Epigenetic therapies targeting histone lysine methylation: complex mechanisms and clinical challenges.

As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation and the enzyme complexes represent a major frontier for therapeutic development. Clinically viable therapies targeting the activities of histone lysine methyltransferases (HKMT) and demethylases (HKDMs) have only recently begun to emerge following FDA approval of the EZH2 inhibitor tazemetostat in 2020 and remain limited to compounds targeting the well-studied SET domain-containing HKMTs and their opposing HKDMs. These include the H3K27 methyltransferases EZH2/EZH1, the singular H3K79 methyltransferase DOT1L, and the H3K4 methyltransferase MLL1/COMPASS as well as H3K9 and H3K36 methyltransferases.

Managing Risk When Working with Orbiviruses with a Special Emphasis on Epizootic Hemorrhagic Disease Virus.

Risk assessment is the cornerstone of working safely with biological agents. The World Health Organization (WHO) Laboratory Biosafety Manual Fourth Edition Monograph on Risk Assessment provides stepwise guidance for completing a risk assessment, from information gathering and identifying hazards to evaluating the risks, developing, and implementing controls and review.To support the development of a mature safety culture within laboratories, it is important that all staff who handle biological agents understand the fundamentals of risk assessment and receive training in identifying hazards created by their work activities (or tasks) and understand how to mitigate the risks arising from carrying out that work.

The dual role of a highly structured RNA (the S fragment) in the replication of foot-and-mouth disease virus.

Secondary and tertiary RNA structures play key roles in genome replication of single-stranded positive sense RNA viruses. Complex, functional structures are particularly abundant in the untranslated regions of picornaviruses, where they are involved in initiation of translation, priming of new strand synthesis and genome circularization. The 5' UTR of foot-and-mouth disease virus (FMDV) is predicted to include a c.

Isotretinoin for Acne in Transgender and Gender-Diverse Individuals Receiving Masculinizing Hormone Therapy.

Importance: Masculinizing gender-affirming hormonal therapy is associated with the development of acne. While isotretinoin is a highly effective acne treatment, little is known about its effectiveness and safety among transgender and gender-diverse individuals receiving gender-affirming hormonal therapy.

Objective: To evaluate clinical outcomes of isotretinoin among transgender and gender-diverse individuals receiving gender-affirming hormonal therapy.

Therapeutic targeting of BET bromodomain and other epigenetic acetylrecognition domain-containing factors.

Development of cancer therapies targeting chromatin modifiers and transcriptional regulatory factors is rapidly expanding to include new targets and novel targeting strategies. At the same time, basic molecular research continues to refine our understanding of the epigenetic mechanisms regulating transcription, gene expression, and oncogenesis. This mini-review focuses on cancer therapies targeting the chromatin-associated factors that recognize histone lysine acetylation.

Transcriptional elongation control of hypoxic response.

The release of paused RNA polymerase II (RNAPII) from promoter-proximal regions is tightly controlled to ensure proper regulation of gene expression. The elongation factor PTEF-b is known to release paused RNAPII via phosphorylation of the RNAPII C-terminal domain by its cyclin-dependent kinase component, CDK9. However, the signal and stress-specific roles of the various RNAPII-associated macromolecular complexes containing PTEF-b/CDK9 are not yet clear.

Lived Experience of Acne and Acne Treatment in Transgender Patients.

Importance: While acne is common in transgender and gender-diverse people and is associated with gender-affirming hormone therapy, little research has examined these factors and their impact in gender minority groups.

Objective: To examine the lived experiences of acne and acne treatment in transgender and gender-diverse participants.

Design, Setting, And Participants: This mixed-methods analysis was conducted at a multidisciplinary gender center at a public safety-net hospital and endocrinology and dermatology clinics at a tertiary academic center from January 4, 2021, to April 7, 2022, using semistructured interviews and surveys.

Somatic mutations of MLL4/COMPASS induce cytoplasmic localization providing molecular insight into cancer prognosis and treatment.

Cancer genome sequencing consortiums have recently catalogued an abundance of somatic mutations, across a wide range of human cancers, in the chromatin-modifying enzymes that regulate gene expression. Defining the molecular mechanisms underlying the potentially oncogenic functions of these epigenetic mutations could serve as the basis for precision medicine approaches to cancer therapy. MLL4 encoded by the gene highly mutated in a large number of human cancers, is a key histone lysine monomethyltransferase within the Complex of Proteins Associated with Set1 (COMPASS) family that regulates gene expression through enhancer function, potentially functioning as a tumor suppressor.

Dermatologic care of patients with differences of sex development.

Background: Differences of sex development (DSD or disorders of sex development) are uncommon congenital conditions, characterized by atypical development of chromosomal, gonadal, or anatomic sex.

Objective: Dermatologic care is an important component of the multidisciplinary care needed for individuals with DSD. This article discusses the most common primary dermatologic manifestations of DSD in addition to the cutaneous manifestations of hormonal and surgical therapies in individuals with DSD.

Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation.

The BET family protein BRD4, which forms the CDK9-containing BRD4-PTEFb complex, is considered to be a master regulator of RNA polymerase II (Pol II) pause release. Because its tandem bromodomains interact with acetylated histone lysine residues, it has long been thought that BRD4 requires these bromodomains for its recruitment to chromatin and transcriptional regulatory function. Here, using rapid depletion and genetic complementation with domain deletion mutants, we demonstrate that BRD4 bromodomains are dispensable for Pol II pause release.

Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations.

Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4.

Adherence to Gender Affirming Hormone Therapy in Transgender Adolescents and Adults: A Retrospective Cohort Study.

Context: Transgender and gender diverse (TGD) individuals often seek gender-affirming hormone therapy (GAHT). While receipt of GAHT has been associated with improved well-being, the risk of GAHT discontinuation and its reasons are not well known.

Objective: There were two main objectives: (1) To investigate the proportion of TGD individuals who discontinue therapy after an average of 4 years (maximum 19 years) since GAHT initiation; and (2) to explore reasons for GAHT discontinuation.

Re-thinking Stepfathers' Contributions: Fathers, Stepfathers, and Child Wellbeing.

Using data from a contemporary cohort of children, we revisit the question of whether children benefit from being close to and engaging in activities with a stepfather. We deploy the Fragile Families and Child Wellbeing Study, a birth cohort study of nearly 5000 children born in US cities in 1998-2000, with a large oversample of nonmarital births. We explore the relationships between stepfathers' closeness and active engagement and youth's internalizing and externalizing behaviors and school connectedness at ages 9 and 15 for between 550 and 740 children (depending on the wave) with stepfathers.

Incidence and Factors Associated With Acne in Transgender Adolescents on Testosterone: A Retrospective Cohort Study.

Objective: This retrospective cohort study aimed to assess incidence and predictors of acne among transgender adolescents receiving testosterone.

Methods: We analyzed records of patients aged <18 years, assigned female at birth, seen at Children's Healthcare of Atlanta Pediatric Endocrinology clinic for testosterone initiation between January 1, 2016, and January 1, 2019, with at least 1-year follow-up documented. Bivariable analyses to determine the association of clinical and demographic factors with new acne diagnosis were performed.

Identification of an immunogenic epitope and protective antibody against the furin cleavage site of SARS-CoV-2.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the global coronavirus disease 2019 (COVID-19) pandemic, contains a unique, four amino acid (aa) "PRRA" insertion in the spike (S) protein that creates a transmembrane protease serine 2 (TMPRSS2)/furin cleavage site and enhances viral infectivity. More research into immunogenic epitopes and protective antibodies against this SARS-CoV-2 furin cleavage site is needed.

Methods: Combining computational and experimental methods, we identified and characterized an immunogenic epitope overlapping the furin cleavage site that detects antibodies in COVID-19 patients and elicits strong antibody responses in immunized mice.

Managing Dermatologic Effects of Gender-Affirming Therapy in Transgender Adolescents.

Transgender adolescents seek gender-affirming medical care to address gender identity and incongruence. Improved understanding of the dermatologic impact of gender-affirming medical care such as pubertal suppression, hormone therapy, and surgeries can enhance patient outcome. Pubertal suppression treats dysphoria associated with development of secondary sex characteristics, including androgen-driven acne.

Stepping back: Impact of pass-fail Step 1 scoring on dermatology applicants.

The United States Medical Licensing Examination (USMLE) Step 1 recently transitioned to a pass-fail system from their three-digit scoring system. The implications of this change will ultimately influence medical students, residency programs, and, most importantly, patients. This article seeks to address some of the varying ethical and practical effects of this conversion to a pass/fail examination.

The RNA pseudoknots in foot-and-mouth disease virus are dispensable for genome replication, but essential for the production of infectious virus.

Non-coding regions of viral RNA (vRNA) genomes are critically important in the regulation of gene expression. In particular, pseudoknot (PK) structures, which are present in a wide range of RNA molecules, have a variety of roles. The 5' untranslated region (5' UTR) of foot-and-mouth disease virus (FMDV) vRNA is considerably longer than in other viruses from the picornavirus family and consists of a number of distinctive structural motifs that includes multiple (2, 3 or 4 depending on the virus strain) putative PKs linked in tandem.

Working Safely with African Swine Fever Virus.

Risk assessment is the cornerstone of working safely with biological agents. The World Health Organization (WHO) Laboratory Biosafety Manual Fourth Edition Monograph on Risk Assessment provides stepwise guidance for carrying out a risk assessment, from gathering information and identifying hazards to evaluating the risks and developing and implementing controls and review.To support the development of a mature safety culture within laboratories, it is important that all staff who handle biological agents understand the process of risk assessment and receive training in identifying hazards and mitigating risk.

Acute care utilization and housing hardships in American children.

Millions of families in the United States are economically vulnerable: one shock can lead to hardship. We use data from the Fragile Families and Child Wellbeing Study to examine the association between acute healthcare utilization - emergency room visits or hospitalizations - and subsequent housing hardships, such as being evicted for financial reasons. Further, we explore whether this association differs by who in the family utilized the care and whether perceived social support protects against hardship when these experiences occur.

Treating Acne in Transgender Persons Receiving Testosterone: A Practical Guide.

Transgender persons who undergo masculinizing hormone therapy experience a wide array of dermatologic effects as they initiate and maintain testosterone therapy. Acne is one of the most common adverse effects for many transmasculine patients receiving testosterone. Acne can worsen body image and mental health, with significant impact on quality of life in transgender patients.