Potential Treatment Research Articles

Abstract 5914: Non-muscle myosin IIA as a promising therapeutic target in breast cancer

Abstract We aimed to determine the role of non-muscle myosin IIA (NMIIA) in breast cancer using various cancer cell lines including estrogen receptor (ER)+, HER2+ and triple negative breast cancers (TNBC). Myosin heavy chain 9 (MYH9) gene encodes for the heavy chain of the hexameric protein NMIIA. We have recently identified that NMIIA serves as a binding partner for HER3 following the inhibition of the HER family member compared to the vehicle control treatment, as observed in HER3 immunoprecipitates. We checked the basal protein and mRNA levels of NMIIA in different breast cancer cell lines and found higher levels of NMIIA in both HER2+ and TNBC cell lines compared to ER+ cell lines. These data correlate with clinical data of primary breast cancer patients with high MYH9 being less likely in ER+ breast cancer patients and more likely in the PAM50 subtypes basal and HER2 enriched breast cancer patients. By employing a pool of four siRNA targeting MYH9, our data indicated a reduction in proliferation of HER2+ and TNBC cell lines when compared to the control siRNA. We have previously found that loss of MYH9 sensitizes to the HER family inhibitor neratinib treatment as assessed by cell proliferation, colony formation on matrigel, cell migration and invasion. We aimed to determine if pharmacological inhibition of the NMIIA pathway would sensitize to neratinib. RhoA-associated kinase (ROCK) serves as a master regulator of NMIIA activity as it directly phosphorylates the regulatory light chain (RLC) of NMIIA. Pharmacological inhibition of ROCK-NMIIA pathway using the ROCK inhibitor GSK269962A alone or in combination with neratinib reduced the cell proliferation in HER2+ cell lines BT474 and MDA-MB-453 as indicated by MTT and cell proliferation assay. It is well known that HER2-targeted therapies cause the upregulation of HER3. Given our identification of NMIIA as one of the interacting partners of HER3, our focus will be on investigating the NMIIA-HER3 signaling axis to elucidate its contribution to an adaptive response to HER2 inhibition and potential treatment resistance. Furthermore, we will explore strategies to target NMIIA in breast cancer. Citation Format: Wasim Feroz, Rosalin Mishra, Mary Kate Kilroy, Joan T. Garrett. Non-muscle myosin IIA as a promising therapeutic target in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5914.

Abstract 4008: DASH CAR-T: accelerating CD276-targeted immunotherapy for pancreatic cancer

Abstract B7 homolog 3 protein (B7-H3), recognized as CD276, is a pivotal immune checkpoint molecule extensively expressed in cancer cells, presenting a limited presence in normal tissues. Immunohistochemical analysis of 150 pancreatic cancer patients revealed positive CD276 staining in 66% of cases, with elevated expression correlating to diminished disease-free survival. Additional findings from an independent study on 59 patients highlighted significantly elevated CD276 levels, particularly in lymph node metastasis and advanced pathology. This study introduces an innovative Chimeric Antigen Receptor T (CAR-T) therapy targeting CD276, leveraging our DASH CAR-T manufacturing platform. Significantly, our approach reduces the ex vivo cell expansion time from 10 days to 1-2 days. T cells were enriched, activated, and transduced with a CD276 CAR-encoding retroviral vector, achieving the final product in 2-3 days. In preclinical models, our shorten-time CAR-T against CD276 exhibited superior expansion and heightened tumor-killing efficacy. Remarkably, DASH CAR-T demonstrated superior tumor control compared to conventional CAR-T, requiring only one-tenth of the dosage. This research advances our understanding of CD276 in pancreatic cancer and presents a transformative approach in CAR-T therapy manufacturing. The shortened production timeline and enhanced therapeutic outcomes underscore the potential clinical impact of our novel CAR-T strategy, offering a more efficient and potent treatment option for pancreatic cancer. Citation Format: Haiying Wang, Tian Deng, Hao Li, Yue Yao, Yuan Tian, Hongwei Wang, Pengfei Jiang. DASH CAR-T: accelerating CD276-targeted immunotherapy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4008.

Identification of an Intravenous Injectable NK1 Receptor Antagonist for Use in Traumatic Brain Injury.

Traumatic brain injuries represent a leading cause of death and disability in the paediatric and adult populations. Moderate-to-severe injuries are associated with blood-brain barrier dysfunction, the development of cerebral oedema, and neuroinflammation. Antagonists of the tachykinin NK1 receptor have been proposed as potential agents for the post-injury treatment of TBI. We report on the identification of EUC-001 as a potential clinical candidate for development as a novel TBI therapy. EUC-001 is a selective NK1 antagonist with a high affinity for the human NK1 receptor (Ki 5.75 × 10-10 M). It has sufficient aqueous solubility to enable intravenous administration, whilst still retaining good CNS penetration as evidenced by its ability to inhibit the gerbil foot-tapping response. Using an animal model of TBI, the post-injury administration of EUC-001 was shown to restore BBB function in a dose-dependent manner. EUC-001 was also able to ameliorate cerebral oedema. These effects were associated with a significant reduction in post-TBI mortality. In addition, EUC-001 was able to significantly reduce functional deficits, both motor and cognitive, that normally follow a severe injury. EUC-001 is proposed as an ideal candidate for clinical development for TBI.

“A Comprehensive Review of Anaemia Associated with Hypothyroidism”

Background: Thyroid hormones play a crucial role in erythropoiesis, both directly and indirectly, with reduced secretion potentially causing anaemia—a commonly overlooked symptom of hypothyroidism. By compiling existing data, discussing recent advancements, identifying root causes, and proposing potential treatment options, this work acknowledges the complexity of the issue and aims to serve as a foundational reference for those in the early stages of research or clinical practice. Methods: To comprehend the concept of this disease condition, a number of medical textbooks were consulted. Various search engines, such as PubMed, Google Scholar, Research Gate, Science Direct, Scopus, etc., were cited to explore the recent advancements and obtain data on the topic in question. Later, all the information and data gathered were organised into a review article. Conclusion: Anemia, often referred to as the “haematological mask” of hypothyroidism, can manifest even before hypothyroidism is clinically diagnosed. Hypothyroidism must be considered as a potential cause when confronted with refractory anemia, as its treatment is pivotal for achieving comprehensive and lasting improvements in haematological parameters.

Targeting Epstein-Barr virus in multiple sclerosis: when and how?

Epidemiological evidence implicates Epstein-Barr virus (EBV) as the cause of multiple sclerosis (MS). However, its biological role in the pathogenesis of MS is uncertain. The article provides an overview of the role of EBV in the pathogenesis of MS and makes a case for targeting EBV as a treatment strategy for MS. EBV potentially triggers autoimmunity via molecular mimicry or immune dysregulation. Another hypothesis, supported by immunological and virological data, indicates that active EBV infection via latent-lytic infection cycling within the central nervous system or periphery drives MS disease activity. This supports testing small molecule anti-EBV agents targeting both latent and lytic infection, central nervous system-penetrant B-cell therapies and EBV-targeted immunotherapies in MS. Immunotherapies may include EBV-specific cytotoxic or chimeric antigen receptors T-cells, therapeutic EBV vaccines and immune reconstitution therapies to boost endogenous EBV-targeted cytotoxic T-cell responses. EBV is the probable cause of MS and is likely to be driving MS disease activity via latent-lytic infection cycling. There is evidence that all licensed MS disease-modifying therapies target EBV, and there is a compelling case for testing other anti-EBV strategies as potential treatments for MS.

Clinical Insights Into the Use of Speech Amplification Devices for Managing Hypophonia: Interviews With Speech-Language Pathologists.

The purpose of this qualitative interview study was to identify themes regarding considerations in the usage of speech amplification device usage for people with Parkinson's disease (PD) and hypophonia from the perspective of speech-language pathologists (SLPs). Eligible participants included SLPs currently practicing in the United States or Canada with experience working with clients with PD for at least 2 years. Ten SLPs participated in 60-min interviews conducted via Zoom. A semistructured interview guide was created prior to the interviews. The interviews were transcribed following their completion, and an iterative coding process was used to identify themes using thematic analysis. Three main themes were identified from the interviews. The first theme encapsulated how clinicians described amplification devices as a potential treatment tool, which highlighted the nuances that may impact selecting an amplification device as a treatment option such as increased hypophonia or dysarthria severity and cognitive decline. The second theme highlighted how device selection depends on the individual needs of the user. Individual client characteristics (such as disease symptoms and individual needs and preferences) may impact the choice of amplification device. The last theme outlined the importance of involving family members in all stages of device use and involving other health care team members on a case-by-case basis. The insights provided by the SLP participants help to understand the clinical decisions that are made when determining device candidacy, selecting a device, and evaluating device success. These insights can be used to improve research studies of augmentative management of hypophonia and guide more personalized management decisions.

Combinational delivery of TLR4 and TLR7/8 agonist enhanced the therapeutic efficacy of immune checkpoint inhibitors to colon tumor.

Immunotherapy is regarded as a potent cancer treatment, with DC vaccines playing a crucial role. Although clinical trials have demonstrated the safety and efficacy of DC vaccines, loading antigens in vitro is challenging, and their therapeutic effects remain unpredictable. Moreover, the diverse subtypes and maturity states of DCs in the body could induce both immune responses and immune tolerance, potentially affecting the vaccine's efficacy. Hence, the optimization of DC vaccines remains imperative. Our study discovered a new therapeutic strategy by using CT26 and MC38 mouse colon cancer models, as well as LLC mouse lung cancer models. The strategy involved the synergistic activation of DCs through intertumoral administration of TLR4 agonist high-mobility group nucleosome binding protein 1 (HMGN1) and TLR7/8 agonist (R848/resiquimod), combined with intraperitoneal administration of TNFR2 immunosuppressant antibody. The experimental results indicated that the combined use of HMGN1, R848, and α-TNFR2 had no effect on LLC cold tumors. However, it was effective in eradicating CT26 and MC38 colon cancer and inducing long-term immune memory. The combination of these three drugs altered the TME and promoted an increase in anti-tumor immune components. This may provide a promising new treatment strategy for colon cancer.

STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment. While MPNSTs are noninflamed "cold" tumors, here, we converted MPNSTs into T cell-inflamed "hot" tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.

Some Drugs Have Two Faces: Paradoxical Colitis in a Patient with Psoriatic Arthritis Previously Treated with Etanercept and IL-17 Inhibitors.

Tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) inhibitors are among the most potent treatments for inflammatory arthropathies including rheumatoid arthritis, psoriasis, and spondyloarthropathies. The availability of these biologic agents have revolutionized the management of these conditions and improved patient outcomes. Though generally safe, these biologics may contribute to the induction or exacerbation of colitis. This paradoxical colitis has been observed in patients on TNF-α inhibitor etanercept and IL-17 inhibitors (secukinumab and ixekizumab). We report a case of a 46-year-old female with psoriasis and psoriatic arthritis who presented with gastrointestinal symptoms after treatment with etanercept and IL-17 inhibitors. She was later diagnosed with paradoxical indeterminate colitis that was masked and treated by subsequent biologics given for her RA and psoriatic arthritis. In this report, we will discuss the importance of considering paradoxical colitis in the differential diagnosis for patients even several years after TNF-α/IL-17 inhibitor initiation and explain why careful consideration must be made when initiating these colitis-inducing agents to treat patients with inflammatory disorders.

Hemadsorption extracorporeal therapy removes cytokines ex vivo in horses.

Plasma cytokine adsorption has shown benefit as an adjunctive therapy in human sepsis but has yet to be investigated in horses. We hypothesized that ex vivo filtration of equine plasma with a novel cytokine adsorption device would significantly reduce concentrations of lipopolysaccharide-stimulated cytokines. We also hypothesized that the device would adsorb medications commonly used to treat sepsis. 8 horses owned by North Carolina State University. Four liters of heparinized whole blood was collected from healthy adult horses (n = 8) and stimulated with lipopolysaccharide (100 ng/mL) for 6 hours (37 °C.) from June 4, 2023, to December 15, 2023. Plasma was filtered through a cytokine adsorption device or sham circuit. Samples were collected at 11 time points for multiplex cytokine analysis. Chemistry analysis was performed before and after filtration. To investigate the impact of the device on medication concentrations, equine plasma containing potassium penicillin, gentamicin, and flunixin meglumine was filtered through the cytokine adsorption device or sham for 6 hours. Drug concentrations before and after filtration were determined by ultra-high-performance liquid chromatography. Prefiltration versus postfiltration sample concentrations were analyzed by Student paired t test using GraphPad Prism 9.0 (P < .05). Filtration of lipopolysaccharide-stimulated equine plasma (n = 8) for 6 hours resulted in significant mean reductions in the cytokines IL-10, IL-5, IL-8, tumor necrosis factor-α (TNF-α), and IL-1β, as well as albumin. Drug concentrations of potassium penicillin, gentamicin, and flunixin meglumine were also significantly reduced by filtration. This work provides proof of concept for further investigation of extracorporeal cytokine adsorption as a potential adjunct treatment for equine sepsis.

Autologous HSCT with novel agent-based induction and consolidation followed by lenalidomide maintenance for untreated multiple myeloma.

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.

Ethical implications of developing RNA-based therapies for cardiovascular disorders.

The awareness concerning RNA-based therapies was boosted significantly after the successful development of COVID-19 vaccines. However, they can potentially lead to significant advances in other areas of medicine, such as oncology or chronic diseases. In recent years, there has been an exponential increase in the number of RNA-based therapies that were evaluated as potential treatments for cardiovascular disorders. One of the areas that was not explicitly assessed about these therapies is represented by their overall ethical framework. Some studies evaluate ethical issues of RNA-based treatments in general or targeting specific disorders (especially neurodegenerative) or interventions for developing RNA-based vaccines. Much less information is available regarding the ethical issues associated with developing these therapeutic strategies for cardiovascular disorders, which is the main aim of this study. We will focus our analysis on three main topics: risk-benefit analysis (including the management of public awareness about these technologies), and justice (in both research and clinical medicine).

Mechanistic Insights and Potential Therapeutic Implications of NRF2 in Diabetic Encephalopathy.

Diabetic encephalopathy (DE) is a complication of diabetes, especially type 2 diabetes (T2D), characterized by damage in the central nervous system and cognitive impairment, which has gained global attention. Despite the extensive research aimed at enhancing our understanding of DE, the underlying mechanism of occurrence and development of DE has not been established. Mounting evidence has demonstrated a close correlation between DE and various factors, such as Alzheimer's disease-like pathological changes, insulin resistance, inflammation, and oxidative stress. Of interest, nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor with antioxidant properties that is crucial in maintaining redox homeostasis and regulating inflammatory responses. The activation and regulatory mechanisms of NRF2 are a relatively complex process. NRF2 is involved in the regulation of multiple metabolic pathways and confers neuroprotective functions. Multiple studies have provided evidence demonstrating the significant involvement of NRF2 as a critical transcription factor in the progression of DE. Additionally, various molecules capable of activating NRF2 expression have shown potential in ameliorating DE. Therefore, it is intriguing to consider NRF2 as a potential target for the treatment of DE. In this review, we aim to shed light on the role and the possible underlying mechanism of NRF2 in DE. Furthermore, we provide an overview of the current research landscape and address the challenges associated with using NRF2 activators as potential treatment options for DE.

Chronic Pain-Related Cognitive Deficits: Preclinical Insights into Molecular, Cellular, and Circuit Mechanisms.

Cognitive impairment is a common comorbidity of chronic pain, significantly disrupting patients' quality of life. Despite this comorbidity being clinically recognized, the underlying neuropathological mechanisms remain unclear. Recent preclinical studies have focused on the fundamental mechanisms underlying the coexistence of chronic pain and cognitive decline. Pain chronification is accompanied by structural and functional changes in the neural substrate of cognition. Based on the developments in electrophysiology and optogenetics/chemogenetics, we summarized the relevant neural circuits involved in pain-induced cognitive impairment, as well as changes in connectivity and function in brain regions. We then present the cellular and molecular alternations related to pain-induced cognitive impairment in preclinical studies, mainly including modifications in neuronal excitability and structure, synaptic plasticity, glial cells and cytokines, neurotransmitters and other neurochemicals, and the gut-brain axis. Finally, we also discussed the potential treatment strategies and future research directions.

A panel of janus kinase inhibitors identified with anti-inflammatory effects protect mice from lethal influenza virus infection.

Influenza remains a significant threat to public health. In severe cases, excessive inflammation can lead to severe pneumonia or acute respiratory distress syndrome, contributing to patient morbidity and mortality. While antivirals can be effective if administered early, current anti-inflammatory drugs have limited success in treating severe cases. Therefore, discovering new anti-inflammatory agents to inhibit influenza-related inflammatory diseases is crucial. Herein, we screened a drug library with known targets using a human monocyte U937 infected with the influenza virus to identify novel anti-inflammatory agents. We also evaluated the anti-inflammatory effects of the hit compounds in an influenza mouse model. Our research revealed that JAK inhibitors exhibited a higher hit rate and more potent inhibition effect than inhibitors targeting other drug targets in vitro. Of the 22 JAK inhibitors tested, 15 exhibited robust anti-inflammatory activity against influenza virus infection in vitro. Subsequently, we evaluated the efficacy of 10 JAK inhibitors using an influenza mouse model and observed that seven provided protection ranging from 40% to 70% against lethal influenza virus infection. We selected oclacitinib as a representative compound for an extensive study to further investigate the in vivo therapeutic potential of JAK inhibitors for severe influenza-associated inflammation. Our results revealed that oclacitinib effectively suppressed neutrophil and macrophage infiltration, reduced pro-inflammatory cytokine production, and ultimately mitigated lung injury in mice infected with lethal influenza virus without impacting viral titer. These findings suggest that JAK inhibitors can modulate immune responses to influenza virus infection and may serve as potential treatments for influenza.IMPORTANCEAntivirals exhibit limited efficacy in treating severe influenza when not administered promptly during the infection. Current steroidal and nonsteroidal anti-inflammatory drugs demonstrate restricted effectiveness against severe influenza or are associated with significant side effects. Therefore, there is an urgent need for novel anti-inflammatory agents that possess high potency and minimal adverse reactions. In this study, 15 JAK inhibitors were identified through a screening process based on their anti-inflammatory activity against influenza virus infection in vitro. Remarkably, 7 of the 10 selected inhibitors exhibited protective effects against lethal influenza virus infection in mice, thereby highlighting the potential therapeutic value of JAK inhibitors for treating influenza.

γ-glutamyl transpeptidase activatable NIR photosensitizer for visualization and selective killing of liver cancer cells

Photodynamic therapy (PDT) is a treatment model that involves using light sources to excite photosensitizers (PSs), generating reactive oxygen species. This method is considered a potential treatment for tumors. However, the non-selective toxicity of traditional PSs to both tumors and normal tissues hinders the advancement of PDT. This lack of selectivity is a major obstacle in the development of effective PDT. The activatable PS can only function in a specific environment, which enhances the selectivity and safety of PDT. In this paper, we focus on GGT (γ-glutamyltranspeptidase) overexpressed in liver cancer as the biological target. We designed and synthesized the activatable PS BrCy-Glu by modifying the substrate of GGT (l-glutamic acid) onto the brominated hemicyanine PS (BrCy-OH). The intramolecular charge transfer (ICT) effect of BrCy-Glu is inhibited, which leads to low fluorescence quantum yield and singlet oxygen yield. However, in the presence of GGT, it can undergo selective hydrolysis and be converted into BrCy-OH through a series of elimination reactions. This process is accompanied by a significant increase in fluorescence quantum yield and singlet oxygen yield. In vitro studies demonstrate that BrCy-Glu is suitable for precise fluorescence identification of liver cancer and selective eradication of cancer cells under light conditions.

Glycerol Phenylbutyrate treatment of two patients with Monocarboxylate Transporter 8 deficiency.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, Vital signs, anthropometric measurements and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients received in the past. NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range but elevated liver transaminases were observed. In the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body-mass index, with minor neuro-developmental changes.

Age-dependent loss of HAPLN1 erodes vascular integrity via indirect upregulation of endothelial ICAM1 in melanoma.

Melanoma, the most lethal form of skin cancer, often has worse outcomes in older patients. We previously demonstrated that an age-related decrease in the secreted extracellular matrix (ECM) protein HAPLN1 has a role in slowing melanoma progression. Here we show that HAPLN1 in the dermal ECM is sufficient to maintain the integrity of melanoma-associated blood vessels, as indicated by increased collagen and VE-cadherin expression. Specifically, we show that HAPLN1 in the ECM increases hyaluronic acid and decreases endothelial cell expression of ICAM1. ICAM1 phosphorylates and internalizes VE-cadherin, a critical determinant of vascular integrity, resulting in permeable blood vessels. We found that blocking ICAM1 reduces tumor size and metastasis in older mice. These results suggest that HAPLN1 alters endothelial ICAM1expression in an indirect, matrix-dependent manner. Targeting ICAM1 could be a potential treatment strategy for older patients with melanoma, emphasizing the role of aging in tumorigenesis.

Perceptions, Experiences, and Patterns of Cannabis Use in Individuals with Mood and Anxiety Disorders in the Context of Cannabis Legalization and Medical Cannabis Program in Canada - A Qualitative Study.

Perceptions of cannabis as a potential medical treatment for mood and anxiety disorders have been increasing in the context of legalizations, availability, and medical cannabis programs, though current evidence predominately indicates risks and negative effects of cannabis use (CU) on mental health outcomes. This study aims to understand motivations, perceptions, effects, and patterns of CU in individuals with mood and anxiety disorders. Thirty-six adult patients diagnosed with mood or anxiety disorders, obsessive-compulsive disorder, or posttraumatic stress disorder who were currently using cannabis completed an in-depth qualitative interview on individual motivations, perceptions, experiences, effects, and patterns of their CU. The thematic analysis focused on phases of CU and sources of cannabis products and information. Reported motivations for initiation of CU included curiosity, peer pressure, and dissatisfaction with conventional treatments. Factors such as psychotropic effects and coping with mental health symptoms and insomnia contributed to the continuation of CU. More negative effects, including cognitive dysfunction, worsening of mood, and anxiety symptoms, were acknowledged with ongoing CU. Concerning findings included common initiation of CU before age 18, combined medical and recreational CU, rare consultation of medical professionals on CU, and potential effects and harms. Findings indicate individual complexity of motivations, perceptions, and patterns of CU in the study population. The reported potential beneficial effects of specific cannabis products should be further investigated. Findings emphasize patient-provider dialogue on both CU and conventional treatments. Information from this study can contribute to and inform the development of education, prevention, and intervention strategies.

Astrogliosis: A review of the astrocytic mechanisms, imaging modes, and treatments in spinal cord injury patients

Astrocytes are cells in the central nervous system (CNS) that are responsible for many things, such as maintaining blood brain barrier (BBB), regulating synapses in the spinal cord, and responding to spinal cord injury (SCI). Astrogliosis, the astrocytic response to spinal cord injuries (SCIs), helps repair CNS damages by regulating different protein filaments, thus limiting axonal growth. Former studies that were demonstrated through laser capture microdissection and immunohistochemistry (IHC) helped to identify important genes involved in experimental therapies for SCIs. Additionally, there are potential clinical treatments options for SCIs such as hydrogels, mesenchymal stem cells and steroids. Increased imaging modalities indicate that excessive astrogliosis can have adverse effects. These imaging techniques include positron emission tomography (PET), magnetic resonance imaging (MRI), and two-photon laser-scanning microscopy (TPLSM). These techniques illuminate greater details of the astrocytic response to SCIs. Despite these findings, astrogliosis is not well understood by the research community. Many of the studies presented in this literature review are experimental attempts to understand the mechanisms of astrogliosis in SCIs. This literature review aims to summarize the methods of each study in visualizing the mechanisms of astrogliosis and how they play a role in SCIs. Furthermore, this paper is aimed to comprehensively bridge the developments in the treatment for SCI patients based on innovative imaging modalities. Compared to prior studies, this review utilizes more recent understandings of the astrogliosis mechanisms to highlight insights into targeted developments, both clinically and preclinically. Some limitations of this literature review include the limited studies on astrogliosis and its impact on SCIs. Nonetheless, there is ongoing potential in the search for treatments for SCIs.