Mediators and Moderators of Childhood Family Adversity and Adult Cortisol Response: The Role of Marital Conflict Behavior

Childhood family adversity influences behavioral and physiological response processes to acute interpersonal stress. Additionally, conflict behaviors in marriage are primary determinants of stress response and related psychological problems in adulthood. As little research has examined these two important literatures simultaneously, further work is warranted to clarify the role of marital conflict behavior in the relation between childhood family adversity and adult cortisol response to conflict. The current study examined relations between childhood family adversity, observed marital conflict behaviors, and salivary cortisol in response to acute marital conflict among 228 different-sex newlywed couples. We examined intrapersonal “actor” effects as candidate mediators of the relation between childhood adversity and cortisol response; and examined interpersonal “partner” effects as candidate moderators of the relation between childhood family adversity and cortisol response. Path analysis using Actor-Partner Interdependence Modeling demonstrated that wives’ childhood family adversity was negatively associated with wives’ cortisol. Wives’ negative conflict behavior (e.g., hostility and distress maintaining attributions) was negatively associated with wives’ cortisol. In the context of higher levels of wives’ negative conflict behavior, husbands’ experiences of childhood family adversity were positively associated with husbands’ cortisol in response to conflict. Results demonstrate the potential lasting impacts of childhood family adversity on later cortisol response to conflict and the important role of wives’ negative conflict behaviors on both husbands and wives. This study adds to the developmental psychopathology and close relationships literature, and further clarifies how stressful childhood experiences and conflict behaviors in marriage “get under the skin” in the form of physiological stress response to conflict

Franchise extension and fiscal structure in the United Kingdom 1820-1913: A new test of the Redistribution Hypothesis

We study the effect of franchise extension on the fiscal structure of central and local governments in the United Kingdom between 1820 and 1913 to revisit the Redistribution Hypothesis - the prediction that franchise extension causes an increase in state-sponsored redistribution. We adopt a novel method of uncovering causality from non-experimental data proposed by Hoover (2001). This method is based on tests for structural breaks in the marginal and conditional distributions of the franchise and fiscal structure time series preceded by a detailed historical narrative analysis. We do not find any compelling evidence that supports the Redistribution Hypothesis

CDK4/6 inhibition in breast cancer: current practice and future directions

The cyclin D/cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma protein (RB) pathway plays a key role in the proliferation of both normal breast epithelium and breast cancer cells. A strong rationale for inhibiting CDK4/6 in breast cancers has been present for many years. However, potent and selective CDK4/6 inhibitors have only recently become available. These agents prevent phosphorylation of the RB tumor suppressor, thereby invoking cancer cell cycle arrest in G1. CDK4/6 inhibitors have transited rapidly from preclinical studies to the clinical arena, and three have already been approved for the treatment of advanced, estrogen receptor (ER)-positive breast cancer patients on account of striking clinical trial results demonstrating substantial improvements in progression-free survival. ER-positive breast cancers harbor several molecular features that would predict their sensitivity to CDK4/6 inhibitors. As physicians gain experience with using these agents in the clinic, new questions arise: are CDK4/6 inhibitors likely to be useful for patients with other subtypes of breast cancer? Are there other agents that could be effectively combined with CDK4/6 inhibitors, beyond endocrine therapy? Is there a rationale for combining CDK4/6 inhibitors with novel immune-based therapies? In this review, we describe not only the clinical data available to date, but also the biology of the CDK4/6 pathway and discuss answers to these questions. In particular, we highlight that CDK4 and CDK6 govern much more than the cancer cell cycle, and that their optimal use in the clinic depends on a deeper understanding of the less well characterized effects of these enzymes

Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study

Immunoterapia; Pembrolizumab; neoplàsies mamàries triple-negativesInmunoterapia; Pembrolizumab; neoplasias mamarias triple-negativasImmunotherapy; Pembrolizumab; triple-negative breast neoplasmsBackground: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, ?1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ?24 weeks), progression-free survival, and overall survival. Results: All enrolled patients (N¼170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ?3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2þ–21.5þ) and in the PD-L1–positive (range, 6.3–21.5þ) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

International Guidelines for Management of Metastatic Breast Cancer: Can Metastatic Breast Cancer Be Cured?

A distinctive subset of metastatic breast cancer (MBC) is oligometastatic disease, which is characterized by single or few detectable metastatic lesions. The existing treatment guidelines for patients with localized MBC include surgery, radiotherapy, and regional chemotherapy. The European School of Oncology-Metastatic Breast Cancer Task Force addressed the management of these patients in its first consensus recommendations published in 2007. The Task Force endorsed the possibility of a more aggressive and multidisciplinary approach for patients with oligometastatic disease, stressing also the need for clinical trials in this patient population. At the sixth European Breast Cancer Conference, held in Berlin in March 2008, the second public session on MBC guidelines addressed the controversial issue of whether MBC can be cured. In this commentary, we summarize the discussion and related recommendations regarding the available therapeutic options that are possibly associated with cure in these patients. In particular, data on local (surgery and radiotherapy) and chemotherapy options are discussed. Large retrospective series show an association between surgical removal of the primary tumor or of lung metastases and improved long-term outcome in patients with oligometastatic disease. In the absence of data from prospective randomized studies, removal of the primary tumor or isolated metastatic lesions may be an attractive therapeutic strategy in this subset of patients, offering rapid disease control and potential for survival benefit. Some improvement in outcome may also be achieved with optimization of systemic therapies, possibly in combination with optimal local treatmen

Global Standards in Action: Insights from Anti-Money Laundering Regulation

As organizations have come under the increasing influence of global rules of all sorts, organization scholars have started studying the dynamics of global regulation. The purpose of this article is to identify and evaluate the contribution to this interdisciplinary field by the ‘Stockholm Centre for Organisational Research’. The latter’s key proposition is that while global regulation often consists of voluntary best practice rules it can nevertheless become highly influential under certain conditions. We assess how innovative this approach is using as a benchmark the state of the art in another field of relevance to the study of global regulation, i.e. ‘International Relations’. Our discussion is primarily theoretical but we draw on the case of global anti-money laundering regulation to illustrate our arguments and for inspirations of how to further elaborate the approach