The Maternal and Infant Environmental Health Riskscape study of perinatal disparities in greater Houston: rationale, study design and participant profiles.

Introduction: The Maternal and Infant Environmental Health Riskscape (MIEHR) Center was established to address the interplay among chemical and non-chemical stressors in the biological, physical, social, and built environments that disproportionately impact perinatal health among Black pregnant people in a large and diverse urban area with documented disparities in the U.S. Methods: The MIEHR cohort is recruiting non-Hispanic Black and non-Hispanic white pregnant people who deliver their infants at major obstetric hospitals in Houston, Texas. At enrollment, all participants are asked to provide urine samples for chemical [metals, cotinine, and polycyclic aromatic hydrocarbons (PAHs)] analyses and blood samples. A subset of the cohort is asked to provide oral and vaginal swabs, and fecal samples. Questionnaire and electronic health record data gather information about residential address history during pregnancy, pregnancy history and prenatal care, sociodemographic and lifestyle factors, experiences of discrimination and stress, and sources of social support. Using information on where a participant lived during their pregnancy, features of their neighborhood environment are characterized. We provide summaries of key individual- and neighborhood-level features of the entire cohort, as well as for Black and white participants separately. Results: Between April 2021 and February 2023, 1,244 pregnant people were recruited. Nearly all participants provided urine samples and slightly less than half provided blood samples. PAH exposure patterns as assessed on 47% of participants thus far showed varying levels depending on metabolite as compared to previous studies. Additionally, analyses suggest differences between Black and white pregnant people in experiences of discrimination, stress, and levels of social support, as well as in neighborhood characteristics. Discussion: Our findings to date highlight racial differences in experiences of discrimination, stress, and levels of support, as well as neighborhood characteristics. Recruitment of the cohort is ongoing and additional neighborhood metrics are being constructed. Biospecimens will be analyzed for metals and PAH metabolites (urine samples), miRNAs (plasma samples) and the microbiome (oral swabs). Once enrollment ends, formal assessments are planned to elucidate individual- and neighborhood-level features in the environmental riskscape that contribute to Black-White disparities in perinatal health.

Association of dietary fat intake and hepatocellular carcinoma among US adults.

BACKGROUND AND AIMS: The role of dietary fat consumption in the etiology of hepatocellular carcinoma (HCC) remains unclear. We investigated the associations of total fat and fatty acids with risk of HCC among US adults in a hospital-based case-control study. METHODS: We analyzed data from 641 cases and 1034 controls recruited at MD Anderson Cancer Center during 2001-2018. Cases were new patients with a pathologically or radiologically confirmed diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck. Cases and controls were frequency-matched by age and sex. Dietary intake was assessed using a validated food frequency questionnaire. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection. RESULTS: Monounsaturated fatty acid (MUFA) intake was inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.49; 95% CI, 0.33-0.72). Total polyunsaturated fatty acid (PUFA) intake was directly associated with HCC risk (highest vs. lowest tertile: OR, 1.82; 95% CI, 1.23-2.70). Omega-6 PUFA was directly associated with HCC risk (highest vs. lowest tertile: OR 2.29; 95% CI, 1.52-3.44). Long-chain omega-3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) intake was also inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.50; 95% CI, 0.33-0.70). No association was observed for saturated fat and HCC risk. CONCLUSION: Our findings support a direct association of omega-6 PUFA intake with HCC and an inverse association of MUFA and long-chain omega-3 PUFA intake with HCC.

Dietary Patterns and Hepatocellular Carcinoma Risk among US Adults.

The objective of this study was to assess the association between dietary patterns and risk of hepatocellular carcinoma (HCC) among US adults in a hospital-based case-control study. We analyzed data from 641 cases and 1002 controls recruited at The University of Texas MD Anderson Cancer Center during 2001-2018. Cases were patients with a pathologically or radiologically confirmed new diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck cancer. Cases and controls were frequency-matched by age and sex. Dietary patterns were identified by principal component analysis. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection. A vegetable-based dietary pattern was inversely associated with HCC risk (highest compared with lowest tertile: OR 0.66, 95% CI 0.46-0.94). A Western diet pattern was directly associated with HCC risk (highest compared with lowest tertile: OR 1.79, 95% CI 1.19-2.69). These findings emphasize the potential role of dietary intake in HCC prevention and clinical management.

Antiproliferative activity of cycloalkanecarboxamide derivatives possessing sulfonate or sulfamate moiety.

A series of cycloalkanecarboxamide-containing sulfonate and sulfamate derivatives were prepared, and their antiproliferative activity was tested against NCI-60 cancer cell lines panel. Compound 1f possessing cyclohexyl and p-(tert-butyl)benzenesulfonate moieties was the most active among all the target compounds. It exerted broad-spectrum anticancer activity against all the nine cancer types involved in the NCI-60 panel. Additionally, compound 1g containing cyclohexyl and p-fluorobenzenesulfonate moieties was the most potent against HT29 colon cancer cell line (IC50 = 4.73 µM) with selectivity index more than 4.23 towards HT29 than normal fibroblasts. It exerts its antiproliferative activity against HT29 through the induction of apoptosis (increasing caspase 3/7 activity) but not necrosis. Structure-activity relationship studies are presented in detail.

Prevalence and correlates of cell phone use among Texas drivers.

INTRODUCTION: Cell phone use while driving restricts peripheral awareness and impairs reaction time. This study assessed the 3-year prevalence of cell phone use (CPU) of drivers and characteristics associated with its use in six cities across Texas, 2011-2013. METHODS: CPU and driver characteristics were observed among motor vehicles (n = 1280) stopped at major intersections in medical and academic campuses. A multivariable logistic regression model described the association between driver characteristics and CPU. RESULTS: The overall prevalence of any CPU was 18.7%. Any type of CPU and talking tended to decline, while texting seemed to increase from 2011 to 2013. CPU was more likely among female drivers (OR = 1.63; 95% CI = 1.21, 2.20), drivers < 25 years of age (OR = 4.12; 95% CI = 2.29, 7.39), and drivers without passengers (OR = 4.40; 95% CI = 2.82, 6.88). CONCLUSION: Despite its dangers, CPU remains popular among Texas drivers. CPU and texting bans should target public health campaigns towards female and younger drivers.

Exploration of ring size in a series of cyclic vicinal diamines with σ1 receptor affinity.

Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl-N'-(4-alkoxybenzyl)piperazines were prepared to explore the effect of ring contraction and expansion on σ receptor affinity and subtype selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vicinal diamines possessed affinity and selectivity for σ(1) receptors. The imidazolidines possessed nanomolar σ(1) affinities (K(i)=6.45-53.5 nM), and relatively low levels of subtype selectivity (σ(2)/σ(1)=58-237). However, the piperazines and diazepanes achieved picomolar σ(1) interactions, with K(i) ranges of 0.05-10.28 and 0.10-0.194 nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimination over the σ(2) receptor, with σ(1) selectivities of 143-16140 and 220-11542, respectively.

Synthesis and in vivo evaluation of [18F]N-(2-benzofuranylmethyl)-N'-[4-(2-fluoroethoxy)benzyl]piperazine, a novel σ1 receptor PET imaging agent.

N-(2-Benzofuranylmethyl)-N'-[4-(2-fluoroethoxy)benzyl]piperazine (6, σ(1)K(i)=2.6 nM) was radiolabeled with fluorine-18 to provide a potential σ(1) receptor radioligand for use in positron emission tomography (PET). Radiofluorination of the appropriate tosylate precursor furnished [(18)F]6 with a specific activity of 45 GBq/µmol, in an average radiochemical yield of 18% and greater than 98% radiochemical purity. MicroPET imaging in Papio hamadryas baboon brain revealed [(18)F]6 uptake consistent with σ receptor distribution, and specificity for σ receptors was demonstrated in a haloperidol pre-treated animal. [(18)F]6 possesses suitable properties for PET imaging of σ(1) receptors, and further investigation of this σ(1) receptor tracer is warranted.

Effects of linker elongation in a series of N-(2-benzofuranylmethyl)-N'-(methoxyphenylalkyl)piperazine σ1 receptor ligands.

In our continued exploration of disubstituted piperazine derivatives as sigma (σ) receptor ligands with central nervous system (CNS) activity, a series of N-(2-benzofuranylmethyl)-N'-(methoxyphenylalkyl)piperazines (16-21 and 26-31) were synthesized, anticipating that these ligands would better suit the structural requirements of the current σ(1) pharmacophore. Affinities of these ligands for σ(1) and σ(2) receptors were investigated by means of radioligand binding assays, with the identification of N-(2-benzofuranylmethyl)-N'-[3-(4-methoxyphenyl)propyl]piperazine (29, K(i)=3.1 nM, σ(2)/σ(1)=45) as a selective σ(1) ligand. The σ(1) affinities and subtype selectivities of piperazines 16-21 and 26-31 were generally comparable to the corresponding benzylic analogs. Additionally, the affinities of 16-21 and 26-31 for the 5-HT(2B) receptor were much lower than the relatively nonselective methoxybenzylic analogs 2-4, indicating that elongation of the alkyl tether generally improved selectivity for σ(1) receptors.

Molecular hybridization of 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecane-3-ol with sigma (σ) receptor ligands modulates off-target activity and subtype selectivity.

A series of N-substituted 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols incorporating the respective arylalkyl subunits from several known sigma (σ) receptor ligands were synthesized and evaluated for their affinity against σ receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4-6) showed good selectivity for σ(1) and σ(2) receptors over multiple dopamine receptors. The molecular hybrid obtained from haloperidol and 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (4, σ(1)K(i)=27 nM, σ(2)K(i)=55 nM) showed reduced affinity for D(1)-D(5) dopamine receptors when compared to haloperidol itself. The compound with the greatest σ(1) affinity in the series, benzamide 4 (σ(1)K(i)=7.6 nM, σ(2)K(i)=225 nM) showed a complete reversal of the subtype selectivity displayed by the highly σ(2) selective parent benzamide, RHM-2 (3, σ(1)K(i)=10412 nM, σ(2)K(i)=13.3 nM).

Trishomocubane as a scaffold for the development of selective dopamine transporter (DAT) ligands.

In our continued exploration of trishomocubane derivatives with central nervous system (CNS) activity, N-arylalkyl-8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (10-13) displaying affinity for the sigma (σ) receptor were also found, in several cases, to interact with the dopamine transporter (DAT). Compound 12 was identified as the first trishomocubane-derived high affinity DAT ligand (K(i) = 1.2 nM), with greater than 8300-fold selectivity over the monoamine transporters NET and SERT, and only low to moderate affinity for σ(1) and σ(2) receptors.

Design, synthesis, and structure-affinity relationships of regioisomeric N-benzyl alkyl ether piperazine derivatives as sigma-1 receptor ligands.

A series of N-(benzofuran-2-ylmethyl)-N'-benzylpiperazines bearing alkyl or fluoroalkyl aryl ethers were synthesized and evaluated at various central nervous system receptors. Examination of in vitro sigma1 {[3H]+-pentazocine} and sigma2 ([3H]DTG) receptor binding profiles of piperazines 11-13 and 25-36 revealed several highly potent and sigma1 selective ligands, notably, N-(benzofuran-2-ylmethyl)-N'-(4'-methoxybenzyl)piperazine (13, Ki=2.7 nM, sigma2/sigma1=38) and N-(benzofuran-2-ylmethyl)-N'-(4'-(2''-fluoroethoxy)benzyl)piperazine (30, Ki=2.6 nM, sigma2/sigma1=187). Structural features for optimal sigma1 receptor affinity and selectivity over the sigma2 receptor were identified. On the basis of its favorable log D value, 13 was selected as a candidate for the development of a sigma1 receptor positron emission tomography radiotracer. [11C]13 showed high uptake in the brain and other sigma receptor-rich organs of a Papio hamadryas baboon. The in vivo evaluation of [11C]13 indicates that this radiotracer is a suitable candidate for imaging the sigma1 receptor in neurodegenerative processes.

Oxo-bridged isomers of aza-trishomocubane sigma (sigma) receptor ligands: Synthesis, in vitro binding, and molecular modeling.

Isomeric oxo-bridged analogs of aza-trishomocubane sigma (sigma) receptor ligands were synthesized and shown to display a reduced affinity for the sigma receptor. In the case of phenethyl derivative 4, there was a concomitant introduction of high-affinity for the alpha(2C) adrenergic receptor, and moderate affinity for the dopamine transporter. Molecular modeling was undertaken to rationalize these results.