Histone deacetylase 11 inhibition promotes breast cancer metastasis from lymph nodes

Lymph node (LN) metastases correspond with a worse prognosis in nearly all cancers, yet the occurrence of cancer spreading from LNs remains controversial. Additionally, the mechanisms explaining how cancers survive and exit LNs are largely unknown. Here, we show that breast cancer patients frequently have LN metastases that closely resemble distant metastases. In addition, using a microsurgical model, we show how LN metastasis development and dissemination is regulated by the expression of a chromatin modifier, histone deacetylase 11 (HDAC11). Genetic and pharmacologic blockade of HDAC11 decreases LN tumor growth, yet substantially increases migration and distant metastasis formation. Collectively, we reveal a mechanism explaining how HDAC11 plasticity promotes breast cancer growth as well as dissemination from LNs and suggest caution with the use of HDAC inhibitors

Weight gain in hormone receptor-positive (HR+) early-stage breast cancer: is it menopausal status or something else?

Purpose: This study investigates weight trajectories in pre- versus postmenopausal breast cancer (BC) survivors diagnosed with hormone receptor-positive tumors, with a specific focus on discerning menopausal status and type of endocrine treatment (ET) as risk factors for weight gain during ET. Methods: We conducted a retrospective review of electronic medical records. Descriptive statistics and Chi-squared and t tests were used to compare pre- and postmenopausal women. Chi-squared tests and ANOVA were used for within-group associations between patient characteristics and weight trajectories. Log-binomial regression models were used to estimate relative risk for weight gain. Results: The final sample was 32% premenopausal (n = 140) and 68% postmenopausal (n = 298). Relative risk (RR) for weight gain during ET was highest in women who were premenopausal (RR = 1.29, 1.03–1.52) and had Stage 3 BC (RR = 2.12, 1.59–2.82), mastectomy (RR = 1.49, 1.19–1.88), axillary node dissection (RR = 1.39, 1.11–1.73), and chemotherapy (RR = 1.80, 1.37–2.36). For each kg of weight gained between BC diagnosis and start of ET, and for each additional year of age, RR of gaining weight during ET decreased (RR = 0.98, 0.97–0.99, and RR = 0.99, 0.98–0.99, respectively). Menopausal status and type of ET were not significant predictors of weight gain. In multivariable analysis, only weight loss between BC diagnosis and start of ET was significant. Conclusion: The association of weight loss prior to ET and subsequent substantial weight gain during ET warrants further investigation

The H1 Forward Proton Spectrometer at HERA

The forward proton spectrometer is part of the H1 detector at the HERA collider. Protons with energies above 500 GeV and polar angles below 1 mrad can be detected by this spectrometer. The main detector components are scintillating fiber detectors read out by position-sensitive photo-multipliers. These detectors are housed in so-called Roman Pots which allow them to be moved close to the circulating proton beam. Four Roman Pot stations are located at distances between 60 m and 90 m from the interaction point.Comment: 20 pages, 10 figures, submitted to Nucl.Instr.and Method

Weight changes in postmenopausal breast cancer survivors over 2 years of endocrine therapy: a retrospective chart review

Purpose: Obesity and weight gain after breast cancer (BC) diagnosis can affect cancer outcomes. This study explores the question of weight change during the first 2 years of endocrine treatment (ET) to identify the independent effects of BC diagnosis and treatment on post-diagnosis weight trajectories in early-stage postmenopausal BC survivors. Methods: The study design is a retrospective chart review. Chi square tests and ANOVA were used to compare patients who gained >2 kg, lost >2 kg, or had stable weight. Log-binomial regression models were used to evaluate associations between patient characteristics and weight trajectories. Results: The final sample is N = 300, with mean age at BC diagnosis of 65 years and 76% white. After 2 years of ET, 39% of study participants had gained >2 kg, 27% had lost >2 kg, and 34% had stable weight. Relative risks (RR) for weight gain were as follows: age at diagnosis = 0.98 (0.96, 0.99), being married = 1.48 (1.04, 2.12), weight change between BC diagnosis and start of ET = 0.98 (0.97, 0.99), Stage II = 1.42 (1.01, 2.01) or Stage III = 1.99 (1.41, 2.82), PR negative = 0.70 (0.51, 0.96), HER2 positive = 1.51 (1.07, 2.13), mastectomy = 1.49 (1.12, 1.98), axillary node dissection = 1.67 (1.27, 2.20), adjuvant chemotherapy = 1.49 (1.02, 2.19), and neoadjuvant chemotherapy = 2.29 (1.67, 3.14). Type of ET (tamoxifen or aromatase inhibitor) was not significant. Conclusions: In our sample of postmenopausal early-stage BC survivors, a majority had stable or lost weight during the first 2 years of ET. Higher disease complexity and associated treatment posed higher RR for weight gain

A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000–1,500 mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50 mg/day and 2.5 mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease >6 months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA + ldCM); median age was 55 (35–80); nearly all had visceral involvement. Despite dose escalation in 90 % of patients, only 17 (57 %) patients ever achieved MPA trough concentrations >50 ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7 %) had stable disease for > 6 months. Skin Nm23 expression increased after 4 weeks of MPA + ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation

Resilience and HIV: a review of the definition and study of resilience

We use a socioecological model of health to define resilience, review the definition and study of resilience among persons living with human immunodeficiency virus (PLWH) in the existing peer-reviewed literature, and discuss the strengths and limitations of how resilience is defined and studied in HIV research. We conducted a review of resilience research for HIV-related behaviors/outcomes of antiretroviral therapy (ART) adherence, clinic attendance, CD4 cell count, viral load, viral suppression, and/or immune functioning among PLWH. We performed searches using PubMed, PsycINFO and Google Scholar databases. The initial search generated 14,296 articles across the three databases, but based on our screening of these articles and inclusion criteria, n = 54 articles were included for review. The majority of HIV resilience research defines resilience only at the individual (i.e., psychological) level or studies individual and limited interpersonal resilience (e.g., social support). Furthermore, the preponderance of HIV resilience research uses general measures of resilience; these measures have not been developed with or tailored to the needs of PLWH. Our review suggests that a socioecological model of health approach can more fully represent the construct of resilience. Furthermore, measures specific to PLWH that capture individual, interpersonal, and neighborhood resilience are needed

Weight trajectories in women receiving systemic adjuvant therapy for breast cancer

Background: Weight gain after breast cancer (BC) diagnosis is a well-known phenomenon; however, it is not a universal phenomenon and identification of patients at highest risk for weight gain is needed. This study investigates weight trajectories in early BC patients at 2 years post-primary treatment, examining potential contributing factors such as age, race, and receipt of chemotherapy, anti-HER-2 therapy, and endocrine treatment (ET). Methods: A single institution cohort of newly diagnosed women age 21 and older with early breast cancer patients (Stage 0–3) were identified by retrospective chart review (diagnosis year 1995 to 2016). Log-binomial regression models for net weight changes at 2 years post-primary treatment including patient demographic, clinical, and treatment characteristics. Results: The final sample of 625 patients included 29% who were non-White and 37% who were pre-menopausal at diagnosis. Body mass index (BMI) at diagnosis was calculated and found to be normal in 33% (BMI 18 to 2 kg, 34% had stable weight ± 2 kg, and 35% had gained > 2 kg. Factors associated with > 2 kg weight gain were menopausal status (pre-menopausal HR 1.65, 95% CI 1.34–2.04, p <.0001), receiving any chemotherapy (HR 1.36, 95% CI 1.04–1.77), and anthracycline-based chemotherapy followed by ET (HR 1.60, CI 1.01–2.45). Anti-HER-2 therapy and transition from pre- to post-menopausal during the 2-year study period were not significant factors in weight gain. In multivariate analysis, menopausal status remained the only significant variable related to weight gain when adjusted for treatment. For all treatment combinations, pre-menopausal women had significantly more weight gain. Conclusions and relevance: Weight gain, weight loss, and stable weight in women with early breast cancer vary greatly by treatment plan. However, pre-menopausal patients have the highest risk for weight gain

The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function

Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in response to thrombin. We discover that Slc44a2 mediates choline transport into mitochondria, where choline metabolism leads to an increase in mitochondrial oxygen consumption and ATP production. Platelets lacking Slc44a2 contain less ATP at rest, release less ATP when activated, and have an activation defect that can be rescued by exogenous ADP. Taken together, our data suggest that mitochondria require choline for maximum function, demonstrate the importance of mitochondrial metabolism to platelet activation, and reveal a mechanism by which Slc44a2 influences thrombosis

Effects of Large CP violating phases on g_{\m}-2 in MSSM

Effects of CP violation on the supersymmetric electro-weak correction to the anomalous magnetic moment of the muon are investigated with the most general allowed set of CP violating phases in MSSM. The analysis includes contributions from the chargino and the neutralino exchanges to the muon anomaly. The supersymmetric contributions depend only on specific combinations of CP phases. The independent set of such phases is classified. We analyse the effects of the phases under the EDM constraints and show that large CP violating phases can drastically affect the magnitude of the supersymmetric electro-weak contribution to $a_{\mu}$ and may even affect its overall sign.Comment: 26 pages Latex file including 4 figure