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.

Selection for oligotrophy among bacteria inhabiting host microbiomes.

IMPORTANCE: Understanding how natural selection has historically shaped the traits of microbial populations comprising host microbiomes would help predict how the functions of these microbes may continue to evolve over space and time. Numerous host-associated microbes have been found to adapt to their host, sometimes becoming obligate symbionts, whereas free-living microbes are best known to adapt to their surrounding environment. Our study assessed the selective pressures of both the host environment and the surrounding external environment in shaping the functional potential of host-associated bacteria. Despite residing within the resource-rich microbiome of their hosts, we demonstrate that host-associated heterotrophic bacteria show evidence of trait selection that matches the nutrient availability of their broader surrounding environment. These findings illustrate the complex mix of selective pressures that likely shape the present-day function of bacteria found inhabiting host microbiomes. Our study lends insight into the shifts in function that may occur as environments fluctuate over time.

Eyes on Topical Ocular Disposition: The Considered Design of a Lead Janus Kinase (JAK) Inhibitor That Utilizes a Unique Azetidin-3-Amino Bridging Scaffold to Attenuate Off-Target Kinase Activity, While Driving Potency and Aqueous Solubility.

An unmet medical need remains for patients suffering from dry eye disease (DED). A fast-acting, better-tolerated noncorticosteroid anti-inflammatory eye drop could improve patient outcomes and quality of life. Herein, we describe a small-molecule drug discovery effort to identify novel, potent, and water-soluble JAK inhibitors as immunomodulating agents for topical ocular disposition. A focused library of known 3-(4-(2-(arylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitriles was evaluated as a molecular starting point. Structure-activity relationships (SARs) revealed a ligand-efficient (LE) JAK inhibitor series, amenable to aqueous solubility. Subsequent in vitro analysis indicated the potential for off-target toxicity. A KINOMEscan selectivity profile of 5 substantiated the likelihood of widespread series affinity across the human kinome. An sp2-to-sp3 drug design strategy was undertaken to attenuate off-target kinase activity while driving JAK-STAT potency and aqueous solubility. Tactics to reduce aromatic character, increase fraction sp3 (Fsp3), and bolster molecular complexity led to the azetidin-3-amino bridging scaffold in 31.

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.

Transgender Attitudes and Beliefs Scale-Spanish (TABS-S) Version: Translation and Initial Evaluation of Psychometric Properties.

Although the field of transprejudice studies has been growing, the literature suggests a need for quality assessments in languages other than English. To address this need, our study translated the Transgender Attitudes and Beliefs Scale (TABS) and evaluated its psychometric properties for use with Spanish-speaking populations. We recruited participants (N = 605) from American and Spanish samples. Results of the confirmatory factor analysis showed adequate fit, confirming the three-factor structure of TABS-Spanish Version (TABS-S). Correlations with existing measures provided evidence for its convergent and discriminant validity. Known-groups validity of the TABS-S was evidenced through confirming previous findings that females show less transgender prejudice than males. Moreover, the internal consistency of the TABS-S scores was high for the total scale (α = .96) and subscales (α = .87-.96). Overall, there is preliminary evidence to suggest that the TABS-S is a valid and reliable scale appropriate for use with Spanish-speaking populations.

Qualitative fit test outcomes for N95 filtering facepiece respirators in health care workers.

BACKGROUND: We analyzed the qualitative fit test results of the filtering facepiece respirators (FFRs) used at our institution to determine their performance and utility. METHODS: We retrospectively analyzed 12,582 qualitative fit testing results for several FFR models among 8,809 health care workers (HCWs). RESULTS: The overall failure rate for HCWs was 15.2%. Nearly one-third (2933/8809, 33.3%) had multiple FFRs fit tested. HCW sex was a statistically significant indicator of fit testing failure (χ2 = 29.9, df = 1, P < .001), with women having a 44% higher likelihood (OR, 1.4; 95% CI: 1.27-1.65) than men. There were statistically significant differences in the failure rate across FFRs (Fig 4, F[5, 12475] = 8.4, P < .001). Fluidshield 46867S had a significantly higher failure rate (49%) than the 3M 1860 (P = .012), 3M 1860S (P < .001), 3M 8210 (P < .001), and Safelife (P < .001) FFRs. CONCLUSIONS: There was a large degree of variation in fit testing results for the FFRs tested. Although we were unable to find an FFR that fit more than 95% of the HCWs successfully, we identified poorly functioning FFRs that can help our institution with decision-making and budgeting for acquisition and stocking appropriate FFRs.

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.

OPA1 Regulates Lipid Metabolism and Cold-Induced Browning of White Adipose Tissue in Mice.

Mitochondria play a vital role in white adipose tissue (WAT) homeostasis including adipogenesis, fatty acid synthesis, and lipolysis. We recently reported that the mitochondrial fusion protein optic atrophy 1 (OPA1) is required for induction of fatty acid oxidation and thermogenic activation in brown adipocytes. In the current study we investigated the role of OPA1 in WAT function in vivo. We generated mice with constitutive or inducible knockout of OPA1 selectively in adipocytes. Studies were conducted under baseline conditions, at thermoneutrality, following high-fat feeding or during cold exposure. OPA1 deficiency reduced mitochondrial respiratory capacity in white adipocytes, impaired lipolytic signaling, repressed expression of de novo lipogenesis and triglyceride synthesis pathways, and promoted adipose tissue senescence and inflammation. Reduced WAT mass was associated with hepatic triglycerides accumulation and glucose intolerance. Moreover, mice deficient for OPA1 in adipocytes had impaired adaptive thermogenesis and reduced cold-induced browning of subcutaneous WAT and were completely resistant to diet-induced obesity. In conclusion, OPA1 expression and function in adipocytes are essential for adipose tissue expansion, lipid biosynthesis, and fatty acid mobilization of WAT and brown adipocytes and for thermogenic activation of brown and beige adipocytes.

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.

Prevention of pulmonary complications in sedated patients undergoing interventional procedures in the nonoperating room anesthesia setting.

PURPOSE OF REVIEW: Nonoperating room anesthesia (NORA) procedures have expanded in number, variety, and complexity. NORA involves all age groups, including frail older adults and patients often considered too sick to tolerate traditional surgical interventions. Postoperative pulmonary complications are a significant source of adverse events in the perioperative setting. We present a review focused on preventing pulmonary complications in the interventional NORA setting. RECENT FINDINGS: NORA locations should function as independent, autonomous ambulatory units. We discuss a strategic plan involving a thorough preoperative evaluation of patients, including recognizing high-risk patients and their anesthetic management. Finally, we offer guidance on the challenges of conducting sedation and anesthesia in patients with coronavirus disease 2019 (COVID-19) or a history of COVID-19. SUMMARY: The demands on the interventional NORA anesthesia team are increasing. Strategic planning, checklists, consistent staffing assignments, and scheduled safety drills are valuable tools to improve patient safety. In addition, through quality improvement initiatives and reporting, NORA anesthetists can achieve reductions in periprocedural pulmonary complications.

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.

Transgender Attitudes and Beliefs Scale (TABS): Validation with a Sample of Self-Identified Christians.

Transgender people suffer from a variety of consequences as victims of anti-transgender prejudice. Christians have been frequently identified as holding negative attitudes toward transgender people; however, there is evidence that these attitudes may be changing. Accurate measurement of attitudes is important in understanding currently held beliefs and to assess potential changes over time. This study tested the validity of the Transgender Attitudes and Beliefs Scale (TABS) for use with the Christian population with a sample of 207 self-identified Christians in the United States. Confirmatory factor analysis (CFA) confirmed the factor structure of TABS: χ2 (374, N = 207) = 821.46, p < 0.001 (normed χ2 = 2.20 < 4); RMSEA = .076 (90%CI = .069; .083), CFI = .926, SRMR = .053. Overall, results suggest that TABS is an appropriate instrument to utilize with the Christian population in the United states.

Case Report: Novel Copy Number Variant 16p11.2 Duplication Associated With Prune Belly Syndrome.

Prune belly syndrome (PBS) is a rare congenital disease that predominantly occurs in males and is identified by its classic triad of abdominal wall musculature deficiencies, cryptorchidism, and urinary tract abnormalities. However, numerous anomalies involving the kidneys, heart, lungs, and muscles have also been reported. A multitude of chromosomal abnormalities have been implicated in its pathogenesis. PBS can occur in association with trisomy 18 and 21. Gene duplications and deletions have also been reported; however, a definite cause of PBS is still unknown. We report the first PBS patient with a copy number variant in 16p11.2.

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.