Virtual Pooled Registry-Cancer Linkage System: an improved method for ascertaining cancer diagnoses.

BACKGROUND: The National Cancer Institute funds many large cohort studies that rely on self-reported cancer data requiring medical record validation. This is labor intensive, costly, and prone to underreporting or misreporting of cancer and disparity-related differential response. US population-based central cancer registries identify incident cancer within their catchment area, yielding all malignant neoplasms and benign brain and central nervous system tumors with standardized data fields. This manuscript describes the development, implementation, and features of a system to facilitate linkage between cohort studies and cancer registries and the release of cancer registry data for matched cohort participants. METHODS: The Virtual Pooled Registry-Cancer Linkage System (VPR-CLS) provides an online system to link cohorts with multiple state cancer registries by 1) securely transmitting a study file to registries, 2) providing an optimized linkage algorithm to generate preliminary match counts, and 3) providing a streamlined process and templated forms for submitting and tracking data requests for cohort participants who matched with registries. RESULTS: In 2022, the VPR-CLS launched with 45 registries, covering 95% of the US state populations and Puerto Rico. Registries have linked with 15 studies having 14 273-10.9 million participants. Except in 1 study, linkage sensitivity ranged from 87.0% to 99.9%. Numerous registries have adopted the VPR-CLS templated institutional review board-registry application (n = 39), templated data use agreement (n = 25), and central institutional review board (n = 16). CONCLUSIONS: The VPR-CLS markedly improves ascertainment of cancer outcomes and is the preferred approach for determination of outcomes from cohort studies, postmarketing surveillance, and clinical trials.

Housing assistance among patients with cancer: SEER-Medicare US Department of Housing and Urban Development data linkage.

BACKGROUND: Lack of stable, affordable housing is an important social determinant of health. Federal housing assistance may buffer against housing vulnerabilities among low-income households, but research examining the association of housing assistance and cancer care has been limited. We introduce a new linkage of Surveillance, Epidemiology, and End Results (SEER) program-Medicare and US Department of Housing and Urban Development (HUD) administrative data. METHODS: Individuals enrolled in HUD public and assisted housing programs between 2006 and 2021 were linked with cancer diagnoses between 2006 and 2019 identified in the SEER-Medicare data from 16 states using Match*Pro (National Institutes of Health, Bethesda, MD) probabilistic linkage software. HUD administrative data include timing and type of housing assistance as well as verified household income. Medicare administrative data are available through 2020. RESULTS: A total of 335 490 unique individuals who received housing assistance at any time point, including 156 794 who received housing assistance around the time of their diagnosis (at least 6 months before diagnosis until 6 months after diagnosis or death), were matched to SEER-Medicare data. A total of 63 251 individuals receiving housing assistance at the time of their diagnosis were aged 66 years and older and continuously enrolled in Medicare parts A and B fee for service; 12 035 had a diagnosis of lung cancer, 8866 of breast cancer, 7261 of colorectal cancer, and 4703 of prostate cancer. CONCLUSIONS: This novel data linkage will be available through the National Cancer Institute and can be used to explore the ways in which housing assistance is associated with cancer diagnosis, care, and outcomes, including the role of housing assistance status in potentially reducing or contributing to inequities across racialized and ethnic groups.

Hedgehog-interacting protein acts in the habenula to regulate nicotine intake.

Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.

Highly glycosylated MUC1 mediates high affinity L-selectin binding at the human endometrial surface.

BACKGROUND: Sialyl-Lewis X/L-selectin high affinity binding interactions between transmembrane O-glycosylated mucins proteins and the embryo have been implicated in implantation processes within the human reproductive system. However, the adhesive properties of these mucins at the endometrial cell surface are difficult to resolve due to known discrepancies between in vivo models and the human reproductive system and a lack of sensitivity in current in vitro models. To overcome these limitations, an in vitro model of the human endometrial epithelial was interrogated with single molecule force spectroscopy (SMFS) to delineate the molecular configurations of mucin proteins that mediate the high affinity L-selectin binding required for human embryo implantation. RESULTS: This study reveals that MUC1 contributes to both the intrinsic and extrinsic adhesive properties of the HEC-1 cellular surface. High expression of MUC1 on the cell surface led to a significantly increased intrinsic adhesion force (148 pN vs. 271 pN, p < 0.001), whereas this adhesion force was significantly reduced (271 pN vs. 118 pN, p < 0.001) following siRNA mediated MUC1 ablation. Whilst high expression of MUC1 displaying elevated glycosylation led to strong extrinsic (> 400 pN) L-selectin binding at the cell surface, low expression of MUC1 with reduced glycosylation resulted in significantly less (≤200 pN) binding events. CONCLUSIONS: An optimal level of MUC1 together with highly glycosylated decoration of the protein is critical for high affinity L-selectin binding. This study demonstrates that MUC1 contributes to cellular adhesive properties which may function to facilitate trophoblast binding to the endometrial cell surface through the L-selectin/sialyl-Lewis x adhesion system subsequent to implantation.

Habenular TCF7L2 links nicotine addiction to diabetes.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

Drug Addiction: Mechanisms of Nicotine Dependence Unmasked by Gene Editing.

New gene editing technologies are enabling exploration of previously intractable features of genetic risk for drug addiction. A recent study using this technology reveals new insights into how a mutation linked to tobacco dependence influences the addictive properties of nicotine.

α5 nAChR modulation of the prefrontal cortex makes attention resilient.

A loss-of-function polymorphism in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene has been linked to both drug abuse and schizophrenia. The α5 nAChR subunit is strategically positioned in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. However, the specific contribution of α5 to PFC-dependent cognitive functions has yet to be illustrated. In the present studies, we used RNA interference to knockdown the α5 nAChR subunit in the PFC of adult rats. We provide evidence that through its contribution to cholinergic modulation of cholinergic modulation of neurons in the PFC, the α5 nAChR plays a specific role in the recovery of attention task performance following distraction. Our combined data reveal the potent ability of this subunit to modulate the PFC and cognitive functions controlled by this brain region that are impaired in disease.

Nicotinic receptor subtypes differentially modulate glutamate release in the dorsal medial striatum.

The dorsal medial striatum is a crucial part of the neural network that subserves dynamic, goal-directed behaviors. Functional output of this nucleus is shaped, in part, by the influence of glutamatergic inputs. Striatal cholinergic systems have the capacity to modulate these excitatory inputs through presynaptic nicotinic acetylcholine receptors (nAChRs); however, the individual contribution of the two major nicotinic receptor subtypes, α4ß2 and α7, to such modulation is not well characterized. In the present experiments, glutamate biosensors were used to monitor nAChR-dependent glutamate release with high temporal precision in the dorsal medial striatum of rats. Both α4ß2 and α7 nAChRs were found to potently modulate glutamate release; however the two receptor subtypes do so in strikingly different ways. α7 nAChRs appear to enhance release from glutamatergic terminals. In contrast, α4ß2 nAChRs act as a brake on glutamate release via an interaction with local dopaminergic inputs and D2 receptors. Combined, the present data reveal the capacity of local striatal cholinergic signaling to dynamically modulate excitatory inputs through nAChRs.

Clinical outcomes from the CDC's Colorectal Cancer Screening Demonstration Program.

BACKGROUND: Colorectal cancer remains the second leading cause of cancer-related deaths among US men and women. Screening rates have been slow to increase, and disparities in screening remain. METHODS: To address the disparity in screening for this high burden but largely preventable disease, the Centers for Disease Control and Prevention (CDC) designed and established a 4-year Colorectal Cancer Screening Demonstration Program (CRCSDP) in 2005 for low-income, under-insured or uninsured men and women aged 50 to 64 years in 5 participating US program sites. In this report, the authors describe the design of the CRCSDP and the overall clinical findings and screening test performance characteristics, including the positive fecal occult blood testing (FOBT) rate; the rates of polyp, adenoma, and cancer detection with FOBTs and colonoscopies; and the positive predicative value for polyps, adenomas, and cancers. RESULTS: In total, 5233 individuals at average risk and increased risk were screened for colorectal cancer across all 5 sites, including 44% who underwent screening FOBT and 56% who underwent screening colonoscopy. Overall, 77% of all individuals screened were women. The FOBT positivity rate was 10%. Results from all screening or diagnostic colonoscopies indicated that 75% had negative results and required a repeat screening colonoscopy in 10 years, 16% had low-risk adenomas and required surveillance colonoscopy in 5 to 10 years, 8% had high-risk adenomas and required surveillance colonoscopy in 3 years, and 0.6% had invasive cancers. CONCLUSIONS: This report documents the successes and challenges in implementing the CDC's CRCSDP and describes the clinical outcomes of this 4-year initiative, the patterns in program uptake and test choice, and the comparative test performance characteristics of FOBT versus colonoscopy. Patterns in final outcomes from the follow-up of positive screening tests were consistent with national registry data.

Diminished trkA receptor signaling reveals cholinergic-attentional vulnerability of aging.

The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain (BF) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno-associated viral vector-based RNA interference (AAV-RNAi) strategy to suppress the expression of tropomyosin-related kinase A (trkA) receptors by cholinergic neurons in the nucleus basalis of Meynert/substantia innominata (nMB/SI) of adult and aged rats. Suppression of trkA receptor expression impaired attentional performance selectively in aged rats. Performance correlated with trkA levels in the nMB/SI. trkA knockdown neither affected nMB/SI cholinergic cell counts nor the decrease in cholinergic cell size observed in aged rats. However, trkA suppression augmented an age-related decrease in the density of cortical cholinergic processes and attenuated the capacity of cholinergic neurons to release acetylcholine (ACh). The capacity of cortical synapses to release ACh in vivo was also lower in aged/trkA-AAV-infused rats than in aged or young controls, and it correlated with their attentional performance. Furthermore, age-related increases in cortical proNGF and p75 receptor levels interacted with the vector-induced loss of trkA receptors to shift NGF signaling toward p75-mediated suppression of the cholinergic phenotype, thereby attenuating cholinergic function and impairing attentional performance. These effects model the abnormal trophic regulation of cholinergic neurons and cognitive impairments in patients with early Alzheimer's disease. This rat model is useful for identifying the mechanisms rendering aging cholinergic neurons vulnerable as well as for studying the neuropathological mechanisms that are triggered by disrupted trophic signaling.

Timeliness of cervical cancer diagnosis and initiation of treatment in the National Breast and Cervical Cancer Early Detection Program.

OBJECTIVES: To examine time intervals from cervical cancer screening to diagnosis and treatment initiation among low-income and uninsured women in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) during two consecutive time periods. METHODS: We analyzed NBCCEDP data for women with abnormal Pap tests (n=100,167), from which 1,417 invasive cervical cancers were diagnosed. We examined two time intervals for this study: diagnostic interval (time from abnormal Pap test to the date of definitive diagnosis) and treatment initiation interval (time from definitive diagnosis to treatment initiation) for two time periods: 1996-2002 and 2003-2009. We compared median time intervals for diagnostic and treatment initiation using the Kruskal-Wallis test. Adjusted proportions (predicted marginals) were calculated using logistic regression to examine diagnosis and treatment within program benchmarks (≤60 days). RESULTS: Median diagnostic intervals decreased overall by 6 days (54 vs. 48 days, p<0.001). This decrease in the median diagnostic interval was noted for all variables examined. The median treatment initiation intervals remained stable over the two time periods. CONCLUSIONS: Women screened by the NBCCEDP receive diagnostic follow-up and initiate treatment within preestablished program guidelines.

Online videos to promote sun safety: results of a contest.

Seventy-percent of Americans search health information online, half of whom access medical content on social media websites. In spite of this broad usage, the medical community underutilizes social media to distribute preventive health information. This project aimed to highlight the promise of social media for delivering skin cancer prevention messaging by hosting and quantifying the impact of an online video contest. In 2010 and 2011, we solicited video submissions and searched existing YouTube videos. Three finalists were selected and ranked. Winners were announced at national dermatology meetings and publicized via a contest website. Afterwards, YouTube view counts were monitored. No increase in video viewing frequency was observed following the 2010 or 2011 contest. This contest successfully identified exemplary online sun safety videos; however, increased viewership remains to be seen. Social media offers a promising outlet for preventive health messaging. Future efforts must explore strategies for enhancing viewership of online content.

Enhancement of attentional performance by selective stimulation of alpha4beta2(*) nAChRs: underlying cholinergic mechanisms.

Impairments in attention are a major component of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Using an operant sustained attention task (SAT), including a distractor condition (dSAT), we assessed the putative pro-attentional effects of the selective alpha4beta2(*) nicotinic acetylcholine receptor (nAChR) agonist S 38232 in comparison with the non-selective agonist nicotine. Neither drug benefited SAT performance. However, in interaction with the increased task demands implemented by distractor presentation, the selective agonist, but not nicotine, enhanced the detection of signals during the post-distractor recovery period. This effect is consistent with the hypothesis that second-long increases in cholinergic activity ('transients') mediate the detection of cues and that nAChR agonists augment such transients. Electrochemical recordings of prefrontal cholinergic transients evoked by S 38232 and nicotine indicated that the alpha4beta2(*) nAChR agonist evoked cholinergic transients that were characterized by a faster rise time and more rapid decay than those evoked by nicotine. Blockade of the alpha7 nAChR 'sharpens' nicotine-evoked transients; therefore, we determined the effects of co-administration of nicotine and the alpha7 nAChR antagonist methyllycaconitine on dSAT performance. Compared with vehicle and nicotine alone, this combined treatment significantly enhanced the detection of signals. These results indicate that compared with nicotine, alpha4beta2(*) nAChR agonists significantly enhance attentional performance and that the dSAT represents a useful behavioral screening tool. The combined behavioral and electrochemical evidence supports the hypothesis that nAChR agonist-evoked cholinergic transients, which are characterized by rapid rise time and fast decay, predict robust drug-induced enhancement of attentional performance.

Timeliness of breast cancer diagnosis and initiation of treatment in the National Breast and Cervical Cancer Early Detection Program, 1996-2005.

OBJECTIVES: To determine the effects of program policy changes, we examined service delivery benchmarks for breast cancer screening in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). METHODS: We analyzed NBCCEDP data for women with abnormal mammogram or clinical breast examination (n=382 416) from which 23 701 cancers were diagnosed. We examined time to diagnosis and treatment for 2 time periods: 1996 to 2000 and 2001 to 2005. We compared median time for diagnostic, treatment initiation, and total intervals with the Kruskal-Wallis test. We calculated adjusted proportions (predicted marginals) with logistic regression to examine diagnosis and treatment within program benchmarks (

Assessment of follow-up for low-grade cytological abnormalities in the National Breast and Cervical Cancer Early Detection Program, 2000-2005.

OBJECTIVE: To assess the management of women in the National Breast and Cervical Cancer Early Detection Program with low-grade squamous intraepithelial lesions (LSIL) before and after the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines for management of abnormal cytology were published in 2002. MATERIALS AND METHODS: We examined the follow-up for 22,342 women with LSIL during 2 periods: 2000-2002 and 2003-2005. RESULTS: The percentage of providers who followed the recommended guidelines with colposcopy for an LSIL Pap test result increased by 9% from the pre-ASCCP to the post-ASCCP period. An increase was seen in every age and racial/ethnic group. Younger women (<30 years) and white women were more likely than comparison groups to be followed by colposcopy rather than a repeat Pap test. CONCLUSIONS: The increase in percentage of women having colposcopy in 2003, 1 year after the new guidelines were published, suggests a change in provider practices consistent with those guidelines.

Primary cardiac diffuse, large B-cell lymphoma in an immunocompetent patient.

Primary cardiac non-Hodgkin's lymphoma is defined as being exclusively located in the heart and/or pericardium, and is extremely rare. This disease occurs mainly in immunocompromised patients and rarely in the immunocompetent. To date, 35 cases of primary cardiac non-Hodgkin's lymphoma have been reported in the literature by Chalabreysse et al in 2002, and 22 of these cases were diffuse, large B-cell lymphoma (DLBCL). We report a rare case of an immunocompetent female with no significant medical history who presented with dyspnea, chest pain and the beginnings of an SVC syndrome. The patient was initially diagnosed with primary cardiac Burkitt's lymphoma when surgical pathology was reviewed. After further investigation by another pathology lab, the tumor was defined as DLBCL, which was confirmed by fluorescence in situ hybridization techniques.

Hyperthermia induces endoplasmic reticulum-mediated apoptosis in melanoma and non-melanoma skin cancer cells.

Hyperthermia has been revived as a promising approach for cancer treatment. To understand the underlying mechanisms of hyperthermic killing of cancer cells, we examined the cytotoxic effects of hyperthermia on various skin cancer cell lines using cell viability, morphological analyses, and caspase activation assays. Hyperthermia induced cytotoxicity in a time- and temperature-dependent manner. At middle dose/time combinations, heat-induced apoptosis, whereas at higher doses, necrosis was the mechanism of cell death. To investigate the mechanisms of hyperthermia-induced apoptosis, we examined the activation of extrinsic (Caspase 8) and intrinsic (Caspase 9) apoptotic pathways. Hyperthermia did not activate Caspases 8 or 9, but did activate Caspase 3/7, suggesting a non-conventional apoptotic pathway. Last, analysis of Grp78 expression and Caspase 12 or 4 activation indicated that hyperthermia induced endoplasmic reticulum-mediated apoptosis. Thus, hyperthermia induced apoptosis in two types of skin cancer cells through endoplasmic reticulum-mediated apoptosis and not through the classical intrinsic or extrinsic apoptosis pathways. Hyperthermia may be a promising treatment for basal cell carcinoma and melanoma, bypassing the antiapoptotic defenses concentrated in the intrinsic and extrinsic apoptosis pathways. These results also raise the possibility that heat may be combined with other approaches for induction of apoptosis to achieve synergistic killing of skin cancers.

A combined approach to women's health is associated with a greater likelihood of repeat mammography in a population of financially disadvantaged women.

INTRODUCTION: Integrating one or more public health programs may improve the ability of programs to achieve common goals. Expanding knowledge on how program integration occurs, how it benefits each individual program, and how it contributes to the achievement of common goals is an important area of inquiry in public health. METHODS: The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) and the Well-Integrated Screening and Evaluation for Women Across the Nation (WISEWOMAN) program combined data from 10 of their overlapping state or tribal programs to calculate prevalence estimates of repeat mammography at 18 months. The data were stratified by whether women attended the combined program or only the NBCCEDP. Logistic regression analyses were conducted to identify factors that were thought to independently contribute to a greater likelihood of a woman receiving a repeat mammogram. RESULTS: Women who participated in both programs were 1.5 to 5.1 times as likely to be rescreened, depending on program location, as women who participated only in the NBCCEDP. WISEWOMAN participants who received a follow-up WISEWOMAN screening for chronic disease risk factors within a year of their initial WISEWOMAN screening were 5 times more likely to return for a follow-up mammogram through the NBCCEDP than were WISEWOMAN participants who did not. DISCUSSION: Participation in both the NBCCEDP and the WISEWOMAN program is associated with a greater likelihood of a woman returning for a follow-up mammogram within 18 months of her initial examination. Collecting more in-depth information on motivational factors and on the association between receipt of multiple services and a woman's engagement in a health program should be the subject of future research.