Matthew L Anderson

Overexpression of high affinity Type I adenosine receptors promotes the growth of uterine leiomyomas

Abstract Leiomyomas are benign proliferations of uterine smooth muscle found in 60% of women. A spatial redistribution of ecto-5'-nucleotidase (CD73, NT5E) that results in reduced extracellular concentrations of adenosine has recently been described in leiomyomas. However, the mechanisms by which altered extracellular adenosine levels contribute to leiomyoma growth remain poorly understood. To address this deficiency, a series of tissue specimens and primary cultures generated from matched specimens of myometrium and leiomyoma were used. Overexpression of Type 1 adenosine receptors (ADORA1) was observed when matched specimens and primary cultures were interrogated by RT-qPCR and western blot. By immunohistochemistry, ADORA1 expression was diffusely observed in myocytes in the leiomyoma complex, with only limited expression in vascular and other structures. Overexpression of ADORA1 was also observed in fibroblasts and multiple smooth muscle subtypes in the leiomyoma complex when single-cell transcriptomics data were interrogated. Incubation with N6-cyclopentyladenosine (CPA), a selective ADORA1 agonist, resulted in decreased proliferation of primary leiomyoma cultures, accompanied by decreased intracellular cAMP and enhanced cyclin D1 and phospho-AKT1 expression. To confirm the specificity of this observation, ADORA1 expression was directly targeted by siRNA, resulting in decreased proliferation, increased intracellular cAMP, and lower levels of cyclin D1 and phospho-AKT1. Collectively, these data indicate that overexpression of the ADORA1 receptor is a robust feature of uterine leiomyomas, where its activation by residual levels of extracellular adenosine potentially contributes to tumor growth by regulating AKT1-mediated signaling.

ITLN1 modulates invasive potential and metabolic reprogramming of ovarian cancer cells in omental microenvironment

AbstractAdvanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer. Further studies demonstrate that ITLN1 suppresses lactotransferrin’s effect on ovarian cancer cell invasion potential and proliferation by decreasing MMP1 expression and inducing a metabolic shift in metastatic ovarian cancer cells. Additionally, ovarian cancer-bearing mice treated with ITLN1 demonstrate marked decrease in tumor growth rates. These data suggest that downregulation of mesothelial cell-derived ITLN1 in the omental tumor microenvironment facilitates ovarian cancer progression.

Qualitative assessment of knowledge and attitudes towards cervical cancer screening among male Latino immigrants in Houston, Texas

Abstract Background Male spouses and partners play an important role in determining a woman’s willingness to participate in cervical cancer screening. However, the attitudes and behaviors by which they influence a woman’s decision to undergo Pap testing remain poorly understood. Methods A series of semi-structured, qualitative interviews were conducted in Spanish with 19 recent Latino immigrants in Houston, Texas. The interview format was designed to establish each individual’s pattern of engagement with the United States healthcare system, assess baseline knowledge of cervical cancer screening and evaluate attitudes and patterns of communication with their female partners regarding health care. Interview questions were constructed using principles of the Theory of Reasoned Action. All interviews were conducted in Spanish. After translation, responses were coded and scored with the goal of identifying themes and key observations. Results Most subjects reported few, if any, interactions with the healthcare system since their arrival in the United States. Although most participants reported being aware that women should be seen by their doctors regularly, fewer than half could clearly indicate the purpose of a Pap test or could state with certainty the last time their female partner had undergone screening. Multiple subjects expressed a general distrust of the health care system and concern for its costs. Approximately half of subjects reported that they accompanied their female partner to the health care provider’s office and none of the participants reported that they were present in examination rooms at the time their partner underwent screening. Multiple participants endorsed that there may be some concerns within their community regarding women receiving frequent gynecologic care and distrust of the healthcare system. Almost all interviewed subjects stated that while they would allow their female partners to see male physicians, they also expressed the opinion that other men might be uncomfortable with this and that women would likely be more comfortable with female physicians. Conclusions Strategies to enhance knowledge of HPV and cancer screening and improve trust in the health care system among male spouses or partners should be explored with the goal of promoting cervical cancer screening among immigrant Latinx populations.

Spatially restricted ecto‐5′‐nucleotidase expression promotes the growth of uterine leiomyomas by modulating Akt activity

Abstract Found in as many as 80% of women, uterine leiomyomas are a frequent cause of abnormal uterine bleeding, pelvic pain, and infertility. Despite their significant clinical impact, the mechanisms responsible for driving leiomyoma growth remain poorly understood. After obtaining IRB permission, expression of ecto‐5′‐nucleotidase ( NT5E, CD73 ) was assessed in matched specimens of myometrium and leiomyoma by real‐time qPCR, Western blot, and immunohistochemistry (IHC). Adenosine concentrations were measured by enzyme‐linked assay. Primary cultures were used to assess the impact of adenosine and/or adenosine receptor agonists on proliferation, apoptosis, and patterns of intracellular signaling in vitro. When compared to matched specimens of healthy myometrium, uterine leiomyomas were characterized by reduced CD73 expression. Largely limited to thin‐walled vascular structures and the pseudocapsule of leiomyomas despite diffuse myometrial distribution. Restricted intra‐tumoral CD73 expression was accompanied by decreased levels of intra‐tumoral adenosine. In vitro, incubation of primary leiomyoma cultures with adenosine or its hydrolysis‐resistant analog 2‐chloro‐adenosine (2‐CL‐AD) inhibited proliferation, induced apoptosis, and reduced proportion of myocytes in S‐ and G2‐M phases of the cell cycle. Decreased proliferation was accompanied by reduced expression of phospho‐Akt, phospho‐Cdk2‐Tyr15, and phospho‐Histone H3. Enforced expression of the A2B adenosine receptor (ADORA2B) and ADORA2B‐selective agonists similarly suppressed proliferation and inhibited Akt phosphorylation. Collectively, these observations broadly implicate CD73 and reduced extracellular concentrations of adenosine as key regulators of leiomyoma growth and potentially identify novel strategies for clinically managing these common tumors.

Self-Sampling for Human Papillomavirus Testing: Acceptability in a U.S. Safety Net Health System

Self-sampling for human papillomavirus testing is increasingly recognized as a strategy to expand cervical cancer screening access and utilization. Acceptability is a key determinant of uptake. This study assesses the acceptability of and experiences with mailed self-sampling kits for human papillomavirus testing among underscreened patients in a safety net health system. A nested telephone survey was administered between 2021 and 2023 to a sample (n=272) of the 2,268 participants enrolled in the Prospective Evaluation of Self-Testing to Increase Screening trial. Trial participants include patients of a safety net health system aged 30-65 years who were not up to date on screening. Participants were asked about barriers to provider-performed screening. Kit users and nonusers were asked about their experiences. Prevalent barriers to provider-performed screening included perceived discomfort of pelvic examination (69.4%), being uncomfortable with male providers (65.4%), and embarrassment (57.0%). Among participants who reported using the mailed kit (n=164), most reported good experiences (84.8%). Most reported self-sampling as more/equally convenient (89.0%), less/equally embarrassing (99.4%), and less/equally stressful (95.7%) than provider-performed screening. Among kit nonusers (n=43), reasons for not using the kit included forgetting about it (76.7%), preferring provider-performed screening (76.7%), and fearing cancer (67.4%). Prospective Evaluation of Self-Testing to Increase Screening trial participants generally had a positive experience with self-sampling for human papillomavirus testing. Increased comfort and reduced embarrassment/anxiety with self-sampling are relevant attributes because these were the most prevalent reported barriers to provider-performed screening. High acceptability suggests potentially high uptake when self-sampling for human papillomavirus testing receives regulatory approval and is available in safety net health systems.