Histone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy.

Lysine acetyltransferases (KATs) are a family of epigenetic enzymes involved in the regulation of gene expression; they represent a promising class of emerging drug targets. The frequent molecular dysregulation of these enzymes, as well as their mechanistic links to biological functions that are crucial to cancer, have led to exploration around the development of small-molecule inhibitors against KATs. Despite early challenges, recent advances have led to the development of potent and selective enzymatic and bromodomain (BRD) KAT inhibitors. In this review we discuss the discovery and development of new KAT inhibitors and their application as oncology therapeutics. Additionally, new chemically induced proximity approaches are presented, offering opportunities for unique target selectivity profiles and tissue-specific targeting of KATs. Emerging clinical data for CREB binding protein (CREBBP)/EP300 BRD inhibitors and KAT6 catalytic inhibitors indicate the promise of this target class in cancer therapeutics.

Common Sense (Radiation) Oncology: Redefining targets in radiotherapy.

In 2023, the Common Sense Oncology (CSO) movement was launched with the goal of recalibrating cancer care to focus on outcomes that matter to patients. We extend the three CSO pillars - evidence generation, interpretation and communication - to radiation oncology and advocate for better evidence demonstrating the value of our modality.

Discovery and Preclinical Development of Novel Intraocular Pressure-Lowering Rho Kinase Inhibitor: Corticosteroid Conjugates.

Purpose: A new class of ocular steroids designed to mitigate steroid-induced intraocular pressure (IOP) elevation while maintaining anti-inflammatory activity was developed. Herein is described the discovery and preclinical characterization of ROCK'Ster compound 1. Methods: Codrugs consisting of a Rho kinase inhibitor (ROCKi) and a corticosteroid were synthesized. Compounds were initially screened in vitro for ROCKi activity and anti-inflammatory activity against the proinflammatory interleukin 23 and bacterial lipopolysaccharide (LPS) pathways. Selected compounds were then screened for solubility, chemical stability, and ex vivo corneal metabolism. Lead compound 1 was evaluated for IOP lowering in the Dutch Belted rabbit and for anti-inflammatory efficacy in both a postcataract surgery model and an allergic eye disease (AED) mouse model. Results: Several ROCK'Sters were found to be potent inhibitors of ROCK (Kis < 50 nM), have high anti-inflammatory activity in vitro (IC50s < 50 nM), display sufficient stability in topical ophthalmic formulations, and have a moderate rate of corneal metabolism. Compound 1 (0.1% and 0.25%, quater in die [QID]-4 times a day) demonstrated IOP-lowering capability without inducing hyperemia in our rabbit model. When compared with the marketed steroids, Durezol® and Pred Forte®, compound 1 (0.1%, 0.25%) demonstrated noninferiority in clinical scoring in a rabbit model of inflammation after surgery. In addition, anti-inflammatory outcomes were observed with compound 1 (0.1%) relative to Lotemax® or vehicle control in an AED mouse model. Conclusion: ROCK'Ster compound 1 is a novel compound suitable for topical ocular dosing that possesses IOP-lowering capability along with similar anti-inflammatory activity compared with marketed steroids.

Communication Between Cancer Patients and Physicians About Complementary and Alternative Medicine: A Systematic Review.

Objectives: Complementary and alternative medicine (CAM) has become increasingly popular among cancer patients and is often used concomitantly with standard cancer therapies. Nonetheless, disclosure of CAM utilization by cancer patients to physicians, along with the provision of information on CAM therapies by physicians, is poor. This review explores the literature to synthesize existing information on communication about CAM usage, reasons for nondisclosure, and the clinical implications thereof. Methods: A search of medical literature published between December 1, 2009, and October 1, 2021 (last searched on April 18, 2022), on communications between physicians and cancer patients about CAM treatments was conducted through MEDLINE and EMBASE. Results were screened for inclusion, dually reviewed, and assessed using the QualSyst quality appraisal instrument. Findings were categorized and synthesized for review. Results: A total of 30 articles were located (n = 8721 total participants), which discussed elements related to patient disclosure of CAM use (n = 16), provider experiences or perceptions related to communication about CAM (n = 3), patterns of this communication (n = 6), and recommendations for effectively discussing CAM with cancer patients (n = 5). Reports indicate that nondisclosure is common throughout the cancer care spectrum. Factors influencing nondisclosure range from patient beliefs and attitudes about their provider, demographic characteristics, disease progression, physician-patient relationship, physician noninquiry, and type of CAM used; ultimately creating a gap in care that may have serious medical implications. Discussion: Many of the studies identified are small and confined to a single-center, hospital-network, or geographic setting, thereby limiting the applicability of findings and recommendations. Nonetheless, improving patient-physician communication is essential in delivering evidence-informed, patient-centered care and crucial for achieving patient satisfaction and positive health outcomes. The lack of adequate CAM dialogue about CAM use increases the risk of adverse interactions with conventional cancer treatments and results in missed opportunities for providers and patients to engage in vital information exchange. Future research and education are necessary to further identify barriers surrounding patient-provider communication about CAM treatments.

Gas Pressure From the Endoscope: An Unexplored Contributor to Morbidity and Mortality?

Background It has been shown that the incidence of venous air embolism and venous carbon dioxide (CO2) embolism is high during endoscopic retrograde cholangiopancreatography (ERCP). We examined insufflating gas flow and maximum pressure produced by three types of commonly used endoscopes because we could not readily locate technical data for endoscope gas flow and maximum emitted pressure in the manufacturer's manuals. Methods We tested the Olympus GIF-Q180 used for esophagogastroduodenoscopy, the CF-Q180 used for colonoscopy, and the TJF-Q180 used for ERCP (Olympus America Inc., Center Valley, Pennsylvania). Under three different clinical gas insufflation scenarios, we measured in vitro maximum gas pressure transduced from a closed space created at the endoscope tip in a worst-case scenario analysis. Results We showed that it is readily possible to generate a pressure (>5-30 times normal central venous pressure) in the air space at the tip of all three endoscopes when insufflation is activated and the gas egress is limited. Conclusions These findings shed additional light on in vivo occurrences of gas embolism during gastrointestinal endoscopy. We postulate that in addition to using exclusively CO2 as the insufflating gas, the risk of gas embolism can be further diminished by regulating insufflating gas pressure at the tip of endoscopes.

Survey of Lifestyle, Past Medical History and Complementary and Alternative Medicine Use Among Adult Patients Participating in the National Cancer Institute's Exceptional Responders Initiative.

INTRODUCTION: The Exceptional Responders Initiative (ERI) at the National Cancer Institute attempts to correlate unusually good outcomes in patients with cancer with genetic targets in tumors and the therapies the patients received. It is not known if other factors might contribute to exceptional responses or outcomes. We explored aspects of the medical history, lifestyle changes, complementary and alternative medicine (CAM) use and communication between health care practitioners and patients who experienced an exceptional response following cancer treatment. METHODS: All subjects whose case was submitted to the ERI were eligible to participate in the survey. A 121-question survey questionnaire was developed to assess aspects of the subject's past medical history, lifestyle (e.g., diet, exercise, spirituality) and use of CAM. RESULTS: Thirty subjects completed and returned the questionnaire from approximately 88 patients invited to participate (approximate response rate = 34%). Approximately 68% were female and 32% were male. Fifty percent of subjects changed their diet after their cancer diagnosis. Eighteen patients (60%) reported using a CAM therapy (not including oral vitamins/minerals or spiritual practices) during their Exceptional Response (ER). CONCLUSION: Multiple factors, including features of the tumor itself, the patient, or the environment, could affect tumor response or patient survival, either solely or in combination with the treatments received. Many patients use other medications, change their diet or physical activity or use CAM interventions after their cancer diagnosis. Investigators attempting to understand the exceptional response phenomenon should acquire rich data sets of their subjects that include information about these factors.

Genome Wide Association Study Uncovers the QTLome for Osmotic Adjustment and Related Drought Adaptive Traits in Durum Wheat.

Osmotic adjustment (OA) is a major component of drought resistance in crops. The genetic basis of OA in wheat and other crops remains largely unknown. In this study, 248 field-grown durum wheat elite accessions grown under well-watered conditions, underwent a progressively severe drought treatment started at heading. Leaf samples were collected at heading and 17 days later. The following traits were considered: flowering time (FT), leaf relative water content (RWC), osmotic potential (ψs), OA, chlorophyll content (SPAD), and leaf rolling (LR). The high variability (3.89-fold) in OA among drought-stressed accessions resulted in high repeatability of the trait (h2 = 72.3%). Notably, a high positive correlation (r = 0.78) between OA and RWC was found under severe drought conditions. A genome-wide association study (GWAS) revealed 15 significant QTLs (Quantitative Trait Loci) for OA (global R2 = 63.6%), as well as eight major QTL hotspots/clusters on chromosome arms 1BL, 2BL, 4AL, 5AL, 6AL, 6BL, and 7BS, where a higher OA capacity was positively associated with RWC and/or SPAD, and negatively with LR, indicating a beneficial effect of OA on the water status of the plant. The comparative analysis with the results of 15 previous field trials conducted under varying water regimes showed concurrent effects of five OA QTL cluster hotspots on normalized difference vegetation index (NDVI), thousand-kernel weight (TKW), and/or grain yield (GY). Gene content analysis of the cluster regions revealed the presence of several candidate genes, including bidirectional sugar transporter SWEET, rhomboid-like protein, and S-adenosyl-L-methionine-dependent methyltransferases superfamily protein, as well as DREB1. Our results support OA as a valuable proxy for marker-assisted selection (MAS) aimed at enhancing drought resistance in wheat.

Surge in testicular torsion in pediatric patients during the COVID-19 pandemic.

BACKGROUND: Testicular torsion is a pediatric surgical emergency, and prompt diagnosis and treatment is imperative. During the COVID-19 pandemic, pediatric patients with symptoms of testicular torsion may be reluctant to seek medical care which increases the likelihood of delayed presentation and the need for an orchiectomy. This observational study sought to determine whether there was a higher number of testicular torsion cases during COVID-19. METHODS: As the first patient with COVID-19 was admitted to our facility on March 6, 2020, we identified male children ages 1-18 years with testicular torsion between March 1-December 31, 2020 (during COVID-19) compared to the same time period between 2015 and 2019 (prior to COVID-19). All patients were evaluated at our Institution's Emergency Department by a pediatric urologist. RESULTS: There were 38 cases of testicular torsion between March 1-December 31, 2020 compared to 15.8 cases on average during the same 10-month period between 2015 and 2019 (a total of 79 cases). There was a statistically significant increase in testicular torsion cases during the COVID-19 pandemic compared to equivalent time periods in 2015-2019 (38 vs. 15.8, p = 0.05). Patients with testicular torsion during the COVID-19 pandemic were younger, had a longer duration of symptoms, and had a higher number of orchiectomies (although not statistically significant). CONCLUSION: During the COVID-19 pandemic, an escalation in testicular torsion cases was observed. Timely assessment, diagnosis, and surgery are crucial to prevent testicular loss and potential infertility in the future. Further evaluation is needed to elucidate the surge in testicular torsion and possible mechanisms.

Quality Assessment of Online Complementary and Alternative Medicine Information Resources Relevant to Cancer.

BACKGROUND: Complementary and alternative medicine (CAM) is often used by cancer patients and survivors in the US. Many people turn to the internet as their first source of information. Health information seeking through the internet can be useful for patients to gain a better understanding of specific CAM treatments to discuss with their healthcare team, but only if the information is comprehensive, high quality, and reliable. The aim of this article is to examine the content, writing/vetting processes, and visibility of cancer CAM online informational resources. METHODS: Online CAM resources were identified by Google and PubMed searches, literature reviews, and through sources listed on various websites. The websites were analyzed through a modified online health information evaluation tool, DISCERN (score range = 1-5). The website's features relevant to the quality assessment were described. RESULTS: Eleven CAM websites were chosen for analysis. The DISCERN analysis showed a range of quality scores from 3.6 to 4.9. Lower DISCERN scores were generally due to deficiencies in describing the writing, editing, and updating processes. A lack of transparency with authorship and references was commonly present. CONCLUSION: Cancer patients interested in CAM need unbiased, evidence-based, reliable, high-quality, easily accessible educational materials. Individuals should use the guidelines followed in this analysis (including DISCERN and Medline Plus) to find reliable sources. Website developers can use CAM Cancer (NAFKAM), Beyond Conventional Cancer Therapies, Memorial Sloan Kettering Cancer Center, breastcancer.org, Office of Dietary Supplements, National Center for Complementary and Integrative Health, and Cancer.gov as models for trustworthy content.

The National Cancer Institute and Cannabis and Cannabinoids Research.

The landscape of both recreational and medicinal cannabis use has changed dramatically over the past decade; however, research examining the risks and benefits of cannabis and cannabinoid use has lagged significantly behind the increased media promotion and their use by the general public and cancer patients. The National Cancer Institute (NCI) has supported cannabis-related research projects and funding opportunity announcements. In addition, NCI organized a virtual symposium on December 15-18, 2020, to discuss recent research findings on the use of cannabis and cannabinoids in relationship to cancer risk, prevention, and care. Specifically, the symposium sought to highlight the state of the science regarding cannabis, including the chemical constituents of cannabis (eg, cannabinoids), and cancer research involving cannabis, including cancer epidemiology, use in cancer patients, cancer biology and prevention, and preclinical and clinical cancer symptom and treatment side effect management with cannabis and cannabinoids as therapeutics. The symposium identified promising areas of future study, current barriers to conducting the research, and strategies to overcome those barriers. The series of papers in this special edition provide a summary of the symposium sessions as well as a synopsis of opportunities and challenges related to conducting research in this area.

Case Report: Rare Presentation of Mixed Germ Cell Tumor in an Infant.

The estimated incidence of pediatric testis tumor is 0.5-2.0 per 100,000 children, accounting for 1-2% of all pediatric tumors. Mixed germ cell tumors (MGCT) in prepubertal males are exceedingly rare, with only one previous case report found in the literature. We report a case of a MGCT in an infant. For prepubertal males, GCTs typically present with a painless scrotal mass, though trauma, testis torsion and hydrocele are also common presentations. Similar to such tumors in postpubertal males, ultrasonography, computed tomography, and tumor markers are integral to determine the best treatment. The patient described in this report presented with a painless scrotal mass. Following orchiectomy, the patient was found to have MGCT that was limited to the testis. With prudent management, these patients tend to have favorable prognoses.

Effects of a Single Rapid Infusion System on Platelet Function in Stored Whole Blood: An Ex Vivo Study.

Introduction Rapid infusion systems (RIS) are used to warm and rapidly infuse crystalloids and blood products. Current guidelines do not approve of platelet transfusion through a RIS, but data supporting these guidelines are scarce. Our hypothesis was that an infusion of whole blood through a RIS would degrade platelet quantity, impede viscoelastic clot strength, and inhibit platelet aggregation response to adenosine diphosphate pathway (ADP) activation. Methods Ten iterations of a simulated scenario of transfusing whole blood via a single brand and make of RIS (Belmont Fluid Management System 2000, Belmont Medical Technologies, Billerica, MA) were performed. Units of whole blood, which were two to nine days old, were leukoreduced prestorage. Blood was used to prime the RIS and then warmed and infused at 100 mL/min into a reservoir. Blood samples were collected before and immediately after infusion. Samples were tested for platelet count, size, and viscoelastic clot strength using thromboelastographic and aggregation assays. Results The study sample (n = 10) included platelets with an average age of 5.3 days. The infusion through the RIS had a detrimental effect on all the maximal amplitudes (MA) of viscoelastic testing: MA ADP (mean difference = -18.7 mm; 95% CI: -24.1 to -13.3, P = 0.004), MA rapid thromboelastography (MA rTEG) (mean difference = -6.0; 95% CI: -10.0 to -2.0, P = 0.008), MA TEG (mean difference = -7.1; 95% CI: -10.9 to -3.4, P = 0.004), mean platelet volume (MPV) (mean difference = -0.3; 95% CI: -0.6 to -0.1, P = 0.02), and platelet count (mean difference = -68.3 × 103/µL; 95% CI: -86.9 to -49.7, P = 0.004). Conclusions Platelet quantity, viscoelastic clot strength, and platelet aggregation response to ADP each decline after infusion through a RIS. Further studies regarding microaggregates and platelet activation are required.

AP-2α-Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis.

In melanoma metastasis, the role of the AP-2α transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2α facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2α interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2α removed activating chromatin marks in the promoters of EZH2 and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment with tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable antimetastatic effects, which were dependent on AP-2α. Single-cell RNA sequencing analysis of a metastatic melanoma mouse model revealed hyperexpansion of Tfap2a High/E2F-activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2α/EZH2 pathway and suggest that AP-2α expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas. SIGNIFICANCE: AP-2α drives melanoma metastasis by upregulating E2F pathway genes including EZH2 through inhibition of the NuRD repression complex, serving as a biomarker to predict responsiveness to EZH2 inhibitors.

AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer.

Activating protein 2 alpha (AP-2α; encoded by TFAP2A) functions as a tumor suppressor and influences response to therapy in several cancer types. We aimed to characterize regulation of the transcriptome by AP-2α in colon cancer. CRISPR-Cas9 and short hairpin RNA were used to eliminate TFAP2A expression in HCT116 and a panel of colon cancer cell lines. AP-2α target genes were identified with RNA sequencing and chromatin immunoprecipitation sequencing. Effects on cell cycle were characterized in cells synchronized with aphidicolin and analyzed by FACS and Premo FUCCI. Effects on invasion and tumorigenesis were determined by invasion assay, growth of xenografts, and phosphorylated histone H3 (PHH3). Knockout of TFAP2A induced significant alterations in the transcriptome including repression of TGM2, identified as a primary gene target of AP-2α. Loss of AP-2α delayed progression through S-phase into G2-M and decreased phosphorylation of AKT, effects that were mediated through regulation of TGM2. Buparlisib (BKM120) repressed in vitro invasiveness of HCT116 and a panel of colon cancer cell lines; however, loss of AP-2α induced resistance to buparlisib. Similarly, buparlisib repressed PHH3 and growth of tumor xenografts and increased overall survival of tumor-bearing mice, whereas, loss of AP-2α induced resistance to the effect of PI3K inhibition. Loss of AP-2α in colon cancer leads to prolonged S-phase through altered activation of AKT leading to resistance to the PI3K inhibitor, Buparlisib. The findings demonstrate an important role for AP-2α in regulating progression through the cell cycle and indicates that AP-2α is a marker for response to PI3K inhibitors. IMPLICATIONS: AP-2α regulated cell cycle through the PI3K cascade and activation of AKT mediated through TGM2. AP-2α induced sensitivity to Buparlisib/BKM120, indicating that AP-2α is a biomarker predictive of response to PI3K inhibitors.

The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study.

BACKGROUND: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses. METHODS: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease. RESULTS: Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations. CONCLUSION: Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.

Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.

Challenges in the Prenatal Diagnosis of Cloaca.

BACKGROUND: Cloaca is a common excretory channel for the genital, urinary, and gastrointestinal tracts. It is considered a severe anorectal malformation caused by failed partitioning of the genital, rectal, and urinary tracts. METHODS: We report 5 infants with cloaca at birth who were identified prenatally by one or more of the following on prenatal ultrasound (US): ambiguous genitalia, a cystic pelvic/abdominal mass, hydronephrosis, ascites, a single umbilical artery, and oligohydramnios. RESULTS: A cystic pelvic/abdominal mass and ambiguous genitalia were each observed in 3 cases by prenatal US. Ambiguous genitalia was observed in all 5 neonates at birth. There were 2 twin pregnancies (dichorionic/diamniotic and monochorionic/monoamniotic), with only 1 twin in a set affected with cloaca. CONCLUSION: Pediatricians should be alert to the prenatal US findings that may raise suspicion of a persistent cloaca to improve both prenatal counseling and family preparation.

Delayed Presentation of Urethral Valves: A Diagnosis That Should Be Suspected Despite a Normal Prenatal Ultrasound.

Background. Congenital urethral obstruction occurs most frequently as a result of urethral valves. The diagnosis is usually confirmed pre- or neonatally. Though not ideal, delayed diagnosis can occur in childhood, adolescence, or adulthood. Despite a normal prenatal ultrasound, there may still be a delayed diagnosis of urethral valves. Methods. We present 4 patients with delayed diagnosis of posterior urethral valves (PUV) and 1 patient with delayed diagnosis of anterior urethral valves (AUV) who were evaluated by a pediatric urologist at our Institution. We determined the age and symptoms at presentation, physical examination, micturating cystourethrogram (MCU) findings prior to the valve ablation, renal function before and after valve ablation, type of valve ablation, and urine culture and sensitivity. The urological courses following urethral valve ablation including urodynamic study findings are described. Results. The median age at presentation was 33 months. All 5 patients presented with decreased urine output and urinary retention. All 5 patients underwent a MCU that demonstrated bladder trabeculations (3 cases), vesicoureteral reflux (3 cases), and bladder diverticula (2 cases). A urethral valve ablation was performed in all cases. Four patients underwent a renal function panel prior to this procedure, and their serum BUN/creatinine levels decreased 1 day postoperatively. Conclusion. Pediatricians should consider urethral valves as causing urethral obstruction although the prenatal ultrasound may be normal. Early diagnosis and prompt treatment of urethral valves may mitigate the potentially devastating morbidities such as renal failure, congestive heart failure, and respiratory distress that may ensue.

TFAP2C regulates carbonic anhydrase XII in human breast cancer.

The expression of carbonic anhydrase XII (CA12) is associated with the expression of estrogen receptor alpha (ERα) in breast cancer and is linked to a good prognosis with a lower risk of metastasis. Transcription Factor Activator Protein 2γ (TFAP2C, AP-2γ) governs luminal breast cancer phenotype through direct and indirect regulation of ERα and ERα-associated genes, GATA3, FOXA1, EGFR, CDH1, DSP, KRT7, FBP1, MYB, RET, KRT8, MUC1, and ERBB2-genes which are responsible for the luminal signature in breast cancer. Herein, utilizing chromatin immunoprecipitation and direct sequencing (ChIP-seq), we show that CA12 is regulated by AP-2γ through binding with its promoter region in luminal breast cancer cell lines and indirectly through a distal estrogen-responsive region in ERα-positive cell lines by upregulation of ERα. CA12 is transcriptionally silenced in basal breast cancer cell lines through histone deacetylation and CpG methylation of the promoter region and can be re-activated with Trichostatin A (histone deacetylase inhibitor) and/or 5-aza-dC (an inhibitor of DNA methylation). Strong concordance in co-expression of CA12 and ESR1 (R2 = 0.1128, p = 0486) and TFAP2C (R2 = 0.1823, p = 0.0105) was found using a panel of primary breast tumor samples (n = 35), supporting a synergetic role of AP-2γ and ERα in activation of CA12. Our results highlight the essential role of AP-2γ in maintaining the luminal breast cancer phenotype and provide evidence that epigenetic mechanisms silence luminal gene expression in the basal phenotype. Additional studies to decipher mechanisms that drive epigenetic silencing of AP-2γ target genes are a critical area for further research.

Scrotal Ultrasound Is Not Routinely Indicated in the Management of Cryptorchidism, Retractile Testes, and Hydrocele in Children.

Cryptorchidism, or undescended testes, is the most common congenital genitourinary anomaly. A failure or delay of treatment may result in reduced fertility or an increased risk of testicular cancer. The American Urological Association (AUA) recommends that a scrotal ultrasound (SUS) not be performed in the preoperative management of cryptorchidism. This study investigated how likely pediatricians were to perform SUS despite the AUA guidelines. We retrospectively studied 243 patients referred to a single pediatric urology practice for clinically diagnosed testis pathology including undescended testis, hydrocele, and retractile testis over a 4-year period (January 1, 2015, to December 30, 2018). A total of 72 patients (29.6%) underwent a SUS ordered by their pediatrician prior to the pediatric urology visit. Pediatricians should be aware that SUS performed prior to pediatric urological evaluation does not alter management and is associated with a significant financial cost in patients with cryptorchidism or hydrocele.