E-Cigarette Exposure Alters Neuroinflammation Gene and Protein Expression in a Murine Model: Insights from Perinatally Exposed Offspring and Post-Birth Mothers.

The use of E-cigarettes, often considered a safer alternative to traditional smoking, has been associated with high rates of cellular toxicity, genetic alterations, and inflammation. Neuroinflammatory impacts of cigarette smoking during pregnancy have been associated with increased risks of adverse childhood health outcomes; however, it is still relatively unknown if the same propensity is conferred on offspring by maternal vaping during gestation. Results from our previous mouse inhalation studies suggest such a connection. In this earlier study, pregnant C57BL/6 mice were exposed daily to inhaled E-cig aerosols (i.e., propylene glycol and vegetable glycerin, [PG/VG]), with or without nicotine (16 mg/mL) by whole-body inhalation throughout gestation (3 h/d; 5 d/week; total ~3-week) and continuing postnatally from post-natal day (PND) 4-21. As neuroinflammation is involved in the dysregulation of glucose homeostasis and weight gain, this study aimed to explore genes associated with these pathways in 1-mo.-old offspring (equivalent in humans to 12-18 years of age). Results in the offspring demonstrated a significant increase in glucose metabolism protein levels in both treatment groups compared to filtered air controls. Gene expression analysis in the hypothalamus of 1 mo. old offspring exposed perinatally to E-cig aerosols, with and without nicotine, revealed significantly increased gene expression changes in multiple genes associated with neuroinflammation. In a second proof-of-principal parallel study employing the same experimental design, we shifted our focus to the hippocampus of the postpartum mothers. We targeted the mRNA levels of several neurotrophic factors (NTFs) indicative of neuroinflammation. While there were suggestive changes in mRNA expression in this study, levels failed to reach statistical significance. These studies highlight the need for ongoing research on E-cig-induced alterations in neuroinflammatory pathways.

The ENGAGE study: evaluation of a conversational virtual agent that provides tailored pre-test genetic education to cancer patients.

PURPOSE: Novel approaches are needed to ensure all patients with cancer have access to quality genetic education before genetic testing to enable informed treatment decisions. The purpose of this study was to test the use of an artificial intelligence (AI) intervention for the delivery of genetic education by non-genetic providers to patients with cancer undergoing active treatment. METHODS: A conversational AI-based application was developed on the HealthFAX platform to provide tailored genetic education to patients with cancer and tested at Johns Hopkins Hospital between April 2021 and Feb 2022. Patients' responses around the adoption, use, and experience of the AI application were assessed. RESULTS: Out of 64 individuals who consented to the study, 51 accessed the tool. The responding participants had a mean age of 61 years (ranging from 30-90 years) with 39 individuals undergoing active treatment for breast cancer and 12 for advanced prostate cancer. All patients chose to complete the tool at home. The median time between study enrollment and AI application initiation was 1 day, and the median time to complete the application was 24 min. All participants in their survey responses felt that the tool was secure, easy to use, liked the convenience of viewing it at home, and felt it provided valuable information. Eighteen percent of participants viewed the application with a family member. Ninety-eight percent of the participants completed their genetic education prior to receiving their test results. In 16%, a pathogenic variant was identified. CONCLUSIONS: The 51 patients who adopted the AI application were highly satisfied with its usability and convenience. Our results support the continued evaluation of this cost-effective AI application in a large-scale study. IMPLICATIONS FOR CANCER SURVIVORS: Tailored pre-test genetic education can be successfully delivered to patients with cancer undergoing active treatment via an AI application at their convenience.

Atraumatic Splenic Rupture due to Chronic Myelomonocytic Leukemia Treated with Partial Splenic Artery Embolization.

Splenic rupture can be categorized into two groups: traumatic and atraumatic. Traumatic rupture is frequently associated with blunt abdominal trauma, while atraumatic splenic rupture (ASR) is more uncommon and has been associated with both benign and malignant hematological disorders. In general, most cases of splenic rupture are managed with splenectomy, which carries significant mortality and morbidity; more recently, splenic artery embolization (SAE) has become a mainstay of management particularly after traumatic rupture. We describe a patient with chronic myelomonocytic leukemia (CMML) who presented to the emergency department for acute abdominal pain and was found to have an ASR. He underwent partial SAE, with postoperative complications of leukocytosis and tumor lysis syndrome (TLS) requiring rasburicase and allopurinol. On follow-up in clinic 2 months post-discharge, the patient was doing well on hydroxyurea, without need for further intervention at that time. In patients with hematologic malignancies presenting with abdominal pain and splenomegaly, it is important to consider ASR as a rare, but possible complication. To our knowledge, this is the only reported patient treated with SAE in the context of ASR from CMML, demonstrating that SAE can be an effective nonoperative strategy for treatment of CMML-associated ASR. This case report also highlights postoperative complications and management in this patient population, specifically a profound leukocytosis and TLS, for which close monitoring should be performed.

Radiation recall dermatitis following letrozole administration in patient with a remote history of radiation therapy.

We report the case of letrozole-induced radiation recall dermatitis (RRD) in a patient with a remote history of radiation therapy. There is only one previously known case of RRD triggered by letrozole in a patient with a recent (<3 month) history of radiation. Previously, only four other cases of aromatase-inhibitor-induced RRD have been reported. This case is significant for cancer care teams considering personalized treatments. In addition, improved long-term outcomes in cancer patients may lead to increases in and underdiagnoses of RRD. Likewise, RRD is patient specific, exacerbating health concerns, and can be difficult to recognize without proper awareness, documentation, and classification of triggering drugs. The authors hope to address these issues in this report.

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

The effect of 1-day multidisciplinary clinic on breast cancer treatment.

PURPOSE: A delay in breast cancer treatment is associated with inferior survival outcomes; however, no clear guidelines exist defining the appropriate time frame from diagnosis to definitive treatment of breast cancer. A multidisciplinary approach for breast cancer treatment can minimize the time from diagnosis to first treatment. We hypothesized single-day multidisciplinary clinic (MDC) may accelerate the time to first treatment on complex breast cancer cases at our institution. METHODS: We identified patients who were treated at Johns Hopkins for stage II or III breast cancer, who were at least 18 years of age, and were seen in a new single-day MDC with coordination between two or three specialties or by specialists from varying disciplines on different days (IDC). Patients who initiated treatment between May 2015 (initiation of MDC clinic) and December 2017 were included in our study. RESULTS: A total of 296 patient records were reviewed independently. The mean (SD) patient age was 55 (13) years. The median time to first neoadjuvant chemotherapy (NACT) was significantly reduced for patients seen in the MDC (12.7 days), compared to those seen at the IDC (24.4 days, logrank p < 0.001). The median time to definitive surgery was similar between groups (31 and 32 days for the MDC and IDC cohorts, respectively). CONCLUSIONS: A single-day MDC visit is associated with a reduced time from diagnosis to NACT. Further studies are needed to determine if a shorter interval can improve the management and the outcome of complex breast cancer cases.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

Preservación alveolar post extracción en zona estética: decisiones clinicas predecibles en sitio severamente afectado / Alveolar ridge preservation in the esthesic zone: predictable decisions in a severly affected site

INTRODUCCIÓN: La valoración particular de sitios severamente comprometidos, involucra considerar los tiempos necesarios de cicatrización, así como evidencia actual en términos de biomateriales y técnicas quirúrgicas con el fin de lograr un tratamiento exitoso. MATERIAL Y MÉTODO: Paciente sexo femenino, 28 años, asiste por dolor e infección en diente 2.1 al Postítulo de Periodoncia UDD. Se observa defecto extenso y lesión que compromete tanto las tablas óseas vestibular como palatina. El tratamiento consistió en: exodoncia y regeneración ósea, instalación del implante 6 meses después de la exodoncia y cirugía de conexión 7 meses después más injerto de tejidos blandos. RESULTADOS: El tratamiento de defectos combinados (tejidos duros y blandos), asociados a procesos infecciosos de larga data, mediante rehabilitación implanto soportada puede ser muy predecible y exitoso en la medida que se respeten los tiempos de regeneración de diferentes estructuras.

INTRODUCTION: The specific assessment of a severely compromised sites involves: the consideration of healing time according to the different kinds of tissues involved and the knowledge of the evidence available concerning biomaterials and surgical techniques. MATERIAL AND METHODS: Female patient attends the postgraduate school of periodontics, UDD University in Santiago de Chile, because of pain and chronic infection compromising tooth 2.1. At clinical evaluation, the site has an extensive defect, with active fistula that compromises the buccal and palatal bone plates. The treatment consisted of exodontia and guided bone regeneration, implantation six months after initial exodontia and abutment connection surgery seven months after implant insertion. RESULTS: the treatment of combined defects associated with a long-standing infectious process can be very predictable and successful, only if the measures of time and tissue handling are considered and applied.

Formaldehyde, Epigenetics, and Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia. The accumulation of ß-amyloid plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein are two hallmarks of AD. The ß-amyloid and tau proteins have been at the center of AD research and drug development for decades. However, most of the clinical trials targeting ß-amyloid have failed. Whereas the safety and efficacy of most tau-targeting drugs have not yet been completely assessed, the first tau aggregation inhibitor, LMTX, failed in a late-stage trial, leading to further recognition of the complexities of AD and reconsideration of the amyloid hypothesis and perhaps the tau hypothesis as well. Multilevel complex interactions between genetic, epigenetic, and environmental factors contribute to the occurrence and progression of AD. Formaldehyde (FA) is a widespread environmental organic pollutant. It is also an endogenous metabolite in the human body. Recent studies suggest that elevation of FA in the body by endogenous and/or exogenous exposure may play important roles in AD development. We have demonstrated that FA reduces lysine acetylation of cytosolic histones, thereby compromising chromatin assembly and resulting in the loss of histone content in chromatin, a conserved feature of aging from yeast to humans. Aging is an important factor for AD progression. Therefore, FA-induced inhibition of chromatin assembly and the loss of histones may contribute to AD initiation and/or development. This review will briefly summarize current knowledge on mechanistic insights into AD, focusing on epigenetic alterations and the involvement of FA in AD development. The exploration of chemical exposures as contributing factors to AD may provide new insights into AD mechanisms and could identify potential novel therapeutic targets.

Microglia Activation and Gene Expression Alteration of Neurotrophins in the Hippocampus Following Early-Life Exposure to E-Cigarette Aerosols in a Murine Model.

Recent epidemiological data indicate that the popularity of electronic cigarettes (e-cigarettes), and consequently nicotine use, is rising in both adolescent and adult populations. As nicotine is a known developmental neurotoxin, these products present a potential threat for those exposed during early life stages. Despite this, few studies have evaluated the toxicity of e-cigarettes on the developing central nervous system. The goal of this study was to assess neurotoxicity resulting from early-life exposure to electronic cigarette aerosols in an in vivo model. Specifically, studies here focused on neuro-parameters related to neuroinflammation and neurotrophins. To accomplish this, pregnant and neonatal C57BL/6 mice were exposed to aerosols produced from classic tobacco flavor e-cigarette cartridges (with [13 mg/ml] and without nicotine) during gestation (∼3 weeks) and lactation (∼3 weeks) via whole-body inhalation. Exposure to e-cigarette aerosols with and without nicotine caused significant reductions in hippocampal gene expression of Ngfr and Bdnf, as well as in serum levels of cytokines IL-1ß, IL-2, and IL-6. Exposure to e-cigarette aerosols without nicotine enhanced expression of Iba-1, a specific marker of microglia, in the cornus ammonis 1 region of the hippocampus. Overall, our novel results indicate that exposure to e-cigarette aerosols, with and without nicotine, poses a considerable risk to the developing central nervous system. Consequently, e-cigarettes should be considered a potential public health threat, especially early in life, requiring further research and policy considerations.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017.

The NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling for hereditary cancer syndromes and risk management recommendations for patients who are diagnosed with a syndrome. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer. The NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. The NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding risk management for carriers of moderately penetrant genetic mutations associated with breast and/or ovarian cancer.

Frontal Cortex Transcriptome Analysis of Mice Exposed to Electronic Cigarettes During Early Life Stages.

Electronic cigarettes (e-cigarettes), battery-powered devices containing nicotine, glycerin, propylene glycol, flavorings, and other substances, are increasing in popularity. They pose a potential threat to the developing brain, as nicotine is a known neurotoxicant. We hypothesized that exposure to e-cigarettes during early life stages induce changes in central nervous system (CNS) transcriptome associated with adverse neurobiological outcomes and long-term disease states. To test the hypothesis, pregnant C57BL/6 mice were exposed daily (via whole body inhalation) throughout gestation (3 h/day; 5 days/week) to aerosols produced from e-cigarettes either with nicotine (13-16 mg/mL) or without nicotine; following birth, pups and dams were exposed together to e-cigarette aerosols throughout lactation beginning at postnatal day (PND) 4-6 and using the same exposure conditions employed during gestational exposure. Following exposure, frontal cortex recovered from ~one-month-old male and female offspring were excised and analyzed for gene expression by RNA Sequencing (RNA-Seq). Comparisons between the treatment groups revealed that e-cigarette constituents other than nicotine might be partly responsible for the observed biological effects. Transcriptome alterations in both offspring sexes and treatment groups were all significantly associated with downstream adverse neurobiological outcomes. Results from this study demonstrate that e-cigarette exposure during early life alters CNS development potentially leading to chronic neuropathology.

Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer.

Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells.

The mechanisms by which arsenic-induced genomic instability is initiated and maintained are poorly understood. To investigate potential epigenetic mechanisms, in this study we evaluated global DNA methylation levels in V79 cells and human HaCaT keratinocytes at several time points during expanded growth of cell cultures following removal of arsenite exposures. We have found altered genomic methylation patterns that persisted up to 40 cell generations in HaCaT cells after the treatments were withdrawn. Moreover, mRNA expression levels were evaluated by RT-PCR for DNMT1, DNMT3A, DNMT3B, HMLH1, and HMSH2 genes, demonstrating that the down regulation of DNMT3A and DNMT3B genes, but not DNMT1, occurred in an arsenic dose-dependent manner, and persisted for many cell generations following removal of the arsenite, offering a plausible mechanism of persistently genotoxic arsenic action. Analyses of promoter methylation status of the DNA mismatch repair genes HMLH1 and HMSH2 show that HMSH2, but not HMLH1, was epigenetically regulated by promoter hypermethylation changes following arsenic treatment. The results reported here demonstrate that arsenic exposure promptly induces genome-wide global DNA hypomethylation, and some specific gene promoter methylation changes, that persist for many cell generations following withdrawal of arsenite, supporting the hypothesis that the cells undergo epigenetic reprogramming at both the gene and genome level that is durable over many cell generations in the absence of further arsenic treatment. These DNA methylation changes, in concert with other known epigenome alterations, are likely contributing to long-lasting arsenic-induced genomic instability that manifests in several ways, including aberrant chromosomal effects.

A Phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation.

Once-weekly administration of bortezomib has reduced bortezomib-induced peripheral neuropathy without affecting response rates, but this has only been demonstrated prospectively in three- and four- drug combinations. We report a phase II trial of alternate dosing and schedule of bortezomib and dexamethasone in newly diagnosed multiple myeloma patients who are not eligible for or refused autologous stem cell transplantation. Bortezomib 1·6 mg/m(2) intravenously was given once-weekly for six cycles, together with dexamethasone 40 mg on the day of and day after bortezomib. Fifty patients were enrolled; 58% did not require any dose modification. The majority of patients had multiple co-morbidities, including cardiovascular (76%) and renal insufficiency (54%), and the median number of medications prior to enrollment was 13. Of all evaluable patients, the overall response rate was 79% and at least 45% had at least a very good partial response. The median time to first response was 1·3 months (range, 0·25-2·4 months). The progression-free and overall survivals were 8 months and 46·5 months, respectively. Twenty-four percent developed worsening neuropathy. We conclude that alternate dosing and scheduling of bortezomib and dexamethasone is both safe and effective for management of newly diagnosed multiple myeloma in frail patients. (ClinicalTrials.gov number, NCT01090921).

The feasibility of an e-mail-delivered intervention to improve nutrition and physical activity behaviors in African American college students.

OBJECTIVES: To evaluate the feasibility and acceptability of an e-mail-delivered program to promote nutrition and physical activity in African American college students. PARTICIPANTS: Forty-seven students (76% female, aged 18-20 years). METHODS: Students participated in a 24-week randomized controlled trial, receiving either general health information or the intervention focused on diet and physical activity. RESULTS: At baseline, 80.9% and 76.0% of participants reported interest in improving diet and physical activity, respectively. Participants evidenced poor nutrition behaviors and 46% were overweight or obese. At 24 weeks, most participants (70% control, 84% intervention) were "somewhat" or "very" satisfied with the program. The program was feasible to administrate, with the exception of measurement of physical activity using accelerometers. CONCLUSIONS: An innovative e-mail-delivered program promoting positive health behaviors appears to be feasible and acceptable in African American college students. Further research is needed to evaluate program efficacy in this population, including prevention of excess weight gain.