Significant Weight Change Research Articles

TOXICOLOGICAL EVALUATION OF OLEANOLIC ACID (PENTACYCLIC TRITERPENOID) EXTRACTED FROM LANTANA CAMARA ROOTS FOLLOWING ORAL EXPOSURE IN WISTAR RATS

Objective: The aim of the present study was to perform an acute toxicity study to obtain information on the possible adverse effects from a single oral administration of Oleanolic acid in Wistar rats as the onset of toxicity, and to determine the range of exposure (to the LD50 cut-off criteria). Following a sub-chronic 90-days Repeated toxicity study by oral route to determine any potential indication of its dose response relationship and determine no observed effect level (NOEL)/ no-observed adverse effect level (NOAEL)/ low observed effect level (LOEL)/ low observed adverse effect level (LOAEL). Methods: A dose level of 2000mg/kg body weight was employed as step one for single acute study. Based on the survival pattern of the previously dosed animals after 48 hours, same dose 2000 mg/kg body weight) was repeated for Step 2 as a confirmatory test. For the 90-day toxicity study, the highest dose was determined as 1000mg/kg Body weight, and the middle and lower doses were 500 and 250mg/kg Body weight respectively. The rat group was held for a 14-day recovery period after the last dose administration, to observe for any persistence or reversal of toxic effects. Results: Results of the acute toxicity study showed no mortality on the dose level of 2000mg/kg body weight with no significant clinical and body weight changes. During the 90-day Repeated dose oral sub-chronic toxicity study, no rats died. There were no significant clinical changes related to the test item in terms of functional evaluation, body weight, food and water consumption, ophthalmological tests, urine analysis, necropsy findings, or organ weight, Hematology, and biochemistry at the highest dose level of 1000 mg/kg bwt. Conclusion: It is concluded that LD50 Cut-off Value of “Oleanolic acid” in from acute oral toxicity study in Wistar Rats is 2000 mg/kg b.wt. In addition, 90 days study have showed no significant changes with respect to any hematological or blood chemical analyses in 1000, 500 and 250 mg/kg bwt groups. Based on histopathological findings, clinical signs and other parameters, it may be concluded that upon repeated once oral administration for consecutive 90 days, the Oleanolic acid (Pentacyclic Triterpenoid) extracted from Lantana camara roots at the dose level of 1000 mg/kg body weight have caused no adverse effect in both sexes of Wistar Rats.

Abstract PO2-13-01: Weight change in early breast cancer-based baseline body mass index and treatment

Abstract Background: Early-stage breast cancer is a common condition with significant effects on health, both as a result of treatment and underlying conditions. Breast cancer has been associated with obesity, weight gain, and diabetes. Little is known about changes in weight after breast cancer diagnoses based on baseline weight. Additionally, weight change may differ due to treatments, such as chemotherapy or hormone therapy. Methods: A retrospective study was conducted using deidentified electronic medical records data from a national health informatics provider and insurer database to identify the cohort. The cohort inclusion criteria included women with a diagnosis of breast cancer, a breast biopsy procedure, and a breast cancer surgery within a 1-year period of time from 2010-2018. Body-mass index (BMI) within 1 month of initial biopsy was collected, and weight at 6 months and 1 year after initial biopsy was used to calculate the percentage change in weight. Treatment with chemotherapy within 1 year of diagnosis and hormone therapy within 6 months was also collected. Patients were divided into standard BMI categories as well as BMI >25 vs. ≤25. ANOVA was used to compare outcomes of weight change based on BMI, chemotherapy, and hormone therapy. Linear regression was used to analyze the effects of age, BMI, chemotherapy, and hormone therapy with weight change at 1 year. Results: In 4,541 patients diagnosed with breast cancer, 3,896 patients had weight available at 6 months and 3,406 had weight available at 1 year. Mean age at diagnosis was 61.5 years (standard deviation (SD) 12.4) with mean BMI of 29.9 at baseline (SD 7.3) and weight of 79.5 kg (SD 20.2). Chemotherapy was administered in 1206 patients (26.6%) and hormone therapy in 1,644 (36.2%) with 210 (4.6%) receiving both therapies. Overall, patients lost a mean of 0.6 kg (0.5% change, SD 5.1) at 6 months and 0.6 kg at 1 year (0.4% change, SD 5.7). At one year, patients with BMI < 25 gained 0.74% of body weight vs. lost 1.1% of weight in BMI >25 (p< 0.001). Patients treated with chemotherapy lost 1.4% body weight vs. lost 0.23% in patients without chemotherapy (p< 0.001) and patients treated with hormone therapy lost 0.12% of body weight vs. lost 1.3% without hormone therapy. A linear regression model including age, BMI, chemotherapy, and hormone therapy to explain weight change at one year was statistically significantly better than a baseline model at explaining the weight change at one year [F(4,2474)=61.05]. Increasing age (b=-0.125; t=-10.546; p< .001; 95% CI for beta :0.14 -0.10), BMI (b=-0.178; t=-9.428; p< .001; 95%CI :0.22 -0.14), and chemotherapy (b=-1.643; t=-4.645; p< .001; 95% CI: 2.4 -0.95) were all significant predictors associated with weight loss at one year while hormone therapy was also a significant predictor but was associated with weight gain (b=0.846; t=2.428; p=.015; 95% CI: 0.16-1.5). Conclusions: Women with early breast cancer experienced significant changes in weight in the year after diagnosis. Women with lower BMI gained weight while those with BMI >25 lost weight. Increasing age, BMI, and treatment with chemotherapy was associated with weight loss while use of hormone therapy was associated with weight gain. Further study of weight changes after breast cancer diagnosis are appropriate to understand outcomes and mitigate effects of treatments. Table 1: Percentage weight change across BMI groups by chemotherapy use Citation Format: Martin Schoen, Deepika Gopukumar, Abhilash Akula, Kaitlin Farrell, Aimee Schad, Leslie Hinyard. Weight change in early breast cancer-based baseline body mass index and treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-01.

Inflammation and weight change related to neurocognitive and functional impairment in diabetes and psychiatric disorders

IntroductionObesity is a global pandemic associated with various cardio-metabolic and psychiatric disorders. Neurocognitive and functional deficits have been associated with several somatic and psychiatric disorders. Adiposity-related inflammation has recently emerged as a key risk factor for neurocognitive and functional impairments. This prospective transdiagnostic study aimed to investigate the role of adiposity-related inflammatory markers in neurocognitive and functional outcomes associated with weight changes. MethodsPeripheral blood inflammatory and oxidative stress biomarkers and neurocognitive and functional performance were assessed twice over 1 year in 165 individuals, including 30 with schizophrenia, 42 with bipolar disorder, 35 with major depressive disorder, 30 with type 2 diabetes mellitus (T2DM), and 28 healthy controls. Participants were stratified by body mass index into categories of type 2 obesity (T2OB; n=30), type 1 obesity (T1OB; n=42), overweight (OW; n=53), and average weight (NW; n=40). Mixed one-way analysis of covariance and linear and binary logistic regression analyses were performed. ResultsCompared with NW, T2OB and T1OB were significantly associated with impaired neurocognitive and functional performance (p<0.01; η2p=0.06–0.12) and higher levels of C-reactive protein and platelets (PLT) (p<0.01; η2p=0.08–0.16), with small-to-moderate effect sizes. IL-6, IL-10, and PLT were key factors for detecting significant weight changes in T1OB and T2OB over time. Regression models revealed that inflammatory and oxidative stress biomarkers and cellular adhesion molecules were significantly associated with neurocognitive and functional performance (p<0.05). DiscussionObesity is characterized by neurocognitive and functional impairments alongside low-grade systemic inflammation. Adiposity-related inflammatory biomarkers may contribute to neurocognitive and functional decline in individuals with T2DM and psychiatric disorders. Our data suggest that these biomarkers facilitate the identification of specific subgroups of individuals at higher risk of developing obesity.

The Effects of Resistance Training Interventions on Weight, Body Mass Index, Body Fat Percentage, and Flexibility in College Students: A Comparison Between Sports and Non-Sports Students

Background. Resistance training is an effective form of exercise that promotes healthy body weight regulation and enhances flexibility. However, discrepancies exist regarding the varying impacts of resistance training based on individuals’ training status across different fitness components, such as body composition and flexibility. Objectives. The primary objective of this study is to assess whether there are significant differences in the outcomes of resistance training responses between trained and untrained groups concerning body composition and flexibility. Materials and methods. This experimental resistance training study involved 60 male students (age = 20.83 ± 0.85 years old) from the same university. The participants were divided into two groups based on their training status: a trained group (S; n = 30) and an untrained group (NS; n = 30). Both groups underwent an identical training regimen, consisting of three sessions per week over a total of four weeks or 12 training sessions. Results. Significant differences were observed in the paired sample T-test analysis between pre-test and post-test results in the untrained group for body weight (t (29) = 7.940, p &lt; 0.001, d = 1.45), body mass index (t (29) = 7.579, p &lt; 0.001, d = 1.38), body fat percentage (t (29) = 9.733, p &lt; 0.001, d = 1.77), and sit-and-reach flexibility (t (29) = -7.714, p &lt; 0.001, d = -1.40). Similarly, the trained group showed significant changes in body weight (t (29) = 2.644, p = 0.013, d = 0.483), body fat (t (29) = 2.561, p = 0.016, d = 0.351), and flexibility (t (29) = -2.543, p = 0.017, d = 0.351), while no substantial difference was found in body mass index (t (29) = 1.925, p = 0.064, d = -0.464). Conclusion. The study found that using resistance training protocols targeting weight reduction with 60-70% of 1 Repetition Maximum (RM) over a one-month intervention period, without stringent calorie restriction, significantly decreased weight and BMI while enhancing flexibility. Notably, regardless of training status disparities, the untrained group demonstrated more expressed improvements compared to the trained group, indicating the influence of training status on response variations to training stimuli.

The Effects of Football Training on Improving Aerobic Skills, Technique, and Anthropometry in Goalkeepers

Objectives. The study aimed to assess the impact of football training, particularly for goalkeepers, on children’s motor skills and aerobic capacity over a 10-month period. Materials and methods. This experimental study focused on evaluating the specific skills of goalkeepers and the aerobic capacities of children who took on the role of goalkeeper after undergoing training. The study involved totally 20 individuals aged 10-14 who played as goalkeepers and who were part of the entire population trained at the Real Madrid Foundation UNY Football School. The changes in the goalkeeperʼs aerobic capacity, reaction speed, and diving, as well as anthropometric measurements were found in the study. The instruments used for this research included a multi-stage fitness test, a test of the goalkeeperʼs reaction and diving skills, as well as height and weight measurements. The data analysis technique used was the t-test to determine differences in variables between the pretest and post-test, with a significance level of less than 0.05 (P &lt; 0.05). Results. The results revealed significant improvements in aerobic endurance (P = 0.004), reaction ability (P = 0.007), and goalkeeper diving (P = 0.002) after 10 months of football training. However, there were no significant changes in height, weight, and BMI, as the P value was greater than 0.05. Conclusions. These findings have important implications for evaluating goalkeeper training programs and provide a basis for recommending more effective ones.

Bioactive and biodegradable cotton fabrics produced via synergic effect of plant extracts and essential oils in chitosan coating system

Functional antibacterial textile materials are in great demand in the medical sector. In this paper, we propose a facile, eco-friendly approach to the design of antibacterial biodegradable cotton fabrics. Cotton fiber fabrics were enhanced with a chitosan coating loaded with plant extracts and essential oils. We employed Fourier-transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS), UV–Vis spectrophotometry, optical microscopy, scanning electron microscopy (SEM), and thermogravimetric analysis (TGA) to characterize the color, structure, and thermal properties of the modified fabrics. The fabrics were found to effectively induce growth inhibition of Gram-positive and Gram-negative bacteria, especially when a synergic system of aloe vera extract and cinnamon essential oil was applied in the coating formulation. Additionally, we observed significant color and weight changes after 5, 10, and 20 days in soil biodegradability tests. Given the straightforward modification process and the use of non-toxic natural materials, these innovative bio-based and biodegradable cotton fabrics show great promise as protective antimicrobial textiles for healthcare applications.

Clinical Applicable Carboxymethyl Chitosan with Gel-Forming and Stabilizing Properties Based on Terminal Sterilization Methods of Electron Beam Irradiation.

Carboxymethyl chitosan (CMC)-based hydrogels have great potential for clinical applications, but a critical sterilization process must be addressed to bring them to market. Compared to ethylene oxide sterilization or heat sterilization, irradiation sterilization avoids alkylation and heat damage, while available studies on γ-irradiated other polysaccharides show that solution polysaccharides are susceptible to degradation or cross-linking. Aiming at the challenges brought by the γ-irradiation process of polysaccharide aqueous solution, this paper innovatively proposes the lyophilized CMC using electron beam (EB) irradiation, which not only avoids the generation of free radicals in the irradiated water leading to the degradation and cross-linking of polysaccharides but also retains the properties of CMC in terms of gel formation, stabilization, and clinical application. We used FTIR, TG, GPC, and microbial load tests to demonstrate that lyophilized CMC did not have significant changes in structure and molecular weight after EB irradiation, complied with the requirements for sterilization, and still had gel stability, thus proving that lyophilized CMC could be used for EB irradiation and met the requirements for clinical application. Therefore, this work is expected to further advance CMC injectable hydrogels toward clinical applications and provide a new direction for the sterilization processes of other polysaccharide hydrogels.

Abstract LB155: Intra-cranial administration of MTL-004, a promising post-resection treatment for glioblastoma

Abstract Objectives Gliomas (GBM), are exceptionally hard to treat, aggressive and genetically heterogeneous tumors. This study reports the control of tumor recurrence and improved survival in male and female rats by combining a single intra-cranial dose of MTL-004 (5-(aziridine-1- yl)-4 hydroxylamino-2-nitrobenzamide), in a bioresorbable paste (a blend of poly DL-lactic acid-co-glycolic acid; (PLGA) and poly ethylene glycol; (PEG)) to surgical resection of primary glioma tumors. Comparison is made with oral temozolomide (TMZ), the current standard of care (SOC), following resection. Experimental procedures On day 0, 2 mm3 tumor fragments were implanted into the brains of healthy female and male Fischer rats. On day 5 rats the growing tumors were removed using microsurgery. Treatments started as follows: •Group 1 (Placebo) received a single intracranial dose of excipient powder in PGLA/PEG paste; •Group 2 (SOC) received 5 daily oral doses of TMZ at 50 mg/kg; •Group 3 (MTL-004) received a single intracranial dose of excipient powder containing 1 mg/kg MTL-004 in PGLA/PEG paste. Results Body Weight Between day 0 and 5, no groups had statistically significant body weight changes. Between days 5 to 9, mean body weight of rats receiving TMZ was significantly reduced. Tumor Volumes Tumor volumes from MRI were evaluated when at least 80% of rats were still alive in each group (day 14 post tumor resection/treatment initiation). Mean tumor volume was significantly higher in the placebo groups compared to MTL-004 and TMZ treatments. Survival Rats were studied for 58-days post tumor resection/treatment. At this time out of twelve rats per group, none or one survived on TMZ, two or no animals were still alive on placebo, and seven or ten rats treated with MTL-004 were still alive (male or female respectively). Post resection median survival time was between 20.5 to 27.5 days for rats treated with oral placebo or TMZ. Rats treated with MTL-004 had a significantly higher survival compared to both placebo and TMZ groups and remained in apparent good health for the 58 days of the study. Conclusions Consistent trends were observed in each group of male and female rats following tumor resection. •PGLA/PEG paste with MTL-004 or without (placebo) or were both well tolerated. •Treatment with MTL-004 in PGLA/PEG paste provided good tumor control, was better tolerated and led to significantly greater survival than oral TMZ or placebo. •Oral TMZ (SOC) provided control of tumor volume but was associated with significant, transient body weight losses and no significant survival gain compared to placebo. Our data highlight significant survival benefits associated with a single intracranial dose of MTL-004 with PLGA/PEG paste post-surgery. In conclusion, surgery followed by MTL-004 in PGLA/PEG paste is a well-tolerated and promising treatment for glioblastoma, suitable for clinical evaluation. Citation Format: Mike Hudson, Sylvie Maubant, Elisabeth Bertrand, Marie Lux, Jordan Longin, Elodie Marie Dit Chatel, Maxime Ramelet, Olivier Duchamp. Intra-cranial administration of MTL-004, a promising post-resection treatment for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB155.

The Positive Impact of Bariatric Surgery on Vascular Health.

Obesity is one of the most prevalent medical conditions in the Western world. There are many risk factors associated with obesity, including cardiovascular and pulmonary risk. Vascular health is not studied in obese patients, and whether obesity has an adverse effect on vascular health in these patients remains unknown. The first objective is to find a correlation between vascular health and obesity and whether obesity can be classified as a risk factor for vascular health. The second objective is to see if weight loss leads to an improvement in vascular health in patients. The study was conducted with pre- and post-surgical methods at Baylor Scott & White (BSWH) Medical Center, Temple, Texas, USA.Ten patients were approached, consented, and prepared to obtain baseline values through WatchPAT and EndoPAT devices prior to their bariatric surgery. Values obtained include their initial weight, respiratory disturbance index, apnea-hypopnea index, oxygen desaturation index, and degree of endothelial dysfunction via the EndoPAT device. Post-surgery, these values were obtained again and compared using Wilcoxon non-parametric analyses with a level of significance at p < 0.05. Our study results demonstrate a correlation between obesity and vascular health as endothelial dysfunction is widely seen. In our patients, after bariatric surgery, we saw a significant weight change (31.2% +11.2, p < 0.0001). There was a significant degree of endothelial function improvement after the weight loss (31.2% +34.7, p < 0.04). Our results indicate that there is a correlation between obesity and vascular health, which also correlates with cardiovascular risk. There is a significant reduction in endothelial dysfunction after weight loss. We believe that obesity is a risk factor for vascular health outcomes.

Effect of Combined Intra-Session Glucose and Fructose Intake on the Performance of Young Super-Sprint Triathletes: A Randomised, Crossover, Blind, Placebo-Controlled Study

Carbohydrate intake is a commonly used strategy in sports, and supplementation for triathletes includes pre-competition, intra-competition, and post-competition intake. The consumption of fructose–glucose improves intestinal transit and gastric emptying. The main purpose of this study was to analyse the effect of intra-session carbohydrate intake in triathletes training in the super-sprint modality. Eleven adolescent triathletes (boys, n = 9, 14.6 years; girls, n = 2, 15.2 years) participated in a crossover, randomised, and blind study on the effect of supplementation with 45 g of carbohydrates (glucose:fructose; 1:2) The participants performed two super-sprint tests (swimming 250 m, cycling 6 km, and running 2 km) with a rest period (2 h) during which they drank a placebo drink (PG) or a carbohydrate drink (SG). The effect on blood glucose was evaluated, but there were no significant changes in glucose values. However, it was higher in the SG after supplementation. No significant differences were found in the cycling, swimming, and running tests, except for RPE in the swimming sector (p &lt; 0.05). Neither were significant changes in body weight observed during the assessments. Supplementation with 45 g of liquid carbohydrates composed of fructose and glucose in a 2:1 ratio was not effective for delaying fatigue or improving performance markers or blood glucose levels in super-sprint triathletes.

Banded One-Anastomosis Gastric Bypass (BOAGB) for Patients Living with Obesity and Extreme Obesity: A Single Institution's Experience.

The prevalence of patients suffering from extreme obesity (body mass index (BMI) ≥ 50) has significantly increased over the past three decades, surpassing the rise in the general population of overweight patients. Weight loss outcomes after bariatric surgery in patients suffering from extreme obesity are less favorable, with a higher incidence of weight regain. Variations of existing bariatric procedures have been proposed to address this issue. One such variation is adding a gastric band to limit the expansion of the newly created pouch. Limited data exist regarding the effectiveness of this procedure, called the banded one-anastomosis gastric bypass (BOAGB) procedure, compared to other bariatric procedures. In this retrospective study, we compared all patients who underwent the BOAGB procedure at the Bariatric Surgery Unit in our Medical Center with a postoperative follow-up of at least 1year with patients who underwent a one-anastomosis gastric bypass (OAGB) or sleeve gastrectomy (SG) procedures. Data collected included demographics, comorbidities, surgical outcomes, complications, and postoperative quality-of-life assessments. One hundred eleven patients were enlisted to our study during the relevant study period-24 patients underwent the BOAGB procedure, 43 underwent OAGB, and 44 underwent a SG. Lost to follow-up beyond 30days was 9% (at 1-year post-surgery, we were able to establish contact with 101 patients). The pre-op BMI was significantly higher in the BOAGB group compared to the other procedures. Additionally, a higher prevalence of diabetes was observed in the BOAGB group. The duration of surgery was significantly longer for the BOAGB procedure. No significant differences were found in surgical complications. Overall, all procedures resulted in significant excess weight loss (EWL) or change in BMI, improvement in comorbidities, and improved quality of life postoperatively. The BOAGB procedure, like OAGB and SG, demonstrated favorable weight loss outcomes and weight maintenance 1year postoperatively without significant differences between the procedures. The BOAGB procedure is relatively new, with good bariatric outcomes and a favorable safety profile. Long-term study is needed to evaluate these various bariatric procedures' efficacy further.

Acute and subacute toxicological evaluation of the ethanol leaf extract of Morus mesozygia stapf. (Moraceae) in rodents

Ethnopharmacological relevanceTraditionally, the Morus mesozygia tree leaf has been used to manage maladies such as peptic ulcer, hyperglycemia, dermatitis, rheumatism, stomach-ache, arthritis, cough, malignancies, and malaria in parts of Africa. Aim of the studyThe study aimed to evaluate the potential of ethanol leaf extract of Morus mesozygia (EEMm) to induce toxicity by employing both acute and sub-acute oral toxicity experimental models. Material and methodsThe extract's cytotoxicity was studied using brine shrimps (Artemia salina) lethality assay (BSLA), while in the acute toxicity test, male and female mice were administered a single oral dose of EEMm (2000 mg/kg). Male and female Wistar rats received repeated doses of 100 or 500 mg/kg EEMm orally for 28 days in the sub-acute toxicity experiment. The phytochemical analysis of EEMm was done using the HPLC. ResultsThe BSLA revealed a moderate cytotoxic potential of the extract, with an LC50 of 567.13 ± 0.27 μg/mL. All the animals survived the acute toxicity test, with no significant changes in the relative organ weights, suggesting that LD50 is greater than 2000 mg/kg. The animal weights did not vary significantly in the sub-acute toxicity test neither were the alterations in biochemical and hematological tests pronounced, although the histoarchitectures of the kidney, liver and spleen indicated slight anomalies in the evaluated animals. The HPLC analysis revealed the presence of quercetin, ferulic acid, rutin, caffeic acid, morin and gallic acid. ConclusionsEthanol leaf extract of Morus mesozygia demonstrated a safe toxicity profile in rodents, supporting its broad folkloric use in African ethnomedicine.

Dietary vitamin A modifies the gut microbiota and intestinal tissue transcriptome, impacting intestinal permeability and the release of inflammatory factors, thereby influencing Aβ pathology.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder with no effective interventions for curing or modifying its progression. However, emerging research suggests that vitamin A in the diet may play a role in both the prevention and treatment of AD, although the exact mechanisms are not fully understood. This study aims to investigate the dietary vitamin A modifies the gut microbiota and intestinal tissue transcriptome, impacting intestinal permeability and the release of inflammatory factors, thereby influencing Aβ pathology shedding light on its potential as a dietary intervention for AD prevention and treatment. The APP/PS1-AD mouse model was employed and divided into three dietary groups: vitamin A-deficient (VAD), normal vitamin A (VAN), and vitamin A-supplemented (VAS) for a 12-week study. Neurobehavioral functions were assessed using the Morris Water Maze Test (MWM). Enzyme-linked immunosorbent assay (ELISA) was used to quantify levels of Diamine Oxidase (DAO), D-lactate, IL-6, IL-1β, and TNF-a cytokines. Serum vitamin A levels were analyzed via LC-MS/MS analysis. Immunohistochemical analysis and morphometry were performed to evaluate the deposition of Aβ in brain tissue. The gut microbiota of APP/PS1 mice was analyzed using 16S rRNA sequencing analysis. Additionally, transcriptomic analysis was conducted on intestinal tissue from APP/PS1 mice. No significant changes in food intake and body weight were observed among the groups. However, the VAD and VAS groups showed reduced food intake compared to the VAN group at various time points. In terms of cognitive function, the VAN group performed better in the Morris Water Maze Test, indicating superior learning and memory abilities. The VAD and VAS groups exhibited impaired performance, with the VAS group performing relatively better than the VAD group. Serum vitamin A concentrations differed significantly among the groups, with the VAS group having the highest concentration. Aβ levels were significantly higher in the VAD group compared to both the VAN and VAS groups. Microbial analysis revealed that the VAS and VAN groups had higher microbial diversity than the VAD group, with specific taxa characterizing each group. The VAN group was characterized by taxa such as Actinohacteriota and Desulfovibrionaceae, while the VAD group was characterized by Parabacteroides and Tannerellaceae. The VAS group showed similarities with both VAN and VAD groups, with taxa like Desulfobacterota and Desulfovibrionaceae being present. The VAD vs. VAS, VAD vs. VAN, and VAS vs. VAN comparisons identified 571, 313, and 243 differentially expressed genes, respectively, which associated with cellular and metabolic processes, and pathway analysis revealed enrichment in pathways related to chemical carcinogenesis, drug metabolism, glutathione metabolism, and immune-related processes. The VAD group exhibited higher levels of D-lactate, diamine oxidase, and inflammatory cytokines (TNF-a, IL-1β, IL-6) compared to the VAN and VAS groups. Dietary vitamin A supplementation modulates the gut microbiota, intestinal permeability, inflammatory factors, and Aβ protein formation, offering insights into the pathogenesis of AD and potential therapeutic avenues for further exploration. This research highlights the intricate interplay between diet, gut microbiota, and neurodegenerative processes, emphasizing the importance of dietary interventions in managing AD-related pathologies.

Porphyrin-based covalent organic frameworks as doxorubicin delivery system for chemo-photodynamic synergistic therapy of tumors

Photodynamic therapy (PDT) is a non-invasive treatment method that has garnered significant attention in recent years. Nanoparticle-based drug delivery systems can achieve targeted drug release, thereby significantly reducing side effects and enhancing therapeutic efficacy. In this study, a covalent organic framework (COF) with an approximately spherical structure connected by azo bonds was synthesized. The synthesized COF was utilized as a hypoxia-responsive carrier for doxorubicin (DOX) drug delivery and was modified with hyaluronic acid (HA). DOX@COF@HA exhibited a reactive release under hypoxic conditions. Under normal oxygen conditions, the release of DOX was 16.9 %, increasing to 60.2 % with the addition of sodium hydrosulfite. In vitro experiments revealed that the group combining photodynamic therapy with chemotherapy exhibited the lowest survival rates for 4T1 and MHCC97-L cells. In vivo experiments further validated the effectiveness of combination therapy, resulting in a tumor volume of only 33 mm3 after treatment, with no significant change in mouse weight during the treatment period. DOX@COF@HA nanoplatforms exhibit substantial potential in tumor treatment.

Abstract 5801: Targeted delivery of Exatecan to tumors via a novel cell-penetrating, anti-DNA antibody

Abstract The formulation of novel chemotherapeutics capable of precisely targeting and damaging tumor cells, while preserving the integrity of healthy tissues, represents a principal challenge and is recognized as one of the biggest achievements in cancer treatment in the last few decades. Antibody-drug conjugates (ADCs) hold significant potential as an effective cancer treatment, by targeting and delivering cytotoxic drugs exclusively to tumor cells that express distinct antigens associated with malignancy. Due to the necessity for specific surface antigens, therapies with ADCs are limited to specific tumor subtypes. In this study, we show the potential of a lupus-derived, cell-penetrating, anti-DNA antibody for delivering of cytotoxic payload to tumors in vivo. We utilized a fully humanized variant, named as V66, which was chemically linked to the Topoisomerase I inhibitor, Exatecan. The primary mechanism involved in V66 cellular penetration is mediated by the Equilibrative Nucleoside Transporter ENT2. The latter shows elevated expression in a substantial subset of cancer types in comparison to healthy tissues, broadening the range of applications for ADCs in tumor therapy. Using labeled V66, we demonstrated specific tumor delivery in vivo, with minimal impact on healthy tissues. In vitro experiments validated the nuclear localization of V66-Exatecan, where it triggers the activation of the DNA damage repair pathway (DDR). As a consequence of the profound DNA damage, exposure to V66-Exatecan leads to cell death, exhibiting low nanomolar EC50 values across a diverse range of cell lines. Furthermore, V66-Exatecan treatment presents synthetic lethality with BRCA2 deficiency, evidenced by a substantial increase in sensitivity. In vivo efficacy studies conducted in BRCA2 deficient tumors revealed a remarkable effectiveness of V66-Exatecan, leading to almost complete tumor regression and substantial improvement in the probability of survival. In addition to the lack of significant weight changes observed throughout the treatment, further toxicological studies conducted in serum and tissues demonstrated the absence of short- and long-term toxicity, with optimal liver and kidney function and the absence of damage to other tissues. Likewise, bone marrow cellularity remained unaffected. Collectively, these studies indicate that V66-Exatecan achieves targeted treatment of tumor cells, where it induces DNA damage leading to cell death. The in vivo application of V66-Exatecan leads to tumor regression without triggering general toxicity that is otherwise associated with Topoisomerase I inhibitors. This work provides the basis to advance a novel nuclear-penetrating ADC for delivering cytotoxic payloads. Citation Format: Zaira Ianniello, Elias Quijano, Peter M. Glazer. Targeted delivery of Exatecan to tumors via a novel cell-penetrating, anti-DNA antibody [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 5801.

Abstract 7549: Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1

Abstract DNA methylation inhibitors such as 5-azacytidine (Aza) and 5-aza-2′-deoxycytidine have been extensively used in patients with hematologic disorders and other neoplasms since their approval by the FDA. However, global DNA demethylating agents can result in intolerable toxicities; therefore, targeted epigenetic modulation is needed. Here, we searched for epigenetic changes with adaptive resistance to anti-VEGF antibody (AVA) in the TME and a novel strategy for targeted demethylation. Methods: We examined methylation and transcriptional changes in orthotopic ovarian cancer models with emergence of AVA resistance. We developed a targeted demethylation strategy for BARD1 to enhance the effectiveness of AVA. We used a novel dCas9-CRISPR-based system for targeted BARD1 CpG demethylation (derived by fusing the deactivated Cas9 [dCas9] with the TET1 catalytic domain) delivered in vivo using a nanoliposomal carrier. Results: We identified BARD1 methylation and reduced expression as lead candidate with AVA resistance; multiple CpG island sites in the BARD1 gene from adaptive AVA-resistant tumors were methylated. Next, we investigated the biological effects of global and targeted DNA methylation. Azacytidine along with AVA therapy was tested in a series of models (fibrosarcoma, PDX and orthotopic ovarian cancer models) and resulted in reduced tumor burden compared with the control and monotherapy groups (p&amp;lt;0.01). Next, to determine whether targeted demethylated BARD1 would have antitumor effects in vivo, we used an orthotopic SKOV3ip1luc ovarian cancer mouse model. Mice were treated with DOPC-dCas9-TET1-sgcontrol- (control) and DOPC-dCas9-TET1-sgBARD1 (sgBARD1). Tumor weight in the sgBARD1-3 group was significantly (p&amp;lt;0.01) reduced compared with the control group with no significant change in mouse body weight. We found that BARD1 expression was significantly increased in sgBARD1-treated group compared with control (p&amp;lt;0.001). Next, to determine whether demethylated BARD1 would combine well with AVA therapy in the SKOV3ip1 model, we combined sgBARD1-3 with bevacizumab (bev); sgBARD1-3 alone led to a significant decrease in tumor burden compared with control groups. Moreover, tumor burden was significantly reduced in the sgBARD1-3 and bevacizumab combination group compared with the sgcontrol group and bev alone group. BARD1 expression was significantly increased in sgBARD1-3-treated and in combination tumor samples compared with controls. To check for potential off-target effects, we tested the efficacy of another sgBARD1 and found that tumor burden in the sgBARD1-1 group was significantly reduced compared with control group. Conclusion: Our novel targeted approach results in robust antitumor effects when combined with AVA therapy in multiple cancer models. Collectively, our findings provide a novel approach for gene targeted demethylation and could have implications for epigenetic therapies. Citation Format: Emine Bayraktar, Cristian Rodriguez-Aguayo, Elaine Stur, Sudhir Kumar, Lingegowda S. Mangala, Nazende Nur Bayram, Pahul Hanjra, Sara Corvigno, Stephen Baylin, Gabriel Lopez-Berestein, Anil K. Sood. Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [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 7549.

Abstract 5752: Enhanced cancer therapy strategies utilizing gelatin-lipidoid hybrid nanoparticles for RNA delivery

Abstract Nanoparticle delivery platforms have provided impetus for the emergence of novel RNA-based cancer therapeutics due to their ability to circumvent the physiological and cellular barriers in the delivery. The clinical success of these strategies hinges primarily on the safety and efficacy of the delivery vehicle. Here, we have developed a gelatin-lipidoid hybrid nanoparticle (GLNP) that utilizes gelatin's biocompatibility, biodegradability, and lipidoids' high transfection efficiency. With GLNP, we have demonstrated the efficacy of delivering siRNA and silencing AXL, a receptor tyrosine kinase commonly associated with cancer progression, metastasis, and drug resistance. siRNA is attached to the surface of GLNP through covalent conjugation with gelatin, while the lipidoid on the system's interior electrostatically complexes with the siRNA. siRNAs are well protected by the GLNP when exposed to serum for at least 48 hours. The GLNP's bivalency significantly enhanced the downregulation of target genes in vitro and in vivo. Furthermore, the bivalent GLNP can simultaneously target and downregulate two oncogenes. Apart from siRNA, GLNP was also able to encapsulate and deliver mRNA, thereby suggesting the potential to simultaneously deliver RNA therapeutics to effect knockdown and expression of target proteins and maximize therapeutic effect. The length of the carbon chain of the lipidoid can be manipulated to influence the physico-chemical properties of the GLNP and its efficiency in encapsulating and delivering RNA drugs. Importantly, gelatin was found to effectively shield the cationic lipidoid and negate its toxicity. Toxicity studies indicate that high doses of GLNPs (up to 48 mg/kg BW) are well-tolerated with no significant changes in body weight, hematology, or serum chemistry. The co-administration of GLNP-siAXL and TKI in PDX models has shown notable control of tumor growth. It is important to note that immune checkpoint blockade (ICB) therapy has shown significant survival benefits in NSCLC patients. However, the therapeutic effect is limited to only 20% of patients due to several resistance mechanisms, such as increased expression of oncogenic proteins. Therefore, our future study will explore GLNP's ability to sensitize NSCLC tumors to immune therapy. Citation Format: Abilash Gangula, Dhananjay Suresh, Agasthya Suresh Babu, Zhaohui Li, Anandhi Upendran, Raghuraman Kannan. Enhanced cancer therapy strategies utilizing gelatin-lipidoid hybrid nanoparticles for RNA delivery [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 5752.

Abstract 6953: Wnt2b deficiency exacerbates colitis and leads to increased tumorigenesis in mice

Abstract Colitis-associated cancer (CAC) is considered the most severe complication of inflammatory bowel disease (IBD). It has been demonstrated that WNT2B deficiency leads to severe intestinal impairment in humans and predisposes to colitis in mice. Evaluating a human cohort from The Cancer Genome Atlas (TCGA), we observed that low expression of WNT2B is associated with poor prognosis of patients with colon cancer. However, the functional roles of WNT2B in CAC development remain unclear, and we hypothesized that WNT2B is involved in the resistance to CAC development during long-term colitis. Thus, we model CAC development using Wnt2b deficient mice subjected to mutagenesis induction with 10 mg/kg Azoxymethane (AOM) and a long-term colitis protocol with three cycles of 2.5% Dextran Sodium Sulfate in the drinking water for three days, followed by a recovery period with autoclaved water. We observed that Wnt2b KO mice had increased susceptibility to colitis and more significant body weight changes than WT mice, especially in the first and second recovery cycles of colitis recovery. The maximum weight loss and disease activity index (DAI) were significantly higher in KO than in WT mice. Interestingly, Wnt2b KO mice developed more tumors, which were more extensive than those observed in WT. Moreover, the histopathological analysis showed that Wnt2b KO had the highest score for ulceration, aberrant crypt foci, and immune cell infiltration. Our data suggest a protective role for WNT2B, conferring resistance to tumor development during colitis. Furthermore, our data provides new insights into the functional roles of Wnt ligands in colon cancer. A better understanding of the factors involved in CAC etiology is critical for improving diagnosis and developing new targeted therapies. We believe WNT2B may emerge as one of these factors and offer novel targets for improved colorectal cancer management. Citation Format: Luiz Fernando Silva Oliveira, Amy E. O'Connell. Wnt2b deficiency exacerbates colitis and leads to increased tumorigenesis in mice [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 6953.

Abstract 1973: Discovery of the first-in-class SHP1 covalent inhibitor for cancer immunotherapy

Abstract Cancer immunotherapy refers to the approach leveraging patients’ immune system against tumor, which has gained tremendous progress hallmarked by immune checkpoint blockade and adoptive cell therapies. However, contemporary strategies suffer from limited responses, adverse side effects, and low tissue penetration due to utilization of macromolecules, calling for more efficacious and safer alternative strategies. SHP1 is a protein tyrosine phosphatase (PTP) primarily expressed in hematopoietic cells and has been shown to negatively regulate immune responses in T cells and natural killer (NK) cells, and SHP1 deletion in these cells has shown to promote their anti-tumor functions. Recent studies also demonstrated that inducible SHP1 knockout inhibited tumor growth in vivo through immune activation. Although presented as an attractive target, no high-quality small molecule inhibitors have been reported for SHP1 due to its undruggable nature. Through high-throughput screening and extensive medicinal chemistry, we have acquired the first-in-class SHP1 covalent inhibitor M029, which shows &amp;gt;25-fold selectivity against SHP2, its closest analogues and &amp;gt;60-fold selectivity against other PTPs and cysteine-based proteins. Further proteomics studies reveal that M029 is superiorly selective for SHP1 in cellulo. Additionally, M029 is stable in 100-fold excessive glutathione with a half-life of &amp;gt;35 hours and non-toxic up to 100 µM to healthy cells, such high stability was also reflected by its oral bioavailability with a F% of 10%. M029 treatment significantly activated T cell receptor signaling in T cells and NK cells killing effects in vitro. Furthermore, oral dosage of M029 significantly delayed tumor progression in mice bearing MC38 tumors through enhanced T cell and NK cell infiltration and activation and prolonging of T cell exhaustion. To validate that the compound acted through immune activation, we dosed the mice with anti-CD8+ or anti-NK1.1 during M029 treatment, both of which abolished the compound efficacy, corroborating with its mechanism of action. Meanwhile, to assess the compound safety, we dosed the mice up to 100 mg/kg for 8 days, where no significant body weight change or cytokine storm were observed. Collectively, we have developed the first SHP1 covalent inhibitor with high selectivity and strong anti-tumor efficacy. This study is the first characterization of pharmacological SHP1 inhibition as cancer immunotherapy and solidified its potential as an immunotherapeutic target. The development of M029 will also enlighten drug discovery strategies against SHP1 or other undruggable PTPs. Citation Format: Zihan Qu, Frederick Nguele Meke, Zheng Zhang, Yunpeng Bai, Aaron D. Krabill, Christine S. Muli, Brenson A. Jassim, Jiajun Dong, Jinyue Li, Nguyen Yuyen, Andy W. Tao, Darci T. Trader, Zhong-Yin Zhang. Discovery of the first-in-class SHP1 covalent inhibitor for cancer immunotherapy [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 1973.

PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer.

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216 + venetoclax in reducing the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b was found to lead to significant tumor growth delay, similar to the DT2216 + venetoclax combination in H146 xenografts, by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future.