Occupational Exposure to Aerosolized Human Papillomavirus: Assessing and Addressing Perceptions of and Barriers to Vaccination of at-Risk Health Care Workers.

OBJECTIVES: This study aimed to assess current vaccination rates among health care workers at risk for occupational human papillomavirus (HPV) exposure and explore factors that influence decisions about HPV vaccination. DESIGN: Using a mixed-methods design, this study included a questionnaire and qualitative focus groups. SETTING: The study took place at an academic medical center. PARTICIPANTS: Participants were 37 health care professionals in occupations at risk for workplace HPV exposure. MAIN OUTCOME MEASURES: The primary qualitative outcome measured was HPV vaccination status. The primary qualitative outcomes assessed were perceptions of occupational HPV exposure risk, protective measures, and HPV vaccination. RESULTS: Most participants were female (86.5%, n = 32) and younger than 35 years (51.4%; n = 19) and therefore would have been eligible to receive the HPV vaccine series as a teenager or young adult. Nearly two-thirds (67.6%; n = 25) of participants had received the HPV vaccine; of those, half were vaccinated as teenagers (52%; n = 13). One-third (n = 4) of those vaccinated as adults reported vaccination due to workplace HPV exposure. Focus groups revealed themes consistent with the Health Belief Model. Most participants recognized their risk of aerosolized HPV exposure in the workplace but felt uneducated about occupational exposure risk and protective measures. Many participants recognized risk of exposure through surgical smoke but perceived that risk was stratified by medical specialty, proximity to surgical field, and personal protective equipment use. Many participants had some level of concern for head and neck lesions with exposure to aerosolized HPV. Most participants recognized the need to protect themselves against workplace HPV exposure. Those who were vaccinated felt that they were better protected against HPV exposure. Almost all participants said that they had not received formal education on workplace HPV exposure risk. Many participants voiced perceived barriers to HPV vaccination. CONCLUSION: Health care workers encounter the HPV virus in a myriad of fields and procedures. Our mixed-methods study demonstrated that at-risk health care workers feel uninformed about their risk of HPV exposure in the workplace, availability of HPV vaccination, and appropriate protective equipment recommendations.

Is Scotland Walking in the Right Direction? A Cross-Sectional Analysis of Trends in Walking by Socioeconomic Status.

BACKGROUND: Walking is a key target behavior for promoting population health. This paper charts the 30-year history of walking policy in Scotland. We assess whether population walking levels among adults in Scotland have changed in recent years and identify the characteristics of those least likely to report any walking. METHODS: We pooled 9 years (2012-2019 and 2021) of data from adult (≥16 y) respondents of the Scottish Health Survey (n = 41,470). The outcomes of interest were the percentage reporting (1) any walking and (2) any walking with an average pace that is of at least moderate intensity. We also investigated the contribution of walking to total nonoccupational moderate to vigorous physical activity. We used linear and logistic regressions to test linear trends over time and to identify inequalities by age, sex, and the Scottish Index of Multiple Deprivation quintile. RESULTS: There was an increase in all measures of walking over the period 2012-2021; for example, the percentage reporting any walking increased by 7 percentage points (81.4%-88.4%). Inequalities still exist by age, sex, and the Scottish Index of Multiple Deprivation but have not grown over time. Inequalities by sex and age are most pronounced in the least affluent Scottish Index of Multiple Deprivation quintiles; less affluent older women are least likely to report any walking. CONCLUSIONS: Scotland appears to be walking in the right direction. Surveillance data support a positive trend after decades of policy and promotion efforts. The policies do not appear to be exacerbating existing inequalities, but narrowing them will require more concentrated efforts.

Assessment of Pregnancy-Related Telehealth Interventions in the United States: A 10-Year Scoping Review.

Introduction: Telehealth use in obstetrics has been demonstrated to improve efficiency, access to care, and pregnancy outcomes. Despite reported successful implementation of these programs, information regarding the program variations and its impact on health care costs and outcomes are scarce. Methods: This is a scoping review of pregnancy-related telehealth studies to understand the current landscape of pregnancy-related telehealth interventions as well as to subset those that are used in high-risk pregnancies. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework to guide this review. Results: A total of 70 articles were included in this scoping review. Of those, 53 (75.7%) studies included a pregnant population and 17 (24.3%) studies focused on a rural and/or urban population. Most studies (n = 56; 80%) included some form of synchronous interaction between provider and participant. Patient outcomes included maternal/infant health outcomes (n = 41; 44.1%), patient satisfaction (n = 9; 9.7%), and attendance/compliance (n = 5; 5.4%). Provider-level outcomes included knowledge change (n = 11; 11.8%) and self-efficacy (n = 3; 3.2%). Other outcomes included assessment of costs and patient/provider feasibility and acceptability of the intervention. Overall, there has been a growing trend in articles published on pregnancy-related telehealth studies since 2011, with 2018 having the most publications in a single year. Conclusion: This review suggests a steadily growing body of literature on pregnancy-related telehealth interventions; however, more research is needed to better understand outcomes of telehealth for pregnancy-related care, especially related to patient satisfaction, health disparities, and cost-benefit.

Outcomes Research on Telemedicine-Delivered Gender-Affirming Health Care for Transgender Youth Is Needed Now: A Call to Action.

This article is a call to action for outcomes research on telemedicine-delivered gender-affirming health care (GAH) for transgender youth. Transgender youth, especially rural youth, are severely underserved and face many obstacles to GAH. Telemedicine reduces access barriers for underserved populations, but telemedicine for this population can be complex. Our literature search identified only five studies exploring the use of telemedicine for GAH for transgender youth. Coronavirus disease 2019 (COVID-19)-related regulatory and reimbursement changes for telemedicine may have increased transgender youths' access to such care. Research is urgently needed to increase understanding regarding access, satisfaction, safety, and health-related outcomes of telemedicine-delivered GAH for transgender youth.

Factors Associated with Remote Patient Monitoring Services Provision by Hospitals and Health Care Systems in the United States.

Purpose: To assess the factors associated with offering remote patient monitoring (RPM) services. Methods: We integrated three datasets: (1) 2019-2020 Area Health Resource Files, (2) 2019 American Community Survey, and (3) 2019 American Hospitals Association annual survey using county Federal Information Processing Standards code to evaluate associations between hospital characteristics and county-level demographic factors with provision of (1) post-discharge, (2) chronic care, (3) other RPM services, and (4) any of these three RPM service categories. These outcomes were analyzed using multi-level, mixed-effects multivariate logistic regression modeling to account for county-level clustering of hospitals. Findings: Among 3,381 hospitals, 1,354 (40.0%) provided any RPM services. Being part of a clinically integrated network (CIN) and private, non-profit (vs. public) ownership were respectively associated with 104.5% (95% confidence interval [CI]: 69.4-146.8%; p < 0.001) and 30.4% (95% CI: 2.5-66.0%; p = 0.031) higher odds of providing any RPM services. Critical access hospital (CAH) designation, for-profit (vs. public) ownership, and location in the South (vs. Northeast) were associated with significantly lowering odds of providing any RPM services by 36.2% (95% CI: 14.2-52.6%; p = 0.003), 70.1% (95% CI: 56.0-79.6%; p < 0.001), and 34.0% (95% CI: 2.8-55.1%; p = 0.035), respectively. Similar trends were found with the various RPM service categories. Conclusions: The factors most associated with provision of any RPM services were hospital-level factors. Specifically, being part of a CIN and private, non-profit ownership had the highest positive associations with offering RPM services whereas location in the South and CAH designation had the strongest negative associations. Further studies are needed to understand the reasons behind these associations.

Building partnerships: A case study of physical activity researchers and practitioners collaborating to build evidence to inform the delivery of a workplace step count challenge.

Background: Walking is an integral part of Scotland's National Physical Activity Strategy, and the charity Paths for All's Workplace Step Count Challenge is a flagship programme within this strategy to promote physical activity. Effectively promoting physical activity requires collaborative engagement between stakeholders. However, there is limited guidance on how to do this. The aim of this case study is to share an example of a partnership between Paths for All and researchers to inform the development and delivery of the Workplace Step Count Challenge. Method: An overview of the partnership, example activities, reflections on opportunities and challenges, and suggestions for future partnership working are considered. Results: The partnership has evolved and strengthened over time through building trust. Many of the research activities provide an evidence base for the intervention. This work is mutually beneficial providing support for the work of the organisation, and opportunities for researchers to undertake "real world" research, leading to formal outputs and funding. The "real world" nature is challenging to integrate the most robust research designs. Recommendations for developing future partnerships were identified. Conclusion: Promoting physical activity effectively requires partnership working, and this paper provides insight into how such partnerships can work to inform future collaborations.

An Assessment of Annual Mortality Attributable to Ambient PM2.5 in Bangkok, Thailand.

Multiple studies indicate that PM2.5 is the most deleterious air pollutant for which there are ambient air quality standards. Daily concentrations of PM2.5 in Bangkok, Thailand, continuously exceed the World Health Organization (WHO) and the Thai National Ambient Air Quality Standards (NAAQSs). Bangkok has only recently begun to measure concentrations of PM2.5. To overcome this paucity of data, daily PM2.5/PM10 ratios were generated over the period 2012-2018 to interpolate missing values. Concentration-response coefficients (ß values) for PM2.5 versus non-accidental, cardiopulmonary, and lung cancer mortalities were derived from the literature. Values were also estimated and were found to be comparable to those reported in the literature for a Chinese population, but considerably lower than those reported in the literature from the United States. These findings strongly suggest that specific regional ß values should be used to accurately quantify the number of premature deaths attributable to PM2.5 in Asian populations. Health burden analysis using the Environmental Benefits Mapping and Analysis Program (BenMAP) showed that PM2.5 concentration in Bangkok contributes to 4240 non-accidental, 1317 cardiopulmonary, and 370 lung cancer mortalities annually. Further analysis showed that the attainment of PM2.5 levels to the NAAQSs and WHO guideline would reduce annual premature mortality in Bangkok by 33%and 75%, respectively.

Highest Priority Health and Health Care Concerns of Transgender and Nonbinary Individuals in a Southern State.

Purpose: Transgender (trans) and nonbinary (NB) individuals experience a number of health and health care disparities when compared with cisgender individuals. While this has been reflected in nationwide surveys of trans/NB people in the United States, few studies capture the unique experiences of trans people living in the South, and fewer studies have collected qualitative data directly from trans/NB people. The purpose of this trans/NB-led initiative was to engage the trans/NB community in a southern state in defining their most pressing health and health care concerns and comparing those results with those reported by their cisgender allies, as well as national samples of trans individuals. Methods: Participants (n=125), who were trans/NB individuals (77%) and their cisgender allies (23%) living in a southern state, completed a survey with open-ended response options and/or participated in trans-led summits. Results: The top three health and health care concerns identified by participants, both trans/NB and cisgender allies, were insurance coverage for transition-related care, access to and availability of transition-related care, and education of health care providers about trans patients and issues. Conclusions: The top concerns from trans/NB participants and cisgender allies reflect health and health care issues frequently reported by the trans/NB community nationwide. Having qualitative data from trans/NB individuals and their allies living in the South enhances our understanding of these commonly reported concerns. Future research, education, and health care practice initiatives should focus on the concerns identified by the trans/NB community.

Induction chemotherapy with carboplatin, nab-paclitaxel and cetuximab for at least N2b nodal status or surgically unresectable squamous cell carcinoma of the head and neck.

BACKGROUND: Although induction studies of TPF in SCCHN have not improved outcomes compared to chemoradiotherapy alone, phase II studies of weekly carboplatin (CbP), paclitaxel and cetuximab (C225) have shown promising results. Nano-albumin-paclitaxel (nab-paclitaxel) based chemotherapy has demonstrated a higher response rate (RR) than solvent-based paclitaxel in squamous cell carcinoma of the lung with favorable toxicity. MATERIALS AND METHODS: Patients with treatment naïve SCCHN of any site with ≥N2b disease or that was unresectable by strict criteria were eligible. Patients were treated with nab-paclitaxel 100 mg/m2, CbP area under the curve (AUC) 2 and C225 400 mg/m2 week 1 then 250 mg/m2 for six weeks, followed by standard of care chemoradiotherapy (CRT). The primary endpoint was clinical response rate to induction therapy as defined by RECIST version 1.1. Secondary measures included toxicity, progression-free survival, overall survival and quality of life as measured by FACT-HN. RESULTS: 38 eligible subjects were treated. Primary sites were: oropharynx (OPX) (25), larynx (3) oral cavity (OC) (9), hypopharynx (1). The most common grade 3 or 4 toxicity during induction was acneiform rash (26%) followed by neutropenia (16%). RR was 76.3%. Median PFS and OS have not been reached (median follow-up of 3.3 years); they were superior in patients with response. CONCLUSIONS: The combination of nab-paclitaxel, CbP and C225 is feasible, tolerable and active against locally advanced SCCHN.

Phase 2 trial of neoadjuvant chemotherapy and transoral endoscopic surgery with risk-adapted adjuvant therapy for squamous cell carcinoma of the head and neck.

BACKGROUND: The objective of this study was to demonstrate the feasibility and efficacy of induction chemotherapy, surgery, and pathology-guided adjuvant therapy to treat transorally resectable squamous head and neck cancer. METHODS: Patients had squamous head and neck cancer that was resectable by the transoral route and advanced-stage disease (American Joint Committee on Cancer stage III-IV, T3-T4 tumors, and/or positive lymph nodes). They received treatment with weekly carboplatin at an area under the curve of 2, plus paclitaxel 135 mg/m2 , and daily lapatinib 1000mg for 6 weeks followed by surgical resection. Pathology that revealed margins <5 mm, extracapsular extension, N2a of N2b lymph node status, perineural invasion, or lymphovascular space invasion resulted in adjuvant radiotherapy concurrent with weekly cisplatin. Pathology with N2c/N3 lymph node status or positive margins resulted in radiation with bolus cisplatin. The primary endpoint was the clinical response rate to induction chemotherapy, and a key secondary endpoint was feasibility. RESULTS: Toxicity was modest, and 37 of 40 patients completed study procedures as planned. The clinical response rate was 93%, the pathologic complete response rate was 36%, and the clinical response did not predict for a pathologic complete response. No patient on study follow-up has recurred or died. Twenty-nine of 39 patients who underwent surgery avoided radiation. Speech and swallowing function were well preserved. CONCLUSIONS: The study met both its primary efficacy endpoint and the secondary feasibility endpoint. Neoadjuvant, systemic therapy and surgical resection followed by risk-adapted adjuvant therapy resulted in high response rates and excellent long-term outcomes and should be further studied. Cancer 2018;124:2986-92. © 2018 American Cancer Society.

Ixabepilone and Carboplatin for Hormone Receptor Positive/HER2-neu Negative and Triple Negative Metastatic Breast Cancer.

BACKGROUND: Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2- metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial. PATIENTS AND METHODS: In the present prospective analysis of hormone receptor-positive (HR+)/HER2- and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity. RESULTS: We enrolled 54 HR+ and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR+ and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane-pretreated patients (ORR, 31.4% and 28.6% for HR+ and TN patients, respectively). The median OS was 17.9 months for HR+ patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment. CONCLUSION: Ixabepilone plus carboplatin is active even in later-line HR+ and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.

Brief Intense Stair Climbing Improves Cardiorespiratory Fitness.

PURPOSE: Sprint interval training (SIT) is a time-efficient strategy to improve cardiorespiratory fitness (CRF); however, most protocols have been studied in laboratory settings and require specialized equipment. We investigated the efficacy of brief intense stair climbing as a practical model of SIT to improve CRF. METHODS: Two separate studies, each consisting of an acute and chronic phase, were conducted in a total of 31 sedentary women (age = 24 ± 10 yr, body mass index = 23 ± 4 kg·m). RESULTS: The acute phase of study 1 established that the mean HR, blood [lactate], and RPE were similar when participants (n = 8) performed an SIT protocol that involved 3 × 20-s "all-out" efforts of either continuously ascending stairs or cycling. The chronic phase demonstrated that CRF, as determined by peak oxygen uptake (V˙O2peak), increased by 12% or ~1 MET (8.27 ± 1.05 to 9.25 ± 1.01 METs, P = 0.002) when participants (n = 12) performed the 3 × 20-s stair climbing protocol 3 d·wk for 6 wk. The acute phase of study 2 established that HR and RPE were similar when participants (n = 11) performed three different stair climbing protocols: the 3 × 20-s continuous ascent model used in study 1 and two 3 × 60-s models of ascending and descending either one or two flights of stairs (P > 0.05). The chronic phase demonstrated that V˙O2peak increased by 7% (8.91 ± 1.30 to 9.51 ± 1.52 METs, P = 0.01) when the same group of participants performed the one-flight 3 × 60-s protocol 3 d·wk for 6 wk. The Cederholm index determined from an oral glucose tolerance test was 57 ± 17 and 64 ± 21 mg·L·mmol·mU·min before and after training, respectively (P = 0.056). CONCLUSION: Brief, intense stair climbing is a practical, time-efficient strategy to improve CRF in previously untrained women.

Cytogenetic and Molecular Characterization of B-Genome Introgression Lines of Brassica napus L.

Brassica napus introgression lines (ILs), having B-genome segments from B. carinata, were assessed genetically for extent of introgression and phenotypically for siliqua shatter resistance. Introgression lines had 7-9% higher DNA content, were meiotically stable, and had almost normal pollen fertility/seed set. Segment introgressions were confirmed by fluorescent genomic in situ hybridization (fl-GISH), SSR analyses, and SNP studies. Genotyping with 48 B-genome specific SSRs detected substitutions from B3, B4, B6, and B7 chromosomes on 39 of the 69 ILs whereas SNP genotyping detected a total of 23 B-segments (≥3 Mb) from B4, B6, and B7 introgressed into 10 of the 19 (C1, C2, C3, C5, C6, C8, C9, A3, A9, A10) chromosomes in 17 ILs. The size of substitutions varied from 3.0 Mb on chromosome A9 (IL59) to 42.44 Mb on chromosome C2 (IL54), ranging from 7 to 83% of the recipient chromosome. Average siliqua strength in ILs was observed to be higher than that of B. napus parents (2.2-6.0 vs. 1.9-4.0 mJ) while siliqua strength in some of the lines was almost equal to that of the donor parent B. carinata (6.0 vs.7.2 mJ). These ILs, with large chunks of substituted B-genome, can prove to be a useful prebreeding resource for germplasm enhancement in B. napus, especially for siliqua shatter resistance.

Green tea extract does not affect exogenous glucose appearance but reduces insulinemia with glucose ingestion in exercise recovery.

We reported that supplementation with green tea extract (GTE) lowered the glycemic response to an oral glucose load following exercise, but via an unknown mechanism (Martin BJ, MacInnis MJ, Gillen JB, Skelly LE, Gibala MJ. Appl Physiol Nutr Metab 41: 1057-1063, 2016. Here we examined the effect of supplementation with GTE on plasma glucose kinetics on ingestion of a glucose beverage during exercise recovery. Eleven healthy, sedentary men (21 ± 2 yr old; body mass index = 23 ± 4 kg/m2, peak O2 uptake = 38 ± 7 ml·kg-1·min-1; means ± SD) ingested GTE (350 mg) or placebo (PLA) thrice daily for 7 days in a double-blind, crossover design. In the fasted state, a primed constant infusion of [U-13C6]glucose was started, and 1 h later, subjects performed a graded exercise test (25 W/3 min) on a cycle ergometer. Immediately postexercise, subjects ingested a 75-g glucose beverage containing 2 g of [6,6-2H2]glucose, and blood samples were collected every 10 min for 3 h of recovery. The rate of carbohydrate oxidation was lower during exercise after GTE vs. PLA (1.26 ± 0.34 vs. 1.48 ± 0.51 g/min, P = 0.04). Glucose area under the curve (AUC) was not different between treatments after drink ingestion (GTE = 1,067 ± 133 vs. PLA = 1,052 ± 91 mM/180 min, P = 0.91). Insulin AUC was lower after GTE vs. PLA (5,673 ± 2,153 vs. 7,039 ± 2,588 µIU/180 min, P = 0.05), despite similar rates of glucose appearance (GTE = 0.42 ± 0.16 vs. PLA = 0.43 ± 0.13 g/min, P = 0.74) and disappearance (GTE = 0.43 ± 0.14 vs. PLA = 0.44 ± 0.14 g/min, P = 0.57). We conclude that short-term GTE supplementation did not affect glucose kinetics following ingestion of an oral glucose load postexercise; however, GTE was associated with attenuated insulinemia. These findings suggest GTE lowers the insulin required for a given glucose load during postexercise recovery, which warrants further mechanistic studies in humans.

Using the galactose-α-1,3-galactose enzyme-linked immunosorbent assay to predict anaphylaxis in response to cetuximab.

BACKGROUND: Cetuximab is a monoclonal antibody against epidermal growth factor receptor with activity against head and neck cancer and colorectal cancer. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%. Previous retrospective data have suggested that the presence of preformed immunoglobulin E antibodies against galactose-α-1,3-galactose in serum can predict anaphylaxis in response to cetuximab. METHODS: Sixty patients were prospectively screened as part of the entry criteria for a phase 2 study of neoadjuvant carboplatin, nab-paclitaxel, and cetuximab. Patients were recruited at 2 academic medical centers known to have high anaphylaxis rates: the University of North Carolina and Vanderbilt. Only patients with a negative laboratory result were treated on the clinical protocol. RESULTS: No patient experienced anaphylaxis; the negative predictive value was thus 100%. Other than smoking history, the demographics were similar for assay-positive subjects and assay-negative subjects. CONCLUSIONS: Subjects with a negative test result can be safely treated with cetuximab. Further research is required regarding the optimal cutoff for positivity and the positive predictive value. Cancer 2016;122:1697-701. © 2016 American Cancer Society.

Rapid Repression of ADP Transport by Palmitoyl-CoA Is Attenuated by Exercise Training in Humans: A Potential Mechanism to Decrease Oxidative Stress and Improve Skeletal Muscle Insulin Signaling.

Mitochondrial ADP transport may represent a convergence point unifying two prominent working models for the development of insulin resistance, as reactive lipids (specifically palmitoyl-CoA [P-CoA]) can inhibit ADP transport and subsequently increase mitochondrial reactive oxygen species emissions. In the current study, we aimed to determine if exercise training in humans diminished P-CoA attenuation of mitochondrial ADP respiratory sensitivity. Six weeks of exercise training increased whole-body glucose homeostasis and skeletal muscle Akt signaling and reduced markers of oxidative stress without reducing maximal mitochondrial H2O2 emissions. To ascertain if enhanced mitochondrial ADP transport contributed to the improvement in the in vivo oxidative state, we determined mitochondrial ADP sensitivity in the presence and absence of P-CoA. In the absence of P-CoA, exercise training reduced mitochondrial ADP sensitivity. In contrast, exercise training increased mitochondrial ADP sensitivity with P-CoA present. We further show that P-CoA noncompetitively inhibits mitochondrial ADP transport and the ability of ADP to attenuate mitochondrial H2O2 emission. Altogether, the current data provide a potential mechanism for how P-CoA contributes to insulin resistance and highlight the ability of exercise training to diminish P-CoA attenuation in mitochondrial ADP transport.

A systematic mutational analysis of a histone H3 residue in budding yeast provides insights into chromatin dynamics.

In previous work using the Saccharomyces cerevisiae model system, a mutant version of histone H3-H3-L61W-was found to confer a variety of abnormal growth phenotypes and defects in specific aspects of the transcription process, including a pronounced alteration in the distribution pattern of the transcription elongation factor Spt16 across transcribed genes and promotion of cryptic transcription initiation within the FLO8 gene. To gain insights into the contribution of the H3-L61 residue to chromatin function, we have generated yeast strains expressing versions of histone H3 harboring all possible natural amino acid substitutions at position 61 (H3-L61X mutants) and tested them in a series of assays. We found that whereas 16 of the 19 H3-L61X mutants support viability when expressed as the sole source of histone H3 in cells, all 19 confer abnormal phenotypes ranging from very mild to severe, a finding that might in part explain the high degree of conservation of the H3-L61 residue among eukaryotes. An examination of the strength of the defects conferred by each H3-L61X mutant and the nature of the corresponding substituted residue provides insights into structural features of the nucleosome required for proper Spt16-gene interactions and for prevention of cryptic transcription initiation events. Finally, we provide evidence that the defects imparted by H3-L61X mutants on Spt16-gene interactions and on repression of intragenic transcription initiation are mechanistically related to each other.

Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study.

BACKGROUND: Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplified and TOP2A-non-amplified disease. METHODS: This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m(2), plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplified and TOP2A-non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649. FINDINGS: 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5-36·7), 2-year DFS was 97·8% (95% CI 94·2-99·2) and 2-year overall survival was 99·5% (95% CI 96·2-99·9) for the 190 patients with TOP2A-amplified disease; 2-year DFS was 97·9% (95% CI 94·9-99·1) and 2-year overall survival was 98·8% (95% CI 96·2-99·6) for the 248 patients with TOP2A-non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58·4%), neutropenia (250, 51·4%), and nausea (217, 44·7%). The most common grade 3-4 toxic effects were neutropenia (229, 47·1%), febrile neutropenia (30, 6·2%), fatigue (21, 4·3%), and diarrhoea (16, 3·3%). Cardiac dysfunction occurred in 29 (6·0%) patients (12 [2·5%] grade 1, 15 [3·1%] grade 2, and two [0·4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction. INTERPRETATION: A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplified early breast cancer, irrespective of TOP2A status. FUNDING: Sanofi.