bluuebunny/crossref_metadata_2025 huggingface dataset:
The Golgi stacking protein GRASP55 is targeted by the natural compound prodigiosin
Authors: Berning Lena , Lenz Thomas , Bergmann Ann Kathrin , Poschmann Gereon , Brass Hannah U. C. , Schlütermann David , Friedrich Annabelle , Mendiburo María José , David Céline , Akgün Seda , Pietruszka Jörg , Stühler Kai , Stork Björn
Published: October 2023

Background

The bacterial secondary metabolite prodigiosin has been shown to exert anticancer, antimalarial, antibacterial and immunomodulatory properties. With regard to cancer, it has been reported to affect cancer cells but not non-malignant cells, rendering prodigiosin a promising lead compound for anticancer drug discovery. However, a direct protein target has not yet been experimentally identified.

Methods

We used mass spectrometry-based thermal proteome profiling in order to identify target proteins of prodigiosin. For target validation, we employed a genetic knockout approach and electron microscopy.

Results

We identified the Golgi stacking protein GRASP55 as target protein of prodigiosin. We show that prodigiosin treatment severely affects Golgi morphology and functionality, and that prodigiosin-dependent cytotoxicity is partially reduced in GRASP55 knockout cells. We also found that prodigiosin treatment results in decreased cathepsin activity and overall blocks autophagic flux, whereas co-localization of the autophagosomal marker LC3 and the lysosomal marker LAMP1 is clearly promoted. Finally, we observed that autophagosomes accumulate at GRASP55-positive structures, pointing towards an involvement of an altered Golgi function in the autophagy-inhibitory effect of this natural compound.

Conclusion

Taken together, we propose that prodigiosin affects autophagy and Golgi apparatus integrity in an interlinked mode of action involving the regulation of organelle alkalization and the Golgi stacking protein GRASP55.
Prevalence of tissue transglutaminase antibodies and IgA deficiency are not increased in juvenile idiopathic arthritis: a case-control study
Authors: Kohli Angela Taneja , Hersh Aimee O. , Ponder Lori , Chan Lai Hin Kimi , Rouster-Stevens Kelly A. , Tebo Anne E. , Kugathasan Subra , Guthery Stephen L. , Bohnsack John F. , Prahalad Sampath
Published: October 2023

Background

The prevalence of Celiac Disease (CD) in Juvenile Idiopathic Arthritis (JIA) has been reported to be 0.1–7% in various small studies. As a result of the limited number of research and their inconclusive results there are no clear recommendations for routine CD screening in asymptomatic patients with JIA. Our aim is to estimate the prevalence of IgA deficiency and tissue transglutaminase (tTG) IgA in a cohort of JIA followed in two large academic medical centers.

Methods

Serum was collected and stored from all subjects and analyzed in a reference laboratory for total IgA (Quantitative Nephelometry) and tTG IgA antibody levels (Semi-Quantitative Enzyme-Linked Immunosorbent Assay). Fisher’s exact tests were performed for statistical significance. Risk estimates (odds ratios) with 95% confidence intervals were calculated.

Results

808 JIA cases and 140 controls were analyzed. Majority were non-Hispanic whites (72% vs. 68% p = 0.309). A total of 1.2% of cases were IgA deficient compared to none of the controls (p = 0.373). After excluding IgA deficient subjects, 2% of cases had tTG IgA ≥ 4u/mL compared to 3.6% of controls (p = 0.216) (OR = 0.5; 95% C.I = 0.1–1.4); and 0.8% of cases had tTG IgA > 10u/mL compared to 1.4% of controls (p = 0.627) (OR = 0.5; 95%C.I = 0.1–2.9).

Conclusions

Using the largest JIA cohort to date to investigate prevalence of celiac antibodies, the prevalence of positive tTG IgA was 0.8% and of IgA deficiency was 1.2%. The results did not demonstrate a higher prevalence of abnormal tTG IgA in JIA. The study did not support the routine screening of asymptomatic JIA patients for CD.
Restrictive versus high-dose oxygenation strategy in post-arrest management following adult non-traumatic cardiac arrest: a meta-analysis
Authors: Macherey-Meyer S. , Heyne S. , Meertens M. M. , Braumann S. , Hueser C. , Mauri V. , Baldus S. , Lee S. , Adler C.
Published: October 2023

Purpose

Neurological damage is the main cause of death or withdrawal of care in comatose survivors of cardiac arrest (CA). Hypoxemia and hyperoxemia following CA were described as potentially harmful, but reports were inconsistent. Current guidelines lack specific oxygen targets after return of spontaneous circulation (ROSC).

Objectives

The current meta-analysis assessed the effects of restrictive compared to high-dose oxygenation strategy in survivors of CA.

Methods

A structured literature search was performed. Randomized controlled trials (RCTs) comparing two competing oxygenation strategies in post-ROSC management after CA were eligible. The primary end point was short-term survival (≤ 90 days). The meta-analysis was prospectively registered in PROSPERO database (CRD42023444513).

Results

Eight RCTs enrolling 1941 patients were eligible. Restrictive oxygenation was applied to 964 patients, high-dose regimens were used in 977 participants. Short-term survival rate was 55.7% in restrictive and 56% in high-dose oxygenation group (8 trials, RR 0.99, 95% CI 0.90 to 1.10, P = 0.90, I2 = 18%, no difference). No evidence for a difference was detected in survival to hospital discharge (5 trials, RR 0.98, 95% CI 0.79 to 1.21, P = 0.84, I2 = 32%). Episodes of hypoxemia more frequently occurred in restrictive oxygenation group (4 trials, RR 2.06, 95% CI 1.47 to 2.89, P = 0.004, I2 = 13%).

Conclusion

Restrictive and high-dose oxygenation strategy following CA did not result in differences in short-term or in-hospital survival. Restrictive oxygenation strategy may increase episodes of hypoxemia, even with restrictive oxygenation targets exceeding intended saturation levels, but the clinical relevance is unknown. There is still a wide gap in the evidence of optimized oxygenation in post-ROSC management and specific targets cannot be concluded from the current evidence.
Testing the combination of Feeling Safe and peer counselling against formulation-based cognitive behaviour therapy to promote psychological wellbeing in people with persecutory delusions: study protocol for a randomized controlled trial (the Feeling Safe-NL Trial)
Authors: Tolmeijer Eva , Waite Felicity , Isham Louise , Bringmann Laura , Timmers Robin , van den Berg Arjan , Schuurmans Hanneke , Staring Anton B. P. , de Bont Paul , van Grunsven Rob , Stulp Gert , Wijnen Ben , van der Gaag Mark , Freeman Daniel , van den Berg David
Published: October 2023

Background

Persecutory delusions are strong threat beliefs about others’ negative intentions. They can have a major impact on patients’ day-to-day life. The Feeling Safe Programme is a new translational cognitive-behaviour therapy that helps patients modify threat beliefs and relearn safety by targeting key psychological causal factors. A different intervention approach, with growing international interest, is peer counselling to facilitate personal recovery. Combining these two approaches is a potential avenue to maximize patient outcomes. This combination of two different treatments will be tested as the Feeling Safe-NL Programme, which aims to promote psychological wellbeing. We will test whether Feeling Safe-NL is more effective and more cost-effective in improving mental wellbeing and reducing persecutory delusions than the current guideline intervention of formulation-based CBT for psychosis (CBTp).

Methods

A single-blind parallel-group randomized controlled trial for 190 out-patients who experience persecutory delusions and low mental wellbeing. Patients will be randomized (1:1) to Feeling Safe-NL (Feeling Safe and peer counselling) or to formulation-based CBTp, both provided over a period of 6 months. Participants in both conditions are offered the possibility to self-monitor their recovery process. Blinded assessments will be conducted at 0, 6 (post-treatment), 12, and 18 months. The primary outcome is mental wellbeing. The overall effect over time (baseline to 18-month follow-up) and the effects at each timepoint will be determined. Secondary outcomes include the severity of the persecutory delusion, general paranoid ideation, patient-chosen therapy outcomes, and activity. Service use data and quality of life data will be collected for the health-economic evaluation.

Discussion

The Feeling Safe-NL Trial is the first to evaluate a treatment for people with persecutory delusions, while using mental wellbeing as the primary outcome. It will also provide the first evaluation of the combination of a peer counselling intervention and a CBT-based program for recovery from persecutory delusions.

Trial registration

Current Controlled Trials ISRCTN25766661 (retrospectively registered 7 July 2022).
A fast and inexpensive genotyping system for the simultaneous analysis of human and Aedes albopictus short tandem repeats
Authors: Albó Timor Andreu , Lucati Federica , Bartumeus Frederic , Caner Jenny , Escartin Santi , Mariani Simone , Palmer John R. B. , Ventura Marc
Published: October 2023

Background

Determination of the interactions between hematophagous mosquitoes and their human hosts is of great importance for better understanding the transmission dynamics of mosquito-borne arboviruses and developing effective strategies to mitigate risk. Genetic analysis of human and mosquito DNA can play a key role in this, but commercial kits for human short tandem repeat (STR) genotyping are expensive and do not allow for the simultaneous STR analysis of host and vector DNA. Here, we present an inexpensive and straightforward STR-loci multiplex system capable of simultaneously amplifying Aedes albopictus and human STRs from blood-fed mosquitoes. Additionally, we examine the effect of storage methods and post-feeding time on the integrity of host DNA.

Methods

Thirty-five STRs (16 human and 19 Ae. albopictus STRs) subdivided in three multiplexes were tested for amplification and scoring reliability. Under laboratory conditions we compared the efficacy of two preservation methods (absolute ethanol vs lysis buffer) on the integrity of host DNA in Ae. albopictus blood meals. We also evaluated the effect of post-feeding time by sacrificing blood-fed mosquitoes at different time intervals after feeding, and we assessed our ability to detect multiple feedings. To determine if the system can be employed successfully under field conditions, we carried out a preliminary study using field-collected Ae. albopictus.

Results

All 35 STRs amplified consistently in the laboratory. Lysis buffer performed better than absolute ethanol in terms of allele peak height and clarity of electropherograms. Complete human DNA profiles could be obtained up to 48 h following the blood meal. Analysis of multiple feedings confirmed that peak heights can be used as a proxy to determine post-feeding time and thus derive the number of different people bitten by a mosquito. In the field trial, amplification was successful for 32 STRs. We found human DNA signal in 38 of the 61 field-collected mosquitoes (62%), of which 34 (89%) had ingested a single blood meal, while four (11%) contained double meals.

Conclusions

Our new genotyping system allows fast and reliable screening of both host and vector species, and can be further adapted to other mosquito species living in close contact with humans.

Graphical Abstract
Preosteoclast plays a pathogenic role in syndesmophyte formation of ankylosing spondylitis through the secreted PDGFB — GRB2/ERK/RUNX2 pathway
Authors: Tang Yulong , Yang Kai , Liu Qingmei , Ma Yanyun , Zhu Hao , Tang Kunhai , Geng Chengchun , Xie Jiangnan , Zhuo Dachun , Wu Wenyu , Jin Li , Xiao Wenze , Wang Jiucun , Zhu Qi , Liu Jing
Published: October 2023

Objectives

Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the sacroiliac joint and spine. However, the real mechanisms of immune cells acting on syndesmophyte formation in AS are not well identified. We aimed to find the key AS-associated cytokine and assess its pathogenic role in AS.

Methods

A protein array with 1000 cytokines was performed in five AS patients with the first diagnosis and five age- and gender-matched healthy controls to discover the differentially expressed cytokines. The candidate differentially expressed cytokines were further quantified by multiplex protein quantitation (3 AS-associated cytokines and 3 PDGF-pathway cytokines) and ELISA (PDGFB) in independent samples (a total of 140 AS patients vs 140 healthy controls). The effects of PDGFB, the candidate cytokine, were examined by using adipose-derived stem cells (ADSCs) and human fetal osteoblast cell line (hFOB1.19) as in vitro mesenchymal cell and preosteoblast models, respectively. Furthermore, whole-transcriptome sequencing and enrichment of phosphorylated peptides were performed by using cell models to explore the underlying mechanisms of PDGFB. The xCELLigence system was applied to examine the proliferation, chemotaxis, and migration abilities of PDGFB-stimulated or PDGFB-unstimulated cells.

Results

The PDGF pathway was observed to have abnormal expression in the protein array, and PDGFB expression was further found to be up-regulated in 140 Chinese AS patients. Importantly, PDGFB expression was significantly correlated with BASFI (Pearson coefficient/p value = 0.62/6.70E − 8) and with the variance of the mSASSS score (mSASSS 2 years − baseline, Pearson coefficient/p value = 0.76/8.75E − 10). In AS patients, preosteoclasts secreted more PDGFB than the healthy controls (p value = 1.16E − 2), which could promote ADSCs osteogenesis and enhance collagen synthesis (COLI and COLIII) of osteoblasts (hFOB 1.19). In addition, PDGFB promoted the proliferation, chemotaxis, and migration of ADSCs. Mechanismly, in ADSCs, PDGFB stimulated ERK phosphorylation by upregulating GRB2 expression and then increased the expression of RUNX2 to promote osteoblastogenesis of ADSCs.

Conclusion

PDGFB stimulates the GRB2/ERK/RUNX2 pathway in ADSCs, promotes osteoblastogenesis of ADSCs, and enhances the extracellular matrix of osteoblasts, which may contribute to pathological bone formation in AS.
The impact of information sphere in the economic security of the country: case of Russian realities
Authors: Okhrimenko Igor , Stepenko Valery , Chernova Olga , Zatsarinnaya Elena
Published: October 2023

Novel information technologies have facilitated not only the development of new industries, but also brought new opportunities and challenges. The range of challenges includes threats related to the information security of not only the commercial, but also the public sector of the national economy, which can adversely affect its stability and competitiveness. In view of this, the problem of ensuring information security (IS) in the economic sphere is of particular relevance. Despite the abundance of studies on IS, the impact of the information sphere on the country’s economic security has not yet been sufficiently studied. The purpose of this article was to identify and systematize threats posed to economic security by the information environment and determine a set of measures to protect the areas at risk. Within the framework of the study, two interrelated models were built. The first systematized the IS threats and challenges, whereas the second demonstrated those IS threats that are directly connected with the state’s economic security. At the same time, the models developed allowed focusing on the protection of objects potentially under threat. The research quintessence was represented by the development of recommendations directed at preventing and minimizing the negative impact of information sphere threats to economic security. Hence, a diversified ecosystem of information and economic security of the state was created. The study findings and recommendations can be used by officials of government bodies and other organizations to develop regulatory documents related to the strategy of ensuring information and economic security at various levels (state, regional, corporate).
Weekly versus triweekly cisplatin treatment in patients with locally advanced nasopharyngeal cancer during concurrent chemoradiotherapy
Authors: Li Xin , Li Lei , Sun Ruimei , Gao Jingyan , Li Zhengfei , Xue Yongyuan , Zhu Lixiu , Xu Tianrui , Sun Chuanzheng , Xi Yan , Xiong Wei
Published: October 2023

Background

For patients with locally advanced nasopharyngeal cancer (LA-NPC), concurrent chemoradiotherapy (CCRT) is the standardized treatment. However, whether a weekly or triweekly cisplatin regimen should be used during CCRT is controversial. Therefore, we conducted this meta-analysis to explore differences in the effects and toxicities of the two regimens.

Methods

We searched PubMed, Embase, and the Cochrane Library (until June 10, 2022). We evaluated overall survival (OS), distant metastasis-free survival (DMFS), locoregional recurrence–free survival (LRFS), disease-free survival (DFS) and grade ≥ 3 adverse events. The effect indices were hazard ratios (HRs) and odds ratios (ORs), and Review Manager software 5.4 (RevMan 5.4) was used for computations.

Results

We identified 7 studies in our analysis. There was no significant difference in OS (HR = 1.00, 95% CI 0.73–1.38, P = 0.99), DMFS (HR = 0.84, 95% CI 0.58–1.22, P = 0.36), LRFS (HR = 0.91, 95% CI 0.63–1.32, P = 0.62) or DFS (HR = 0.93, 95% CI 0.56–1.56; P = 0.78) between the weekly and triweekly cisplatin regimens. We found that the weekly cisplatin regimen was more likely to cause grade ≥ 3 hematological toxicity events than the triweekly cisplatin regimen. In addition, subgroup analyses revealed that patients undergoing CCRT and CCRT plus adjuvant chemotherapy (AC) had similar OS or DFS.

Conclusion

Weekly and triweekly cisplatin regimens had similar efficacy for LA-NPC. The triweekly regimen may replace the weekly regimen for LA-NPC because of lower toxicity. Larger data accumulation and more multicenter clinical trials may be needed to verify these results.
Pregnancy outcomes of intrauterine insemination in young patients with diminished ovarian reserve: a multicenter cohort study
Authors: Zhao Min , Huan Qing , Huang Lisa , Yang Lin , Dong Meng
Published: October 2023

Background

To date, there is no consensus on whether intrauterine insemination (IUI) treatment is required in young patients with diminished ovarian reserve (DOR). Pregnancy outcomes in young DOR patients undergoing IUI are controversial. The existing studies are all single-center studies, with no existing multicenter cohort studies. The purpose of this multicenter study was to investigate the pregnancy outcomes of young DOR patients undergoing IUI.

Methods

This multicenter cohort study included a total of 4600 cycles in 2204 infertile patients who underwent IUI treatment in three reproductive medical centers between September 2018 and January 2022. The research subjects were divided into two groups according to their serum anti-Müllerian hormone (AMH) levels. Propensity score matching (PSM) was used to match the research subjects at a ratio of 1:4. The pregnancy outcomes in the two groups were compared.

Results

There was no significant difference in the clinical pregnancy rates (CPR), biochemical rates, and ectopic pregnancy rates between the two groups (P > 0.05). There were, however, significant differences in the miscarriage rates between the groups (P < 0.05). The live birth rates (LBR) were 6.6 vs. 9.9 between the two groups. The multivariable logistic regression models reveal that body mass index, AMH were significantly correlated with CPR; AMH were significantly correlated with LBR; BMI, follicle stimulating hormone were significantly correlated with miscarriage rate.

Conclusions

The clinical pregnancy rate of DOR patients was not significantly different from that of NOR patients; however, the miscarriage rates were significantly different from those of NOR patients.
Bacterial contamination of healthcare workers’ mobile phones in Africa: a systematic review and meta-analysis
Authors: Zenbaba Demisu , Sahiledengle Biniyam , Beressa Girma , Desta Fikreab , Teferu Zinash , Nugusu Fikadu , Atlaw Daniel , Shiferaw Zerihun , Gezahegn Bereket , Mamo Ayele , Desalegn Tesfaye , Negash Wogene , Negash Getahun , Mama Mohammedaman , Nigussie Eshetu , Chattu Vijay Kumar
Published: October 2023

Background

Mobile phones are potential reservoirs for pathogens and sources of healthcare-associated infections. More microbes can be found on a mobile phone than on a man's lavatory seat, the sole of a shoe, or a door handle. When examining patients, frequent handling of mobile phones can spread bacteria. Nevertheless, evidence of bacterial contamination of mobile phones used by healthcare workers in Africa was inconclusive. Thus, this meta-analysis and systematic review was conducted to estimate the pooled prevalence of bacterial contamination of mobile phones used by healthcare workers and the most frequent bacterial isolates in Africa.

Methods

We systematically retrieved relevant studies using PubMed/MEDLINE, POPLINE, HINARI, Science Direct, Cochrane Library databases, and Google Scholar from July 1, 2023 to August 08, 2023. We included observational studies that reported the prevalence of bacterial contamination of mobile phones among healthcare workers. The DerSimonian–random Laird's effect model was used to calculate effect estimates for the pooled prevalence of bacterial contamination in mobile phones and a 95% confidence interval (CI).

Results

Among 4544 retrieved studies, 26 eligible articles with a total sample size of 2,887 study participants were included in the meta-analysis. The pooled prevalence of mobile phone bacterial contamination among healthcare workers was 84.5% (95% CI 81.7, 87.4%; I2 = 97.9%, p value < 0.001). The most dominant type of bacteria isolated in this review was coagulase-negative staphylococci (CONS) which accounted for 44.0% of the pooled contamination rate of mobile phones used by healthcare workers, followed by Staphylococcus aureus (31.3%), and Escherichia coli (10.7%).

Conclusions

In this review, the contamination of mobile phones used by HCWs with various bacterial isolates was shown to be considerable. The most prevalent bacteria isolates were coagulase-negative staphylococci, Staphylococcus aurous, and Escherichia coli. The prevalence of bacterial contamination in mobile phones varies by country and sub-region. Hence, healthcare planners and policymakers should establish norms to manage healthcare workers' hand hygiene and disinfection after using mobile phones.
Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis
Authors: Zheng Wenjie , Bian Saiyan , Qiu Shi , Bishop Colin E. , Wan Meimei , Xu Nuo , Sun Xieyin , Sequeira Russel Clive , Atala Anthony , Gu Zhifeng , Zhao Weixin
Published: October 2023

Background

Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms.

Methods

The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-β1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations.

Results

TGF-β1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-β1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2).

Conclusion

Pd-MSCs-EVs ameliorated TGF-β1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis.
Concurrent Chemotherapy and Pelvic Radiation Therapy Compared With Pelvic Radiation Therapy Alone as Adjuvant Therapy After Radical Surgery in High-Risk Early-Stage Cancer of the Cervix
Authors: Peters William A. , Liu P.Y. , Barrett Rolland J. , Stock Richard J. , Monk Bradley J. , Berek Jonathan S. , Souhami Luis , Grigsby Perry , Gordon William , Alberts David S.
Published: October 2023

PURPOSE

To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma.

PATIENTS AND METHODS

Patients with clinical stage IA2, IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m2 and a 96-hour infusion of fluorouracil 1,000 mg/m2/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT.

RESULTS

Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 ( P = .003) and 1.96 ( P = .007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group.

CONCLUSION

The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.
FRI002 IGF-1R Targeting As A Strategy For Reducing Obesity And Improving Metabolism
Authors: Al-Samerria Sarmed , Farooq Saad , Candidate M S , Nandankar Nimisha , Negron Ariel Negron L , Radovick Sally
Published: October 2023

Disclosure: S. Al-Samerria: None. S. Farooq: None. N. Nandankar: None. A.L. Negron: None. S. Radovick: None.

There has been a significant increase in the prevalence of obesity over the past four decades, and it is projected that by 2030, the majority of the global population will fall into the overweight or obese categories if this trend continues. In a previous study, we reported that the ablation of the IGF-1R in GHRH neurons and somatotrophs (S-GIGFRKO) resulted in a sustained decrease in weight gain velocity due to increased lipolysis and higher energy expenditure, despite no changes in caloric intake. To evaluate the effects of a high-fat diet (HFD) on this metabolic phenotype, we challenged S-GIGFRKO mice with a 60% HFD beginning at 4 weeks of age. The S-GIGFRKO mice on the HFD showed normal linear growth, but after 8 weeks on the HFD, both males and females exhibited a sustained decrease in weight gain velocity compared to control mice on the HFD. Metabolic analysis revealed that the male and female S-GIGFRKO mice had higher oxygen consumption, lower carbon dioxide production, reduced body fat mass, increased energy expenditure, and improved glucose tolerance compared to the control mice on the HFD. No differences in food intake or total activity were observed between the two groups. These results demonstrate the important role of the GHRH-GH axis in regulating energy expenditure and fat metabolism, despite an environmental challenge induced by a HFD.

Presentation: Friday, June 16, 2023
FRI003 Oxytocin Response To Feeding Predicts Reward-driven Calorie Consumption In Adults With Obesity
Authors: Boutin Regine , Wronski Marie-Louis , Maso Ana Aulinas , Muhammed Maged , Galbiati Francesca , Kerem Liya , Carter Sue , Nazarloo Hans , Davis John M , Holman Katherine , Gydus Julia , Smith Sarah , Asanza Elisa , Plessow Franziska , Lawson Elizabeth Austen
Published: October 2023

Disclosure: R. Boutin: None. M. Wronski: None. A. Aulinas Maso: None. M. Muhammed: None. F. Galbiati: None. L. Kerem: None. S. Carter: None. H. Nazarloo: None. J.M. Davis: None. K. Holman: None. J. Gydus: None. S. Smith: None. E. Asanza: None. F. Plessow: None. E.A. Lawson: Consulting Fee; Self; OXT Therapeutics. Stock Owner; Self; OXT Therapeutics.

Objectives: Oxytocin (OXT) is a hypothalamic peptide hormone that reduces reward-related food intake and is under investigation as a potential weight loss therapy. Activation of OXT neurons in appetite pathways results in suppression of posterior pituitary release of OXT to the circulation, such that peripheral OXT levels (in response to feeding) may reflect the opposite of central OXT activity. While a relationship between peripheral OXT response to feeding and appetite has been reported in healthy females, there are no data related to OXT levels and appetite or eating behavior in individuals with obesity. We hypothesized that in individuals with obesity, higher OXT levels in response to feeding would be associated with greater reward-driven food intake assessed during a Cookie Taste Test. Methods: In a cross-sectional study of 53 adults with obesity (56% females; age [mean±SD] 33.7±6.2 years; BMI 36.9±4.9 kg/m2), participants presented after an overnight fast and were provided with a standard 400 kcal mixed meal. We sampled blood before and 30, 60 and 120 minutes after the meal for OXT levels and calculated area under the curve (AUC) as an integrated measure of OXT response to feeding. After receiving a subsequent snack, subjects ate as many cookies as needed to rate the cookies on various characteristics (i.e. sweetness, texture, delectability). We logarithmically transformed non-normal data to achieve a normalized distribution and used Pearson correlation to evaluate the relationship between OXT AUC and number of calories eaten during the Cookie Taste Test (behavioral marker of reward-related eating). Results: OXT AUC in response to a standardized meal predicted subsequent calories consumed at the Cookie Taste Test (R=0.30, p=0.036), such that those with higher OXT levels consumed more calories. Conclusions: Consistent with our hypothesis, peripheral OXT response to a standardized meal predicted subsequent reward-driven caloric intake in adults with obesity. These data suggest that endogenous OXT is involved in regulation of hedonic eating and supports targeting OXT pathways in the treatment of obesity.

Presentation: Friday, June 16, 2023
FRI021 Adipocyte Subpopulations Regulate The Lipolytic Response And Inflammatory Cytokine Action In Obesity
Authors: Huang Jun , Sharma Rita , Puri Vishwajeet , Lee Kevin Y
Published: October 2023

Disclosure: J. Huang: None. R. Sharma: None. K.Y. Lee: None.

Previously, our lab has utilized gene expression profiling and lineage tracing analysis to uncover three developmentally and functionally distinct subpopulations of white adipocytes with stable and unique gene expression profiles, which were termed Type 1, 2, and 3 adipocytes, respectively. This study extends these findings to investigate the role of Type 2 adipocytes in obesity. We found that the proportion of Type 2 preadipocytes and adipocytes in each adipose tissue was stable through time, but was dynamically regulated by high-fat diet (HFD) induced obesity in a depot-specific manner with a 59.34% increase in the perigonadal fat depots. Histological examination of fat depots after HFD-induced obesity revealed that over 80% of recruited macrophages, organized into crown-like structures, were found in direct contact with Type 2 adipocytes indicating increased necrosis or apoptosis of this adipocyte subpopulation. In addition, treatment of macrophage-derived inflammatory cytokine TNFα increased lipolysis specifically in Type 2 adipocytes by 11.9%, with no effects on other adipocytes. As previous studies have shown that inflammatory cytokines promote lipolysis in adipose tissue, at least in part, through the reduction of FSP27 (fat specific protein 27), we assessed the contribution of Type 2 adipocytes by overexpressing FSP27 specifically in this population (Type2Ad-hFSP27tg mice) during the development of obesity. We found that HFD-fed male Type2Ad-hFSP27tg mice had improved glucose tolerance and insulin sensitivity, with no change in body weight. These metabolic changes may, at least in part, be explained by the reduced basal and stimulated lipolysis rate in the visceral fat of Type2Ad-hFSP27tg mice compared with control mice. Although over-expression of FSP27 in primary Type 2 adipocytes is sufficient to acutely reduce TNFα-induced apoptosis, no reduction of macrophage infiltration was found in HFD-fed Type2Ad-hFSP27tg visceral fat after 18 weeks of HFD. Taken together, these results strongly suggest that adipocyte subpopulations contribute to the regulation of obesity-associated inflammation and lipolytic response in adipose tissue.

Presentation: Friday, June 16, 2023
FRI044 Racial Differences In Outcomes Of Hospitalizations For COVID-19 With Morbid Obesity: Insights From The National Inpatient Sample
Authors: Gajjar Rohan Ashwinbhai , Ahluwalia Daksh , Kumar Manoj , Rai Sumina , Shaka Hafeez , Stroger John H
Published: October 2023

Disclosure: R.A. Gajjar: None. D. Ahluwalia: None. M. Kumar: None. S. Rai: None. H. Shaka: None.

Introduction: The prevalence of obesity has risen across the globe over the past two decades and has remained high in the United States. In addition, obesity has surfaced as an independent risk factor for severe COVID-19 infection. We sought to investigate the impact of racial differences on hospitalizations for COVID-19 with morbid obesity using a nationally representative sample. Methods: The National Inpatient Sample database for 2020 was queried to identify adult hospitalizations with a primary diagnosis of COVID-19 and a secondary diagnosis of morbid obesity, using International Classification of Diseases – 10 Clinical Modification (ICD-10-CM) codes. The primary outcome studied was inpatient mortality, while secondary outcomes included inpatient complications, mean length of stay (LOS), and mean total hospital charge (THC). Multivariate logistic and linear regression analyses were used to adjust for possible confounders and to analyze the outcomes. Results: A total of 130,570 hospitalizations for COVID-19 with morbid obesity were identified, of which 48% were Caucasians, 25% were African Americans, and 19% were Hispanics. Our analysis revealed that Hispanics were associated with significantly higher adjusted odds of inpatient mortality (Adjusted Odds Ratio [aOR]: 1.4, [95% CI: 1.23-1.60], p <0.001), increased mean LOS (1.25 days, [95% CI: 0.87-1.64], p <0.001), and higher mean THC ($34,554, [95% CI: 25,316-43,791], p <0.001) as compared to Caucasians; whereas African Americans had significantly lower adjusted odds of inpatient mortality (aOR: 0.85, [95% CI: 0.76-0.96], p=0.011) when compared to Caucasians. Additionally, complications such as sepsis (aOR 1.74, [95% CI: 1.50-2.03], p <0.001), acute respiratory failure (ARF) (aOR: 1.15, [95% CI: 1.05-1.25], p=0.003), need for intubation (aOR: 1.27, [95% CI: 1.22-1.43], p <0.001), mechanical ventilation (aOR: 1.26, [95% CI: 1.13-1.41], p <0.001), requirement of pressor support (aOR: 1.74, [95% CI: 1.32-2.31], p <0.001), the necessity of blood transfusion (aOR: 1.68, [95% CI: 1.40-2.02], p <0.001) were significantly higher in Hispanics when compared to Caucasians. Conclusion: In this retrospective analysis of admissions for COVID-19 with morbid obesity, we discovered that the Hispanic subpopulation had elevated odds of mortality, along with a greater length of hospital stay and increased cost of hospitalization when compared to Caucasians. Additionally, Hispanics had higher odds of inpatient complications such as sepsis, ARF, need for mechanical ventilation/intubation, vasopressors, and blood transfusions. Our study highlights the existence of racial disparities that significantly affect outcomes in admissions for COVID-19 with morbid obesity.

Presentation: Friday, June 16, 2023
FRI048 Cardiometabolic Risk Markers In Children With Obesity And Variants In MC4R Pathway Related Genes
Authors: Salama Mostafa , Kumar Seema , e Vairo Filippo Pinto , Hentz Roland
Published: October 2023

Disclosure: M. Salama: None. S. Kumar: None. F. Pinto e Vairo: None. R. Hentz: None.

Objective: The association between disrupted melanocortin 4 receptor (MC4R) pathway function and childhood obesity is well established. Several variants in MC4R pathway related genes have been implicated to influence cardiometabolic parameters including lipid metabolism and glucose homeostasis. We compared the cardiometabolic risk markers in children with obesity and MC4R related clinically reported genetic variants relative to children with obesity and no MC4R related genetic variants. Methods: This was a retrospective case-control study conducted by chart review of children (age <18 years) with obesity who underwent a multi-gene panel testing for monogenic obesity between February 2020 and November 2022. Children were divided into two groups according to their genetic test results: The first group was of children with clinically reported variants (pathogenic, likely pathogenic, risk allele or variant of uncertain significance) within the MC4R pathway), and the second group was of children with no reported variants in the MC4R pathway (negative genetic testing or variants in non-MC4R related genes). Data on systolic and diastolic blood pressure percentiles, fasting lipid panel, fasting blood glucose, hemoglobin A1c and ALT were extracted. Tests for group differences were performed using the independent two-sample t-test, Wilcoxon rank-sum test, Chi-Square test, or Fisher’s exact test as appropriate for each variable type and test assumptions. Results: Data on a total of 91 children were reviewed. Mean age at testing was 11 years (SD: 4) and mean peak BMI% of the 95th percentile was 158 (SD: 28). 36 patients had clinically reported variants in the MC4R pathway, and 55 patients had no reported MC4R related variants. The blood pressure percentiles, fasting glucose, hemoglobin A1C, total cholesterol, high density lipoprotein cholesterol and low-density lipoprotein cholesterol were not different between both groups. Conclusion: In this pilot study, among children with obesity, variants in the MC4R pathway related genes were not associated with cardiometabolic risk markers. Larger studies are warranted to assess the correlation between MC4R pathway genes and cardiometabolic risk.

Presentation: Friday, June 16, 2023
SAT648 The Role Of Olfactory Marker Protein On Adipogenesis
Authors: Bao Yaru , Cho Yoon Hee , Lee Eun Jig
Published: October 2023

Disclosure: Y. Bao: None. Y. Cho: None. E. Lee: None.

Olfactory marker protein (OMP) plays a role in regulating the of olfactory transduction but is also expressed in adipose tissue. OMP serves as a regulating buffer for cyclic AMP (cAMP) levels; thus, we hypothesized that Omp may play a role in modulating adipocyte differentiation, a cAMP-dependent process. To determine the role of OMP in adipogenesis, we examined the differences in body weight, adipose tissue mass, and adipogenic or thermogenic gene expression of normal and Omp-knockout (KO) mice fed a high-fat diet. The cAMP production, adipogenic gene expression, and cAMP response element binding protein (CREB) phosphorylation were measured during differentiation in 3T3-L1 preadipocytes and mouse embryonic fibroblasts (MEFs). Finally, RNA sequencing was performed to find out why adipogenesis was reduced when Omp was deleted. We observed a decrease in body weight, adipose tissue mass, and the size of adipocytes in Omp-KO mice. We confirmed low cAMP production and CREB phosphorylation in adipogenesis induced in Omp-/- MEFs, and nuclear factor kappa B activation due to significantly reduced IκBα expression. Collectively, our results suggest that loss of OMP function inhibits adipogenesis through affecting adipocyte differentiation.

Presentation: Saturday, June 17, 2023
SAT136 Severe Lactic Acidosis Due To Metformin Use.
Authors: Khan Areej
Published: October 2023

Disclosure: A. Khan: None.

Lactic acidosis is an important cause of metabolic acidosis. Broadly, etiology can be divided into type A (impaired tissue oxygenation), type B (systemic hypoperfusion), and D-lactic acidosis. One such etiology which deserves mentioning is metformin associated lactic acidosis (MALA). The incidence of MALA is more notable in the setting of kidney dysfunction, hepatic failure, and alcohol use. Severe acidosis due to Metformin is an emergency and warrants timely management to avoid further hemodynamic compromise. 73-year-old female with a history of hypertension and type II diabetes mellitus (on metformin) presented to the hospital with acute onset of abdominal pain, nausea, and vomiting. She reported having intermittent vomiting and diarrhea for three days prior to admission, and describes the abdominal pain as 10/10, sharp with radiation to the lower back, and worsening 6 hours prior to arrival. She denies fever, melena, hematochezia, change in appetite. She was brought to the hospital via EMS and was given fentanyl for her pain. Vitals on arrival were stable. On exam, she appeared in distress due to pain, with diffuse tenderness in her abdomen, with normal cardiac and lung exam. Labs showed leukocytosis 15 K/mm3, hemoglobin 11.1 gm/dl, hyperkalemia 5.7 mEq/L, bicarb <5 mEq/L, creatinine 13.4 mg/dl, BUN 107 mg/dl, venous lactate 15.1 mmol/l, lipase 435 U/L, ammonia 229 umol/L, with normal AST, ALT and ALP, and troponin. Urinalysis was negative. Initial ABG showed an unreadable pH, which was then repeated, and pH was noted to be 6.72, pCO2 of 29.4 mm/hg, CTA angiography was negative for dissection, mesenteric or bowel ischemia. Soon she was noted to be hypotensive and went into shock requiring pressors, bicarbonate drip, and broad-spectrum antibiotics. She eventually was intubated for airway protection. Subsequently, she was admitted to the ICU for possibly combined hypovolemic and septic shock with multi-organ dysfunction, severe lactic acidosis, acute kidney failure, and respiratory failure. Nephrology was consulted and dialysis was initiated. It was postulated that the presentation was likely due to metformin associated lactic acidosis (MALA). She required dialysis daily for 4 days and ultimately her kidney function improved. On discharge, she was not dialysis dependent. The case above illustrates the severity of lactic acidosis that can occur due to Metformin use. It is important to bear in mind that such presentation, may not necessarily occur on initiation of Metformin, but rather at any point of use. More importantly, its of utmost importance to consider effective therapeutic options like dialysis once severe academia is noted to allow correction of metformin induced acid-base disorder. Mortality estimates of MALA have been around 25-50%, highlighting the significance of prompt treatment of this condition.

Presentation: Saturday, June 17, 2023
SAT141 A Case Of Non-islet Cell Tumor Hypoglycemia Which Was Ameliorated By Pazopanib Treatment
Authors: Yamamoto Naoki , Yamamoto Masaaki , Kiyota Naomi , Inaba Yuiko , Kanie Keitaro , Urai Shin , Suzuki Masaki , Sasaki Yuriko , Oi Yuka , Tsujimoto Yasutaka , Motomura Yuma , Ohmachi Yuka , Bando Hironori , Iguchi Genzo , Nagao Mototsugu , Fukuda Izumi , Fukuoka Hidenori , Ogawa Wataru
Published: October 2023

Disclosure: N. Yamamoto: None. M. Yamamoto: None. N. Kiyota: None. Y. Inaba: None. K. Kanie: None. S. Urai: None. M. Suzuki: None. Y. Sasaki: None. Y. Oi: None. Y. Tsujimoto: None. Y. Motomura: None. Y. Ohmachi: None. H. Bando: None. G. Iguchi: None. M. Nagao: None. I. Fukuda: None. H. Fukuoka: None. W. Ogawa: None.

Introduction: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by insulin-like growth factor II (IGF-II) hypersecretion from the tumors. It is characterized by incompletely processed big IGF-II with potent insulin-like activity. We present a case of NICTH complicated with solitary fibrous tumor (SFT) which was ameliorated with the administration of pazopanib, a multi-targeted tyrosine kinase inhibitor. Clinical Case: A 57-year-old man went into a coma and was hospitalized. His plasma glucose levels were 26 mg/dL, and he regained consciousness after glucose administration, leading to a diagnosis of hypoglycemic coma. Moreover, a contrast-enhanced CT scan showed multiple tumors in his liver and right kidney. He was referred to our hospital for further management. After 5 hours of fasting, he had a cold sweat, and his plasma glucose levels dropped to 32 mg/dL with suppressed serum insulin levels of 0.2 U/mL. Serum 3-hydroxybutyrate levels were as low as 21 μmol/L, and plasma glucose levels increased to 83 mg/dL after glucagon administration, suggesting an agent mimicking insulin. Percutaneous liver biopsy was performed, and the tumors were diagnosed with SFT. Immunoblotting for his serum showed big IGF-II, leading to a diagnosis of NICTH, and hypoglycemia due to hypersecretion of IGF-II. Due to multiple metastases, surgery was not indicated and pazopanib was administered. Hypoglycemia during the night was prevented by glucose infusion through the central venous port, and he was discharged. Three months later, when he was re-hospitalized for thrombophlebitis of the right jugular vein, hypoglycemia did not occur even after 10 hours of fasting and CT scan showed the necrotic change of the tumor. Two weeks later of pazopanib discontinuation due to the thrombogenic adverse effect, hypoglycemia recurred accompanied by the tumor enlargement. When the anticoagulation therapy regressed the thrombosis and pazopanib was re-administered, hypoglycemia improved reproducibly and remained stable for more than 2 years although the tumor showed gradual progression. Conclusion: This is the first case in which pazopanib was effective in suppressing NICTH associated with SFT.

Presentation: Saturday, June 17, 2023