Biological Underpinnings Research Articles

Advances in the management of higher-risk myelodysplastic syndromes: future prospects.

Higher-risk myelodysplastic syndromes (HR-MDS) are defined using a number of prognostic scoring systems that include the degree of cytopenias, percentage of blasts, cytogenetic alterations, and more recently genomic data. HR-MDS encompasses characteristics such as progressive cytopenias, increased bone marrow blasts, unfavorable cytogenetics, and an adverse mutational profile. Survival is generally poor, and patients require therapy to improve outcomes. Hypomethylating agents (HMAs), such as azacitidine, decitabine, and more recently, oral decitabine/cedazuridine, are the only approved therapies for HR-MDS. These are often continued until loss of response, progression, or unacceptable toxicity. Combinations including an HMA plus other drugs have been investigated but have not demonstrated better outcomes compared to single-agent HMA. Moreover, in a disease of high genomic complexity such as HR-MDS, therapy targeting specific genomic abnormalities is of interest. This review will examine the biological underpinnings of HR-MDS, its therapeutic landscape in the frontline and relapsed settings, as well as the impact of hematopoietic stem cell transplantation, the only known curative intervention for this disease.

Abstract PO4-14-05: Germline and acquired genetic variants and long-term cancer-related fatigue among survivors of early-stage breast cancer (BC)

Abstract BACKGROUND: Previous studies suggested that bio-behavioral models explain part of the variability of cancer-related fatigue, and pro-inflammatory and age-related processes emerged as contributors to persistent fatigue. However, the biological underpinnings of this complex symptom, including its relevant genomic correlates, are still poorly understood. We aimed to comprehensively explore the association of genetic variants with long-term cancer-related fatigue. METHODS: We used the prospective, multicenter, longitudinal CANcer TOxicity cohort, enrolling patients at diagnosis of stage I-III BC (NCT01993498). Outcomes included severe (≥40/100) global (EORTC QLQ-C30) as well as physical, emotional, and cognitive (FA12) fatigue at year (Y)1, Y2, and Y4 after BC diagnosis. Applying a hypothesis-driven approach, we investigated (i) germline genetic variants in a pre-specified Genetic Risk Index (GRI) assaying expression-regulating single nucleotide polymorphisms (SNPs) in the promoter regions of 3 pro-inflammatory cytokine genes (IL1B [rs16944], IL6 [rs1800795], and TNF [rs1800629]; Bower J, JCO 2013; N=9035), and (ii) age-related expansions of hematopoietic clones carrying recurrent acquired mutations, commonly defined as clonal hematopoiesis of indeterminate potential (CHIP; NGS with unique molecular identifiers for 17 genes [including DNMT3A, TET2, ASXL1, PPM1D, ATM, JAK2, and TP53]; N=1219). The contribution of GRI and CHIP to fatigue was assessed by multivariable logistic regression models. Taking an agnostic approach, we then performed a genome-wide association study (GWAS) of fatigue and 1,894,511 germline SNPs (Illumina InfiniumExome24/Illumina GSA24; N=9056). All genetic variants were assessed at BC diagnosis. Tested associations were adjusted by validated clinical predictors (Di Meglio A, JCO 2022). RESULTS: In the overall cohort (N=9056) mean age was 56.5 years (SD 11.2), 51.0% had stage II or III BC, 52.6% received chemotherapy, and 82.1% endocrine therapy. The prevalence of severe fatigue was 26.1% at diagnosis and increased to 36.5%, 34.3%, and 32.6% at Y1, Y2, and Y4 after diagnosis, respectively. Most patients (77.4%) had 3-6 high-frequency alleles across the 3 SNPs in the pro-inflammatory GRI. Among patients with available CHIP data, 15.2% and 3.7% had a Variant Allele Frequency (VAF) >2% and >10%, respectively. The pro-inflammatory GRI was not associated with fatigue outcomes. We found significant associations between CHIP and severe long-term global fatigue at Y4 (adjusted OR [95%CI]: VAF ≥2% vs < 2%, 1.64 [1.08-2.51], p=0.021; VAF ≥10% vs < 10%, 2.22 [1.00-4.94], p=0.050). The GWAS identified several regions (each including ≥2 SNPs) as associated with severe fatigue outcomes (suggestive p-value cut-off < 5 × 10−5; see Table for number of identified regions by outcome and respective nearby genes). Overlap in biological pathways was observed in some of the gene regions associated with global and physical fatigue, but not for emotional or cognitive fatigue. Common biological processes that were associated (FDR < 0.05) with such genes included synaptic transmission, hemoglobin-oxygen binding, and response to stress. CONCLUSIONS: This study provides suggestive association data between gene variants and long-term cancer-related fatigue. While previously reported associations with pro-inflammatory GRI were not confirmed, some biological processes that may inform the mechanistic understanding of this symptom emerged, including associations with aging and response to stress that warrant further exploration. ///: marks different regions. All association analyses were adjusted by age, body mass index, smoke behavior, pre-treatment fatigue, pain, insomnia, and anxiety, and by the first ten axes of principal component analysis of the genetic data to control for population stratification. There was no overlap in biological pathways for the gene regions associated with emotional or cognitive fatigue (gene regions not shown). Table. Genes in proximity of regions associated with severe fatigue outcomes Citation Format: Antonio Di Meglio, Emilie Thomas, Youenn Drouet, Jean-Baptiste Micol, Davide Soldato, Maria Alice Franzoi, Martina Pagliuca, Julie Havas, Anne-Laure Martin, Sibille Everhard, Celine Besse, Anne Boland, Christophe Marzac, Nathalie Droin, Sandrine Boyault, Marina Rousseau, Olivier Trédan, Paul Cottu, Christelle Jouannaud, Marion Fournier, Laurence Vanlemmens, Charles Coutant, Asma Dhaini Merimeche, Baptiste Sauterey, Florence Joly, Mario Campone, Florence Lerebours, Marie-Ange Mouret-Reynier, Olivier Rigal, Thierry Petit, Sophie Guillermet, Antoine Arnaud, Mahmoud Ibrahim, Sylvie Giacchetti, Florence Dalenc, Johanna Wassermann, Olivier Arsène, Ariane Darut-Jouve, Aurélie Bertaut, Fabrice André, Jean-Francois Deleuze, Alain Viari, Ines Vaz Luis. Germline and acquired genetic variants and long-term cancer-related fatigue among survivors of early-stage breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-05.

Quantitative proteomics of dorsolateral prefrontal cortex reveals an early pattern of synaptic dysmaturation in children with idiopathic autism.

Autism spectrum disorder (ASD) is a developmental disorder with a rising prevalence and unknown etiology presenting with deficits in cognition and abnormal behavior. We hypothesized that the investigation of the synaptic component of prefrontal cortex may provide proteomic signatures that may identify the biological underpinnings of cognitive deficits in childhood ASD. Subcellular fractions of synaptosomes from prefrontal cortices of age-, brain area-, and postmortem-interval-matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of data revealed the enrichment of ASD risk genes that participate in slow maturation of the postsynaptic density (PSD) structure and function during early brain development. Proteomic analysis revealed down regulation of PSD-related proteins including AMPA and NMDA receptors, GRM3, DLG4, olfactomedins, Shank1-3, Homer1, CaMK2α, NRXN1, NLGN2, Drebrin1, ARHGAP32, and Dock9 in children with autism (FDR-adjusted P < 0.05). In contrast, PSD-related alterations were less severe or unchanged in adult individuals with ASD. Network analyses revealed glutamate receptor abnormalities. Overall, the proteomic data support the concept that idiopathic autism is a synaptopathy involving PSD-related ASD risk genes. Interruption in evolutionarily conserved slow maturation of the PSD complex in prefrontal cortex may lead to the development of ASD in a susceptible individual.

Abstract PO1-09-01: Patient Advocates, Oncologists &amp; Research Scientists Collaborate to Address PostPartum Breast Cancer

Abstract The incidence of young women (YW=&amp;lt; 45) with aggressive breast cancer (BC) has been increasing and BC in younger women tends to be diagnosed in more advanced stages1. A group of advocates, oncologists and scientists have established an advocate-researcher dialogue to address this. A key finding we are highlighting and sharing with the community is that postpartum BC (PPBC) is a "free biomarker" for increased risk of metastatic disease. We report our efforts to understand the biologic underpinnings of PPBC, strategize to disseminate information, and accomplish our longterm goals to reduce BC incidence and mortality in YW. Interactions Between Childbirth &amp; BC The interactions between the reproductive life phases and BC are complex. We are taught that having children and nursing them is protective against BC. What is complicated is the fact that after childbirth, women overall are at a 10-30% increased risk for getting early onset BC. For women &amp;lt; 30 at the time of their last baby, this increased risk converts to a protective effect about 10 years after childbirth, such that in later life they have a lower risk of getting BC in comparison to women who have not given birth. However for women who have children after 30, the risk remains increased for many decades. The peak window of time for YW to get BC is within 10 years after childbirth and diagnoses during this window are PPBC. The global trend of women delaying childbirth until they are older is one factor contributing to increased PPBC2. While lactation can be protective, this protection is seen most robustly against triple negative BC (TNBC). This protective effect is seen most strongly in women who nurse for about 6 months. In some who do not nurse, especially black women, risk for TNBC can be increased3. When women get diagnosed with PPBC several things are known4: The frequency of the different subtypes of BC (ER+,PR+,Her2+) is similar to BC diagnosed in YW overall, so most PPBC is ER+ Her2- While there is no difference in the % of women who will have Her2+ or TNBC among PPBC cases, more women with PPBC will have + lymph nodes at diagnosis Of women who get diagnosed with BC &amp;lt; 45, about half will occur in this PP window accounting for about 50% of all early onset BC Studies have shown that PPBC has a higher tendency towards developing metastatic disease in comparison to BC in women without children or in women diagnosed more than 10 years since last childbirth4. Research is ongoing to identify why this increased risk is occurring and how treatment can be tailored to eliminate this risk. Adherence to therapy and participation in clinical trials is crucial. Clinical trials should capture when a woman had her last child as a routine datapoint so PPBC can be researched more broadly. This datapoint - age of her youngest child when she was diagnosed - is essentially a "free biomarker" indicating risk for metastasis. Advocate-Researcher Outreach Efforts Production of a podcast episode "Rising Rates of BC &amp; MBC in YW" on www.OurMBCLife.org produced by SHARE Cancer Support Discussion with other advocates and organizations to raise awareness Approach donors to increase funding for research in PPBC Summary BC in YW is increasing and YW with recent childbirth are at increased risk. Raising health awareness in a proactive, non-alarming manner is an important advocacy goal YW diagnosed within 10 years of a recent childbirth represent a unique subset of BC called PPBC Age of youngest child at time of diagnosis is an important free biomarker for risk and should be added to medical histories Increase funding is essential to determine why PPBC has different outcomes and how treatments can be tailored to ensure the wellness of our young mothers

Brain on Fire: How Brain Infection and Neuroinflammation Drive Worldwide Epilepsy Burden

Roughly 80% of the global burden of epilepsy resides in low- and middle-income countries (LMICs; WHO, 2022). Despite numerous new therapies for the treatment of epilepsy, the number of patients who remain resistant to available medications is unchanged. Additionally, no therapy has yet been clinically proven to prevent or attenuate the development of epilepsy in at-risk individuals. Unfortunately, access to next generation therapies in LMICs is low, the stigma associated with epilepsy remains high, and access to adequate resources is unchanged. Thus, the global epilepsy burden disproportionately falls on LMICs such that strategies to conscientiously integrate global epilepsy risk factors into preclinical research may meaningfully advance 21st century epilepsy therapies. Brain infections are one of the main risk factors for epilepsy in resource-poor settings. Further, both infection- and autoimmune-associated encephalitis contribute to worldwide epilepsy risk and remain relatively understudied. For example, clinical SARS CoV-2 infection can induce rare instances of encephalopathy and acute seizures. Among viruses known to cause acute brain infection, enteroviruses increase risk for encephalitis-induced epilepsy, but are not associated with risk for other neurodevelopmental disorders (eg, autism spectrum or attentional deficit hyperactivity disorders). Naturally occurring models of viral infection-induced epilepsy therefore provide an exquisite opportunity to uncover novel contributors to epileptogenesis. Moreover, the convergent neuroinflammatory pathways that are associated with viral infection-induced encephalitis and autoimmune encephalitis reflect an untapped therapeutic opportunity to meaningfully reduce the global burden of epilepsy. This review summarizes the latest advances in translational research integrating encephalitis-induced seizure and epilepsy models, in tandem with progress in clinical diagnosis of inflammation and virally mediated epilepsy. This improved awareness of the shared biological underpinnings of epileptogenesis following brain infection or autoimmune encephalitis is anticipated to beneficially impact the global burden of epilepsy.

Assessment of Left Lung Remodeling With Magnetic Resonance Imaging in a Murine Model Following Exposure to Douglas Fir Smoke.

Wildland firefighters (WLFFs) experience lung function decline due to occupational exposure to fire smoke. WLFFs typically do not wear respiratory personal protective equipment, and if they do, it is a simple bandana, which is not effective at filtering smoke. To pinpoint the biological underpinnings of abnormal respiratory function following 3-7 years of WLFF service, we exposed mice to Douglas fir smoke (DFS) over 8 weeks. Following exposure, we assessed changes in lung structure through Magnetic Resonance Imaging (MRI) and histological analysis, which was supported by immunohistochemistry staining. With MRI, we found that the signal decay time, T2*, from ultrashort echo time (UTE) images was significantly shorter in mice exposed to DFS compared to air controls. In addition, the variation in T2* was more heterogeneously distributed throughout the left lung in DFS-exposed mice, compared to air controls. As confirmed by histological analysis, shorter T2* was caused by larger parenchyma airspace sizes and not fibrotic remodeling. Destruction of the alveolar spaces was likely due to inflammation, as measured by an influx of CD68+ macrophages and destruction due to enhanced neutrophil elastase. In addition, measurements of airspace dimensions from histology were more heterogeneously distributed throughout the lung, corroborating the enhanced relative dispersion of T2*. Findings from this study suggest that the decline in lung function observed in WLFFs may be due to emphysema-like changes in the lung, which can be quantified with MRI.

Latest Insights and Therapeutic Advances in Myelodysplastic Neoplasms.

Myelodysplastic syndromes/neoplasms (MDSs) encompass a range of hematopoietic malignancies, commonly affecting elderly individuals. Molecular alterations in the hematopoietic stem cell compartment drive disease pathogenesis. Recent advancements in genomic profiling have provided valuable insights into the biological underpinnings of MDSs and have expanded therapeutic options, particularly for specific molecularly defined subgroups. This review highlights the diagnostic principles, classification updates, prognostic stratification systems, and novel treatments, which could inform future clinical trials and enhance the management of adult MDS patients, particularly for specific molecularly defined subgroups.

Stroma-infiltrating T cell spatiotypes define immunotherapy outcomes in adolescent and young adult patients with melanoma

The biological underpinnings of therapeutic resistance to immune checkpoint inhibitors (ICI) in adolescent and young adult (AYA) melanoma patients are incompletely understood. Here, we characterize the immunogenomic profile and spatial architecture of the tumor microenvironment (TME) in AYA (aged ≤ 30 years) and older adult (aged 31–84 years) patients with melanoma, to determine the AYA-specific features associated with ICI treatment outcomes. We identify two ICI-resistant spatiotypes in AYA patients with melanoma showing stroma-infiltrating lymphocytes (SILs) that are distinct from the adult TME. The SILhigh subtype was enriched in regulatory T cells in the peritumoral space and showed upregulated expression of immune checkpoint molecules, while the SILlow subtype showed a lack of immune activation. We establish a young immunosuppressive melanoma score that can predict ICI responsiveness in AYA patients and propose personalized therapeutic strategies for the ICI-resistant subgroups. These findings highlight the distinct immunogenomic profile of AYA patients, and individualized TME features in ICI-resistant AYA melanoma that require patient-specific treatment strategies.

Influences of amyloid-β and tau on white matter neurite alterations in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer’s disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-β with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-β, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-β exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB.

Plasma metabolomic markers underlying skeletal muscle mitochondrial function relationships with cognition and motor function.

Lower skeletal muscle mitochondrial function is associated with future cognitive impairment and mobility decline, but the biological underpinnings for these associations are unclear. We examined metabolomic markers underlying skeletal muscle mitochondrial function, cognition and motor function. We analysed data from 560 participants from the Baltimore Longitudinal Study of Aging (mean age: 68.4years, 56% women, 28% Black) who had data on skeletal muscle oxidative capacity (post-exercise recovery rate of phosphocreatine, kPCr) via 31P magnetic resonance spectroscopy and targeted plasma metabolomics using LASSO model. We then examined which kPCr-related markers were also associated with cognition and motor function in a larger sample (n = 918, mean age: 69.4, 55% women, 27% Black). The LASSO model revealed 24 metabolites significantly predicting kPCr, with the top 5 being asymmetric dimethylarginine, lactic acid, lysophosphatidylcholine a C18:1, indoleacetic acid and triacylglyceride (17:1_34:3), also significant in multivariable linear regression. The kPCr metabolite score was associated with cognitive or motor function, with 2.5-minute usual gait speed showing the strongest association (r = 0.182). Five lipids (lysophosphatidylcholine a C18:1, phosphatidylcholine ae C42:3, cholesteryl ester 18:1, sphingomyelin C26:0, octadecenoic acid) and 2 amino acids (leucine, cystine) were associated with both cognitive and motor function measures. Our findings add evidence to the hypothesis that mitochondrial function is implicated in the pathogenesis of cognitive and physical decline with aging and suggest that targeting specific metabolites may prevent cognitive and mobility decline through their effects on mitochondria. Future omics studies are warranted to confirm these findings and explore mechanisms underlying mitochondrial dysfunction in aging phenotypes.

Genetic associations between circulating immune cells and periodontitis highlight the prospect of systemic immunoregulation in periodontal care

Periodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of ‘predictive, preventive, and personalized’ periodontics. The present study incorporated genetic proxies identified through genome-wide association studies for circulating immune cells and periodontitis into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genes S100A9 and S100A12, located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to comprehend the biological underpinnings and ascertain the clinical relevance thoroughly.

Uric acid, high density lipoprotein cholesterol levels and their ratio are related to microbial enterotypes and serum metabolites in females with a blood stasis constitution

BackgroundBlood stasis constitution in traditional Chinese medicine (TCM) is believed to render individuals more susceptible to metabolic diseases. However, the biological underpinnings of this constitutional imbalance remain unclear.MethodsThis study explored the association between blood stasis constitution, serum metabolic markers including uric acid (UA), high-density lipoprotein cholesterol (HDLC), their ratio (UHR), serum metabolites, and gut microbiota. Clinical data, fecal and serum samples were acquired from 24 individuals with a blood stasis constitution and 80 individuals with a balanced constitution among healthy individuals from Guangdong. Gut microbiota composition analysis and serum metabolomics analysis were performed.ResultsFemales with a blood stasis constitution had higher UA levels, lower HDLC levels, and higher UHR in serum, suggesting a higher risk of metabolic abnormalities. Analysis of the gut microbiome revealed two distinct enterotypes dominated by Bacteroides or Prevotella. Intriguingly, blood stasis subjects were disproportionately clustered within the Bacteroides-rich enterotype. Metabolomic analysis identified subtle differences between the groups, including lower phenylalanine and higher trimethylaminoacetone levels in the blood stasis. Several differential metabolites displayed correlations with HDLC, UA, or UHR, unveiling potential new markers of metabolic dysregulation.ConclusionsThese findings elucidate the intricate interplay between host constitution, gut microbiota, and serum metabolites. The concept of blood stasis offers a unique perspective to identify subtle alterations in microbiome composition and metabolic pathways, potentially signaling underlying metabolic vulnerability, even in the presence of ostensibly healthy profiles. Continued investigation of this TCM principle may reveal critical insights into the early biological processes that foreshadow metabolic deterioration.

Genetic associations between circulating immune cells and periodontitis highlight the prospect of systemic immunoregulation in periodontal care.

Periodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of 'predictive, preventive, and personalized' periodontics. The present study incorporated genetic proxies identified through genome-wide association studies for circulating immune cells and periodontitis into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genes S100A9 and S100A12, located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to comprehend the biological underpinnings and ascertain the clinical relevance thoroughly.

Gray matter volume associations in youth with ADHD features of inattention and hyperactivity/impulsivity.

Prior research has shown smaller cortical and subcortical gray matter volumes among individuals with attention-deficit/hyperactivity disorder (ADHD). However, neuroimaging studies often do not differentiate between inattention and hyperactivity/impulsivity, which are distinct core features of ADHD. The present study uses an approach to disentangle overlapping variance to examine the neurostructural heterogeneity of inattention and hyperactivity/impulsivity dimensions. We analyzed data from 10,692 9- to 10-year-old children from the Adolescent Brain Cognitive Development (ABCD) Study. Confirmatory factor analysis was used to derive factors representing inattentive and hyperactive/impulsive traits. We employed structural equation modeling to examine these factors' associations with gray matter volume while controlling for the shared variance between factors. Greater endorsement of inattentive traits was associated with smaller bilateral caudal anterior cingulate and left parahippocampal volumes. Greater endorsement of hyperactivity/impulsivity traits was associated with smaller bilateral caudate and left parahippocampal volumes. The results were similar when accounting for socioeconomic status, medication, and in-scanner motion. The magnitude of these findings increased when accounting for overall volume and intracranial volume, supporting a focal effect in our results. Inattentive and hyperactivity/impulsivity traits show common volume deficits in regions associated with visuospatial processing and memory while at the same time showing dissociable differences, with inattention showing differences in areas associated with attention and emotion regulation and hyperactivity/impulsivity associated with volume differences in motor activity regions. Uncovering such biological underpinnings within the broader disorder of ADHD allows us to refine our understanding of ADHD presentations.

Diffusion time-related structure-function coupling reveals differential association with inter-individual variations in body mass index

Body mass index (BMI) is an indicator of obesity, and recent neuroimaging studies have demonstrated that inter-individual variations in BMI are associated with altered brain structure and function. However, the mechanism underlying the alteration of structure-function correspondence according to BMI is under-investigated. In this study, we studied structural and functional connectivity derived from diffusion MRI tractography and inter-regional correlations of functional MRI time series, respectively. We combined the structural and functional connectivity information using the Riemannian optimization approach. First, the low-dimensional principal eigenvectors (i.e., gradients) of the structural connectivity were generated by applying diffusion map embedding with varying diffusion times. A transformation was identified so that the structural and functional embeddings share the same coordinate system, and subsequently, the functional connectivity matrix was simulated. Then, we generated gradients from the simulated functional connectivity matrix. We found the most apparent cortical hierarchical organization differentiating between low-level sensory and higher-order transmodal regions in the middle of the diffusion time, indicating that the hierarchical organization of the brain may reflect the intermediate mechanisms of mono- and polysynaptic communications. Associations between the functional gradients and BMI were strongest when the hierarchical structure was the most evident. Moreover, the gradient-BMI association map was related to the microstructural features, and the findings indicated that the BMI-related structure-function coupling was significantly associated with brain microstructure, particularly in higher-order transmodal areas. Finally, transcriptomic association analysis revealed the potential biological underpinnings specifying gene enrichment in the striatum, hypothalamus, and cortical cells. Our findings provide evidence that structure-function correspondence is strongly coupled with BMI when hierarchical organization is the most apparent and that the associations are related to the multiscale properties of the brain, leading to an advanced understanding of the neural mechanisms related to BMI.

Abstract 1846: Integrative histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic characterization of renal cell carcinoma

Abstract Although histologically defined subtypes exist, renal cell carcinoma (RCC) is a heterogenous disease, resulting in various treatment outcomes and prognosis. Here, we conduct comprehensive profiling of RCC with histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic analyses on tumor and paired adjacent normal tissues from 113 patients. RCC tumors are distinctly separated from corresponding normal tissues through multi-omics clustering, a distinction further supported by pathway analysis. In addition, various hallmarks of cancer were differentially observed at the individual patient level, highlighting the intertumoral heterogeneity of RCC. Proteomic subtyping classifies RCC tumors into four subtypes (C1-4) with distinct phosphoproteomic, genomic, and transcriptomic characteristics with prognostic and predictive implications. Among these subtypes, C1-3 were almost composed of clear cell RCC (ccRCC; 96.8%), whereas C4 was composed of non-clear cell RCC (nccRCC) or other types of cancer (100.0%). Among each subtype, C1 (N=37) exhibits the strongest adaptive immune response and angiogenesis with favorable prognosis after surgical resection. C2 (N=39) was characterized with enrichment in DNA repair pathways and alteration in VHL (100.0%) along with BAP1 (24.0%) genes. C3 (N=19) was associated with enrichment in inflammatory response with dismal prognosis and therapeutic resistance to tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors. C4 (N=18) was exclusively enriched with nccRCC with active mitochondrial and oxidation phosphorylation. Transglutaminase 2 (TGM2), a crosslinking enzyme, is identified as a potential marker with therapeutic implication for ccRCC. Collectively, this study reports a large-scale multi-omics-based approach of RCC, providing insights into biologic underpinning and evidence for rational treatment selection as well as linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Citation Format: Woo Sun Kwon, Chang Gon Kim, Harim Koo, Woo Kyun Bae, Eu Chang Hwang, Won Sik Ham, Nam Hoon Cho, Jason K. Sa, Jong Bae Park, Sun Young Rha. Integrative histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic characterization of renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1846.

Abstract 751: Gut microbiome and breast cancer: Report from a case-control study in Vietnam

Abstract The importance of gut microbiome on human health is being increasingly recognized. The gut microbiota may play a critical role in breast cancer etiology, likely through the roles of the gut microbiota in estrogen and nutrient metabolism as well as in immune regulation. However, evidence on associations between breast cancer and gut microbiota is limited and inconsistent. Using resources from the Vietnamese Breast Cancer Case-Control Study (VBCS), we evaluated differences in gut microbiome profiles between women with breast cancer and healthy women. Pre-treatment tool samples of 162 incident breast cancer cases (age: 50.0±9.5) and stool samples of 370 age-matched controls (age: 49.7±9.0) were included in the study. The gut microbiome was measured using shotgun metagenomic sequencing. Differences in gut microbiome α-diversity and β-diversity between breast cancer patients and healthy controls were evaluated via linear regression models and PERMANOVA testing, respectively. Case-control differences in gut microbial taxa abundance were assessed through the differential abundance analysis with adjustment for potential confounders, including age, income levels, residence, menopausal status, reproductive factors, body mass index, comorbidity, dietary intake, and physical activity. An association with a false discovery rate (FDR) &amp;lt;0.1 was considered statistically significant. No significant difference between breast cancer patients and healthy controls was observed for α- and β-diversities. A total of 2,905 gut microbial taxa were evaluated. Among them, significant case-control differences were found in the abundance of one phylum, two classes, four orders, three families, four gena, and 67 species (all p&amp;lt;0.05 and FDR &amp;lt;0.1). Compared to healthy controls, breast cancer patients had a decreased abundance of species Pauljensenia keddieii, Bifidobacterium bifidum (phylum Actinobacteriota), Clostridium Q symbiosum, Faecalicatena fissicatena, Massilioclostridium methylpentosum, Parvimonas micra (phylum Firmicutes A), Leptotrichia wadei (phylum Fusobacteriota), Enterococcus D gallinarum, Lactobacillus H fermentum, Gemella haemolysans B, genus Streptococcus and its 24 species such as S. anginosus C, S. constellatus, S. equinus, S. infantis I, S. mitis, S. oralis, S. pseudopneumoniae O (phylum Firmicutes) (all p&amp;lt;0.05 and FDR &amp;lt;0.1). The species Clostridium Q symbiosum showed the strongest association, with a log2 fold-change (SE) of -2.02 (0.45), p=7.35 × 10−6; FDR=0.006. Additionally, breast cancer patients had an increased abundance of three species belonging to the phylum Firmicutes A including MGYG-HGUT-03165, MGYG-HGUT-04111, and MGYG-HGUT-00903, compared to healthy controls (p&amp;lt;0.05 and FDR &amp;lt;0.1). These results suggest that the gut microbiome of breast cancer differs from that of control women. Additional analyses are ongoing to reveal the biological underpinning of the observed associations. Citation Format: Sang Minh Nguyen, Huong T. Tran, Jirong Long, Martha J. Shrubsole, Hui Cai, Yaohua Yang, Thuan V. Tran, Wei Zheng, Xiao-Ou Shu. Gut microbiome and breast cancer: Report from a case-control study in Vietnam [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 751.

MYB alternative promoter activity is increased in adenoid cystic carcinoma metastases and is associated with a specific gene expression signature

ObjectiveAdenoid cystic carcinoma (ACC) is a head and neck cancer with a poor long-term prognosis that shows frequent local recurrences and distant metastases. The tumors are characterized by MYB oncogene activation and are notoriously unresponsive to systemic therapies. The biological underpinnings behind therapy resistance of disseminated ACC are largely unknown. Here, we have studied the molecular and clinical significance of MYB alternative promoter (TSS2) usage in ACC metastases. Materials and methodsMYB TSS2 activity was investigated in primary tumors and metastases from 26 ACC patients using RNA-sequencing and quantitative real-time PCR analysis. Differences in global gene expression between MYB TSS2 high and low cases were studied, and pathway analyses were performed. ResultsMYB TSS2 activity was significantly higher in ACC metastases than in primary tumors (median activity 15.1 vs 3.0, P = 0.0003). MYB TSS2 high ACC metastases showed a specific gene expression signature, including increased expression of multi-drug resistance genes and canonical MYB target genes, and suppression of the p53 and NOTCH pathways. ConclusionsCollectively, our findings indicate that elevated MYB TSS2 activity is associated with metastases, potential drug resistance, and augmented MYB-driven gene expression in ACC. Our study advocates the need for new therapies that specifically target MYB and drug resistance mechanisms in disseminated ACC.

Group differences in OXT methylation between patients with Major Depressive Disorder and healthy controls: A pre-registered replication study

Depression is linked to stress which leaves traces in the epigenetic signature of genes. The oxytocin system is implicated in allostatic processes promoting adaption to environmental stressors. Interactions of the oxytocin system with the environment, e.g., methylation of the gene coding for oxytocin (OXT), are candidates for the investigation of the biological underpinnings of depression. Recently, we found hypomethylation of OXT in patients with Major Depressive Disorder (MDD) compared to healthy controls (HC). Since the replicability of findings is a key point of criticism in (epi‑)genetic research, we aimed to confirm our previous findings in a pre-registered study (data was stored in a database prior to pre-registration) within a new sample of n = 85 patients with MDD and n = 85 HC. We investigated OXT DNA-methylation in peripheral blood samples, stressful life events and depression severity. In accordance with our previous study, we found hypomethylation of OXT in patients with MDD compared to HC. Methylation was not associated with stressful life events. Patients reported significantly more stressful life events compared to HC. Our study revealed that hypomethylation of OXT can be demonstrated in a reproducible fashion and provides further evidence for the involvement of the oxytocin system in depression.

Phosphoproteomic analysis of APP/PS1 mice of Alzheimer's disease by DIA based mass spectrometry analysis with PRM verification

Traditional Chinese medicine has been utilized in China for approximately thousands of years in clinical settings to prevent Alzheimer's disease (AD) and enhance memory, despite the lack of a systematic exploration of its biological underpinnings. Exciting research has corroborated the beneficial effects of tetrahydroxy stilbene glycoside (TSG), an extract derived from Polygonum multiflorum, in delaying learning and memory impairment in a model that mimics AD. Therefore, the primary objective of this study is to investigate the major function of TSG upon protein regulation in AD. Herein, a novel approach, encompassing data independent acquisition (DIA), DIA phosphorylated proteomics, and parallel reaction monitoring (PRM), was utilized to integrate quantitative proteomic data collected from APP/PS1 mouse model exhibiting toxic intracellular aggregation of Aβ. Initially, we deliberated upon both single and multi-dimensional data pertaining to AD model mice. Furthermore, we authenticated disparities in protein phosphorylation quantity and expression, phosphorylation function, and ultimately phosphorylation kinase analysis. In order to validate the results, we utilized PRM ion monitoring technology to identify potential protein or peptide biomarkers. In the mixed samples, targeted detection of 50 target proteins revealed that 26 to 33 target proteins were stably detected by PRM. In summary, our findings provide new candidates for AD biomarker, which have been identified and validated through protein researches conducted on mouse brains. This offers a wealth of potential resources for extensive biomarker validation in neurodegenerative diseases. SignificanceDIA phosphorylated proteomics technique was used to detect and analyze phosphorylated proteins in brain tissues of mice with AD. Data were analyzed by various bioinformatics tools to explore the phosphorylation events and characterize them related to TSG. The results of DIA were further verified by PRM. Besides, we mapped the major metabolite classes emerging from the analyses to key biological pathways implicated in AD to understand the potential roles of the molecules and the interactions in triggering symptom onset and progression of AD. Meanwhile, we clarified that in the context of AD onset and TSG intervention, the changes in proteins, protein phosphorylation, phosphorylation kinases, and the internal connections.