Stop Disease Progression Research Articles

A quasi-experimental study on couple-based exercise program improving cardiac rehabilitation exercise compliance in post-PCI patients

BackgroundPercutaneous coronary intervention (PCI) helps treat coronary artery disease but only provides short-term relief and doesn’t stop disease progression. Exercise rehabilitation can improve outcomes for patients after PCI and lower the risk of death and new heart problems, but many patients struggle to stick with their exercise routines. Spouses play a crucial role in supporting patients and helping them stay committed to their rehabilitation. This study aims to evaluate the effectiveness of a couple-based exercise program in improving exercise adherence among post-PCI patients.MethodsThis study used a quasi-experimental design, 70 dyads were recruited for a 12-week investigation. Participants were divided into an intervention group to receive the Couple-Based exercise program and a control ensemble for conventional exercise-based cardiac rehabilitation. The primary parameter under examination was exercise adherence. Secondary endpoints encompass exercise self-efficacy, the 6-minute walk test, the 9-item Patient Health Questionnaire, and the Generalized Anxiety Disorder Scale. Data were harvested at baseline and post-intervention (12 weeks).ResultFollowing a three-month monitoring period, noticeable differences were observed in the Couples exercise group compared to the control group in the realms of exercise adherence, exercise self-efficacy, the 6-minute walk test, and anxiety-depression indices (P < 0.05).ConclusionA couple-based exercise program developed based on a developmental-contextual framework improves exercise adherence and exercise self-efficacy, enhances cardiac function and exercise capacity, and improves anxiety and depression in post-coronary arteriography patients. This approach is likely to be an effective way to improve rehabilitation outcomes, leading to the broader goal of improving patient prognosis and reducing adverse cardiovascular events.Trial registrationThe study’s registration was recorded with the Chinese Clinical Trials Registry (12/04/2022, registration number ChiCTR2200058600).

Noncoding RNAs in rheumatoid arthritis: modulators of the NF-κB signaling pathway and therapeutic implications.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation and gradual tissue destruction. New research has shown how important noncoding RNAs (ncRNAs) are for changing immune and inflammatory pathways, such as the WNT signaling pathway, which is important for activating synovial fibroblasts and osteoblasts to work. This article examines the current understanding of several ncRNAs, such as miRNAs, lncRNAs, and circRNAs, that influence NF-κB signaling in the pathogenesis of RA. We investigate how these ncRNAs impact NF-κB signaling components, altering cell proliferation, differentiation, and death in joint tissues. The paper also looks at how ncRNAs can be used as potential early detection markers and therapeutic targets in RA because they can change important pathogenic pathways. This study highlights the therapeutic potential of targeting ncRNAs in RA therapy techniques, with the goal of reducing inflammation and stopping disease progression. This thorough analysis opens up new possibilities for understanding the molecular foundations of RA and designing novel ncRNA-based treatments.

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.

Novel Piperazine Based Compounds Target Alzheimer's Disease Relevant Amyloid β42 and Tau Derived Peptide AcPHF6, and the Lead Molecule Increases Viability in the Flies Expressing Human Tau Protein.

Alzheimer's disease (AD) is the leading form of dementia in the United States and the world. The pathophysiology of AD is complex and multifaceted. Accumulation of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of AD. The aggregation of amyloid β (senile plaques) and tau tangles (NFTs) results in the death of neurons in the cortex and hippocampus, which manifests itself in cognitive decline and memory loss. Current therapies rely on conventional approaches that have only treated the underlying symptoms without disease modification. Data from clinical studies point to a complex role of amyloid β (Aβ) in a way that enhances the tau phenotype throughout the disease process. To address the co-pathogenic role of Aβ and tau, we undertook development of multitarget compounds aiming at both tau and Aβ to slow or stop disease progression and provide neuroprotection. Here, we demonstrate a dose-dependent effect of the novel test compounds that inhibit aggregation of AcPHF6 (a shorter version of tau protein) and Aβ1-42 peptides in thioflavin T fluorescent assays. The compounds were also shown to disaggregate preformed aggregates dose dependently. To further validate these findings, circular dichroism experiments were carried out to examine the nature of inhibition. Additionally, transmission electron microscopy experiments were carried out to gain insights into the morphologies of aggregates obtained from dose-dependent inhibition of AcPHF6 and Aβ1-42 as well as dissociation of preformed aggregates from these peptides. Compounds D-687 and D-688 reversed Aβ1-42 induced toxicity in SH-SH5Y cells, significantly demonstrating neuroprotective properties. Finally, in a study with Drosophila melanogaster expressing human tau protein isoform (2N4R) in all the neurons, compound D-688 significantly increased the survival of flies compared to vehicle treated controls. Future studies will further examine the neuroprotective properties of these lead compounds in various animal models.

Targeting modulation of intestinal flora through oral route by an antimicrobial nucleic acid-loaded exosome-like nanovesicles to improve Parkinson’s disease

Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases. It is usually accompanied by motor and non-motor symptoms that seriously threaten the health and the quality of life. Novel medications are urgently needed because current pharmaceuticals can relieve symptoms but cannot stop disease progression. The microbiota-gut-brain axis (MGBA) is closely associated with the occurrence and development of PD and is an effective therapeutic target. Tetrahedral framework nucleic acids (tFNAs) can modulate the microbiome and immune regulation. However, such nucleic acid nanostructures are very sensitive to acids which hinder this promising approach. Therefore, we prepared exosome-like nanovesicles (Exo@tac) from ginger that are acid resistant and equipped with tFNAs modified by antimicrobial peptides (AMP). We verified that Exo@tac regulates intestinal bacteria associated with the microbial-gut-brain axis in vitro and significantly improves PD symptoms in vivo when administered orally. Microbiota profiling confirmed that Exo@tac normalizes the intestinal flora composition of mouse models of PD. Our findings present a novel strategy for the development of PD drugs and the innovative delivery of nucleic acid nanomedicines.

Quality of life among people with mental illness attending a psychiatric outpatient clinic in Ethiopia: a structural equation model.

Mental illness is one of the most severe, chronic, and disabling public health problems that affects patients' Quality of life (QoL). Improving the QoL for people with mental illness is one of the most critical steps in stopping disease progression and avoiding complications of mental illness. Therefore, we aimed to assess the QoL and its determinants in patients with mental illness in outpatient clinics in Northwest Ethiopia in 2023. A facility-based cross-sectional study was conducted among people with mental illness in an outpatient clinic in Ethiopia. The sampling interval was decided by dividing the total study participants who had a follow-up appointment during the data collection period (2400), by the total sample size 638, with the starting point selected by lottery method. The interviewer-administered WHOQOL BREF-26 tool was used to measure the quality of life (QoL) of people with mental illness. The domains of QoL were identified, and indirect and direct effects of variables were calculated using structural equation modelling with SPSS-28 and Amos-28 software. A p-value of < 0.05 and a 95% CI were used to evaluate statistical significance. A total of 636 (99.7%) participants agreed to participate and completed the data collection. The mean score of overall QoL of people with mental illness in the outpatient clinic was 49.6 ± 10 Sd. The highest QoL was found in the physical health domain (50.67 ± 9.5 Sd), and the lowest mean QoL was found in the psychological health domain (48.41 ± 10 Sd). Rural residence, drug nonadherence, suicidal ideation, not getting counselling, moderate or severe subjective severity, family does not participate in patient care and a family history of mental illness had an indirect negative effect on QoL. Alcohol use and psychological health domain had direct positive effect on QoL. Furthermore, objective severity of illness, having low self-esteem, and having history of mental illness in the family had both direct and indirect effect on QoL. Furthermore, sociodemographic factors (rural residence, illiterate educational status, not married marital status), social support-related factors (poor self-esteem, family not participating in patient care), substance use factors (alcohol use, tobacco use) and clinical factors (high objective and subjective severity of illness, not getting counselling, suicidal ideation, higher number of episodes, comorbid illness, family history of mental illness, poor drug adherence) directly and indirectly affected QoL. In this study, the QoL of people with mental illness was poor, with the psychological health domain the most affected. Sociodemographic factors, social support-related factors, drug use factors, and clinical factors, directly and indirectly affected QoL through the mediator variables of physical health domains, psychological health domains, social relation health domains, and environmental health domains. In order to improve the QoL of people with mental illnesses, we recommend that emphasis be given to addressing the QoL of those with mental illness, including the development of policy and practice responses that address the above identified factors.

Evolution of Phytophthora infestans on its potato host since the Irish potato famine

Phytophthora infestans is a major oomycete plant pathogen, responsible for potato late blight, which led to the Irish Potato Famine from 1845–1852. Since then, potatoes resistant to this disease have been bred and deployed worldwide. Their resistance (R) genes recognize pathogen effectors responsible for virulence and then induce a plant response stopping disease progression. However, most deployed R genes are quickly overcome by the pathogen. We use targeted sequencing of effector and R genes on herbarium specimens to examine the joint evolution in both P. infestans and potato from 1845–1954. Currently relevant effectors are historically present in P. infestans, but with alternative alleles compared to modern reference genomes. The historic FAM-1 lineage has the virulent Avr1 allele and the ability to break the R1 resistance gene before breeders deployed it in potato. The FAM-1 lineage is diploid, but later, triploid US-1 lineages appear. We show that pathogen virulence genes and host resistance genes have undergone significant changes since the Famine, from both natural and artificial selection.

Dual FKRP/FST gene therapy normalizes ambulation, increases strength, decreases pathology, and amplifies gene expression in LGMDR9 mice

Recent clinical studies of single gene replacement therapy for neuromuscular disorders have shown they can slow or stop disease progression, but such therapies have had little impact on reversing muscle disease that was already present. In order to reverse disease in patients with muscular dystrophy, new muscle mass and strength must be rebuilt at the same time that gene replacement prevents subsequent disease. Here, we show that treatment of FKRPP448L mice with a dual FKRP/FST gene therapy packaged into a single AAV vector can build muscle strength and mass that exceed levels found in wild-type mice and can induce normal ambulation endurance in a one-hour walk test. Dual FKRP/FST therapy also showed more even increases in muscle mass and amplified muscle expression of both genes relative to either single gene therapy alone. These data suggest that treatment with a single AAV bearing dual FKRP/FST gene therapies can overcome loss of ambulation by improving muscle strength at the same time it prevents subsequent muscle damage. This design platform could be used to create therapies for other forms of muscular dystrophy that may improve patient outcomes.

Arginine, glycine, and creatine supplementation improves symptoms in a female with creatine transporter deficiency.

X-linked creatine transporter deficiency is caused by hemizygous or heterozygous pathogenic variants in SLC6A8 that cause neuropsychiatric symptoms because of impaired uptake of creatine into tissues throughout the body. Small cohorts have suggested that supplementation of creatine, arginine, and glycine can stop disease progression in males, but only six cases of supplementation in females have been published. Here, we present a female with a de-novo pathogenic SLC6A8 variant who had ongoing weight loss, mild intellectual disability, and neuropsychiatric symptoms. Magnetic resonance spectroscopy of the brain showed reduced creatine on all acquired spectra. The patient was started on creatine-monohydrate, l -arginine, and l -glycine supplementation, and she had significant symptomatic improvement within the following 3 weeks. After 8 months of supplementation, magnetic resonance spectroscopy showed improved creatine concentrations with normalizing semiquantitative ratios with other brain metabolites. Current data supports clinicians trialing creatine, arginine, and glycine supplements for female patients with creatine transporter deficiency.

#1549 The effect of sglt2 inhibitors (dapaglifozin) on albuminuria in patients of diabetic nephropathy above standard of care

Abstract Background and Aims Albuminuria is the hallmark of diabetic nephropathy (DN) and progression of albuminuria denotes declining renal functions culminating in End Stage Renal Disease. Intensive blood glucose control (HbA1c &amp;lt;7%), intensive blood pressure control (&amp;lt;130/90 mmHg), blockade of Renin Angiotensin Aldosterone System (RAAS) by Angiotensin converting enzyme inhibitors (ACE-i) and Angiotensin receptor blockers (ARBs) constitute the standard line of care for treatment of DN with proteinuria. Sodium Glucose cotransporter 2 inhibitors (SGLT2i) are drugs are recently introduced for proteinuria reduction with no data available in this part of the world. Hence, I, observed the antiproteinuric effect of SGLT2i in patients who have type2 diabetes mellitus (T2DM) with albuminuria and who are already on maximum doses of ACE-I or ARBs. My study population was on dapaglifozin due to easy availability and low cost. Method it is an observational study including patients who attended the out-patient clinic of Nephrology, at Medica Hospital, Kolkata between July 2022 to February 2023. Inclusion criteria: Exclusion criteria: Quantitative estimation of urine albumin was performed using the VITROS Chemistry Products mALB Reagent along with the VITROS Chemistry Products Calibrator Kit 24 on the VITROS 5,1 FS Chemistry System and the VITROS 5600 Integrated System. Blood sugar was measured by glucose oxidase method. eGFR by CKD EPI equation. Statistical Methodology Continuous variables were presented with mean and standard deviation and tested for normal distribution by the Kolmogorov-Smirnov test. Categorical variables were summarized using frequency and percentages. For testing of related samples, Wilcoxon sign ranked test is used. Statistical analyses were performed using the SPSS software with version 26.0. Results A total of 100 patients were included in the study, of which 3 patients were lost to follow up and 2 patients discontinued the study at 3 months due to fall in eGFR below 25 ml/min/1.73 m2 and 4 patients discontinued after 3 months because of fungal genital infections. After Dapaglifozin administration, a significant reduction in Urine Albumin-creatinine ratio (UACR) was observed, by a percentage decrease of 37.3% (p&amp;lt;0.001) at 3 months and of 70.2% (p&amp;lt;0.001) at 6 months from baseline. Similarly, there was an acute reduction in eGFR from baseline. A percentage decrease by 5.16% (p&amp;lt;0.001) was observed at 3 months &amp; a decrease by 5.69% (p&amp;lt;0.001) at 6 months from baseline. Conclusion Conventional approaches reduce but have not been able to stop disease progression in Diabetic Kidney Disease (DKD). SGLT2i can protect against the onset of DKD, slow disease progression independently. They have an antiproteinuric effect in patients with diabetic nephropathy which was sustained throughout the follow-up period in my study. Studies have also shown that SGLT2i reduce major adverse cardiovascular events in patients with T2DM and established cardiovascular disease. With the new results of EMPA-KIDNEY trial, SGLT2i are being used at even lower eGFR (&amp;lt;25 ml/min/1.73 m2 till on hemodialysis) and such vast health benefits, invention of SGLT2i are is a boon to the mankind.

Luteolin regulating synthesis and catabolism of osteoarthritis chondrocytes via activating autophagy

Osteoarthritis (OA) is a prevalent bone and joint disease characterized by degeneration. The dysregulation between chondrocyte synthesis and breakdown is a key factor in OA development. Targeting the degenerative changes in cartilage tissue degradation could be a potential treatment approach for OA. Previous research has established a strong link between autophagy and the regulation of chondrocyte functions. Activating autophagy has shown promise in mitigating cartilage tissue degeneration. Currently, osteoarthritis treatment primarily focuses on symptom management, as there is no definitive medication to stop disease progression. Previous studies have demonstrated that luteolin, a flavonoid present in Chinese herbal medicine, can activate autophagy and reduce the expression of MMP1 and ADAMTS-5. This study utilized an in vitro osteoarthritis model with chondrocytes stimulated by IL-1β, treated with varying concentrations of luteolin. Treatment with luteolin notably increased the levels of synthesis factors Aggrecan and Collagen II, while decreasing the levels of decomposition factors MMP-1 and ADAMTS-5. Moreover, inhibition of autophagy by Chloroquine reversed the imbalances in chondrocyte activities induced by IL-1β. In an in vivo model of knee osteoarthritis induced by medial meniscal instability (DMM), luteolin was administered as a therapeutic regimen. After 12 weeks, knee cartilage tissues from mice were analyzed. Immunofluorescence and immunohistochemical staining revealed a decrease in P62 expression and an increase in Beclin-1 in the cartilage tissues. Additionally, cartilage wear in the knee joints of mice was alleviated by safranin O and fast green staining. Our study findings underscore the significant role of luteolin in effectively rebalancing chondrocyte activities disrupted by IL-1β. Our results strongly indicate that luteolin has the potential to be developed as a novel therapeutic agent for the treatment of osteoarthritis, offering promising prospects for future drug development.

Profile and risk factors of sight-threatening retinopathy of prematurity: Experience from SNCU in North India.

This research aimed to identify the clinical profile and risk factors of retinopathy of prematurity (ROP) among "at-risk" newborns treated at a sick newborn care unit (SNCU) located at high altitude in North India, with the intention of contributing to formulate regional and national ROP screening guidelines. In a prospective observational study from 2021 to 2022, outborn and inborn babies eligible for ROP screening were screened. Total 39/122 screened neonates had laser for Type 1 ROP, and 22/39 (56.4%) had aggressive ROP (AROP). The average birth weight (BW) was 1803.87 g, and the average gestational age was 34 weeks. Respiratory distress, bronchopulmonary dysplasia, sepsis, and apnea were present in 57.3%, 13%, 52.5%, and 25.4%, respectively. Sight-threatening ROP was present in 50% below 28+6 weeks, 27% between 29 and 30+6 weeks, 52% between 31 and 33+6 weeks, and 15% with gestation >34 weeks. Two babies with Type 1 ROP weighed >2 kg and one had AROP. Upon regression analysis, BW <1500 g, gestation <32 weeks, oxygen >48 h, clinical sepsis, total SNCU stay >14 days, continuous positive airway pressure support with oxygen >50%, and >10 days to achieve full feeds were associated with severe ROP. Caffeine to treat apnea and kangaroo mother care reduced ROP. None had short-term unfavorable outcome. With similar infrastructure and work force shortage in most SNCUs, these findings can be generalized. The burden of Type 1 and AROP is increasing, as seen in higher gestation and BWs. This needs revision of ROP screening criteria at local and national level. It is crucial to emphasize on the importance of pediatrician and ophthalmologist collaboration, early ROP screening, diagnosis, and treatment to stop disease progression to severe ROP.

Innovative pathological network-based multitarget approaches for Alzheimer's disease treatment.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and isa major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities towardtwo or more drug targets of interest. These multitarget-directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade.

Identifying Progression-Specific Alzheimer's Subtypes Using Multimodal Transformer.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet its current treatments are limited to stopping disease progression. Moreover, the effectiveness of these treatments remains uncertain due to the heterogeneity of the disease. Therefore, it is essential to identify disease subtypes at a very early stage. Current data-driven approaches can be used to classify subtypes during later stages of AD or related disorders, but making predictions in the asymptomatic or prodromal stage is challenging. Furthermore, the classifications of most existing models lack explainability, and these models rely solely on a single modality for assessment, limiting the scope of their analysis. Thus, we propose a multimodal framework that utilizes early-stage indicators, including imaging, genetics, and clinical assessments, to classify AD patients into progression-specific subtypes at an early stage. In our framework, we introduce a tri-modal co-attention mechanism (Tri-COAT) to explicitly capture cross-modal feature associations. Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (slow progressing = 177, intermediate = 302, and fast = 15) were used to train and evaluate Tri-COAT using a 10-fold stratified cross-testing approach. Our proposed model outperforms baseline models and sheds light on essential associations across multimodal features supported by known biological mechanisms. The multimodal design behind Tri-COAT allows it to achieve the highest classification area under the receiver operating characteristic curve while simultaneously providing interpretability to the model predictions through the co-attention mechanism.

Abstract 5330: Intestine-specific homeobox edits macrophage polarization in the disease microenvironment by activating inflammasome activity

Abstract Inflammasome activity has a pivotal role in the innate immune system, highlighting its importance in the development of various inflammatory diseases, including cancers. However, the specific impact of inflammasome-produced cytokines from tumor cells on disease progression remains uncertain. In this study, we show that the expression levels of inflammasome-related genes (NLRP1 and NLRP3), combined with levels of the intestine-specific homeobox (ISX), significantly correlate with factors like lesion count, disease stage, and lymph vascular invasion. Tumor cells enhance the secretion of key cytokines such as IL-1β and IL-18, exacerbating disease progression via the ISX-TWIST1 complex. In terms of mechanism, transcriptomic analysis and molecular evidence reveal that ISX interacts with the basic helix-loop-helix (bHLH) domain of TWIST1 through its homeobox domain. This interaction forms a transcriptional complex that activates inflammasomes by directly binding to the conserved sequence "-GGDWYR-" in promoter regions of several NF-κB and inflammasome-related genes (NFKBs, RELs, NLRP1, NLRP3, NEK7, AIM2, and ASC). Elevated levels of IL-18, induced by active inflammasomes, lead to the shift of M0 macrophages into the M2-like phenotype within the hepatic microenvironment. In mice with liver-specific ISX mutations, inflammasome-related genes and activities were eliminated, stopping disease progression in an acute hepatic disease model. These findings underscore the critical role of the ISX-TWIST1 complex in liver disease and tumor progression on both mechanistic and clinical levels. They also offer new insights for potential preventive and therapeutic targets in liver disease. Citation Format: Li-Ting Wang, Shih-Hsien Hsu. Intestine-specific homeobox edits macrophage polarization in the disease microenvironment by activating inflammasome activity [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 5330.

Heat therapy in rheumatic and musculoskeletal diseases - an overview of clinical and molecular effects.

Rheumatic and musculoskeletal diseases (RMDs) usually lead to morphological and functional deficits of various extend, increased morbidity and a considerable loss of quality of life. Modern pharmacological treatment has become effective and can stop disease progression. Nonetheless, disease progression is often only slowed down. Moreover, pharmacological treatment does not improve functionality per se. Therefore, multimodal treatment of rheumatic disorders with physical therapy being a key element is of central importance for best outcomes. In recent years, research into physical medicine shifted from a sole investigation of its clinical effects to a combined investigation of clinical effects and potential changes in the molecular level (e.g., inflammatory cytokines and the cellular autoimmune system), thus offering new explanations of clinical effects of physical therapy. In this review we provide an overview of studies investigating different heat applications in RMDs, their effect on disease activity, pain and their influence on the molecular level.

Abstract C089: A novel role of p53 in pancreatic acinar cell identity

Abstract Pancreatitis is an inflammatory disease that affects acinar cells in the exocrine pancreas, and can be triggered by several factors, such as alcohol abuse, smoking and familial genetic alterations. Pancreatic injury associated with pancreatitis is characterized by inflammation, acinar cell death, and acinar-to-ductal metaplasia (ADM), a regenerative process in which metaplastic cells proliferate and re-differentiate into acinar cells. Recurrent pancreatitis can cause persistent ADM, impairing exocrine function and causing precancerous lesions known as pancreatic intraepithelial neoplasia (PanIN) that can initiate pancreatic ductal adenocarcinoma (PDAC), a nearly always fatal disease. Importantly, the lack of treatment options for pancreatitis patients reinforces the need for strategies that could resolve pancreatic damage and stop disease progression. We have recently shown that pancreatic cells harboring a hyperactive variant of p53 display increased resistance to developing acute pancreatitis induced by cerulein (a secretagogue which mimics cholecystokinin). Here, we show that p53 activation using the drug Nutlin-3a can repair the damage caused by cerulein-induced pancreatitis, and reduce the formation of PanIN lesions. This repair is achieved exclusively at low doses of Nutlin-3a, which cause a mild p53 activation, and is entirely dependent on the presence of the p53 gene. We have also identified novel p53 target genes relevant to acinar identity from ChIP-seq and RNA-seq data, and validated their dependence on p53 in mouse embryonic fibroblasts and in pancreatic precancerous lesions. Lastly, we have observed expression of p53 in the developing pancreas at embryonic day 15.5, indicating a potential function of p53 in pancreatic development. Our findings suggest a novel role of p53 in rescuing acinar cells from damage, and that p53 activation may be used as a treatment for pancreatitis and pancreatic cancer prevention. Citation Format: Jennifer J. Twardowski, Stephano S. Mello, Thomas I. Heist. A novel role of p53 in pancreatic acinar cell identity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C089.

Tofacitinib for the Treatment of Refractory Progressive Vitiligo: A Retrospective Case Series

Treatment of progressive vitiligo aims to halt the spread of the disease and facilitate repigmentation of lesions. JAK inhibitor has been shown some therapeutic effects on vitiligo, but the data for the progressive vitiligo are limited. This retrospective study was performed to evaluate the efficacy and safety of oral tofacitinib in 25 refractory progressive vitiligo patients who experienced failure to previous steroid treatments. 16 (64%) of the 25 patients noted stopping disease progression, and nearly half of the 16 cases halted progression within one month. 10 (40%) patients had repigmentation in varying degrees. Combination with phototherapy was a key factor affecting the rate of repigmentation. Oral tofacitinib might be a potentially effective treatment for intractable progressive vitiligo. The limitations of the study include the retrospective, single-centre study with small sample size and lack of comparison with other systemic therapies.

OmicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases

Treatments for neurodegenerative disorders remain rare, but recent FDA approvals, such as lecanemab and aducanumab for Alzheimer disease (MIM: 607822), highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use summary-data-based Mendelian randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer disease, 3 amyotrophic lateral sclerosis (MIM: 105400), 5 Lewy body dementia (MIM: 127750), 46 Parkinson disease (MIM: 605909), and 9 progressive supranuclear palsy (MIM: 601104) target genes passing multiple test corrections (pSMR_multi<2.95×10-6 and pHEIDI>0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics, classifying 41 novel targets, 3 known targets, and 115 difficult targets (of these, 69.8% are expressed in the disease-relevant cell type from single-nucleus experiments). Our novel class of genes provides a springboard for new opportunities in drug discovery, development, and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as riluzole in Alzheimer disease. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community.

Effect of treatment on the activity of PREP and Transglutaminase-IgA(Ttg-IgA) and other biomolecules in patients with celiac disease (CeD)

Celiac disease (CeD) is a long-term inflammatory disorder of the small intestine, triggered by the ingestion of gluten in genetically susceptible individuals. When gluten is consumed, it leads to damage to the intestinal lining, resulting in poor absorption of nutrients. Although nutrient malabsorption is a significant risk for various complications associated with CeD, genetic, immune, and environmental factors also play key roles. The clinical presentation of CeD can vary widely, ranging from no symptoms to severe symptoms, reflecting its impact on multiple organ systems. Currently, the only evidence-based treatment is a gluten-free diet (GFD), which can fully repair the intestinal damage and stop disease progression. If left undiagnosed, CeD can lead to serious complications in both children and adults.