Pub Date : 2024-02-07DOI: 10.21203/rs.3.rs-3912105/v1
Sydney Houlton, Jatin Vaidya, Patrick Breheny, Lane Strathearn
Abstract Oxytocin is a neuropeptide associated with prosocial behaviors, such as parent-child bonding, eye contact, and sexual activity. Intranasally-administered oxytocin has been widely used to study its effects on the brain using functional magnetic resonance imaging. Head motion is a significant confounding variable which was assessed as part of a double blind, placebo-controlled crossover study. Twenty-four mothers with drug addiction problems were initially recruited, along with 22 healthy control mothers, to test whether intranasal oxytocin enhances functional brain responses to images of their own versus unknown infant faces. Significant differences in head motion between oxytocin/placebo conditions and addiction/control groups were discovered. Administration of intranasal oxytocin was associated with more frequent counts of head motion exceeding 3 mm of framewise displacement, independent of group status (z=2.89, p=0.004). This effect was seen more strongly in the control group (z=2.30, p=0.02) than the addiction group (z=1.77, p=0.08). The addiction group was more likely to show increased head motion, independent of oxytocin or placebo condition (z=2.21, p=0.03). When examining the mean head motion across all time points, as opposed to the count of large movements, oxytocin’s effect was limited to the addiction group (z=2.58, p=0.01), with a significant group by condition interaction effect observed. Intranasally-administered oxytocin may therefore have a confounding effect on functional MRI scanning results via its independent effect on head motion. These findings should be examined and replicated in other clinical populations.
{"title":"Intranasal Oxytocin Increases Head Motion During Functional MRI Scanning","authors":"Sydney Houlton, Jatin Vaidya, Patrick Breheny, Lane Strathearn","doi":"10.21203/rs.3.rs-3912105/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3912105/v1","url":null,"abstract":"Abstract Oxytocin is a neuropeptide associated with prosocial behaviors, such as parent-child bonding, eye contact, and sexual activity. Intranasally-administered oxytocin has been widely used to study its effects on the brain using functional magnetic resonance imaging. Head motion is a significant confounding variable which was assessed as part of a double blind, placebo-controlled crossover study. Twenty-four mothers with drug addiction problems were initially recruited, along with 22 healthy control mothers, to test whether intranasal oxytocin enhances functional brain responses to images of their own versus unknown infant faces. Significant differences in head motion between oxytocin/placebo conditions and addiction/control groups were discovered. Administration of intranasal oxytocin was associated with more frequent counts of head motion exceeding 3 mm of framewise displacement, independent of group status (z=2.89, p=0.004). This effect was seen more strongly in the control group (z=2.30, p=0.02) than the addiction group (z=1.77, p=0.08). The addiction group was more likely to show increased head motion, independent of oxytocin or placebo condition (z=2.21, p=0.03). When examining the mean head motion across all time points, as opposed to the count of large movements, oxytocin’s effect was limited to the addiction group (z=2.58, p=0.01), with a significant group by condition interaction effect observed. Intranasally-administered oxytocin may therefore have a confounding effect on functional MRI scanning results via its independent effect on head motion. These findings should be examined and replicated in other clinical populations.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-06DOI: 10.21203/rs.3.rs-3906170/v1
I-Ping Chen, Yasuyuki Fujii, Iichiro Okabe, Ayano Hatori, Shyam Sah, Jitendra Kanaujiya, Melanie Fisher, Rachael Norris, Mark Terasaki, Ernst Reichenberger
Abstract Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and flaring metaphyses of long bones. Many patients with CMD suffer from neurological symptoms. To date, the pathogenesis of CMD is not fully understood. Treatment is limited to decompression surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a R239Q mutation in CX43. Cx43 KI/KI mice replicate many features of AR CMD in craniofacial and long bones. In contrast to Cx43 +/+ littermates, Cx43 KI/KI mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones, leading to an expanded bone marrow cavity and increased cortical bone thickness. Although formation of Cx43 +/+ and Cx43 KI/KI resting OCs are comparable, on bone chips the actively resorbing Cx43 KI/KI OCs resorb less bone. Cortical bones of Cx43 KI/KI mice have an increase in degenerating osteocytes and empty lacunae. Osteocyte dendrite formation is decreased with reduced expression levels of Fgf23 , Sost , Tnf-α , IL-1β , Esr1 , Esr2 , and a lower Rankl/Opg ratio. Female Cx43 KI/KI mice display a more severe phenotype. Sexual dimorphism in bone becomes more evident as mice age. Our data show that the CX43R239Q mutation results in mislocalization of CX43 protein and impairment of gap junction and hemichannel activity. Different from CX43 ablation mouse models, the CX43R239Q mutation leads to the AR CMD-like phenotype in Cx43 KI/KI mice not only by loss-of-function but also via a not yet revealed dominant function.
{"title":"Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia","authors":"I-Ping Chen, Yasuyuki Fujii, Iichiro Okabe, Ayano Hatori, Shyam Sah, Jitendra Kanaujiya, Melanie Fisher, Rachael Norris, Mark Terasaki, Ernst Reichenberger","doi":"10.21203/rs.3.rs-3906170/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3906170/v1","url":null,"abstract":"Abstract Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and flaring metaphyses of long bones. Many patients with CMD suffer from neurological symptoms. To date, the pathogenesis of CMD is not fully understood. Treatment is limited to decompression surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a R239Q mutation in CX43. Cx43 KI/KI mice replicate many features of AR CMD in craniofacial and long bones. In contrast to Cx43 +/+ littermates, Cx43 KI/KI mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones, leading to an expanded bone marrow cavity and increased cortical bone thickness. Although formation of Cx43 +/+ and Cx43 KI/KI resting OCs are comparable, on bone chips the actively resorbing Cx43 KI/KI OCs resorb less bone. Cortical bones of Cx43 KI/KI mice have an increase in degenerating osteocytes and empty lacunae. Osteocyte dendrite formation is decreased with reduced expression levels of Fgf23 , Sost , Tnf-α , IL-1β , Esr1 , Esr2 , and a lower Rankl/Opg ratio. Female Cx43 KI/KI mice display a more severe phenotype. Sexual dimorphism in bone becomes more evident as mice age. Our data show that the CX43R239Q mutation results in mislocalization of CX43 protein and impairment of gap junction and hemichannel activity. Different from CX43 ablation mouse models, the CX43R239Q mutation leads to the AR CMD-like phenotype in Cx43 KI/KI mice not only by loss-of-function but also via a not yet revealed dominant function.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-06DOI: 10.21203/rs.3.rs-3874821/v1
Steven Chan, Mohsen Hosseini, V. Voisin, Ali Chegini, Angelica Varesi, S. Cathelin, D. M. Ayyathan, Alex Liu, Yitong Yang, Vivian Wang, Abdula Maher, Eric Grignano, Julie Haines, Angelo D'Alessandro, Kira Young, Yiyan Wu, Martina Fiumara, Samuele Ferrari, L. Naldini, Federico Gaiti, Shraddha Pai, Aaron Schimmer, Gary D. Bader, John Dick, Stephanie Z. Xie, Jennifer J. Trowbridge
Abstract Clonal hematopoiesis (CH) arises when a hematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type (WT) HSCs, resulting in its clonal expansion. Individuals with CH are at an increased risk of developing hematologic neoplasms and a range of age-related inflammatory illnesses1-3. Therapeutic interventions that suppress the expansion of mutant HSCs have the potential to prevent these CH-related illnesses; however, such interventions have not yet been identified. The most common CH driver mutations are in the DNA methyltransferase 3 alpha (DNMT3A) gene with arginine 882 (R882) being a mutation hotspot. Here we show that murine hematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, which is equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with WT cells and are dependent on this metabolic reprogramming for their competitive advantage. Importantly, treatment with metformin, an oral anti-diabetic drug with inhibitory activity against complex I in the electron transport chain (ETC), reduced the fitness of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we discovered that metformin acts by enhancing the methylation potential in Dnmt3aR878H/+ HSPCs and reversing their aberrant DNA CpG methylation and histone H3K27 trimethylation (H3K27me3) profiles. Metformin also reduced the fitness of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against illnesses associated with DNMT3AR882 mutation-driven CH in humans.
{"title":"Metformin reduces the clonal fitness of Dnmt3aR878H hematopoietic stem and progenitor cells by reversing their aberrant metabolic and epigenetic state","authors":"Steven Chan, Mohsen Hosseini, V. Voisin, Ali Chegini, Angelica Varesi, S. Cathelin, D. M. Ayyathan, Alex Liu, Yitong Yang, Vivian Wang, Abdula Maher, Eric Grignano, Julie Haines, Angelo D'Alessandro, Kira Young, Yiyan Wu, Martina Fiumara, Samuele Ferrari, L. Naldini, Federico Gaiti, Shraddha Pai, Aaron Schimmer, Gary D. Bader, John Dick, Stephanie Z. Xie, Jennifer J. Trowbridge","doi":"10.21203/rs.3.rs-3874821/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3874821/v1","url":null,"abstract":"Abstract Clonal hematopoiesis (CH) arises when a hematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type (WT) HSCs, resulting in its clonal expansion. Individuals with CH are at an increased risk of developing hematologic neoplasms and a range of age-related inflammatory illnesses1-3. Therapeutic interventions that suppress the expansion of mutant HSCs have the potential to prevent these CH-related illnesses; however, such interventions have not yet been identified. The most common CH driver mutations are in the DNA methyltransferase 3 alpha (DNMT3A) gene with arginine 882 (R882) being a mutation hotspot. Here we show that murine hematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, which is equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with WT cells and are dependent on this metabolic reprogramming for their competitive advantage. Importantly, treatment with metformin, an oral anti-diabetic drug with inhibitory activity against complex I in the electron transport chain (ETC), reduced the fitness of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we discovered that metformin acts by enhancing the methylation potential in Dnmt3aR878H/+ HSPCs and reversing their aberrant DNA CpG methylation and histone H3K27 trimethylation (H3K27me3) profiles. Metformin also reduced the fitness of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against illnesses associated with DNMT3AR882 mutation-driven CH in humans.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-06DOI: 10.21203/rs.3.rs-3878807/v1
Stefano Romeo, O. Jamialahmadi, A. De Vincentis, F. Tavaglione, F. Malvestiti, R. Li-Gao, R. Mancina, Marcus Alvarez, Kyla Gelev, Samantha Maurotti, U. Vespasiani‐Gentilucci, Frits Rosendaal, Julia Kozlitina, P. Pajukanta, François Pattou, Luca Valenti
Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses an excess of triglycerides in the liver, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence of MASLD coexisting with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity and identified 27 novel genetic loci associated with MASLD. Among these loci , we replicated 6 in several independent cohorts. Next, we generated two partitioned polygenic risk scores (PRS) based on the mechanism of genetic association with MASLD encompassing intra-hepatic lipoprotein retention. The two PRS suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease.
{"title":"Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease","authors":"Stefano Romeo, O. Jamialahmadi, A. De Vincentis, F. Tavaglione, F. Malvestiti, R. Li-Gao, R. Mancina, Marcus Alvarez, Kyla Gelev, Samantha Maurotti, U. Vespasiani‐Gentilucci, Frits Rosendaal, Julia Kozlitina, P. Pajukanta, François Pattou, Luca Valenti","doi":"10.21203/rs.3.rs-3878807/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3878807/v1","url":null,"abstract":"Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses an excess of triglycerides in the liver, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence of MASLD coexisting with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity and identified 27 novel genetic loci associated with MASLD. Among these loci , we replicated 6 in several independent cohorts. Next, we generated two partitioned polygenic risk scores (PRS) based on the mechanism of genetic association with MASLD encompassing intra-hepatic lipoprotein retention. The two PRS suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-06DOI: 10.21203/rs.3.rs-3904996/v1
F. Vallelonga, Matteo Valente, Marta Maria Tangari, Anna Covolo, V. Milazzo, C. Stefano, G. Sobrero, M. Giudici, Alberto Milan, Franco Veglio, L. Lopiano, Simona Maule, A. Romagnolo
Abstract Purpose. Neurogenic orthostatic hypotension (nOH) is a frequent non-motor feature of Parkinson’s disease (PD), associated with adverse outcomes. Recently, 24-hour ambulatory BP monitoring (ABPM) has been shown to diagnose nOH with good accuracy (in the presence of at least 2 episodes of systolic BP drop ≥ 15 mmHg compared to the average 24-h). This study aims at evaluating the prognostic role of ABPM-hypotensive episodes in predicting PD disability milestones and mortality and comparing it to well-defined prognostic role of nOH. Methods. PD patients who underwent ABPM from January 2012 to December 2014 were retrospectively enrolled and assessed for the development of falls, fractures, dementia, bed/wheelchair confinement, hospitalization, mortality, during an up-to-10-year follow-up. Results. Ninety-nine patients (male 74%; age: 64.0 ± 10.1 years; PD duration: 6.4 ± 4.0 years) were enrolled. At baseline, 38.4% of patients had ABPM-hypotensive episodes and 46.5% had bedside nOH. At Kaplan-Meier analysis patients with ABPM-hypotensive episodes had an earlier onset of falls (p = 0.001), fractures (p = 0.004), hospitalizations (p = 0.009), bed/wheelchair confinement (p = 0.032), dementia (p = 0.001), and showed a shorter survival (8.0vs9.5 years; p = 0.009). At Cox regression analysis (adjusted for age, disease duration, Charlson Comorbidity Index, and H&Y stage at baseline) a significant association was confirmed between ABPM-hypotensive episodes and falls (OR:3.626; p = 0.001), hospitalizations (OR:2.016; p = 0.038), and dementia (OR:2.926; p = 0.008), while bedside nOH was only associated with falls (OR 2.022; p = 0.039) and dementia (OR:1.908; p = 0.048). Conclusion. The presence of at least two ABPM-hypotensive episodes independently predicted the development of falls, dementia, and hospitalization, showing a stronger prognostic value than the simple bedside assessment.
{"title":"Hypotensive episodes at 24-h Ambulatory Blood Pressure Monitoring predict adverse outcomes in Parkinson’s Disease","authors":"F. Vallelonga, Matteo Valente, Marta Maria Tangari, Anna Covolo, V. Milazzo, C. Stefano, G. Sobrero, M. Giudici, Alberto Milan, Franco Veglio, L. Lopiano, Simona Maule, A. Romagnolo","doi":"10.21203/rs.3.rs-3904996/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3904996/v1","url":null,"abstract":"Abstract Purpose. Neurogenic orthostatic hypotension (nOH) is a frequent non-motor feature of Parkinson’s disease (PD), associated with adverse outcomes. Recently, 24-hour ambulatory BP monitoring (ABPM) has been shown to diagnose nOH with good accuracy (in the presence of at least 2 episodes of systolic BP drop ≥ 15 mmHg compared to the average 24-h). This study aims at evaluating the prognostic role of ABPM-hypotensive episodes in predicting PD disability milestones and mortality and comparing it to well-defined prognostic role of nOH. Methods. PD patients who underwent ABPM from January 2012 to December 2014 were retrospectively enrolled and assessed for the development of falls, fractures, dementia, bed/wheelchair confinement, hospitalization, mortality, during an up-to-10-year follow-up. Results. Ninety-nine patients (male 74%; age: 64.0 ± 10.1 years; PD duration: 6.4 ± 4.0 years) were enrolled. At baseline, 38.4% of patients had ABPM-hypotensive episodes and 46.5% had bedside nOH. At Kaplan-Meier analysis patients with ABPM-hypotensive episodes had an earlier onset of falls (p = 0.001), fractures (p = 0.004), hospitalizations (p = 0.009), bed/wheelchair confinement (p = 0.032), dementia (p = 0.001), and showed a shorter survival (8.0vs9.5 years; p = 0.009). At Cox regression analysis (adjusted for age, disease duration, Charlson Comorbidity Index, and H&Y stage at baseline) a significant association was confirmed between ABPM-hypotensive episodes and falls (OR:3.626; p = 0.001), hospitalizations (OR:2.016; p = 0.038), and dementia (OR:2.926; p = 0.008), while bedside nOH was only associated with falls (OR 2.022; p = 0.039) and dementia (OR:1.908; p = 0.048). Conclusion. The presence of at least two ABPM-hypotensive episodes independently predicted the development of falls, dementia, and hospitalization, showing a stronger prognostic value than the simple bedside assessment.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.21203/rs.3.rs-3845793/v1
Vilma Gabbay, Benjamin Ely, Julia Vileisis, Z. Petrovic, Ana Cicvaric, Gregory Asnis, S. Kim-Schulze, Jelena Radulovic
Abstract Studies in adults have linked stress-related activation of the immune system to the manifestation of psychiatric conditions. Using a translational design, this study aimed to examine the impact of social stress on immune activity in adolescents and on neuronal activity in a preclinical mouse model. Participants were 31 adolescents (ages 12–19), including 25 with mood and anxiety symptoms. Whole-blood samples were collected before and after the Trier Social Stress Test (TSST), a stress-inducing public speaking task, then cultured for 6 hours in the presence and absence of the inflammatory endotoxin lipopolysaccharide (LPS). Effects of TSST and LPS on 41 immune biomarkers were examined using repeated-measures analysis of variance. Separately, juvenile (8-week-old) male mice were non-stressed or exposed to reminder social defeat then intraperitoneally injected with saline or LPS (n = 6/group). Brains were perfused and collected for immunohistochemistry and confocal microscopy at 0, 1, 6, and 24 hours post-injection. Activity was determined by the density of cFos-positive neurons in the paraventricular hypothalamus, paraventricular thalamus, and basolateral amygdala, regions known to show sustained activation to immunological challenge. Analyses in the adolescent study indicated a strong effect of LPS but no effects of TSST or TSST×LPS interaction on immune biomarkers. Similarly, reminder social defeat did not induce sustained neuronal activity changes comparable to LPS immunological challenge in juvenile mice. Our convergent findings across species suggest that the acute immune response to stress documented in adults is not present in youth. Thus, aging and chronicity effects may play an important role in the inflammatory response to acute psychosocial stress.
{"title":"Immune and Neural Response to Acute Social Stress in Adolescent Humans and Rodents","authors":"Vilma Gabbay, Benjamin Ely, Julia Vileisis, Z. Petrovic, Ana Cicvaric, Gregory Asnis, S. Kim-Schulze, Jelena Radulovic","doi":"10.21203/rs.3.rs-3845793/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3845793/v1","url":null,"abstract":"Abstract Studies in adults have linked stress-related activation of the immune system to the manifestation of psychiatric conditions. Using a translational design, this study aimed to examine the impact of social stress on immune activity in adolescents and on neuronal activity in a preclinical mouse model. Participants were 31 adolescents (ages 12–19), including 25 with mood and anxiety symptoms. Whole-blood samples were collected before and after the Trier Social Stress Test (TSST), a stress-inducing public speaking task, then cultured for 6 hours in the presence and absence of the inflammatory endotoxin lipopolysaccharide (LPS). Effects of TSST and LPS on 41 immune biomarkers were examined using repeated-measures analysis of variance. Separately, juvenile (8-week-old) male mice were non-stressed or exposed to reminder social defeat then intraperitoneally injected with saline or LPS (n = 6/group). Brains were perfused and collected for immunohistochemistry and confocal microscopy at 0, 1, 6, and 24 hours post-injection. Activity was determined by the density of cFos-positive neurons in the paraventricular hypothalamus, paraventricular thalamus, and basolateral amygdala, regions known to show sustained activation to immunological challenge. Analyses in the adolescent study indicated a strong effect of LPS but no effects of TSST or TSST×LPS interaction on immune biomarkers. Similarly, reminder social defeat did not induce sustained neuronal activity changes comparable to LPS immunological challenge in juvenile mice. Our convergent findings across species suggest that the acute immune response to stress documented in adults is not present in youth. Thus, aging and chronicity effects may play an important role in the inflammatory response to acute psychosocial stress.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.21203/rs.3.rs-3854490/v1
N. García-Sancha, R. Corchado-Cobos, A. Blanco-Gómez, O. C. Puértolas, Mercè Marzo-Castillejo, Sonia Castillo-Lluva, D. Alonso-López, Javier De Las Rivas, Julio Pozo, Alberto Orfao, Luis Valero-Juan, Carmen Patino-Alonso, David Perera, Ashok R. Venkitaraman, J. Mao, Hang Chang, Marina Mendiburu-Eliçabe, Patricia González-García, Eduardo Caleiras, Isabel Peset, M. B. G. Cenador, F. J. García-Criado, J. Pérez-Losada
Abstract Post-pregnancy breast cancer often carries a poor prognosis, posing a major clinical challenge. The increasing trend of later-life pregnancies exacerbates this risk, highlighting the need for effective chemoprevention strategies. Current options, limited to selective estrogen receptor modulators, aromatase inhibitors, or surgical procedures, offer limited efficacy and considerable side effects. Here, we report that cabergoline, a dopaminergic agonist, reduces the risk of breast cancer post-pregnancy in a Brca1/P53 -deficient mouse model, with implications for human breast cancer prevention. We show that a single dose of cabergoline administered post-pregnancy significantly delayed the onset and reduced the incidence of breast cancer in Brca1/P53 -deficient mice. Histological analysis revealed a notable acceleration in post-lactational involution over the short term, characterized by increased apoptosis and altered gene expression related to ion transport. Over the long term, histological changes in the mammary gland included a reduction in the ductal component, decreased epithelial proliferation, and a lower presence of recombinant Brca1/P53 target cells, which are precursors of tumors. These changes serve as indicators of reduced breast cancer susceptibility. Additionally, RNA sequencing identified gene expression alterations associated with decreased proliferation and mammary gland branching. Our findings highlight a mechanism wherein cabergoline enhances the protective effect of pregnancy against breast cancer by potentiating postlactational involution. Notably, a retrospective cohort study in women demonstrated a markedly lower incidence of post-pregnancy breast cancer in those treated with cabergoline compared to a control group. Our work underscores the importance of enhancing postlactational involution as a strategy for breast cancer prevention, and identifies cabergoline as a promising, low-risk option in breast cancer chemoprevention. This strategy has the potential to revolutionize breast cancer prevention approaches, particularly for women at increased risk due to genetic factors or delayed childbirth, and has wider implications beyond hereditary breast cancer cases. (*) Equal contribution as first authors.
{"title":"Cabergoline as a Novel Strategy for Post-Pregnancy Breast Cancer Prevention in Mice and Human","authors":"N. García-Sancha, R. Corchado-Cobos, A. Blanco-Gómez, O. C. Puértolas, Mercè Marzo-Castillejo, Sonia Castillo-Lluva, D. Alonso-López, Javier De Las Rivas, Julio Pozo, Alberto Orfao, Luis Valero-Juan, Carmen Patino-Alonso, David Perera, Ashok R. Venkitaraman, J. Mao, Hang Chang, Marina Mendiburu-Eliçabe, Patricia González-García, Eduardo Caleiras, Isabel Peset, M. B. G. Cenador, F. J. García-Criado, J. Pérez-Losada","doi":"10.21203/rs.3.rs-3854490/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3854490/v1","url":null,"abstract":"Abstract Post-pregnancy breast cancer often carries a poor prognosis, posing a major clinical challenge. The increasing trend of later-life pregnancies exacerbates this risk, highlighting the need for effective chemoprevention strategies. Current options, limited to selective estrogen receptor modulators, aromatase inhibitors, or surgical procedures, offer limited efficacy and considerable side effects. Here, we report that cabergoline, a dopaminergic agonist, reduces the risk of breast cancer post-pregnancy in a Brca1/P53 -deficient mouse model, with implications for human breast cancer prevention. We show that a single dose of cabergoline administered post-pregnancy significantly delayed the onset and reduced the incidence of breast cancer in Brca1/P53 -deficient mice. Histological analysis revealed a notable acceleration in post-lactational involution over the short term, characterized by increased apoptosis and altered gene expression related to ion transport. Over the long term, histological changes in the mammary gland included a reduction in the ductal component, decreased epithelial proliferation, and a lower presence of recombinant Brca1/P53 target cells, which are precursors of tumors. These changes serve as indicators of reduced breast cancer susceptibility. Additionally, RNA sequencing identified gene expression alterations associated with decreased proliferation and mammary gland branching. Our findings highlight a mechanism wherein cabergoline enhances the protective effect of pregnancy against breast cancer by potentiating postlactational involution. Notably, a retrospective cohort study in women demonstrated a markedly lower incidence of post-pregnancy breast cancer in those treated with cabergoline compared to a control group. Our work underscores the importance of enhancing postlactational involution as a strategy for breast cancer prevention, and identifies cabergoline as a promising, low-risk option in breast cancer chemoprevention. This strategy has the potential to revolutionize breast cancer prevention approaches, particularly for women at increased risk due to genetic factors or delayed childbirth, and has wider implications beyond hereditary breast cancer cases. (*) Equal contribution as first authors.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.21203/rs.3.rs-3617246/v1
David Zarrin, Abhinav Suri, Karen McCarthy, Bilwaj Gaonkar, Bayard Wilson, Geoffrey Colby, Robert Freundlich, Luke Macyszyn, Eilon Gabel
Abstract Background Cerebral vasospasm (CV) is a feared complication occurring in 20-40% of patients following subarachnoid hemorrhage (SAH) and is known to contribute to delayed cerebral ischemia. It is standard practice to admit SAH patients to intensive care for an extended period of vigilant, resource-intensive, clinical monitoring. We used machine learning to predict CV requiring verapamil (CVRV) in the largest and only multi-center study to date. Methods SAH patients admitted to UCLA from 2013-2022 and a validation cohort from VUMC from 2018-2023 were included. For each patient, 172 unique intensive care unit (ICU) variables were extracted through the primary endpoint, namely first verapamil administration or ICU downgrade. At each institution, a light gradient boosting machine (LightGBM) was trained using five-fold cross validation to predict the primary endpoint at various timepoints during hospital admission. Receiver-operator curves (ROC) and precision-recall (PR) curves were generated. Results A total of 1,750 patients were included from UCLA, 125 receiving verapamil. LightGBM achieved an area under the ROC (AUC) of 0.88 an average of over one week in advance, and successfully ruled out 8% of non-verapamil patients with zero false negatives. Minimum leukocyte count, maximum platelet count, and maximum intracranial pressure were the variables with highest predictive accuracy. Our models predicted “no CVRV” vs “CVRV within three days” vs “CVRV after three days” with AUCs=0.88, 0.83, and 0.88, respectively. For external validation at VUMC, 1,654 patients were included, 75 receiving verapamil. Predictive models at VUMC performed very similarly to those at UCLA, averaging 0.01 AUC points lower. Conclusions We present an accurate (AUC=0.88) and early (>1 week prior) predictor of CVRV using machine learning over two large cohorts of subarachnoid hemorrhage patients at separate institutions. This represents a significant step towards optimized clinical management and improved resource allocation in the intensive care setting of subarachnoid hemorrhage patients.
{"title":"Machine Learning Predicts Cerebral Vasospasm in Subarachnoid Hemorrhage Patients","authors":"David Zarrin, Abhinav Suri, Karen McCarthy, Bilwaj Gaonkar, Bayard Wilson, Geoffrey Colby, Robert Freundlich, Luke Macyszyn, Eilon Gabel","doi":"10.21203/rs.3.rs-3617246/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3617246/v1","url":null,"abstract":"Abstract Background Cerebral vasospasm (CV) is a feared complication occurring in 20-40% of patients following subarachnoid hemorrhage (SAH) and is known to contribute to delayed cerebral ischemia. It is standard practice to admit SAH patients to intensive care for an extended period of vigilant, resource-intensive, clinical monitoring. We used machine learning to predict CV requiring verapamil (CVRV) in the largest and only multi-center study to date. Methods SAH patients admitted to UCLA from 2013-2022 and a validation cohort from VUMC from 2018-2023 were included. For each patient, 172 unique intensive care unit (ICU) variables were extracted through the primary endpoint, namely first verapamil administration or ICU downgrade. At each institution, a light gradient boosting machine (LightGBM) was trained using five-fold cross validation to predict the primary endpoint at various timepoints during hospital admission. Receiver-operator curves (ROC) and precision-recall (PR) curves were generated. Results A total of 1,750 patients were included from UCLA, 125 receiving verapamil. LightGBM achieved an area under the ROC (AUC) of 0.88 an average of over one week in advance, and successfully ruled out 8% of non-verapamil patients with zero false negatives. Minimum leukocyte count, maximum platelet count, and maximum intracranial pressure were the variables with highest predictive accuracy. Our models predicted “no CVRV” vs “CVRV within three days” vs “CVRV after three days” with AUCs=0.88, 0.83, and 0.88, respectively. For external validation at VUMC, 1,654 patients were included, 75 receiving verapamil. Predictive models at VUMC performed very similarly to those at UCLA, averaging 0.01 AUC points lower. Conclusions We present an accurate (AUC=0.88) and early (>1 week prior) predictor of CVRV using machine learning over two large cohorts of subarachnoid hemorrhage patients at separate institutions. This represents a significant step towards optimized clinical management and improved resource allocation in the intensive care setting of subarachnoid hemorrhage patients.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.21203/rs.3.rs-3914650/v1
Neelum Aziz Yousafzai, Lamyae El Khalki, Wei Wang, Justin Szpendyk, K. Sossey-Alaoui
Abstract Background Kindlin-2, an adaptor protein, is dysregulated in various human cancers, including triple negative breast cancer (TNBC), where it drives tumor progression and metastasis by influencing several cancer hallmarks. One well-established role of Kindlin-2 involves the regulation of integrin signaling, achieved by directly binding to the cytoplasmic tail of the integrin β subunit. In this study, we present novel insights into Kindlin-2's involvement in stabilizing the β1-Integrin:TGF-β type 1 receptor (TβRI) complexes, acting as a physical bridge that links β1-Integrin to TβRI. The loss of Kindlin-2 results in the degradation of this protein complex, leading to the inhibition of downstream oncogenic pathways. Methods Our methodology encompassed a diverse range of in vitro assays, including CRISPR/Cas9 gene editing, cell migration, 3D tumorsphere formation and invasion, solid binding, co-immunoprecipitation, cell adhesion and spreading assays, as well as western blot and flow cytometry analyses, utilizing MDA-MB-231 and 4T1 TNBC cell lines. Additionally, preclinical in vivo mouse models of TNBC tumor progression and metastasis were employed to substantiate our findings. Results The investigation revealed that the direct interaction between Kindlin-2 and β1-Integrin is mediated through the C-terminal F3 domain of Kindlin-2, while the interaction between Kindlin-2 and TβRI is facilitated through the F2 domain of Kindlin-2. Disruption of this bridge, achieved via CRISPR/Cas9-mediated knockout of Kindlin-2, led to the degradation of β1-Integrin and TβRI, resulting in the inhibition of oncogenic pathways downstream of both proteins, subsequently hindering tumor growth and metastasis. Treatment of Kindlin-2-deficient cells with the proteasome inhibitor MG-132 restored the expression of both β1-Integrin and TβRI. Furthermore, the rescue of Kindlin-2 expression reinstated their oncogenic activities both in vitro and in vivo. Conclusions This study identifies a novel function of Kindlin-2 in stabilizing the β1-Integrin:TβR1 complexes and regulating their downstream oncogenic signaling. The translational implications of these findings are substantial, potentially unveiling new therapeutically targeted pathways crucial for the treatment of TNBC tumors.
{"title":"Kindlin-2 Regulates the Oncogenic Activities of Integrins and TGF-β In Triple Negative Breast Cancer Progression and Metastasis","authors":"Neelum Aziz Yousafzai, Lamyae El Khalki, Wei Wang, Justin Szpendyk, K. Sossey-Alaoui","doi":"10.21203/rs.3.rs-3914650/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3914650/v1","url":null,"abstract":"Abstract Background Kindlin-2, an adaptor protein, is dysregulated in various human cancers, including triple negative breast cancer (TNBC), where it drives tumor progression and metastasis by influencing several cancer hallmarks. One well-established role of Kindlin-2 involves the regulation of integrin signaling, achieved by directly binding to the cytoplasmic tail of the integrin β subunit. In this study, we present novel insights into Kindlin-2's involvement in stabilizing the β1-Integrin:TGF-β type 1 receptor (TβRI) complexes, acting as a physical bridge that links β1-Integrin to TβRI. The loss of Kindlin-2 results in the degradation of this protein complex, leading to the inhibition of downstream oncogenic pathways. Methods Our methodology encompassed a diverse range of in vitro assays, including CRISPR/Cas9 gene editing, cell migration, 3D tumorsphere formation and invasion, solid binding, co-immunoprecipitation, cell adhesion and spreading assays, as well as western blot and flow cytometry analyses, utilizing MDA-MB-231 and 4T1 TNBC cell lines. Additionally, preclinical in vivo mouse models of TNBC tumor progression and metastasis were employed to substantiate our findings. Results The investigation revealed that the direct interaction between Kindlin-2 and β1-Integrin is mediated through the C-terminal F3 domain of Kindlin-2, while the interaction between Kindlin-2 and TβRI is facilitated through the F2 domain of Kindlin-2. Disruption of this bridge, achieved via CRISPR/Cas9-mediated knockout of Kindlin-2, led to the degradation of β1-Integrin and TβRI, resulting in the inhibition of oncogenic pathways downstream of both proteins, subsequently hindering tumor growth and metastasis. Treatment of Kindlin-2-deficient cells with the proteasome inhibitor MG-132 restored the expression of both β1-Integrin and TβRI. Furthermore, the rescue of Kindlin-2 expression reinstated their oncogenic activities both in vitro and in vivo. Conclusions This study identifies a novel function of Kindlin-2 in stabilizing the β1-Integrin:TβR1 complexes and regulating their downstream oncogenic signaling. The translational implications of these findings are substantial, potentially unveiling new therapeutically targeted pathways crucial for the treatment of TNBC tumors.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.21203/rs.3.rs-3911085/v1
Lyndsay Harshman, Elliot Stalter, Silvia Verhofste, John Dagle, Emily Steinbach, P. Eyck, Linder Wendt, Jeffrey Segar
Abstract Objective Evaluate the impact of a sodium (Na) supplementation protocol based upon urine Na concentration on growth parameters and morbidities. Study Design Retrospective cohort study of infants 26 0/7 -33 6/7 weeks gestational age (GA) cared for before (2012-15, n = 225) and after (2016-20, n = 157) implementation of the protocol. Within- and between-group changes over time were assessed using repeated measures generalized linear models. Results For infants 26 0/7 -29 6/7 weeks GA, utilization of the protocol was associated with increased mean body weight z-score at 8-weeks postnatal age, increased mean head circumference z-score at 16-weeks postnatal age, and decreased time on mechanical ventilation (all p < 0.02). No impact on growth was identified for infants 30–33 6/7 weeks GA. Incidences of hypertension, hypernatremia, bronchopulmonary dysplasia, and culture positive sepsis were unaffected by the protocol. Conclusion Protocolized Na supplementation results in improved growth and reduced time on invasive mechanical ventilation in extremely preterm infants without increasing incidence of morbidities.
{"title":"Somatic growth outcomes in response to an individualized neonatal sodium supplementation protocol","authors":"Lyndsay Harshman, Elliot Stalter, Silvia Verhofste, John Dagle, Emily Steinbach, P. Eyck, Linder Wendt, Jeffrey Segar","doi":"10.21203/rs.3.rs-3911085/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3911085/v1","url":null,"abstract":"Abstract Objective Evaluate the impact of a sodium (Na) supplementation protocol based upon urine Na concentration on growth parameters and morbidities. Study Design Retrospective cohort study of infants 26 0/7 -33 6/7 weeks gestational age (GA) cared for before (2012-15, n = 225) and after (2016-20, n = 157) implementation of the protocol. Within- and between-group changes over time were assessed using repeated measures generalized linear models. Results For infants 26 0/7 -29 6/7 weeks GA, utilization of the protocol was associated with increased mean body weight z-score at 8-weeks postnatal age, increased mean head circumference z-score at 16-weeks postnatal age, and decreased time on mechanical ventilation (all p < 0.02). No impact on growth was identified for infants 30–33 6/7 weeks GA. Incidences of hypertension, hypernatremia, bronchopulmonary dysplasia, and culture positive sepsis were unaffected by the protocol. Conclusion Protocolized Na supplementation results in improved growth and reduced time on invasive mechanical ventilation in extremely preterm infants without increasing incidence of morbidities.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：