Current Applications and Future Directions of Circulating Tumor Cells in Colorectal Cancer Recurrence.

The ability to predict or detect colorectal cancer (CRC) recurrence early after surgery enables physicians to apply appropriate treatment plans and different follow-up strategies to improve patient survival. Overall, 30-50% of CRC patients experience cancer recurrence after radical surgery, but current surveillance tools have limitations in the precise and early detection of cancer recurrence. Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor and enter the bloodstream. These can provide real-time information on disease status. CTCs might become novel markers for predicting CRC recurrence and, more importantly, for making decisions about additional adjuvant chemotherapy. In this review, the clinical application of CTCs as a therapeutic marker for stage II CRC is described. It then discusses the utility of CTCs for monitoring cancer recurrence in advanced rectal cancer patients who undergo neoadjuvant chemoradiotherapy. Finally, it discusses the roles of CTC subtypes and CTCs combined with clinicopathological factors in establishing a multimarker model for predicting CRC recurrence.

Short-term outcomes of short- and long-course chemoradiotherapy prior to total mesorectal excision for locally advanced rectal tumors: A single-center study in Taiwan utilizing propensity score matching.

BACKGROUND: Locally advanced rectal tumors are typically treated with neoadjuvant chemoradiotherapy. Short-course chemoradiotherapy (SCRT, 2,500 cGy in five fractions) is a convenient alternative to concurrent chemoradiotherapy with long-course radiotherapy (CCRT, 4,500 cGy in 25 fractions) without sacrificing efficacy. We aimed to compare the short-term outcomes of SCRT and CCRT in patients with mid- and low- rectal tumors who underwent total mesorectal excision using real-world data. METHODS: We retrospectively reviewed the data of patients with locally advanced rectal cancer who underwent radical resection after neoadjuvant chemoradiotherapy from 2011 to 2022. We analyzed the clinicopathological findings and prognostic factors for disease-free and overall survival in the SCRT and CCRT groups and compared the outcomes using propensity score matching. RESULTS: Among the 66 patients in the two groups, no disparities were noted in the demographic features, pathological remission, or downstaging rates. Nonetheless, the SCRT group exhibited superior 3-year disease-free survival (81.8% vs. 62.1%, p = 0.011), whereas the overall survival did not differ significantly between the two groups. The initial carcinoembryonic antigen (CEA) levels and neoadjuvant SCRT were associated with the recurrence rates [hazard ratio (HR) 1.13-4.10; HR 0.19-0.74], but the harvested lymph node count was not (HR 0.51-1.97). CONCLUSION: Among patients with locally advanced rectal cancer, SCRT combined with four cycles of FOLFOX was shown to enhance short-term disease-free survival. Factors impacting recurrence include the initial CEA level and SCRT, but not the harvested lymph node count.

Innovative Strategies Against Superbugs: Developing an AI-CDSS for Precise Stenotrophomonas maltophilia Treatment.

OBJECTIVES: The World Health Organization named Stenotrophomonas maltophilia a critical multi-drug resistant threat, necessitating rapid diagnostic strategies. Traditional culturing methods require up to 96 hours, including 72 hours for bacterial growth, identification with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) through protein profile analysis, and 24 hours for antibiotic susceptibility testing. In this study, we aimed at developing an artificial intelligence-clinical decision support system (AI-CDSS) by integrating MALDI-TOF MS and machine learning to quickly identify levofloxacin and trimethoprim/sulfamethoxazole resistance in S. maltophilia, optimizing treatment decisions. METHODS: We selected 8,662 S. maltophilia from 165,299 MALDI-TOF MS-analyzed bacterial specimens, collected from a major medical center and four secondary hospitals. We exported mass-to-charge values and intensity spectral profiles from MALDI-TOF MS .mzML files to predict antibiotic susceptibility testing results, obtained with the VITEK-2 system using machine learning algorithms. We optimized the models with GridSearchCV and 5-fold cross-validation. RESULTS: We identified distinct spectral differences between resistant and susceptible S. maltophilia strains, demonstrating crucial resistance features. The machine learning models, including random forest, light-gradient boosting machine, and XGBoost, exhibited high accuracy. We established an AI-CDSS to offer healthcare professionals swift, data-driven advice on antibiotic use. CONCLUSIONS: MALDI-TOF MS and machine learning integration into an AI-CDSS significantly improved rapid S. maltophilia resistance detection. This system reduced the identification time of resistant strains from 24 hours to minutes after MALDI-TOF MS identification, providing timely and data-driven guidance. Combining MALDI-TOF MS with machine learning could enhance clinical decision-making and improve S. maltophilia infection treatment outcomes.

Discovery of oral chemotherapeutic reversal agents for treating multidrug resistance cancer.

The major limitation of cancer treatment is multidrug resistance (MDR), which leads to the inactivation of chemotherapeutic drugs and greater than 90% mortality. To solve this ordeal, we applied ligand-based drug design and bioiosteric replacement strategy from an indazole to a pyrazole ring to discover compounds 27 and 43 with good potential for reversing drug resistance in combination with paclitaxel, and their reversal fold values were 53.2 and 51.0 at 5 µM, respectively, against an MDR cancer cell line (KBvin). Based on the PK profile results, we selected compound 43 with a longer half-life for mechanistic and animal experiments. Combination treatment with compound 43 and paclitaxel-induced apoptosis and enhanced subG1 by decreasing mitochondrial membrane potential in KBvin cells. In addition, 43 also inhibited P-gp function by interfering with ATPase activity. Meanwhile, cotreatment with compound 43 and paclitaxel significantly suppressed tumor growth (TGI = 55.5%) at a dose of 200 mg/kg (PO) in a xenograft model and showed no obvious liver or kidney toxicity by H&E staining. Overall, compound 43 may serve as a safe and effective oral resistance reversal chemotherapeutic agent.

The salvage lenvatinib-based regimen provides survival benefit in patients with refractory metastatic colorectal cancer.

Salvage treatment for refractory metastatic colorectal cancer (mCRC) has yet to be identified. We aimed to evaluate the efficacy of a salvage lenvatinib-based regimen for refractory mCRC. In total, 371 patients were categorized into lenvatinib-based and non-lenvatinib-based groups. In the lenvatinib-based group, patients who received lenvatinib at a dosage of 10 mg/day were categorized into lenvatinib/chemotherapy and lenvatinib/immunotherapy subgroups. We reported overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. OS1 was used to measure the time from disease progression after TAS-102 and regorafenib treatment to death, while OS2 was used to measure the time from TAS-102 or regorafenib treatment to death. Propensity score matching analysis was employed to compare the characteristics between the lenvatinib-based and non-lenvatinib-based groups. Next-generation sequencing (NGS) information was analyzed using R software. The lenvatinib-based group exhibited longer OS than did the non-lenvatinib-based group (OS1, 11.4 vs. 3.7 months; OS2, 27.2 vs. 8.2 months). The disease control rate (DCR) and objective response rate (ORR) of the lenvatinib-based regimens were 69.4% and 6.1%, respectively. Lenvatinib/chemotherapy and lenvatinib/immunotherapy had similar PFS, OS, DCR, and ORR. The adverse effects were manageable. After propensity score matching, the lenvatinib-based group continued to exhibit significantly longer OS1 and OS2 than did the non-lenvatinib-based group. NGS analysis revealed that GNAS and KRAS alterations were associated with a worse treatment response and prolonged survival, respectively. In conclusion, a moderate-dose salvage lenvatinib-based regimen demonstrated promising clinical activity and tolerability in treating refractory mCRC.

Investigation of metal concentration distribution and corresponding health exposure assessment of fabricated metal product manufacturers.

The fabricated metal product industries were identified as producers of variable and heterogeneous pollution. Workers in these manufacturing facilities are exposed to multiple pollutants present at variable concentrations. Specific known adverse health effects include bladder cancer associated with metalworking fluid exposure and lung cancer associated with electroplating processes. To reduce the incidence of these adverse effects, the main challenge is to identify the most hazardous pollutants within this complex exposure environment and evaluate the corresponding health potentials. In this study, exposure indices were formulated to assess multiple metal exposures with the ultimate goal of providing relevant information for exposure reduction and control measures. Fifteen plants, including metal mold manufacturing, metal casting, and surface treatment plants, were investigated in terms of total concentration, summation of corresponding ratio to threshold limit value (STLVr), hazard index (HI), and incremental cancer risk. The results revealed that emissions of aluminum, iron, and manganese were primarily found in the metal mold manufacturing/casting plants, while emissions of chromium, nickel, and zinc were found in surface treatment plants. STLVr and HI were more useful than the total concentration for identifying hazardous metals, which were chromium and nickel, and could specify the facilities that were in need of control measures. As for cancer risk, the metal mold manufacturing/casting plants had lower risk than the surface treatment plants, and the contributing metals for these two plant types were cobalt and chromium, respectively. This study established a useful procedure to evaluate health hazards and cancer risk. The resulting information is useful for prioritizing mitigation control of multiple metal exposures.

Integrating Genetic and Transcriptomic Data to Identify Genes Underlying Obesity Risk Loci.

Genome-wide association studies (GWAS) have identified numerous body mass index (BMI) loci. However, most underlying mechanisms from risk locus to BMI remain unknown. Leveraging omics data through integrative analyses could provide more comprehensive views of biological pathways on BMI. We analyzed genotype and blood gene expression data in up to 5,619 samples from the Framingham Heart Study (FHS). Using 3,992 single nucleotide polymorphisms (SNPs) at 97 BMI loci and 20,692 transcripts within 1 Mb, we performed separate association analyses of transcript with BMI and SNP with transcript (PBMI and PSNP, respectively) and then a correlated meta-analysis between the full summary data sets (PMETA). We identified transcripts that met Bonferroni-corrected significance for each omic, were more significant in the correlated meta-analysis than each omic, and were at least nominally associated with BMI in FHS data. Among 308 significant SNP-transcript-BMI associations, we identified seven genes (NT5C2, GSTM3, SNAPC3, SPNS1, TMEM245, YPEL3, and ZNF646) in five association regions. Using an independent sample of blood gene expression data, we validated results for SNAPC3 and YPEL3. We tested for generalization of these associations in hypothalamus, nucleus accumbens, and liver and observed significant (PMETA<0.05 & PMETA

The survival outcome differs between left-sided colon cancer and middle/low rectal cancer after colorectal hepatic metastasectomy.

BACKGROUND: The clinical outcomes between left-sided colon cancer and middle/low rectal cancer seem to be different. This study aimed to examine the effect of primary tumor location regarding the left-sided colon and middle/low rectum on the overall survival (OS) of patients who underwent colorectal hepatic metastasectomy. METHODS: Patients who underwent colorectal hepatic metastasectomy were retrospectively enrolled. Patients were classified into 2 groups according to the primary tumor location (left-sided colon and middle/low rectum). Categorical variables were compared using the chi-square test or Fisher exact test, and continuous variables were analyzed using the Student t test. Survival was analyzed using the Kaplan-Meier method and log-rank test. The prognostic factors were analyzed by univariate and multivariate analyses using Cox proportional hazards regression models. RESULTS: Overall, 365 patients were enrolled. Patients with left-sided colon cancer had significantly better OS than those with middle/low rectal cancer (hazard ratio [HR], 0.725; P = .018), with median OS estimates of 48 and 38 months, respectively. In the subgroup analysis of RAS mutations, patients with left-sided colon cancer had significantly prolonged OS compared with those with middle/low rectum cancer (HR, 0.608; P = .034), with median OS estimates of 49 and 26 months, respectively. This observation was limited to patients with RAS mutations. CONCLUSION: According to our findings, patients with middle/low rectal cancer had poorer survival outcome and should not be categorized together with patients with left-sided colon cancer in terms of OS after colorectal hepatic metastasectomy.

The alteration of fecal microbial and metabolic profile of gallstone patients in Taiwan: Single-center study.

BACKGROUND: Gallstone disease is a common health problem worldwide. The role of the gut microbiota in gallstone pathogenesis remains obscure. Our aim was to evaluate the association and crosstalk between gut microbiota, gut metabolomic, and metabolic parameters in cholesterol gallstone patients, pigmented gallstone patients, and controls. METHODS: We collected stool samples from healthy individuals and patients with gallstones in our hospital from March 2019 to February 2021. 16s rRNA sequencing was performed, followed by differential abundance analyses. Measurement of bile acids and short-chain fatty acids was conducted via targeted metabolomics. RESULT: Thirty healthy individuals and 20 gallstone patients were recruited. The intergroup difference of microbial composition was significant between control and gallstone patients. The control group had more abundant Faecalibacterium , Prevotella 9 , and Bacteroides plebeius DSM 17135 . The cholesterol stones group had higher Desulfovibrionaceae and Bacteroides uniformis than the other two groups, while the pigment stone group had more abundant Escherichia-Shigella . In the analysis of metabolites, only n-butyric acid had a significantly higher concentration in the controls than in the gallstone group ( p < 0.01). The level of 3α-hydroxy-12 ketolithocholic acid, deoxycholic acid, and cholic acid showed no intergroup differences but was correlated to the serum cholesterol level and bacterial richness and evenness. CONCLUSION: Our study revealed the key taxa that can discriminate between individuals with or without gallstones. We also identified metabolites that are possibly associated with metabolic parameter and bacterial diversity. However, the correlation of the metabolites to certain clusters of bacteria should be analyzed in a larger cohort.

A taxonomic revision of the genus Angelica (Apiaceae) in Taiwan with a new species A. aliensis.

BACKGROUND: Angelica L. sensu lato is a taxonomically complex genus, and many studies have utilized morphological and molecular features to resolve its classification issues. In Taiwan, there are six taxa within Angelica, and their taxonomic treatments have been a subject of controversy. In this study, we conducted a comprehensive analysis incorporating morphological and molecular (cpDNA and nrDNA) characteristics to revise the taxonomic treatments of Angelica in Taiwan. RESULTS: As a result of our research, we have revised the classification between A. dahurica var. formosana and A. pubescens and merged two varieties of A. morrisonicola into a single taxon. A new taxon, A. aliensis, has been identified and found to share a close relationship with A. tarokoensis. Based on the morphological and molecular characteristics data, it has been determined that the former three taxa should be grouped into the Eurasian Angelica clade, while the remaining four taxa should belong to the littoral Angelica clade. Furthermore, Angelica species in Taiwan distributed at higher altitudes displayed higher genetic diversity, implying that the central mountain range of Taiwan serves as a significant reservoir of plant biodiversity. Genetic drift, such as bottlenecks, has been identified as a potential factor leading to the fixation or reduction of genetic diversity of populations in most Angelica species. We provide key to taxa, synopsis, phenology, and distribution for each taxon of Taiwan. CONCLUSIONS: Our comprehensive analysis of morphological and molecular features has shed light on the taxonomic complexities within Angelica in Taiwan, resolving taxonomic issues and providing valuable insights into the phylogenetic relationships of Angelica in Taiwan.

Medial circumflex femoral artery perforator flap to reconstruct a complex rectovaginal fistula: A case report.

Reconstruction of complex rectovaginal fistula is challenging, and it has a high recurrence rate. Traditional reconstruction included a local flap or a myocutaneous flap reconstruction, which is either difficult in radiated cases or that the flap is too thick for flap inset and requires multiple times of revision. Here we report successful rectovaginal fistula repair using a pedicled medial circumflex femoral artery perforator flap (MCFAP). A retrospective chart review was done to collect the information of this 63-year-old female patient who had rectovaginal fistula (RVF) resulting from concurrent radiochemotherapy for cervical cancer. She received direct repair of the RVF, but it recurred. We applied a pedicle perforator flap to successfully repair the defect. The fistula was repaired by separating the posterior vaginal wall from the anterior rectal wall. The anterior wall of the rectum was primarily repaired, leaving a defect of 4 × 5 cm in the posterior vaginal wall. A pedicled MCFAP flap was harvested from her right medial thigh and transferred via a subcutaneous tunnel for reconstruction of the posterior vaginal wall defect. The postoperative course was uneventful. Postoperative gastrointestinal series showed no more RVF, and her colostomy was taken down one year after the reconstruction. This first experience suggests that a pedicle perforator flap can be used successfully for reconstruction of a rectovaginal fistula.

Genetic risk converges on regulatory networks mediating early type 2 diabetes.

Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet ß cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and ß cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3-5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by ß cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the ß cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by ß cells. RFX6 perturbation in primary human islet cells alters ß cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.

Development of a Genetically Engineered Mouse Model Recapitulating LKB1 and PTEN Deficiency in Gastric Cancer Pathogenesis.

The LKB1 and PTEN genes are critical in gastric cancer (G.C.) development. LKB1, a robust tumor suppressor gene, encodes a serine/threonine kinase that directly triggers the activation of AMPK-an integral cellular metabolic kinase. The role of the LKB1 pathway extends to maintaining the stability of epithelial junctions by regulating E-cadherin expression. Conversely, PTEN, a frequently mutated tumor suppressor gene in various human cancers, emerges as a pivotal negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. This study is set to leverage the H+/K+ ATPase Cre transgene strain to precisely target Cre recombinase expression at parietal cells within the stomach. This strategic maneuver seeks to selectively nullify the functions of both LKB1 and PTEN in a manner specific to the stomach, thereby instigating the development of G.C. in a fashion akin to human gastric adenocarcinoma. Moreover, this study endeavors to dissect the intricate ways in which these alterations contribute to the histopathologic advancement of gastric tumors, their potential for invasiveness and metastasis, their angiogenesis, and the evolving tumor stromal microenvironment. Our results show that conditional deletion of PTEN and LKB1 provides an ideal cancer microenvironment for G.C. tumorigenesis by promoting cancer cell proliferation, angiogenesis, and metastasis.

Design and synthesis of pyrazole derivatives against neutrophilic inflammation.

Neutrophils are the most abundant immune cells. However, neutrophil dysregulation leads to acute and chronic inflammation and is involved in various diseases. The aim of this study was to develop anti-inflammatory agents in human neutrophils. A drug screening was conducted on in-house compounds with the potential to inhibit the respiratory burst, which involves the generation of superoxide anions in human neutrophils. Bioisosteric replacement was then applied to design more active derivatives. The most potent inhibitors of superoxide anion generation activity were compounds 58 and 59, which had IC50 values of 13.30 and 9.06 nM, respectively. The inhibitory effects of 58 and 59 were reversed by H89, a PKA inhibitor. PDE selective screening indicated that the best inhibitory effects were PDE4B1 and PDE4D2, and the inhibitory activities were 83% and 85%, respectively, at a 10 µM concentration of 59. The final molecular simulation experiment highlighted the slightly different binding poses of 58 and 59 in the PDE4 active site. An in vivo pharmacokinetic study revealed that the half-life of 59 was approximately 79 min when using intravenous bolus administration. This work introduced a new class structure of PDE4 inhibitors resulting in potent neutrophil inactivation activity, with the aim of contributing to new anti-inflammatory drug discovery.

Novel (-)-arctigenin derivatives inhibit signal transducer and activator of transcription 3 phosphorylation and P-glycoprotein function resensitizing multidrug resistant cancer cells in vitro and in vivo.

Multidrug resistance (MDR) is considered one of the significant chemotherapy failures of cancer patients and resulting in tumor recurrence and refractory cancer. The collateral sensitivity phenomenon is suggested as a potential alternative therapy for coring multidrug resistance in cancer. To achieve better effects and reduce toxicity, a polypharmacology strategy was applied. Arctigenin has been reported as a signal transducer and activator of transcription 3 (STAT3) inhibitor as an anticancer drug with low toxicity. However, the effective dosage of arctigenin was too high for re-sensitization in MDR cell lines. Therefore, we have designed and synthesized arctigenin derivatives and have evaluated their chemoreversal effects in KBvin and KB cells. The results conveyed that compounds 9, 10, and 12 displayed significant collateral sensitivity effects on MDR cancer cells, and the corresponding calculated RF values were 32, 174, and 133, respectively. In addition, compounds 9, 10, and 12 were identified to influence the activation of STAT3 and the function of P-glycoprotein in KBvin cells. Combining the active compounds (9, 10, and 12) with paclitaxel significantly inhibits MDR tumor growth in a zebrafish xenograft tumor model without toxicity. Thus, this study provided novel effective arctigenin derivatives and is considered a potential co-treatment with paclitaxel for treating MDR tumors.

Detection of distant relatedness in biobanks for identification of undiagnosed carriers of a Mendelian disease variant: application to Long QT Syndrome.

Rare genetic diseases are typically studied in referral populations, resulting in underdiagnosis and biased assessment of penetrance and phenotype. To address this, we developed a generalizable method of genotype inference based on distant relatedness and deployed this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. We identified 9 LQT5 families referred to a single specialty clinic, each carrying p.Asp76Asn, the most common LQT5 variant. We uncovered recent common ancestry and a single shared haplotype among probands. Application to a non-referral population of 69,819 BioVU biobank subjects identified 22 additional subjects sharing this haplotype, subsequently confirmed to carry p.Asp76Asn. Referral and non-referral carriers had prolonged QTc compared to controls, and, among carriers, QTc polygenic score additively associated with QTc prolongation. Thus, our novel analysis of shared chromosomal segments identified undiagnosed cases of genetic disease and refined the understanding of LQT5 penetrance and phenotype.

In vitro and in silico cholinesterase inhibitory potential of metabolites from Laurencia snackeyi (Weber-van Bosse) M. Masuda.

Alzheimer's disease (AD) is a neurodegenerative disease that causes deterioration in intelligence and psychological activities. Yet, till today, no cure is available for AD. The marine environment is an important sink of bioactive compounds with neuroprotective potential with reduced adverse effects. Recently, we collected the red algae Laurencia snackeyi from Terumbu Island, Malaysia which is known to be rich in halogenated metabolites making it the most sought-after red algae for pharmaceutical studies. The red alga was identified based on basic morphological characteristics, microscopic observation and chemical data from literature. The purplish-brown algae was confirmed a new record. In Malaysia, this species is poorly documented in Peninsular Malaysia as compared to its eastern continent Borneo. Thus, this study intended to investigate the diversity of secondary metabolites present in the alga and its cholinesterase inhibiting potential for AD. The extract inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of  14.45 ± 0.34 µg mL-1 and 39.59 ± 0.24 µg mL-1, respectively. Subsequently, we isolated the synderanes, palisadin A (1), aplysistatin (2) and 5-acetoxypalisadin B (3) that was not exhibit potential. Mass spectrometry analysis detected at total of 33 additional metabolites. The computational aided molecular docking using the AChE and BChE receptors on all metabolites shortlisted 5,8,11,14-eicosatetraynoic acid (31) and 15-hydroxy-1-[2-(hydroxymethyl)-1-piperidinyl]prost-13-ene-1,9-dione (42) with best inhibitory properties, respectively with the lowest optimal combination of S-score and RMSD values. This study shows the unexplored potential of marine natural resources, however, obtaining sufficient biomass for detailed investigation is an uphill task. Regardless, there is a lot of potential for future prospects with a wide range of marine natural resources to study and the incorporation of synthetic chemistry, in vivo studies in experimental design. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03725-6.

Sex-specific associations between adipokine profiles and carotid-intima media thickness in the Cameron County Hispanic Cohort (CCHC).

BACKGROUND: Adipokines are hormones secreted from adipose tissue and are associated with cardiometabolic diseases (CMD). Functional differences between adipokines (leptin, adiponectin, and resistin) are known, but inconsistently reported associations with CMD and lack of studies in Hispanic populations are research gaps. We investigated the relationship between subclinical atherosclerosis and multiple adipokine measures. METHODS: Cross-sectional data from the Cameron County Hispanic Cohort (N = 624; mean age = 50; Female = 70.8%) were utilized to assess associations between adipokines [continuous measures of adiponectin, leptin, resistin, leptin-to-adiponectin ratio (LAR), and adiponectin-resistin index (ARI)] and early atherosclerosis [carotid-intima media thickness (cIMT)]. We adjusted for sex, age, body mass index (BMI), smoking status, cytokines, fasting blood glucose levels, blood pressure, lipid levels, and medication usage in the fully adjusted linear regression model. We conducted sexes-combined and sex-stratified analyses to account for sex-specificity and additionally tested whether stratification of participants by their metabolic status (metabolically elevated risk for CMD as defined by having two or more of the following conditions: hypertension, dyslipidemia, insulin resistance, and inflammation vs. not) influenced the relationship between adipokines and cIMT. RESULTS: In the fully adjusted analyses, adiponectin, leptin, and LAR displayed significant interaction by sex (p < 0.1). Male-specific associations were between cIMT and LAR [ß(SE) = 0.060 (0.016), p = 2.52 × 10-4], and female-specific associations were between cIMT and adiponectin [ß(SE) = 0.010 (0.005), p = 0.043] and ARI [ß(SE) = - 0.011 (0.005), p = 0.036]. When stratified by metabolic health status, the male-specific positive association between LAR and cIMT was more evident among the metabolically healthy group [ß(SE) = 0.127 (0.015), p = 4.70 × 10-10] (p for interaction by metabolic health < 0.1). However, the female-specific associations between adiponectin and cIMT and ARI and cIMT were observed only among the metabolically elevated risk group [ß(SE) = 0.014 (0.005), p = 0.012 for adiponectin; ß(SE) = - 0.015 (0.006), p = 0.013 for ARI; p for interaction by metabolic health < 0.1]. CONCLUSION: Associations between adipokines and cIMT were sex-specific, and metabolic health status influenced the relationships between adipokines and cIMT. These heterogeneities by sex and metabolic health affirm the complex relationships between adipokines and atherosclerosis.