Targeting of microRNA-22 Suppresses Tumor Spread in a Mouse Model of Triple-Negative Breast Cancer.

microRNA-22 (miR-22) is an oncogenic miRNA whose up-regulation promotes epithelial-mesenchymal transition (EMT), tumor invasion, and metastasis in hormone-responsive breast cancer. Here we show that miR-22 plays a key role in triple negative breast cancer (TNBC) by promoting EMT and aggressiveness in 2D and 3D cell models and a mouse xenograft model of human TNBC, respectively. Furthermore, we report that miR-22 inhibition using an LNA-modified antimiR-22 compound is effective in reducing EMT both in vitro and in vivo. Importantly, pharmacologic inhibition of miR-22 suppressed metastatic spread and markedly prolonged survival in mouse xenograft models of metastatic TNBC highlighting the potential of miR-22 silencing as a new therapeutic strategy for the treatment of TNBC.

Do Health Care Organizations Have Legitimate Responsibilities beyond the Delivery of Health Care? Insights from Citizenship Theory.

Many health care organizations made public commitments to become antiracist in the wake of George Floyd's murder. These actions raise questions about the appropriateness of health care's engagement in racial justice and social justice movements generally. We argue that health care organizations can be usefully thought of as having two roles: a functional role to care for the sick and a meta-role as an organizational citizen. Fulfilling the role of citizen may require participating in the pursuit of social justice, including efforts to achieve racial equity. The demands of these two roles will need to be balanced, but the role of organizational citizen has been largely ignored and merits serious attention.

Should Lack of Social Support Prevent Access to Organ Transplantation?

Transplantation programs commonly rely on clinicians' judgments about patients' social support (care from friends or family) when deciding whether to list them for organ transplantation. We examine whether using social support to make listing decisions for adults seeking transplantation is morally legitimate, drawing on recent data about the evidence-base, implementation, and potential impacts of the criterion on underserved and diverse populations. We demonstrate that the rationale for the social support criterion, based in the principle of utility, is undermined by its reliance on tenuous evidence. Moreover, social support requirements may reinforce transplant inequities, interfere in patients' personal relationships, and contribute to biased and inconsistent listing procedures. As such, accommodating the needs of patients with limited social support would better balance ethical commitments to equity, utility, and respect for persons in transplantation. We suggest steps for researchers, transplantation programs, and policymakers to improve fair use of social support in transplantation.

Review of migraine incidence and management in obstetrics and gynaecology.

PURPOSE: Migraines are the third most prevalent disorder, and seventh-highest specific cause of disability worldwide. Migraines have a multitude of underlying aetiologies; the pathology may come as a result of hormonal treatment or as a sole symptom during menstrual cycle or pregnancy, with variable intensity and duration. In addition, clinicians should be fully aware of the potential complications and well-versed in management options. METHODS: A systematic review of the incidence, symptoms, treatment options and complications among women suffering from migraines in gynaecology, as well as obstetrical cases has been performed. The significance of migraines as a marker in antenatal care and contraception treatment has also been investigated. RESULTS: The incidence of migraines in gynaecological and obstetrical cases, and contraceptive users were 11.7-12.5 %, 9-38.5 %, and 16.7-54.7% respectively. There is an average six-fold increase in the risk of stroke in women who take combined hormonal contraception and suffer from migraines. Four papers with 1565 patients proposed the combination of triptans along with the progesterone only pill. Desogestrel 75mcg/day was found to reduce the intensity of migraines compared to the combined hormonal contraceptives. The risk of gestational hypertension, pre-eclampsia, low birth weight, and preterm birth was found to be increased in pregnant women suffering from migraines. CONCLUSION: Migraines have a high incidence in gynaecology and obstetrics. Health care providers must include screening questions when history taking to identify women with migraines and effectively manage them. Proper follow-up and treatment is required for all women with migraines in order to minimize the risk of cerebrovascular events, and negative pregnancy outcomes. Women with migraines are advised to avoid combined hormonal contraception and use progesterone only pills.

Excluding patients from transplant due to social support: Results from a national survey of transplant providers.

Social support is used to determine transplant eligibility despite lack of an evidence base and vague regulatory guidance. It is unknown how many patients are disqualified from transplantation due to inadequate support, and whether providers feel confident using these subjective criteria to determine eligibility. Transplant providers (n = 551) from 202 centers estimated that, on average, 9.6% (standard deviation = 9.4) of patients evaluated in the prior year were excluded due to inadequate support. This varied significantly by United Network for Organ Sharing region (7.6%-12.2%), and by center (21.7% among top quartile). Significantly more providers used social support in listing decisions than believed it ought to be used (86.3% vs 67.6%). Nearly 25% believed that using social support in listing determinations was unfair or were unsure; 67.3% felt it disproportionately impacted patients of low socioeconomic status. Overall, 42.4% were only somewhat or not at all confident using social support to determine transplant suitability. Compared to surgical/medical transplant providers, psychosocial providers had 2.13 greater odds of supporting the criteria (P = .03). Furthermore, 69.2% supported revised guidelines for use of social support in listing decisions. Social support criteria should be reconsidered in light of the limited evidence, potential for disparities, practice variation, low provider confidence, and desire for revised guidelines.

Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism.

The mitogen-activated protein kinase (MAPK) pathway is frequently aberrantly activated in advanced cancers, including metastatic prostate cancer (CaP). However, activating mutations or gene rearrangements among MAPK signaling components, such as Ras and Raf, are not always observed in cancers with hyperactivated MAPK. The mechanisms underlying MAPK activation in these cancers remain largely elusive. Here we discover that genomic amplification of the PPP1CA gene is highly enriched in metastatic human CaP. We further identify an S6K/PP1α/B-Raf signaling pathway leading to activation of MAPK signaling that is antagonized by the PML tumor suppressor. Mechanistically, we find that PP1α acts as a B-Raf activating phosphatase and that PML suppresses MAPK activation by sequestering PP1α into PML nuclear bodies, hence repressing S6K-dependent PP1α phosphorylation, 14-3-3 binding and cytoplasmic accumulation. Our findings therefore reveal a PP1α/PML molecular network that is genetically altered in human cancer towards aberrant MAPK activation, with important therapeutic implications.

A non-cell-autonomous role for Pml in the maintenance of leukemia from the niche.

Disease recurrence after therapy, due to the persistence of resistant leukemic cells, represents a fundamental problem in the treatment of leukemia. Elucidating the mechanisms responsible for the maintenance of leukemic cells, before and after treatment, is therefore critical to identify curative modalities. It has become increasingly clear that cell-autonomous mechanisms are not solely responsible for leukemia maintenance. Here, we report a role for Pml in mesenchymal stem cells (MSCs) in supporting leukemic cells of both CML and AML. Mechanistically, we show that Pml regulates pro-inflammatory cytokines within MSCs, and that this function is critical in sustaining CML-KLS and AML ckit+ leukemic cells non-cell autonomously.

Litigation Provides Clues to Ongoing Challenges in Implementing Insurance Parity.

Over the past twenty-five years, thirty-seven states and the US Congress have passed mental health and substance use disorder (MH/SUD) parity laws to secure nondiscriminatory insurance coverage for MH/SUD services in the private health insurance market and through certain public insurance programs. However, in the intervening years, litigation has been brought by numerous parties alleging violations of insurance parity. We examine the critical issues underlying these legal challenges as a framework for understanding the areas in which parity enforcement is lacking, as well as ongoing areas of ambiguity in the interpretation of these laws. We identified all private litigation involving federal and state parity laws and extracted themes from a final sample of thirty-seven lawsuits. The primary substantive topics at issue include the scope of services guaranteed by parity laws, coverage of certain habilitative therapies such as applied behavioral analysis for autism spectrum disorders, credentialing standards for MH/SUD providers, determinations regarding the medical necessity of MH/SUD services, and the application of nonquantitative treatment limitations under the 2008 federal parity law. Ongoing efforts to achieve nondiscriminatory insurance coverage for MH/SUDs should attend to the major issues subject to private legal action as important areas for facilitating and monitoring insurer compliance.

The management of polyps in female reproductive organs.

Polyps of the lower reproductive tract are found in 7.8-50% of women. It has been hypothesized that cytogenetic modifications on chromosomes 6, 7 and 12 as well as epigenetic factors involving enzyme and metabolic activities may cause polyps to develop. Cervical polyps found in 2-5% of cases are of low clinical significance and can cause, although rarely, post coital bleedings. Cervical polyps grow during pregnancy and mucorrhoea. Trans vaginal ultrasound (TVU) provides an excellent diagnostic technique to diagnose the size and the anatomic location of endometrial polyps (EPs). In asymptomatic young woman with small EPs <10 mm in size, conservative management can be safely followed by monitoring the polyp growth. EPs located at the fundal and tubocornual regions mechanically affect fertility and disturb normal cellular function due to chronic inflammation. In cases where Eps are a cause of subfertility mechanical hysteroscopic resection is advisable. When the sole reason for infertility is an EP, the patient often becomes spontaneously pregnant shortly after removal. EP Detection in either peri- or post-menopausal age, in symptomatic or asymptomatic patients calls for meticulous hysteroscopic examination and polypectomy is mandatory. Endometrial curettage is also recommended to rule out sub clinical endometrial hyperplasia or cancer. Hysteroscopic surgery for large EPs using bipolar resectoscopes, hysteroscopic morcellators or shavers are considered equally efficient and safe under general anaesthesia. Recurrence rate of EPs after resection is unknown. The recent advances in TVU and hysteroscopy, however, should provide an accurate diagnosis and effective treatment of polyp in the female reproductive tract with minimal recurrence or surgery complications. The significantly increased incidence of colorectal polyps in cohorts that also had EPs might indicate that patients with EPs should be also referred for colonoscopy. EPs have the lowest incidence of malignant transformation as compared to colon, urinary bladder, oropharyngeal, nasal and laryngeal carcinomas.

The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function.

BRAF drives tumorigenesis by coordinating the activation of the RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathways governing BRAF kinase activity and protein stability remain undefined. Here, we report that in primary cells with active APCFZR1, APCFZR1 earmarks BRAF for ubiquitination-mediated proteolysis, whereas in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization. Moreover, we identified FZR1 as a direct target of ERK and CYCLIN D1/CDK4 kinases. Phosphorylation of FZR1 inhibits APCFZR1, leading to elevation of a cohort of oncogenic APCFZR1 substrates to facilitate melanomagenesis. Importantly, CDK4 and/or BRAF/MEK inhibitors restore APCFZR1 E3 ligase activity, which might be critical for their clinical effects. Furthermore, FZR1 depletion cooperates with AKT hyperactivation to transform primary melanocytes, whereas genetic ablation of Fzr1 synergizes with Pten loss, leading to aberrant coactivation of BRAF/ERK and AKT signaling in mice. Our findings therefore reveal a reciprocal suppression mechanism between FZR1 and BRAF in controlling tumorigenesis.Significance: FZR1 inhibits BRAF oncogenic functions via both APC-dependent proteolysis and APC-independent disruption of BRAF dimers, whereas hyperactivated ERK and CDK4 reciprocally suppress APCFZR1 E3 ligase activity. Aberrancies in this newly defined signaling network might account for BRAF hyperactivation in human cancers, suggesting that targeting CYCLIN D1/CDK4, alone or in combination with BRAF/MEK inhibition, can be an effective anti-melanoma therapy. Cancer Discov; 7(4); 424-41. ©2017 AACR.See related commentary by Zhang and Bollag, p. 356This article is highlighted in the In This Issue feature, p. 339.

Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations.

Chromosomal translocations encode oncogenic fusion proteins that have been proven to be causally involved in tumorigenesis. Our understanding of whether such genomic alterations also affect non-coding RNAs is limited, and their impact on circular RNAs (circRNAs) has not been explored. Here, we show that well-established cancer-associated chromosomal translocations give rise to fusion circRNAs (f-circRNA) that are produced from transcribed exons of distinct genes affected by the translocations. F-circRNAs contribute to cellular transformation, promote cell viability and resistance upon therapy, and have tumor-promoting properties in in vivo models. Our work expands the current knowledge regarding molecular mechanisms involved in cancer onset and progression, with potential diagnostic and therapeutic implications.

A tale of two states: do consumers see mental health insurance parity when shopping on state exchanges?

All insurance products sold on the health insurance exchanges established by the Affordable Care Act are required to offer mental health and substance use disorder benefits in compliance with requirements of the Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA). This column identifies two dimensions of parity compliance that consumers observe while shopping for insurance products offered on two state-run exchanges. The authors discuss a number of apparent discrepancies with the requirements of MHPAEA in these observable dimensions, emphasizing the potential impact of these factors on consumers' decisions about plan enrollment. The analysis reveals a nuanced picture of how insurance issuers are presenting behavioral health benefits to potential enrollees and illustrates broader concerns about parity compliance and the potential for selection on the exchanges. Four specific discrepancies are highlighted as areas for further evaluation.