tbuckley/cabot-search huggingface dataset:
Outcomes in Nonmetastatic Hormone Receptor–Positive HER2-Negative Pure Mucinous Breast Cancer: A Multicenter Cohort Study
Authors: Ryan Ying Cong Tan, Whee Sze Ong, Kyung-Hun Lee, Seri Park, Jabed Iqbal, Yeon Hee Park, Jeong Eon Lee, Jong Han Yu, Ching-Hung Lin, Yen-Shen Lu, Makiko Ono, Takayuki Ueno, Yoichi Naito, Tatsuya Onishi, Geok-Hoon Lim, Su-Ming Tan, Han-Byoel Lee, Jiwon Koh, Wonshik Han, Seock-Ah Im, Veronique Kiak Mien Tan, Nitar Phyu, Fuh-Yong Wong, Puay Hoon Tan, Yoon-Sim Yap
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties. Methods: Individual patient-level data from 6 centers on stage I–III hormone receptor–positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC. Results: Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43–0.80), RFS (HR, 0.70; 95% CI, 0.56–0.89), and OS (HR, 0.71; 95% CI, 0.53–0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non–breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08–5.40), radiotherapy (HR, 0.44; 95% CI, 0.23–0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09–0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups. Conclusions: Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.
Molecular subgroups of T-cell acute lymphoblastic leukemia in adults treated according to pediatric-based GMALL protocols
Authors: Martin Neumann, Thomas Beder, Lorenz Bastian, Sonja Hänzelmann, Miriam Bultmann, Nadine Wolgast, Alina Hartmann, Heiko Trautmann, Jutta Ortiz-Tanchez, Cornelia Schlee, Michael Schroeder, Lars Fransecky, Sebastian Vosberg, Walter Fiedler, Nael Alakel, Lisa Heberling, Mustafa Kondakci, Michael Starck, Stefan Schwartz, Simon Raffel, Carsten Müller-Tidow, Folker Schneller, Albrecht Reichle, Thomas Burmeister, Philipp A. Greif, Monika Brüggemann, Nicola Gökbuget, Claudia D. Baldus
Journal: Leukemia (2024)

Abstract In contrast to B-cell precursor acute lymphoblastic leukemia (ALL), molecular subgroups are less well defined in T-lineage ALL. Comprehensive studies on molecular T-ALL subgroups have been predominantly performed in pediatric ALL patients. Currently, molecular characteristics are rarely considered for risk stratification. Herein, we present a homogenously treated cohort of 230 adult T-ALL patients characterized on transcriptome, and partly on DNA methylation and gene mutation level in correlation with clinical outcome. We identified nine molecular subgroups based on aberrant oncogene expression correlating to four distinct DNA methylation patterns. The subgroup distribution differed from reported pediatric T-ALL cohorts with higher frequencies of prognostic unfavorable subgroups like HOXA or LYL1/LMO2. A small subset (3%) of HOXA adult T-ALL patients revealed restricted expression of posterior HOX genes with aberrant activation of lncRNA HOTTIP. With respect to outcome, TLX1 ( n = 44) and NKX2-1 ( n = 4) had an exceptionally favorable 3-year overall survival (3y-OS) of 94%. Within thymic T-ALL, the non TLX1 patients had an inferior but still good prognosis. To our knowledge this is the largest cohort of adult T-ALL patients characterized by transcriptome sequencing with meaningful clinical follow-up. Risk classification based on molecular subgroups might emerge and contribute to improvements in outcome.
Critical role of the gut microbiota in immune responses and cancer immunotherapy
Authors: Zehua Li, Weixi Xiong, Zhu Liang, Jinyu Wang, Ziyi Zeng, Damian Kołat, Xi Li, Dong Zhou, Xuewen Xu, Linyong Zhao
Journal: Journal of Hematology & Oncology (2024)

The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.
Effect of Cangrelor on Infarct Size in ST-Segment–Elevation Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention: A Randomized Controlled Trial (The PITRI Trial)
Authors: Heerajnarain Bulluck, Jun Hua Chong, Jennifer Bryant, Annitha Annathurai, Ping Chai, Mervyn Chan, Ashish Chawla, Chee Yang Chin, Yiu-Cho Chung, Fei Gao, Hee Hwa Ho, Andrew Fu Wah Ho, John Hoe, Syed Saqib Imran, Chi-Hang Lee, Benji Lim, Soo Teik Lim, Swee Han Lim, Boon Wah Liew, Patrick Lim Zhan Yun, Marcus Eng Hock Ong, Valeria Paradies, Xuan Ming Pung, Julian Cheong Kiat Tay, Lynette Teo, Boon Ping Ting, Aaron Wong, Evelyn Wong, Timothy Watson, Mark Y. Chan, Yeo Khung Keong, Jack W.C. Tan, Derek J. Hausenloy, Jack W.C. Tan, Derek J. Hausenloy, Chee-Tang Chi, Julian Tay, Pung Xuan Ming, Kamalesh Anbalakan, Keh Yann San, Kenneth Chew, Michelle Chan, Hong Rilong, Kui Swee Leng, Lim Soo Teik, Audry Lee, Felix Maverick Rubillar, James Cai, Jonathan Yap, Wong Ning Yan, Ho Kay Woon, Lim Fang Yi, Shen Xia Yen, Ruan Xucong, Yeo Khung Keong, Jun Hua Chong, Jennifer Bryant, Terrance Chua, Chee Yang Chin, Valeria Paradies, Aaron Wong, Leong Bahru, Tina Teo, Tan Ru San, Tang Hak Chiaw, Calvin Chin, Florence Ang, Min-Tun Kyaw, S. Priyalatha, Jia-Mei Chua, Deborah Yip, Rosalind Lee, Katherina Oh, Ho Pei Yi, Leow Wanshan, Syamimi Atiqa Binte Rahmat, Gan Yar Chze, Derek J. Hausenloy, Fei Gao, Shi Yan Tan, Mervyn Chan, Lateef Fatimah, Andrew Ho, Wee Choon Peng Jeffrey, Swee Han Lim, Marcus Ong Eng Hock, Evelyn Wong, Kenneth Tan Boon Kiat, Anantharaman Venkataraman, Mark Y. Chan, Chi-Hang Lee, Chai Ping, Low Fatt Hoe Adrian, Chan Koo Hui, Loh Poay Huan, Wang Yi-Ting Laureen, Chen Zhengfeng Jason, Mayank Dalakoti, Perryn Ng, Sia Ching Hui, Shaun Chook, Alfred Yip, Ng Zhe Yan, Andie Hartanto Djohan, Marie Houdmont, Nicholas Chew, Siew Jiamin, Faclin Ng, Lynette Teo, Ching Ching Ong, Junda Song, Choong Kuang Low, Nair Shalini, Joseph Francis Prabath, Hee-Hwa Ho, Tasha Mahadi, Timothy Watson, Paul Ong, Koo Xin Ni, Tony Chai Jun Hui, Ho Yue Ting, Khoo Zhi Lin Deanna, Deborah Lee Jin Hyun, Li Ki Fung Cliff, Randal Low Jun Bang, Tan Joo Hor, Ng Ke Xuan Jessica, Chua Jia Min, Ong Wei Sheng Jonathan, Teoh Xuyan, Chiang Shu Qi Benita, Eran Sim Wen Jun, Ang An Shing, Quek Jia-ling Stephanie, Pang Rui Yi, Bin Ahmad Hatib Muhammad Alimi, Lee Jin Hyun, Lim Shiane, Tan Chong Keat, Ng Shonda, John Hoe, Jack Tan, Chin Chee Yang, Fam Jian Ming, Siti Raudha, Annitha Annathurai, Boon Ping Ting, Ashish Chawla, Syed Saqib Imran, Patrick Lim Zhan Yun, Alvin Tan, Benji Lim, Boon Wah Liew, Yong Thon Hon
Journal: Circulation (2024)

The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarction (MI) size in the preclinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction in patients with ST-segment-elevation MI undergoing primary percutaneous coronary intervention.
The long noncoding RNA CARDINAL attenuates cardiac hypertrophy by modulating protein translation
Authors: Xin He, Tiqun Yang, Yao Wei Lu, Gengze Wu, Gang Dai, Qing Ma, Mingming Zhang, Huimin Zhou, Tianxin Long, Youchen Yan, Zhuomin Liang, Chen Liu, William T. Pu, Yugang Dong, Jingsong Ou, Hong Chen, John D. Mably, Jiangui He, Da-Zhi Wang, Zhan-Peng Huang
Journal: Journal of Clinical Investigation (2024)

One of the features of pathological cardiac hypertrophy is enhanced translation and protein synthesis. Translational inhibition has been shown to be an effective means of treating cardiac hypertrophy, although system-wide side effects are common. Regulators of translation, such as cardiac-specific long non-coding RNAs (lncRNAs), could provide new, more targeted, therapeutic approaches to inhibit cardiac hypertrophy. Therefore, we generated mice lacking a previously identified lncRNA named CARDINAL to examine its cardiac function. We demonstrate that CARDINAL is a cardiac-specific, ribosome associated lncRNA and show that its expression is induced in the heart upon pathological cardiac hypertrophy; its deletion in mice exacerbates stress-induced cardiac hypertrophy and augments protein translation. In contrast, overexpression of CARDINAL attenuates cardiac hypertrophy in vivo and in vitro, and suppresses hypertrophy-induced protein translation. Mechanistically, CARDINAL interacts with developmentally regulated GTP binding protein 1 (DRG1) and blocks its interaction with DRG family regulatory protein 1 (DFRP1); as a result, DRG1 is downregulated, thereby modulating the rate of protein translation in the heart in response to stress. This study provides evidence for the therapeutic potential of targeting cardiac-specific lncRNAs to suppress disease-induced translational changes and to treat cardiac hypertrophy and heart failure.
l-2-Hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models
Authors: Anirban Kundu, Garrett J Brinkley, Hyeyoung Nam, Suman Karki, Richard Kirkman, Madhuparna Pandit, EunHee Shim, Hayley Widden, Juan Liu, Yasaman Heidarian, Nader H Mahmoudzadeh, Alexander J Fitt, Devin Absher, Han-Fei Ding, David K Crossman, William J Placzek, Jason W Locasale, Dinesh Rakheja, Jonathan E McConathy, Rekha Ramachandran, Sejong Bae, Jason M Tennessen, Sunil Sudarshan
Journal: Journal of Clinical Investigation (2024)

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule L-2-hdroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similar to other oncometabolites, L-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L-2HG remodels amino acid metabolism in renal cancer cells through the combined effects on histone methylation and RNA N6-methyladenosine (m6A). The combined effects of L-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high L-2HG kidney cancers demonstrates reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high L-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors.
Fibulin-2 is an extracellular matrix inhibitor of oligodendrocytes relevant to multiple sclerosis
Authors: Samira Ghorbani, Cenxiao Li, Brian M Lozinski, Dorsa Moezzi, Charlotte D'Mello, Yifei Dong, Frank Visser, Hongmin Li, Claudia Silva, Mohammadparsa Khakpour, Colin J Murray, Marie-Ève Tremblay, Mengzhou Xue, V Wee Yong
Journal: Journal of Clinical Investigation (2024)

Impairment of oligodendrocytes and myelin contributes to neurological disorders including multiple sclerosis (MS), stroke and Alzheimer's disease. Regeneration of myelin (remyelination) decreases the vulnerability of demyelinated axons, but this repair process commonly fails with disease progression. A contributor to inefficient remyelination is the altered extracellular matrix (ECM) in lesions that remains to be better defined. We have identified fibulin-2 (FBLN2) as a highly upregulated ECM component in lesions of MS and stroke, and in proteome databases of Alzheimer's disease and traumatic brain injury. Focusing on MS, the inhibitory role of FBLN2 was suggested in the experimental autoimmune encephalomyelitis (EAE) model in which genetic FBLN2 deficiency improved behavioral recovery by promoting the maturation of oligodendrocytes and enhancing remyelination. Mechanistically, when oligodendrocyte progenitors were cultured in differentiation media, FBLN2 impeded their maturation into oligodendrocytes by engaging the Notch pathway, leading to cell death. Adeno-associated virus-deletion of FBLN2 in astrocytes improved oligodendrocyte numbers and functional recovery in EAE and generated new myelin profiles after lysolecithin-induced demyelination. Collectively, our findings implicate FBLN2 as a hitherto unrecognized injury-elevated ECM, and a therapeutic target, that impairs oligodendrocyte maturation and myelin repair.
Global, regional, and national burden of heatwave-related mortality from 1990 to 2019: A three-stage modelling study
Authors: Qi Zhao, Shanshan Li, Tingting Ye, Yao Wu, Antonio Gasparrini, Shilu Tong, Aleš Urban, Ana Maria Vicedo-Cabrera, Aurelio Tobias, Ben Armstrong, Dominic Royé, Eric Lavigne, Francesca de’Donato, Francesco Sera, Haidong Kan, Joel Schwartz, Mathilde Pascal, Niilo Ryti, Patrick Goodman, Paulo Hilario Nascimento Saldiva, Michelle L. Bell, Yuming Guo
Journal: PLoS Medicine (2024)

Background The regional disparity of heatwave-related mortality over a long period has not been sufficiently assessed across the globe, impeding the localisation of adaptation planning and risk management towards climate change. We quantified the global mortality burden associated with heatwaves at a spatial resolution of 0.5°×0.5° and the temporal change from 1990 to 2019. Methods and findings We collected data on daily deaths and temperature from 750 locations of 43 countries or regions, and 5 meta-predictors in 0.5°×0.5° resolution across the world. Heatwaves were defined as location-specific daily mean temperature ≥95th percentiles of year-round temperature range with duration ≥2 days. We first estimated the location-specific heatwave-mortality association. Secondly, a multivariate meta-regression was fitted between location-specific associations and 5 meta-predictors, which was in the third stage used with grid cell-specific meta-predictors to predict grid cell-specific association. Heatwave-related excess deaths were calculated for each grid and aggregated. During 1990 to 2019, 0.94% (95% CI: 0.68–1.19) of deaths [i.e., 153,078 cases (95% eCI: 109,950–194,227)] per warm season were estimated to be from heatwaves, accounting for 236 (95% eCI: 170–300) deaths per 10 million residents. The ratio between heatwave-related excess deaths and all premature deaths per warm season remained relatively unchanged over the 30 years, while the number of heatwave-related excess deaths per 10 million residents per warm season declined by 7.2% per decade in comparison to the 30-year average. Locations with the highest heatwave-related death ratio and rate were in Southern and Eastern Europe or areas had polar and alpine climates, and/or their residents had high incomes. The temporal change of heatwave-related mortality burden showed geographic disparities, such that locations with tropical climate or low incomes were observed with the greatest decline. The main limitation of this study was the lack of data from certain regions, e.g., Arabian Peninsula and South Asia. Conclusions Heatwaves were associated with substantial mortality burden that varied spatiotemporally over the globe in the past 30 years. The findings indicate the potential benefit of governmental actions to enhance health sector adaptation and resilience, accounting for inequalities across communities.
The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development
Authors: Jing Du, Pan Liu, Yalu Zhou, Sol Misener, Isha Sharma, Phoebe Leeaw, Benjamin R Thomson, Jing Jin, Susan E Quaggin
Journal: Journal of Clinical Investigation (2024)

Lymphedema is a debilitating disease with no effective cure and affects an estimated 250 million individuals worldwide. Prior studies have identified mutations in piezo-type mechanosensitive ion channel component 1 (PIEZO1), angiopoietin 2 (ANGPT2), and tyrosine kinase with Ig-like and EGF-like domains 1 (TIE1) in patients with primary lymphedema. Here, we identified crosstalk between these molecules and showed that activation of the mechanosensory channel PIEZO1 in lymphatic endothelial cells (LECs) caused rapid exocytosis of the TIE ligand ANGPT2, ectodomain shedding of TIE1 by disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), and increased TIE/PI3K/AKT signaling, followed by nuclear export of the transcription factor FOXO1. These data establish a functional network between lymphedema-associated genes and provide what we believe to be the first molecular mechanism bridging channel function with vascular signaling and intracellular events culminating in transcriptional regulation of genes expressed in LECs. Our study provides insights into the regulation of lymphatic function and molecular pathways involved in human disease.
Mutational profiling of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder does not resemble nodal peripheral T-cell lymphomas with a follicular helper T-cell phenotype
Authors: Marta Rodríguez, Marcos Rebollo-González, Jesús Frutos Díaz-Alejo, Rebeca Manso, Francisco Javier Díaz de la Pinta, Juan Torre-Castro, Socorro María Rodríguez-Pinilla
Journal: British Journal of Dermatology (2024)

We performed targeted next-generation sequencing of 62 genes, previously described as being mutated in T-cell lymphomas, in 15 formalin-fixed paraffin-embedded samples from patients with primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder.
Treating epidermolytic ichthyosis and ichthyosis with confetti with epidermal autografts cultured from revertant skin
Authors: Kana Tanahashi, Michihiro Kono, Takenori Yoshikawa, Yuika Suzuki, Masukazu Inoie, Yachiyo Kuwatsuka, Fumie Kinoshita, Takuya Takeichi, Masashi Akiyama
Journal: British Journal of Dermatology (2024)

No efficient treatment has yet been established for epidermolytic ichthyosis (EI), which is caused by pathogenic variants of KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) have multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism.
Shear stress and pathophysiological PI3K involvement in vascular malformations
Authors: Salim Abdelilah-Seyfried, Roxana Ola
Journal: Journal of Clinical Investigation (2024)

Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding the catalytic α subunit of PI3Kα (PIK3CA). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA-related vascular anomalies, or "PIKopathies," range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA-related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low-perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA's role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA's role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.
Hypersensitive blood vessels in Clarkson disease
Authors: Emmanuel Nwadozi, Lena Claesson-Welsh
Journal: Journal of Clinical Investigation (2024)

Idiopathic systemic capillary leak syndrome (ISCLS) is a rare, recurrent condition with dramatically increased blood vessel permeability and, therefore, induction of systemic edema, which may lead to organ damage and death. In this issue of the JCI, Ablooglu et al. showed that ISCLS vessels were hypersensitive to agents known to increase vascular permeability, using human biopsies, cell culture, and mouse models. Several endothelium-specific proteins that regulate endothelial junctions were dysregulated and thereby compromised the vascular barrier. These findings suggest that endothelium-intrinsic dysregulation underlies hyperpermeability and implicate the cytoplasmic serine/threonine protein phosphatase 2A (PP2A) as a potential drug target for the treatment of ISCLS.
Pathophysiology of cerebral small vessel disease: a journey through recent discoveries
Authors: Nicolas Dupré, Antoine Drieu, Anne Joutel
Journal: Journal of Clinical Investigation (2024)

Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related small vessel pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, small deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% of ischemic strokes and the vast majority of spontaneous intracerebral hemorrhage and is also the most important vascular contributor to dementia. Despite its high prevalence and potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview of the recent advances in this field. We summarize recent data highlighting the remarkable continuum between monogenic and multifactorial cSVDs involving NOTCH3, HTRA1, and COL4A1/A2 genes. Taking a vessel-centric view, we discuss possible cause-and-effect relationships between risk factors, structural and functional vessel changes, and disease manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction is rightly considered a central feature of cSVD, the contributions of smooth muscle cells, pericytes, and other perivascular cells warrant continued investigation.