Significant Body Weight Loss Research Articles

Biomarker potential of nuclear Nrf2 activation in the ABC subtype of diffuse large B‑cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma characterized by distinct subtypes and heterogeneous treatment outcomes. Oxidative stress and the dysregulation of related regulatory genes are prevalent in DLBCL, prompting an investigation into the nuclear factor erythroid 2-related factor 2 (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) signaling pathway and associated genes. The present study assessed pathological specimens and clinical data from 43 newly diagnosed patients with DLBCL, comparing the associations and correlations between the expression of Nrf2, Keap1, microtubule-associated protein 1 light chain 3β (LC3B) and nitrotyrosine and the activated B-cell (ABC) and germinal center B-cell (GCB) subtypes of DLBCL using immunohistochemistry and digital image analysis software. Nuclear Nrf2 activation was observed in 33.3% of patients with DLBCL ABC, demonstrating a higher prevalence of hepatitis B surface antigen positivity, calcium ions and significant body weight loss (P<0.05). Total Nrf2 expression was associated with the DLBCL GCB subtype and inversely correlated with Keap1 expression in the DLBCL ABC subtype. Furthermore, a positive correlation was demonstrated between Nrf2 and LC3, indicating that total Nrf2 is inhibited by Keap1 and regulates LC3 expression. The ABC subtype was also associated with lower white blood cell counts and more frequent chemotherapy courses than the GCB subtype. These findings suggest that nuclear Nrf2 could be a biomarker for DLBCL clinical diagnosis.

Biochemical perturbations associated with Salmonella gallinarum infection in laying hens:Is oxidative stress implicated?

The aim of this study was to investigate some biochemical and tissue changes associated with Salmonella gallinarum infection in laying hens (LHs), and the complicities of oxidative stress (OS). Fifty LHs were assigned to two groups of 25 LHs infected with S. gallinarum (109 cfu*mL-1 of S. gallinarum) and 25 uninfected controls. Biochemical assays and histopathology were carried out following standard procedures. There was a significant loss of body weight, drop in egg production, as well as 28% mortality in the infected group. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and superoxide dismutase (SOD) activities, as well as serum total protein, globulin, total cholesterol, total bilirubin, uric acid, creatinine and malondialdehyde (MDA) levels were significantly higher, whereas serum albumin levels were significantly lower in infected LHs. There were inflammatory, degenerative and necrotic changes observed in the affected organs. Considering the significant elevation in MDA levels coupled with elevated SOD activity in the infected LHs, OS may play a significant role in the pathology of fowl typhoid and may suggest a possible treatment of infected layers with antioxidants.

Effects of Vitamin C on Aluminum Chloride- Induced Neurotoxicity on the Hippocampal Cortex of Adult Wistar Male Rats

This study aimed to evaluate the neuroprotective effects of Vitamin C on aluminum chloride (AlCl₃)- induced brain damage, focusing on behavioral, biochemical, and histomorphological outcomes in a rodent model. Study Design: A total of 42 healthy male rats were randomly assigned to three groups: control, AlCl₃ -only, and AlCl₃ plus Vitamin C (500 mg/kg and 1000 mg/kg). The AlCl₃ groups received daily doses of AlCl₃, while the Vitamin C groups received concurrent Vitamin C supplementation. Methodology: Body weight, behavioral changes, biochemical markers of oxidative stress (MDA, SOD, GSH), and inflammation (TNF-α, IL-6) were assessed. Histomorphological analysis of the hippocampus was performed to evaluate structural damage. Behavioral assessments included locomotor and exploratory activity tests. Biochemical analyses measured oxidative stress and antioxidant enzyme activities. Results: AlCl₃ administration resulted in significant body weight loss, increased oxidative stress (elevated MDA, and SOD levels), and heightened inflammation (elevated TNF-α and IL-6). Behavioral tests showed increased excitatory activities, and increased anxiety levels as seen in increased rearing and grooming activities. Histomorphological examination revealed significant hippocampal damages as seen in the pale staining, shrunken pyramidal cells. Vitamin C co- administration mitigated these adverse effects, demonstrating reduced body weight loss, lower oxidative stress, decreased inflammation, and improved behavioral performance. Histological analysis indicated less hippocampal damage in the Vitamin C treated groups. Conclusion: As an antioxidant, Vitamin C effectively attenuates the neurotoxic effects of AlCl₃ by reducing oxidative stress and inflammation, and by protecting the hippocampal cellular integrity. These findings suggest that Vitamin C holds potential as a therapeutic agent for mitigating neurotoxicity induced by aluminum compounds.

Sex-Specific Adherence to the Mediterranean Diet in Obese Individuals.

Adherence to the Mediterranean diet (MedDiet) has long been associated with several health benefits, including a reduced risk of heart disease, diabetes, and obesity. The MedDiet is characterized by a high consumption of foods such as fruits, vegetables, whole grains, fish, and olive oil, along with a moderate intake of red meat and red wine with meals. Some studies report significant differences between men and women in susceptibility to obesity, with women at a higher prevalence of obesity than men. One unexplored aspect, however, concerns the sex difference in MedDiet adherence, which could be influenced by various factors, such as health perceptions, food preferences, and cultural influences. The aim of this study is to assess the effectiveness and impact of MedDiet adherence in men and women, with a focus on its influence on health and well-being, as well as its ability to promote sex equity in healthcare outcomes. Moreover, we aim to measure the overall health improvements in men and women participating in a MedDiet program, including changes in body composition and overall quality of life. This study highlights that the MedDiet is associated with more significant body weight loss in women, although their increase in MedDiet adherence was lower than in men. Trial registration: NCT01890070. Registered 24 June 2013.

Integrated transcriptomic and proteomic analyses reveal the effects of chronic benzene exposure on the central nervous system in mice

Benzene exposure is known to cause serious damage to the human hematopoietic system. However, recent studies have found that chronic benzene exposure may also cause neurological damage, but there were few studies in this issue. The aim of this study was to investigate the mechanism of damage to the central nervous system (CNS) by chronic benzene exposure with a multi-omics analysis. We established a chronic benzene exposure model in C57BL/6J mice by gavage of benzene-corn oil suspension, identified the differentially expressed proteins (DEPs) and differentially expressed genes (DEGs) in mice brain using 4D Label-free proteomic and RNA-seq transcriptomic. We observed that the benzene exposure mice had a significant loss of body weight, reduction in complete blood counts, abnormally high MRI signals in brain white matter, as well as extensive brain edema and neural demyelination. 162 DEPs were identified by the proteome, including 98 up-regulated and 64 down-regulated proteins. KEGG pathway analysis of DEPs showed that they were mainly involved in the neuro-related signaling pathways such as metabolic pathways, pathways of neurodegeneration, chemical carcinogenesis, Alzheimer disease, and autophagy. EPHX1, GSTM1, and LIMK1 were identified as important candidate DEGs/DEPs by integrated proteomic and transcriptomic analyses. We further performed multiple validation of the above DEGs/DEPs using fluorescence quantitative PCR (qPCR), parallel reaction monitoring (PRM), immunohistochemistry, and immunoblotting to confirm the reliability of the multi-omics study. The functions of these DEGs/DEPs were further explored and analyzed, providing a theoretical basis for the mechanism of nerve damage caused by benzene exposure.

Haematobiochemical Alterations in Rabbit Mange

Mange in rabbits is an economically important parasitic disease which cause significant loss in productivity, body weight and fur quality. Forty eight rabbits with clinical signs of alopecia, anorexia, pruritis, skin erosions and dry crust like lesions on extremities, ears, nose and face were brought to Veterinary Clinical Complex, Rajendranagar and Hyderabad. Skin scrapings were collected, processed and examined under microscope to detect mite infestation. Different mites i.e. Sarcoptes scabiei, Psoroptes cuniculi, Notoedres cuniculi, Demodex cuniculi and Cheyletiella parasitivorax were noticed in rabbits. Haematological examination revealed a significant (p&lt;0.05) decrease in haemoglobin, PCV, RBC count and a significant (p&lt;0.05) increase in TLC count in affected rabbits. Serum analysis showed a significant (p&lt;0.05) increase in ALT and AST levels in infected rabbits. Treatment with ivermectin along with proper management resulted in recovery from mange in rabbits.

Ivermectin Synergizes with Modulated Electro-hyperthermia and Improves Its Anticancer Effects in a Triple-Negative Breast Cancer Mouse Model.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options. Modulated electro-hyperthermia (mEHT) is a novel adjuvant cancer therapy that induces selective cancer damage. However, mEHT upregulates heat shock protein beta 1 (HSPB1), a cancer-promoting stress chaperone molecule. Thus, we investigated whether ivermectin (IVM), an anthelmintic drug, may synergize with mEHT and enhance its anticancer effects by inhibiting HSPB1 phosphorylation. Isogenic 4T1 TNBC cells were inoculated into BALB/c mice and treated with mEHT, IVM, or a combination of both. IVM synergistically improved the tumor growth inhibition achieved by mEHT. Moreover, IVM downregulated mEHT-induced HSPB1 phosphorylation. Thus, the strongest cancer tissue damage was observed in the mEHT + IVM-treated tumors, coupled with the strongest apoptosis induction and proliferation inhibition. In addition, there was no significant body weight loss in mice treated with mEHT and IVM, indicating that this combination was well-tolerated. In conclusion, mEHT combined with IVM is a new, effective, and safe option for the treatment of TNBC.

Comparison of Clinical Outcomes and Postoperative Nutritional Status Between Early and Late Oral Feeding After Esophagectomy: An Open Labeled Randomized Controlled Trial.

To compare nutritional and postoperative outcomes between early oral feeding and late oral feeding with jejunostomy feeding support after esophagectomy. Esophagectomy is associated with substantial body weight loss and malnutrition, impacting the prognosis of esophageal cancer patients. Despite many studies on post-esophagectomy nutritional support, optimal strategies remain elusive. This study investigates the impact of jejunostomy feeding with late oral feeding compared to conventional oral feeding on nutritional and postoperative outcomes. We performed a single-center prospective open-labelled randomized controlled trial between 2020 and 2022. Patients aged 18 to 75 years with resectable esophageal cancer were randomly assigned to undergo either early oral feeding (early group) or late oral feeding with jejunostomy feeding support (late group) after esophagectomy. The primary endpoint was body weight loss from preoperative body weight at postoperative 4-5 weeks and 4 months. Other perioperative and nutritional outcomes were also evaluated. We randomly assigned 29 patients to the early group and 29 patients to the late group. The late group exhibited significantly less body weight loss at both postoperative 4-5 weeks (8.3% vs. 5.6%; P =0.002) and 4 months (15.0% vs. 10.5%; P =0.003). The total calorie intake and protein intake were higher in the late group for both postoperative 4-5 weeks (1800kcal/day vs. 1100kcal/day; P <0.001) and 4 months (1565kcal/day vs. 1200kcal/day; P =0.010). Sixty percentage of early group changed to malnutrition state, while 40% of the late group changed to malnutrition. The complication rate and length of hospital stays were similar. The late group demonstrated prevention of significant body weight loss, enhanced nutritional intake, and reduces malnutrition without compromising short-term surgical outcomes.

Ameliorating Effects of Intermittent Fasting on Cardiac Dysfunctions in Experimentally Induced thyrotoxicosis in Adult Rats. Role of Ghrelin Hormone

Abstract Background Cardiovascular complications of hyperthyroidism have high morbidity and mortality rates. The cardioprotective effect of intermittent fasting (IF) in addition to the concomitant rise of blood ghrelin hormone level during IF have gained attention, but their effects on thyrotoxic hearts are still unclear. Therefore, we aimed to investigate the impacts of IF on hearts of rats subjected to induced thyrotoxicosis (TH) elucidating the role of ghrelin hormone in the assumed cardio protection. Methods Forty-five adult male Wistar Albino rats in 3 groups: control group, thyrotoxic group, injected IP with L-thyroxine100 μg/kg/day, 5 days/week for 4 weeks and intermittent fasting-treated thyrotoxic group, subjected to alternative day fasting regimen for 4 weeks. cardiac functions were assessed by in-vivo studies (ECG recording and arterial blood pressure evaluation) and in-vitro studies (responses to isoproterenol infusion using Langendorff’s preparation). Results Compared to the TH rats, intermittent fasting showed significant body weight loss, decreased left ventricular and whole heart absolute weights, with significant decrease of heart rate (HR) and prolongation of P-R interval in ECG. The baseline values of PT/LV, HRT and MFR/LV as well as their maximal responses and their delta changes in response to isoproterenol infusion were increased and were positively correlated to ghrelin hormone. Ghrelin hormone was increased in IF rats reaching the control group value and showed positive correlation with GPx and BCL-2. Conclusions IF conferred partial cardioprotective effects against thyrotoxicosis. These effects were attributed – at least partially- to normalization of ghrelin hormone which has anti-inflammatory, antioxidant as well as anti-apoptotic effects.

Exercise improves surrogate measures of liver histological response in metabolic dysfunction-associated steatotic liver disease.

Exercise is recommended for the management of metabolic dysfunction-associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12-20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI-measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. Eighty-eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5-fold (OR [95%CI]: 4.86 [1.72, 13.8], p = .002) greater odds of ≥30% relative reduction in MRI-measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). Exercise training led to clinically meaningful improvements in surrogate serum- and imaging-based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight-neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD.

Superior Mesenteric Artery Syndrome: A Case of SMA Syndrome

&lt;p&gt;在噁心嘔吐、食慾不振的病人中，有一群因症狀不具特異性、不易診斷而可能造成延誤治療者，是上腸繫膜動脈症候群(superior mesenteric artery syndrome)病人。因十二指腸第三部分受到上腸繫膜動脈和腹主動脈壓迫造成十二指腸阻塞症狀。此症候群盛行率低，診斷不易，易發生在體重快速減輕的病人上。這篇個案報告將介紹這個少見的症候群的臨床症狀、診斷標準、治療與預後。當面對噁心嘔吐、食慾不振的病人時，上腸繫膜動脈症候群是個不可忽略的鑑別診斷。&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;&lt;p&gt;Among the patients experiencing the symptoms of nausea and poor appetite, some will finally be diagnosed with superior mesenteric artery (SMA) syndrome, an unusual syndrome with various symptoms deriving from proximal intestinal obstruction caused by the compression of the third portion of duodenum due to the narrowing space between superior mesenteric artery and abdominal aorta. SMA syndrome has a low prevalence around 0.1-0.3%, occurring mostly in patients with significant weight loss and leading to mesenteric fat pad loss. In this case report, a 46-year-old woman with significant body weight loss was diagnosed with SMA syndrome. When examining patients reporting unintentional weight loss and symptoms of nausea and poor appetite, SMA syndrome should be taken into consideration as a rare but important differential diagnosis.&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;

Malnutrition and cachexia are associated with poor CAR T-cell therapy outcomes including survival

Background & AimsChimeric Antigen Receptor (CAR) T-cell therapy has emerged as a revolutionary treatment for patients with refractory or relapsed B-cell malignancies. However, a significant proportion of patients experience negative outcomes, including severe inflammatory toxicities and relapse. Cachexia and malnutrition are known secondary syndromes in many cancer patients, attributed to the effects of active malignancy, systemic inflammation, and cumulative treatment burden; however, further research is required to accurately characterise these issues in CAR T-cell patients. The aims of this service evaluation were to explore the changes in nutritional status (malnutrition and cachexia) in CAR T-cell therapy patients and the potential impact on patient outcomes including survival. Additionally, we describe the utilisation of dietetic resources in this specific patient population in a London tertiary referral centre. MethodsAdult haematology patients receiving licensed CD19-targeting CAR T-cell therapy at University College London Hospital between 01/04/19 and 01/09/21 were included. Data were collected from the time of treatment consent, and throughout admission to day of discharge: body weight (BW), C-reactive protein, albumin, lactate dehydrogenase, nutrition-risk screening scores (hospital-specific) and dietetic input. Clinical outcomes such as 12-month all-cause mortality, intensive care unit (ICU) admission, high-grade toxicities, and length of hospital stay (LoS) were also recorded. Cachexia and malnutrition were defined using the modified Glasgow Prognostic Score (mGPS) and Global Leadership Initiative on Malnutrition (GLIM) consensus, respectively. Results114 patients (55.6±15.1 years; 57% males) with B-cell non-Hodgkin’s lymphoma (n=109) and B-cell acute lymphoblastic leukaemia (n=5), receiving axicabtagene ciloleucel (n=89) and tisagenlecleucel (n=25) were included. Median LoS for treatment was 34 (27-38) days. Prior to treatment, 31.5% of patients developed malnutrition, with pre-cachexia/refractory cachexia (mGPS) identified in 43.6% of patients. This altered nutritional status pre-treatment was significantly associated with adverse patient outcomes post-infusion; mGPS was independently associated with inferior overall survival (HR=3.158, CI=1.36-7.323, p=0.007), with malnutrition and mGPS associated with increased LoS (p=0.037), sepsis (p=0.022) and ICU admission (p=0.039). During admission, patients experienced significant BW loss (-5.6% (-8.8 to -2.4); p=<0.001), with 68.4% developing malnutrition. Malnutrition screening during admission identified 57% patients at-risk, with 66.6% of patients referred to dietetics; however, there was a lack of malnutrition screening and dietetic referrals prior to treatment. ConclusionPre-treatment malnutrition and cachexia was significantly associated with adverse CAR T patient outcomes, including mGPS cachexia status independently associated with inferior overall survival. Further research in this novel space is essential to confirm the extent and impact of nutritional issues, to assist with implementing dietetic pathways, and to identify potential interventions with a view to optimising outcomes.

Tailored nutritional interventions: A precision approach to managing gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a risk to maternal-fetal health due to uncertain diagnostic criteria and treatment options. Luo's study demonstrated the efficacy of customized nutritional therapies in controlling GDM. Tailored strategies led to significant body weight loss, improved glucolipid metabolism, and fewer prenatal and newborn problems. This holistic approach, which emphasizes the notion of 'chrononutrition', takes into account optimal meal timing that is in sync with circadian rhythms, as well as enhanced sleep hygiene. Implementing tailored dietary therapy, managing meal timing, and ensuring appropriate sleep may improve results for women with GDM, opening up a possible avenue for multi-center trials.

The synergy of 177Lu-FAPI-46 with tyrosine kinase inhibitor in a sarcoma patient-derived xenograft mouse model

BackgroundGiven the heterogeneity and high mortality associated with metastatic soft tissue sarcoma, this study aims to evaluate the therapeutic efficacy of combining 177Lu-FAPI-46 with Pazopanib against this malignancy. MethodsPatient-derived xenograft (PDX)-bearing mice were randomly divided into three groups: the control group, the 177Lu-FAPI-46 monotherapy group, and the 177Lu-FAPI-46 combined with Pazopanib therapy group. Therapeutic efficacy was regularly monitored. ResultsThe microPET imaging showed a 0.84-fold decrease in the T/M ratio of 68Ga-FAPI-46 on day 7/8 post combination therapy, while the control group exhibited a 1.23-fold increase. Combination therapy significantly inhibited tumor proliferation, as evidenced by reduced Ki-67 and increased caspase 3 expressions. Notably, there was no significant body weight loss observed in any group. ConclusionThis study successfully demonstrated the reduction in FAP expression and suppression of tumor volume in sarcoma PDX following the combination therapy of 177Lu-FAPI-46 with Pazopanib.

Generation of a lethal mouse model expressing human ACE2 and TMPRSS2 for SARS-CoV-2 infection and pathogenesis

Mouse models expressing human ACE2 for coronavirus disease 2019 have been frequently used to understand its pathogenesis and develop therapeutic strategies against SARS-CoV-2. Given that human TMPRSS2 supports viral entry, replication, and pathogenesis, we established a double-transgenic mouse model expressing both human ACE2 and TMPRSS2 for SARS-CoV-2 infection. Co-overexpression of both genes increased viral infectivity in vitro and in vivo. Double-transgenic mice showed significant body weight loss, clinical disease symptoms, acute lung injury, lung inflammation, and lethality in response to viral infection, indicating that they were highly susceptible to SARS-CoV-2. Pretreatment with the TMPRSS2 inhibitor, nafamostat, effectively reduced virus-induced weight loss, viral replication, and mortality in the double-transgenic mice. Moreover, the susceptibility and differential pathogenesis of SARS-CoV-2 variants were demonstrated in this animal model. Together, our results demonstrate that double-transgenic mice could provide a highly susceptible mouse model for viral infection to understand SARS-CoV-2 pathogenesis and evaluate antiviral therapeutics against coronavirus disease 2019.

PATIENT EXPERIENCES OF A VIRTUALLY SUPERVISED EXERCISE PROGRAM FOR ADULTS WITH ADVANCED CANCER AND CACHEXIA – A QUALITATIVE STUDY

INTRODUCTION &amp; AIMS People with advanced cancer and cachexia experience significant body weight loss, impairing physical function and lowering quality of life (QOL). Effective, evidence-based treatments for cancer cachexia are lacking, leaving patients with unmet needs. Exercise holds promise to improve patient QOL. However, information on patients’ experiences of exercise, including their ability to cope with structured exercise, is limited. The aim of this qualitative study was to explore patient experiences completing a structured, supervised exercise program for people with cachexia due to advanced cancer. METHODS Semi-structured interviews were conducted with participants enrolled in a phase II feasibility, randomized controlled trial to explore their experiences of an 8-week virtually supervised exercise program delivered via videoconference technology. Interviews were analysed using reflexive thematic analysis. RESULTS Seventeen participants completed interviews (female n = 9, 53%). Main interview themes included: 1) Deciding to exercise involves balancing concerns and expectations, 2) The exercise program is a positive experience, and 3) Moving forward after the exercise program. While some participants initially held doubts about their physical capabilities and exercise safety, most wanted to exercise to enhance their wellbeing. Participants described the exercise program as a positive experience, offering diverse benefits. Some would have preferred in-person exercise, but all agreed the virtual format increased exercise convenience. Participants emphasized the need to extend the program to others in similar circumstances. They underscored the necessity and desire for ongoing support to sustain their new exercise habits. CONCLUSION Based on patient experiences, virtually supervised exercise programming appears to be feasible and meaningful to people with advanced cancer and cachexia.

Evaluating the Efficacy of a Polyherbal Formulation in Ameliorating Arthritis Induced by Complete Freund’s Adjuvant

Background: This study investigates the antiarthritic potential of a polyherbal formulation (PHF) comprising extracts from Tinospora cordifolia, Rosa damescena, and Acacia leucoploea in a rat model of rheumatoid arthritis (RA). RA is a chronic autoimmune disorder with debilitating consequences. PHF's impact on joint inflammation, bone degradation, and cartilage preservation were evaluated. Methods: Arthritis was induced using complete Freund’s adjuvant (CFA), and animals were treated with PHF (200 and 400 mg/kg), prednisolone, or control treatments for 28 days. Parameters including body weight, paw volume, arthritis severity score, hematological parameters, serum markers (creatinine, ALP, total proteins), cytokine levels (IL-1β, IL-6, TNF-α, IL-10), and radiographic changes were assessed. Results: CFA-treated rats exhibited significant body weight loss, paw edema, increased arthritis severity scores, altered hematological parameters, and elevated serum markers compared to normal controls. PHF treatment at both doses mitigated body weight loss, reduced paw edema, and improved arthritis severity scores. Hematological changes induced by CFA were also attenuated by PHF treatment. Serum creatinine, ALP, and total protein levels, elevated in CFA-treated rats, were significantly improved by PHF. Furthermore, PHF modulated cytokine levels, decreasing IL-6, IL-1β, and TNF-α while increasing IL-10. Radiographic analysis displayed reduced joint damage in PHF-treated rats compared to CFA controls. Conclusion: This comprehensive investigation highlights PHF's potential to mitigate the inflammatory processes associated with RA, as evidenced by improved clinical, hematological, and biochemical parameters. The study underscores the promise of traditional botanical compounds in managing RA and suggests PHFs as novel therapeutic options. Further mechanistic studies are warranted to elucidate the exact pathways involved.

Single Amino Acid Substitution in the Matrix Protein of Rabies Virus Is Associated with Neurovirulence in Mice.

Rabies is a fatal encephalitic infectious disease caused by the rabies virus (RABV). RABV is highly neurotropic and replicates in neuronal cell lines in vitro. The RABV fixed strain, HEP-Flury, was produced via passaging in primary chicken embryonic fibroblast cells. HEP-Flury showed rapid adaptation when propagated in mouse neuroblastoma (MNA) cells. In this study, we compared the growth of our previously constructed recombinant HEP (rHEP) strain-based on the sequence of the HEP (HEP-Flury) strain-with that of the original HEP strain. The original HEP strain exhibited higher titer than rHEP and a single substitution at position 80 in the matrix (M) protein M(D80N) after incubation in MNA cells, which was absent in rHEP. In vivo, intracerebral inoculation of the rHEP-M(D80N) strain with this substitution resulted in enhanced viral growth in the mouse brain and a significant loss of body weight in the adult mice. The number of viral antigen-positive cells in the brains of adult mice inoculated with the rHEP-M(D80N) strain was significantly higher than that with the rHEP strain at 5 days post-inoculation. Our findings demonstrate that a single amino acid substitution in the M protein M(D80N) is associated with neurovirulence in mice owing to adaptation to mouse neuronal cells.

Doxorubicin causes cachexia, sarcopenia, and frailty characteristics in mice.

While chemotherapy treatment can be lifesaving, it also has adverse effects that negatively impact the quality of life. To investigate the effects of doxorubicin chemotherapy on body weight loss, strength and muscle mass loss, and physical function impairments, all key markers of cachexia, sarcopenia, and frailty. Seventeen C57/BL/6 mice were allocated into groups. 1) Control (n = 7): mice were exposed to intraperitoneal (i.p.) injections of saline solution. 2) Dox (n = 10): mice were exposed to doxorubicin chemotherapy cycles (total dose of 18 mg/kg divided over 15 days). The body weight loss and decreased food intake were monitored to assess cachexia. To assess sarcopenia, we measured muscle strength loss using a traction method and evaluated muscle atrophy through histology of the gastrocnemius muscle. To evaluate physical function impairments and assess frailty, we employed the open field test to measure exploratory capacity. Doxorubicin administration led to the development of cachexia, as evidenced by a significant body weight loss (13%) and a substantial decrease in food intake (34%) over a 15-day period. Furthermore, 90% of the mice treated with doxorubicin exhibited sarcopenia, characterized by a 20% reduction in traction strength (p<0,05), a 10% decrease in muscle mass, and a 33% reduction in locomotor activity. Importantly, all mice subjected to doxorubicin treatment were considered frail based on the evaluation of their overall condition and functional impairments. The proposed model holds significant characteristics of human chemotherapy treatment and can be useful to understand the intricate relationship between chemotherapy, cachexia, sarcopenia, and frailty.

Abstract LB023: A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics

Abstract The therapeutic efficacy of a novel oral Paclitaxel formulation was evaluated and compared in Balb/c nude mice bearing PDX NSCLC, gastric cancer, liver cancer, breast cancer, and ovarian cancer treated with Abraxane, Taxol, Lenvatinib and Sorafenib. Therapeutic parameters including tumor volume, tumor growth inhibition (TGI), and treatment-to-control ratio (T/C) were compared among different treatment groups. The drug tolerance, cytotoxicity and safety profile of the oral Paclitaxel formulations were evaluated in Balb/c nude mice and beagle dogs. The tumor distribution of Paclitaxel in NCI-N87 gastric cancer-bearing mice after administration of oral Paclitaxel formulation and Paclitaxel Injection was investigated. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Albumin-bound Paclitaxel for Injectable Suspension at 30 mg/Kg and Paclitaxel Injection at 15 mg/Kg for NCI-N87 gastric cancer-bearing mice, while the same 100 mg/Kg dose demonstrated noninferior therapeutic efficacy to Abraxane and significant better therapeutic efficacy than Taxol in Hs467T gastric cancer-bearing mice. The oral Paclitaxel formulation administrated at 180 mg/Kg demonstrated noninferior therapeutic efficacy compared with Lenvatinib at 40 mg/Kg, and significant better therapeutic efficacy than Sorafenib at 30 mg/Kg for Hep G2 liver cancer-bearing mice, while the oral paclitaxel at 180 mg/Kg showed inferior therapeutic efficacy than Lenvatinib at 30 mg/Kg but noninferior therapeutic efficacy to Sorafenib at 30 mg/Kg for Huh-7 liver cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Abraxane for Injectable Suspension at 30 mg/Kg and Taxol at 15 mg/Kg for NCI-H358 NSCLC-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane for Injectable Suspension at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for MDA-MB-231 breast cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for SK-OV-3 ovarian cancer-bearing mice. The gastric tumor distribution of Paclitaxel between 6-24 hour was similar after oral and intravenous administration. The Maximum Tolerated Dose (MTD) of the oral Paclitaxel was determined to be ≥ 200 mg/Kg in mice and ≥ 8.0 mg/Kg in beagle dogs when dosing at Q3DX3Weeks, there were no significant body weight losses, tissue damages and animal death observed during the long-term safety assessment study. The oral Paclitaxel formulation demonstrated better or noninferior therapeutic efficacy in five different PDX tumor-bearing mice compared with standard treatment drugs, good safety and low cytotoxicity at high doses in long-term safety and toxicity studies were observed in both mice and beagle dogs. The oral Paclitaxel formulation showed promising therapeutic potential for various cancer treatment and conducting “chemotherapy at home” with lower medical costs. Citation Format: Hui Yu Huang, Richard Jun Huang. A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics [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 LB023.