes of clinical trials for high-risk neurological medical devices that received FDA premarket approval from 2001 to 2022

Neurological medical devices have revolutionized the management of neurological disorders, providing diagnostic, therapeutic, and monitoring solutions. High-risk neurological devices, such as deep brain stimulation and neurostimulators, offer groundbreaking treatments, emphasizing patient benefits while considering risks. To gain FDA approval, high-risk Class III devices necessitate premarket approval (PMA) applications with pivotal clinical trials, often assessing patient-reported outcomes (PROs). This article analyzes FDA-approved high-risk neurological devices from 2001 to 2022 via the PMA pathway. It explores device characteristics and pivotal clinical trials, and PRO incorporation. Of the 23 identified devices, pain neurology devices (30.4 %) predominated. All devices were therapeutic, with varying study designs. Pain neurology devices notably emphasized PRO endpoints as expected. This study underscores the significance of PROs in assessing device efficacy and safety, offering insights into regulatory processes and patient-centered care in neurological disorder management.

Psilocybin Therapy for Depression: A Review of Current Molecular Knowledge

Depression, affecting over 264 million people globally, presents significant treatment challenges, often due to the limited efficacy and adverse effects of traditional antidepressants and the accessibility issues associated with psychotherapy. Recent advancements in psychedelic-assisted therapy, particularly using psilocybin, a naturally occurring compound found in “magic mushrooms”, shows promising potential for treating major depressive disorder (MDD) and treatment-resistant depression (TRD). This review explores the historical context, clinical trial outcomes, and the biological mechanisms underlying psilocybin’s effects. Clinical studies from 2016 to 2023 indicate that psilocybin, in combination with psychological support, significantly reduces depressive symptoms, with benefits lasting up to several months after a single dose treatment. The molecular action of psilocybin involves its conversion to psilocin, which interacts with serotonin receptors, notably the 5-HT2A receptor, influencing neurotransmitter systems and promoting anti-inflammatory responses and neuroplasticity. The review also discusses the safety profile of psilocybin, highlighting its low risk for dependency and minimal adverse effects compared to traditional treatments. Finally, the therapeutic advantages of psilocybin over conventional antidepressants are evaluated, emphasizing its rapid and sustained antidepressant effects, which contribute to its potential as a groundbreaking treatment for depression.

Technological developments in electric-based DBS

Modern electric-based deep brain stimulation (DBS) surgery has been a groundbreaking treatment modality since its first successful application in 1987. There have been many developments in electrical-based DBS technology over the years. We can divide these into titles as implants, stimulation parameters and developments in programming. Apart from that, the technique is in a constant state of evolution in parallel with the developments in many fields such as stereotactic localization, electrophysiology, radiological imaging, data processing and artificial intelligence. In the coming years, many developments are expected that will affect both the implant components, the stimulation parameters and the follow-up and programming processes of the patients.

From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment.

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nonetheless, newly approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have a 50% responder rate ranging from 27 to 71.0%, whereas CGRP receptor inhibitors have a 50% responder rate ranging from 56 to 71%. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge of PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines.

Generation of Bi-Specific Chimeric Antigen Receptor (CAR) T Cell Therapy for the Treatment of AIDS-Related B Cell Malignancies from Healthy Donors and HIV Patients

Introduction: Individuals with human immunodeficiency virus (HIV) face a substantially greater likelihood of developing cancers compared to the general population. The prevalence of cancer diagnosis among HIV-positive individuals ranges from 25% to 40%. Non-Hodgkin lymphoma (NHL) stands out as the most prevalent cancer type associated with people living with HIV/AIDS (PLWHA). NHL primarily manifests in two forms in PLWHA: Burkitt lymphoma, which poses an 18-fold higher risk, and diffuse large B cell lymphoma (DLBCL), accounting for 75% of cases. The advent of chimeric antigen receptor (CAR) T cell therapies, notably CD19-targeting CAR T cells, has emerged as a groundbreaking treatment for B cell NHL. Unfortunately, PLWHA has been excluded from participating in all of these clinical trials for years due to safety concerns and the challenges associated with manufacturing CAR T cell products from HIV-positive donors. Recent researches explored the feasibility of developing CD19-targeting CAR T cell products utilizing cells from HIV-positive donors with lymphoma. Although these studies have provided promising evidence that alleviates concerns regarding the safety profile and limited effectiveness of CAR T cell therapy in this particular population, they do not address the underlying HIV condition. We previously generated CAR T cells targeting either lymphoma (CD19-CAR) or HIVgp120 (N6-CAR) that show efficacy against their respective diseases in clinical and preclinical testing, respectively. We hypothesized that a dual construct capable of targeting both antigens could simultaneously target lymphoma cells and HIV-infected cells in a same individual. We report our experience developing a bi-specific N6-huCD19 CAR T cell platform that can target both antigens in a single therapeutic product. Methods: We engineered 3 bi-specific CAR candidate designs including 2 tandem and 1 loop constructs. These constructs were developed by integrating a humanized (hu) CD19 single-chain variable fragment (scFv) and an N6 scFv from an anti-HIV broadly neutralizing antibody (bNAb) into a backbone of a 2 nd-generation CAR construct. The bi-specific tandem CAR constructs consisted of N6 and huCD19 scFvs fused with a G4S linker in either huCD19-N6 or N6-huCD19 orientation. The loop-CAR was generated by fusing huCD19(VL):N6(VH):N6(VL):huCD19(VH) with a whitlow linker. All constructs included the CD4 transmembrane domain, a double-mutated IgG4 Fc spacer, 4-1BB co-stimulatory and CD3-zetta signaling domains, and EGFRt separated by a T2A ribosomal skip sequence (Fig.1). We tested the 3 bi-specific constructs in healthy donor-derived T cells using cytotoxicity co-culture assay against either Raji (CD19+) or 8E5 (gp120+) target cells. We generated N6-huCD19 CAR T cells from HIV-positive patients and confirmed the functionality of these CAR T cells against tumor cells. Results: The functional assessment of all 3 bi-specific CAR constructs revealed their efficacy against CD19 and HIVgp120 antigens. However, the N6-huCD19 tandem CAR T cells demonstrated comparable and better efficacy against both antigens. Notably, the N6-huCD19 tandem CAR T cells exhibited the capability to sequentially target either a single antigen or alternate between the 2 antigens (Fig.2). We successfully generated N6-huCD19 tandem CAR T cells using HIV-positive donors, signifying the practicality of this approach within the context of PLWHA. Remarkably these HIV donor-derived N6-huCD19 CAR T cells effectively killed tumor cells expressing CD19 or HIVgp120 antigens, thus confirming their dual functionality against these 2 antigens. Conclusion: Here we demonstrate the development of the novel N6-huCD19 bi-specific CAR T cells with functionality against both CD19 and HIVgp120 antigens. We also showed the feasibility of generating these CAR T cells from HIV-donors. This strategy could potentially provide life-saving approach tailored for treatment of HIV-patients who develop CD19+ lymphomas.

Emerging role of MicroRNA-Based theranostics in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), with its high mortality and short survival rate, continues to be one of the deadliest malignancies despite relentless efforts and several technological advances. The poor prognosis of HCC and the few available treatments are to blame for the low survival rate, which emphasizes the importance of creating new, effective diagnostic markers and innovative therapy strategies. In-depth research is being done on the potent biomarker miRNAs, a special class of non-coding RNA and has shown encouraging results in the early identification and treatment of HCC in order to find more viable and successful therapeutics for the disease. It is beyond dispute that miRNAs control cell differentiation, proliferation, and survival and, depending on the genes they target, can either promote tumorigenesis or suppress it. Given the vital role miRNAs play in the biological system and their potential to serve as ground-breaking treatments for HCC, more study is required to fully examine their theranostic potential.

THE THERAPEUTIC POTENTIAL OF PSYCHEDELICS FOR MENTAL HEALTH DISORDERS: A REVIEW OF CURRENT EVIDENCE

The purpose of this review article is to give a summary of the literature on the use of psychedelic drugs, such as psilocybin, LSD, ayahuasca, and MDMA, in the treatment of various mental health conditions, such as depression, anxiety, PTSD, and substance use disorders. This review's main goal is to highlight recent human studies on the use of particular psychedelic drugs, like psilocybin, LSD, MDMA, and ayahuasca, in the treatment of various psychiatric illnesses, such as treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. There will also be a discussion of the safety and effectiveness as reported from both human and animal studies. Research has shown that psychedelics have the potential to become ground-breaking treatments for mental health disorders that are resistant to traditional therapies.

Revolutionary Immunotherapy for Merkel Cell Carcinoma: Retifanlimab-Dlwr (Zynyz) Receives FDA Approval

Approval of Retifanlimab-dlwr (brand name Zynyz) represents a significant breakthrough in the field of dermatology, providing a promising treatment option for patients diagnosed with this highly aggressive and rare form of Merkel Cell Carcinoma (MCC). Traditionally, treatment options for MCC have been limited, with surgery, radiation, and chemotherapy are the mainstays. Retifanlimab-dlwr debut will mark a milestone in the treatment of MCC. Clinical trials have shown impressive results, with a significant number of patients experiencing durable responses to the therapy. Retifanlimab-dlwr is a monoclonal antibody that targets the programmed cell death protein 1 (PD-1), which is expressed on immune cells and helps to reactivate the body's immune response against cancer cells. The impending use of Retifanlimab-dlwr not only provides a groundbreaking treatment option for MCC but also paves the way for further advancements in immunotherapy and personalized medicine

Mesenchymal stem cell therapy for wound healing: An update to 2022

The skin is an organ that performs complex functions of both the innate and adaptive immune systems. It serves as the first physical barrier to protect the body from environmental factors. Skin also carries aesthetic value in people's desire for eternal youth. Skin lesions are often unwanted, causing open wounds that can be contagious or permit infection of the body, scars, skin aging, and loss of skin function, with long-term psychological consequences. The application of stem cell therapy based on mesenchymal stem cells (MSCs) is constantly developing in the field of skin regeneration, which is highly regarded as a therapy for patients suffering skin lesions from burns, deep wounds, cosmetic surgery, or genetic diseases. MSC therapy has shed light on groundbreaking treatments in immune, anti-inflammatory, and regenerative medicine, including for skin diseases. Additionally, the development of stem cells seems to limit skin aging. It is gradually becoming an integral technique at hospitals as a regular therapy for illness, as well as a cosmetic intervention. This review seeks to introduce the skin system and its related disorders; highlight the common characteristics and mechanisms of MSCs; and analyze updated clinical applications and experiments to date in MSC therapy for regenerative biomedicine and skin diseases.

Human muscle in gene edited pigs for treatment of volumetric muscle loss.

Focusing on complex extremity trauma and volumetric muscle loss (VML) injuries, this review highlights: 1) the current pathophysiologic limitations of the injury sequela; 2) the gene editing strategy of the pig as a model that provides a novel treatment approach; 3) the notion that human skeletal muscle derived from gene edited, humanized pigs provides a groundbreaking treatment option; and 4) the impact of this technologic platform and how it will advance to far more multifaceted applications. This review seeks to shed insights on a novel treatment option using gene edited pigs as a platform which is necessary to overcome the clinical challenges and limitations in the field.

P491: PREDICTIVE FACTORS OF DIFFERENTIATION SYNDROME IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA

Background: Differentiation syndrome (DS) may be a life-threatening complication in patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and anthracycline chemotherapy. Identifying high risk patients enables a more efficient follow up and an optimal prophylaxis strategy. Aims: The aim of this study was to analyze the incidence, characteristics, and the risk factors of DS occurring during induction treatment in APL patients treated with ATRA and anthracycline. Methods: We conducted a retrospective single-center study, including patients diagnosed with APL between 2010 and 2019 in our department and treated with ATRA and chemotherapy according to PETHEMA protocols LPA99 and LPA2005. Obesity, renal failure and a high risk (according to the Sanz score) represented an indication for a DS prophylaxis prescription, using whether prednisone (LPA99) or dexamethasone (LPA2005). A univariate and a multivariate analysis were conducted, in order to identify predictive factors of DS. Results: Ninety patients were included in our study, with an average age of 34 years old. According to Frankel’s diagnostic criteria, 16 patients (18%) experienced a DS, with a mean age of 39 years [13-71 years], and a sex ratio of 0.6. Half of this group was classified as high risk according to the Sanz score, 44% as intermediate risk, and 6% as low risk. A severe differentiation syndrome was described in 7 patients (44%). The syndrome occurred at a median of 4 days after the start of induction therapy [2-26 days]. A Prophylaxis had been prescribed for 10 patients (62.5%): 8 were classified as high risk, and 2 had obesity. In order to identify the risk factors of DS, the following parameters were analyzed: age, sex, performance status, Body Mass Index, clinical presentation at diagnosis, treatment protocol, Sanz score, creatinine level, LDH level, hemoglobin level, white blood cell (WBC) count, platelets, cytological type, PML-RARa variant, CD2, CD15, CD34, CD56 expression, fibrinogen level, prothrombin time, presence of disseminated intravascular coagulopathy (DIC), occurrence of bleeding and thromboembolic complications, and corticosteroid prophylaxis. The univariate analysis identified a statistically significant difference between the group of patients with DS and the one without, for the following factors: WBC greater than 50G/L (31,3% versus 8,1%; p=0,02), the presence of DIC at diagnosis (81.3% versus 18.7%; p=0.01), the expression of CD34 (p=0.017), the LDH level (a median of 307 versus 590; p=0.026), and the treatment protocol LPA 99(11 patients (68.8%) treated according to LPA99 versus 5 (31,3%) treated according to LPA2005; p=0.003). Upon multivariate analysis, WBC count greater than 50 G/L (p=0,007), the presence of DIC at diagnosis (p=0,03), and the treatment protocol LPA99 (p=0,02), remained independent risk factors of DS (Table1). Image:Summary/Conclusion: Differentiation syndrome is a significant complication secondary to the ground-breaking treatment of APL. It is necessary to accurately identify high risk patients in order to elaborate effective risk-adapted prophylaxis and treatment.

Nanotechnology-Based Strategies To Combat Against Infectious Diseases

Infectious diseases are caused by various smart pathogens like bacteria, fungi, viruses, and parasites, claiming more than 17M lives globally (1). Currently, we are in the middle of a pandemic that originated from an infectious disease. The Infectious diseases are caused by various smart pathogens like bacteria, fungi, viruses, and parasites, claiming more than 17M lives globally (1). Currently, we are in the middle of a pandemic that originated from an infectious disease. The available therapies, medical facilities, and research–development teams of each country were exploited, and yet the novel coronavirus claimed ~4,065,876 lives to date. These smart pathogens keep tweaking themselves, posing challenges to treatment therapy such as antibiotic/antiviral drugs resistance, tolerance, and newer strategies to survive inside host cells. For instance, emergence and spread of the Methicillin-resistant Staphylococcus aureus (MRSA) bacterial resistance constitute a toll on human and animal health, food security, environmental sustainability, and socioeconomic development, triggering the tripartite organizations (Food and Agriculture Organization of the United Nations, FAO; World Organization for Animal Health; and World Health Organization, WHO) to layout a blueprint for tackling such resistance threats the coming five to ten years. Moreover, the novel coronavirus and drug-resistant species of influenza viruses highlighted the urgent need for new antiviral therapies (2). Most of the antibiotics and antiviral agents exhibit low stability, less solubility, extraordinary potential of drug-drug interaction, high occurrence of toxicity or adverse effects, short-half life, and low concentration at the site of infection (3). Thus, there is a desperate need for ground-breaking treatment approaches to combat these evolving infectious diseases.

The Potential Role of Small-Molecule PERK Inhibitor LDN-0060609 in Primary Open-Angle Glaucoma Treatment.

Primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma. Emerging evidence suggests that Endoplasmic Reticulum (ER) stress and the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated Unfolded Protein Response (UPR) signaling pathway play a key role in POAG pathogenesis. Thus, the main aim of the study was to evaluate the effectiveness of the PERK inhibitor LDN-0060609 in cellular model of glaucoma using primary human trabecular meshwork (HTM) cells. To evaluate the level of the ER stress marker proteins, Western blotting and TaqMan gene expression assay were used. The cytotoxicity was measured by XTT, LDH assays and Giemsa staining, whereas genotoxicity via comet assay. Changes in cell morphology were assessed by phase-contrast microscopy. Analysis of apoptosis was performed by caspase-3 assay and flow cytometry (FC), whereas cell cycle progression by FC. The results obtained have demonstrated that LDN-0060609 triggered a significant decrease of ER stress marker proteins within HTM cells with induced ER stress conditions. Moreover, LDN-0060609 effectively increased viability, reduced DNA damage, increased proliferation, restored normal morphology, reduced apoptosis and restored normal cell cycle distribution of HTM cells with induced ER stress conditions. Thereby, PERK inhibitors, such as LDN-0060609, may provide an innovative, ground-breaking treatment strategy against POAG.