medRxiv (Cold Spring Harbor Laboratory)最新文献

{"title":"Brain-wide Disruptions of Anatomical Connectivity in Antipsychotic-Naive First Episode Psychosis","authors":"Sidhant Chopra, Priscila T Levi, Alexander Holmes, Edwina R Orchard, Ashlea Segal, Shona M Francey, Brian ODonoghue, Vanessa Cropley, Barnaby Nelson, Jessica Graham, Lara Baldwin, Hok Pan Yuen, Kelly Allott, Mario Alvarez-Jimenez, Susy Harrigan, Christos Pantelis, Stephen J Wood, Patrick McGorry, Alex Fornito","doi":"10.1101/2023.11.10.23298391","DOIUrl":"https://doi.org/10.1101/2023.11.10.23298391","url":null,"abstract":"OBJECTIVE: Disruptions of axonal connectivity are thought to be a core pathophysiological feature of psychotic illness, but whether they are present early in the illness, prior to antipsychotic exposure, and whether they can predict clinical outcome remains unknown. METHODS: We acquired diffusion-weighted MRI to map axonal connectivity between each pair of 319 parcellated brain regions in 61 antipsychotic-naive individuals with First Episode Psychosis (FEP; 15-25 years, 46% female) and a demographically matched sample of 27 control participants, along with clinical follow-up data in patients 3 months and 12 months after the scan. We used connectome-wide analyses to map disruptions of inter-regional pairwise connectivity coupled with connectome-based predictive modelling to predict longitudinal change in symptoms and functioning. RESULTS: Individuals with FEP showed disrupted connectivity in a brain-wide network linking all brain regions when compared with controls (pFWE=.03). Baseline structural connectivity significantly predicted change in functioning over 12 months (r=.44; pFWE=.041), such that lower connectivity within fronto-striato-thalamic systems predicted worse functional outcomes. CONCLUSIONS: Brain-wide reductions of structural connectivity exist during the early stages of psychotic illness and cannot be attributed to antipsychotic medication. Moreover, baseline measures of structural connectivity can predict change in patient functional outcomes up to one year after engagement with treatment services.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"18 5","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135086577","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}

{"title":"Patterns of Glucose Metabolism in [18F]FDG PET Indicate Regional Variability and Neurodegeneration in the Progression of Alzheimer's Dementia","authors":"John J. Lee, Tom Earnest, Sung Min Ha, Abdalla Bani, Deydeep Kothapelli, Peiwang Liu, Aristeidis Sotiras","doi":"10.1101/2023.11.10.23298396","DOIUrl":"https://doi.org/10.1101/2023.11.10.23298396","url":null,"abstract":"In disorders of cognitive impairment, such as Alzheimer's disease, neurodegeneration is the final common pathway of disease progression. Modulating, reversing, or preventing disease progression is a clinical imperative most likely to succeed following accurate and explanatory understanding of neurodegeneration, requiring enhanced consistency with quantitative measurements and expanded interpretability of complex data. The on-going study of neurodegeneration has robustly demonstrated the advantages of accumulating large amounts of clinical data that include neuroimaging, motiving multi-center studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI). Demonstrative advantages also arise from highly multivariate analysis methods, and this work reports advances provided by non-negative matrix factorization (NMF). NMF revealed patterns of covariance for glucose metabolism, estimated by positron emission tomography of [18F]fluorodeoxyglucose, in 243 healthy normal participants of ADNI. Patterns for glucose metabolism provided cross-sectional inferences for 860 total participants of ADNI with and without cerebral amyloidosis and clinical dementia ratings (CDR) ranging 0-3. Patterns for glucose metabolism were distinct in number and topography from patterns identified in previous studies of structural MRI. They were also distinct from well-establish topographies of resting-state neuronal networks mapped by functional magnetic resonance imaging. Patterns for glucose metabolism identified significant topographical landmarks relating age, sex, APOE e4 alleles, amyloidosis, CDR, and neurodegeneration. Patterns involving insular and orbitofrontal cortices, as well as midline regions of frontal and parietal lobes demonstrated the greatest neurodegeneration with progressive Alzheimer's dementia. A single pattern for the lateral parietal and posterior superior temporal cortices demonstrated preserved glucose metabolism for all diagnostic groups, including Alzheimer's dementia. Patterns correlated significantly with topical terms from the Neurosynth platform, thereby providing semantic representations for patterns such as attention, memory, language, fear/reward, movement and motor planning. In summary, NMF is a data-driven, principled, supervised statistical learning method that provides interpretable patterns of neurodegeneration. These patterns can help inform the understanding and treatment of Alzheimer's disease.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"19 2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135086713","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}

{"title":"Examining the Efficacies of Different Machine Learning Algorithms on Predicting Future Potential Death from Heart Failure","authors":"Osama Osman Radi","doi":"10.1101/2023.11.11.23298416","DOIUrl":"https://doi.org/10.1101/2023.11.11.23298416","url":null,"abstract":"1 in every 5 deaths is from heart failure. If this heart failure was able to be predicted, medical practitioners would be able to issue the proper preventative measures in order to prevent the fatal heart attack. As machine learning is gaining its place in medicine, one of the most commonly asked questions is which machine learning algorithms can be used where. This paper aims to find which machine learning algorithm is most efficacious in predicting future fatal heart disease. Two machine learning algorithms were evaluated in this study; namely linear regression models and k-nearest-neighbors models. The K-Nearest-Neighbors model was found to be most efficacious with an accuracy between 96.67% and 100% in predicting future heart failure. The reliability of this algorithm in predicting death from heart failure will surely prove useful in the future of treating at-risk patients.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"20 11","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135086861","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}

{"title":"Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer`s disease","authors":"Kyan Younes, Viktorija Smith, Emily Johns, Mackenzie L. Carlson, Joseph Winer, Zihuai He, Victor W. Henderson, Michael D. Greicius, Christina B. Young, Elizabeth C. Mormino","doi":"10.1101/2023.11.10.23296836","DOIUrl":"https://doi.org/10.1101/2023.11.10.23296836","url":null,"abstract":"Importance: Understanding asymmetry in spatial tau positron emission tomography (PET) patterns in Alzheimer's disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored. Objective: To investigate whether asymmetric tau PET burden is associated with behavioral symptoms and cognitive profiles. Design: This cross-sectional study analyzed temporal lobe tau PET laterality, alongside memory, executive, language, and behavioral data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Setting: Cognitively unimpaired (CU) and impaired (CI) from ADNI with available tau PET. Participants: A temporal tau laterality index was calculated to define 'asymmetry-extreme' groups (individuals with laterality indices greater than two standard deviations from the mean). In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated controlling for age, sex, education, and the tau burden on the contralateral side. Main Outcomes and Measures: The study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory, and composite scores for memory, executive function, and language. Results: 858 individuals (mean age=73.9+/-7.7 years, 434 (50%) females) were included, comprising 438 CU (53.4%) and 420 CI participants (48.9%). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Worse behavioral symptoms were observed with higher right, temporal tau (B(SE)=5.13(2.4), p-value=0.04) whereases worse language performance was associated with greater left temporal tau (B(SE)=0.37(0.1), p-value=0.04). Worse memory and executive function were associated with higher tau in both right and left temporal lobes. Within these extreme groups, four patterns of tau PET uptake were observed: anterior temporal, typical AD, typical AD with frontal involvement, and posterior. Similar associations were seen in the full cohort analysis, right temporal tau was associated with worse behavior (B(SE)=7.19 (2.9), p-value=0.01) and left temporal tau was associated with worse language (B(SE)=1.4(0.2), p-value<0.0001). Conclusions and Relevance: Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Deeper characterization of behavioral and socioemotional measures is needed to understand right sided asymmetry in the context of AD. Key Points Question: What is the influence of tau asymmetry on behavior and cognition in Alzheimer`s disease? Findings: In this cross-sectional study, elevated right temporal tau levels were linked to heightened behavioral symptoms, whereas increased left temporal tau levels were associated with greater language symptoms. Four distinct right/left asymmetric tau patterns were present: ante","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"7 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135041815","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}

{"title":"Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women","authors":"Andrea M Brennan, Paul M Coen, Theresa Mau, Megan Hetherington-Rauth, Frederico G.S. Toledo, Erin E Kershaw, Peggy M Cawthon, Philip A Kramer, Sofhia V Ramos, Anne B Newman, Steven R Cummings, Daniel E Forman, Reichelle X Yeo, Giovanna DiStefano, Iva Miljkovic, Jamie N Justice, Anthony J.A. Molina, Michael J Jurczak, Lauren M Sparks, Stephen B Kritchevsky, Bret H Goodpaster","doi":"10.1101/2023.11.10.23298359","DOIUrl":"https://doi.org/10.1101/2023.11.10.23298359","url":null,"abstract":"Objective: Examine the association of ectopic adipose tissue (AT) with skeletal muscle (SM) mitochondrial bioenergetics in older adults. Methods: Cross-sectional data from 829 older adults ≥70 years was used. Total abdominal, subcutaneous, and visceral AT; and thigh muscle fat infiltration (MFI) was quantified by MRI. SM mitochondrial energetics were characterized using in vivo 31P-MRS (ATPmax) and ex vivo high-resolution respirometry (maximal oxidative phosphorylation (OXPHOS)). ActivPal was used to measure PA (step count). Linear regression models adjusted for covariates were applied, with sequential adjustment for BMI and PA. Results: Independent of BMI, total abdominal (standardized (Std.) β=-0.21; R2=0.09) and visceral AT (Std. β=-0.16; R2=0.09) were associated with ATPmax (p<0.01), but not after further adjustment for PA (p≥0.05). Visceral AT (Std. β=-0.16; R2=0.25) and thigh MFI (Std. β=-0.11; R2=0.24) were negatively associated with carbohydrate-supported maximal OXPHOS independent of BMI and PA (p<0.05). Total abdominal AT (Std. β=-0.19; R2=0.24) and visceral AT (Std. β=-0.17; R2=0.24) were associated with fatty acid-supported maximal OXPHOS independent of BMI and PA (p<0.05). Conclusions: Skeletal MFI and abdominal visceral, but not subcutaneous AT, are inversely associated with SM mitochondrial bioenergetics in older adults independent of BMI. Associations between ectopic AT and in vivo mitochondrial bioenergetics are attenuated by PA.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"16 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135043047","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}

{"title":"Initial clinical evidence on biperiden as antiepileptogenic after traumatic brain injury. A Randomized Clinical Trial","authors":"Maira Licia Foresti, Eliana Garzon, Mariana Teichner de Moraes, Rafael P Valeriano, Joao Paulo Santiago, Gustavo Mercenas dos Santos, Natalia Mata Longo, Carla Baise, Joaquina C Andrade, Maria Alice Susemihl, Maria da Graca Naffah Mazzacoratti, Wellingson Silva Paiva, Almir Ferreira Andrade, Manoel Jacobsen, Luiz E Mello","doi":"10.1101/2023.11.10.23298341","DOIUrl":"https://doi.org/10.1101/2023.11.10.23298341","url":null,"abstract":"There is currently no available drug to prevent the development of post-traumatic epilepsy. Preclinical studies support the potential use of anticholinergics. To evaluate whether treatment with biperiden has the potential to prevent post-traumatic epilepsy. Randomized, double-blind, placebo-controlled clinical trial, conducted between 2018- 2022. Adult patients with acute traumatic brain injury (TBI) following eligibility criteria were randomly assigned to placebo or biperiden groups. Biperiden or placebo was initiated within 12 h after trauma and repeated every 6 h for 10 days. Clinical evaluation was performed at 1, 3, 6, 12, 18, and 24 months after TBI to investigate seizures incidence. The primary outcome was a change in the incidence of post-traumatic epilepsy. Secondary outcomes included frequency of seizures, mortality and adverse events. Of 123 patients recruited, 1 declined and 1 was ineligible. After randomization, 11 (8.9%) participants were discontinued from the study. The mean (SD) age of the 112 remaining participants was 43.5 (17.6) years, and 19/112 (16.9%) were female. Of these, 27 (21.9%) participants died and 3 (2.4%) were lost in the follow-up. Of the remaining 82 (66.6%) participants, 61 (49.5%) completed the study. Data analysis indicated lack of evidence of biperiden for either, the incidence of post-traumatic epilepsy (2.6, 95%CI, 0.65-10.57; P = .170) or the mortality rate (1.57, 95%CI, 0.73-3.38; P=.248). Constipation (43.9%) was the most common adverse event observed. The frequency of late post-traumatic seizures was higher for biperiden group (2.03, 95%CI = 0.912-3.1597; p <0.001). There was insufficient evidence regarding the effect of biperiden in preventing post-traumatic epilepsy after TBI. The combined effect of variables known to have an impact on the likelihood of developing late post-traumatic seizures and its unbalanced frequency in the different groups is an aspect to be considered and underpins the need for larger studies.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"19 5","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135043225","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}

{"title":"Digital Voice-Based Biomarker for Monitoring Respiratory Quality of Life: Findings from the Colive Voice Study","authors":"Vladimir Despotovic, Abir Elbeji, Kevser Fuenfgeld, Megane Pizzimenti, Hanin Ayadi, Petr Nazarov, Guy Fagherazzi","doi":"10.1101/2023.11.11.23298300","DOIUrl":"https://doi.org/10.1101/2023.11.11.23298300","url":null,"abstract":"Regular monitoring of respiratory quality of life (RQoL) is essential in respiratory healthcare, facilitating prompt diagnosis and tailored treatment for chronic respiratory diseases. Voice alterations resulting from respiratory conditions create unique audio signatures that can potentially be utilized for disease screening or monitoring. Analyzing data from 1908 participants from the Colive Voice study, which collects standardized voice recordings alongside comprehensive demographic, epidemiological, and patient-reported outcome data, we evaluated various strategies to estimate RQoL from voice, including handcrafted acoustic features, standard acoustic feature sets, and advanced deep audio embeddings derived from pretrained convolutional neural networks. We compared models using clinical features alone, voice features alone, and a combination of both. The multimodal model combining clinical and voice features demonstrated the best performance, achieving an accuracy of 70.34% and an area under the receiver operating characteristic curve (AUROC) of 0.77; an improvement of 5% in terms of accuracy and 7% in terms of AUROC compared to model utilizing voice features alone. Incorporating vocal biomarkers significantly enhanced the predictive capacity of clinical variables across all acoustic feature types, with a net classification improvement (NRI) of up to 0.19. Our digital voice-based biomarker is capable of accurately predicting RQoL, either as an alternative to or in conjunction with clinical measures, and could be used to facilitate rapid screening and remote monitoring of respiratory health status.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"14 2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135086328","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}

{"title":"The cross-sectional correlation between the oxidative balance score and cardiometabolic risk factors and its potential correlation with longitudinal mortality in patients with cardiometabolic risk factors.","authors":"lai qiancheng, Liu Ye, Jun Luo, Cheng Zhang, shao yue","doi":"10.1101/2023.11.10.23298401","DOIUrl":"https://doi.org/10.1101/2023.11.10.23298401","url":null,"abstract":"Abstract Background: This study sought to analyze the correlation between oxidative balance score (OBS) and cardiometabolic risk factors (CMRFs) and mortality in individuals with CMRFs. Methods: Data were chosen from the National Health and Nutrition Examination Survey. The survey-weighted multivariable logistic regression models were implemented to explore the relationship between OBS and the risk of CMRFs. Then, Cox proportional hazard models were employed to estimate the impact of OBS on mortality in individuals with CMRFs. Results: Following multivariate adjustment, the subjects in the highest quartile exhibited a 46% reduction in the risk of CMRFs, a 33% reduction in the risk of diabetes, a 31% reduction in the risk of hypertension, and a 36% reduction in the risk of hyperlipidemia, compared with those in the lowest quartile. Furthermore, each 1-unit increase in OBS was remarkably negatively correlated with the prevalence of CMRFs, diabetes, hypertension, and hyperlipidemia. The correlation between OBS and CMFRs was found to be mediated by serum ?-glutamyltransferase (GGT) and white blood cells (WBC), and the mediation effect of GGT levels and WBC, accounting for 6.90% and 11.51%, respectively. Lastly, the multivariate Cox regression model revealed that elevated OBS, irrespective of whether it was treated as a categorical or continuous variable, exhibited a significant association with decreased mortality from all causes, cardiovascular disease, and cancer. Conclusions: An increased OBS might reflect a lower risk of CMRFs and a favorable prognosis for individuals with CMRFs. Moreover, WBC and GGT may play a potential mediating role between OBS and CMRFs.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135086581","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}

{"title":"The potential effect of romosozumab on perioperative management for instrumentation surgery","authors":"Koji Ishikawa, Soji Tani, Tomoaki Toyone, Koutaro Tsuchiya, Tomoko Towatari, Yusuke Oshita, Ryo Yamamura, Takashi Nagai, Toshiyuki Shirahata, Katsunori Inagaki, Yoshifumi Kudo","doi":"10.1101/2023.11.09.23298298","DOIUrl":"https://doi.org/10.1101/2023.11.09.23298298","url":null,"abstract":"Background: Age-related changes in bone health increase the risk for complications in elderly patients undergoing orthopedic surgery. Osteoporosis is a key therapeutic target that needs to be addressed to ensure successful instrumentation surgery. The effectiveness of pharmacological interventions in orthopedic surgery, particularly the new drug romosozumab, is still unknown. We aim to evaluate the effect of 3-month romosozumab treatment on biomechanical parameters related to spinal instrumentation surgery, using the Quantitative Computed Tomography (QCT)-based Finite Element Method (FEM). Methods: This open-labeled, prospective study included 81 patients aged 60 to 90 years, who met the osteoporosis criteria and were scheduled for either romosozumab or eldecalcitol treatment. Patients were assessed using blood samples, dual-energy absorptiometry (DXA), and QCT. Biomechanical parameters were evaluated using FEM at baseline and 3 months post-treatment. The primary endpoints were biomechanical parameters at 3 months, while secondary endpoints included changes in regional volumetric bone mineral density around the pedicle (P-vBMD) and vertebral body (V-vBMD). Results: Romosozumab treatment led to significant gains in P-vBMD, and V-vBMD compared to eldecalcitol at 3 months. Notably, the romosozumab group showed greater improvements in all biomechanical parameters estimated by FEM at 3 months compared to the eldecalcitol group. Conclusion: Romosozumab significantly increased the regional vBMD as well as biomechanical parameters, potentially offering clinical benefits in reducing post-operative complications in patients with osteoporosis undergoing orthopedic instrumentation surgery. This study highlights the novel advantages of romosozumab treatment and advocates further research on its effectiveness in perioperative management.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"21 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135041677","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}

{"title":"Mutation in CDC42 gene set as a response biomarker for immune checkpoint inhibitor therapy","authors":"Kun Wang, Yingying Zhang, Zhaoming Su, Bei Wang, Yuanyang Zhou, Xiaochu Tong, Chengying Xie, Xiaomin Luo, Sulin Zhang, Mingyue Zheng","doi":"10.1101/2023.11.10.23298355","DOIUrl":"https://doi.org/10.1101/2023.11.10.23298355","url":null,"abstract":"Background Immunotherapy has proven notably effective in treating tumors across diverse patient populations. However, some patients do not respond to immune checkpoint inhibitors (ICIs). Thus, there is a need for reliable biomarkers that can predict clinical responses to ICI treatment accurately. Methods Our focus is on CDC42, a protein that stimulates multiple signaling pathways, promoting tumor growth. We hypothesize that its defective function may indicate a patient's response to ICI therapy. We consider CDC42, along with its downstream binding and effector proteins, as a gene set. This is because their mutation could result in defective CDC42 function. We investigated the mutations in the CDC42 gene set as a potential biomarker for clinical benefits from ICI treatment. We also examined whether the combined use of a CDC42 inhibitor and ICI could enhance the efficacy of ICI. Results The presence of mutations in the CDC42 gene set correlated with improved overall survival (OS: p = 2.9E-4) and progression-free survival (PFS: p = 2.92E-6). Furthermore, our analysis of immune response landscapes among different CDC42 gene set statuses supports its potential as a biomarker for ICI therapy. Animal experiments also revealed that combining the CDC42 inhibitor (ML141) with anti-PD-1 blockade can synergistically reduce tumor growth. Conclusions Our study suggests that the CDC42 gene set could serve as a novel biomarker for the clinical response to ICI treatment. This finding also provides insight into the potential of combining ICI and CDC42 inhibitor use.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"8 9","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135042494","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}