EMT and MET: necessary or permissive for metastasis?

Epithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition (MET) have been suggested to play crucial roles in metastatic dissemination of carcinomas. These phenotypic transitions between states are not binary. Instead, carcinoma cells often exhibit a spectrum of epithelial/mesenchymal phenotype(s). While epithelial/mesenchymal plasticity has been observed preclinically and clinically, whether any of these phenotypic transitions are indispensable for metastatic outgrowth remains an unanswered question. Here, we focus on epithelial/mesenchymal plasticity in metastatic dissemination and propose alternative mechanisms for successful dissemination and metastases beyond the traditional EMT/MET view. We highlight multiple hypotheses that can help reconcile conflicting observations, and outline the next set of key questions that can offer valuable insights into mechanisms of metastasis in multiple tumor models

Understanding Treatment Refusal Among Adults Presenting for HIV-Testing in Soweto, South Africa: A Qualitative Study

HIV treatment initiatives have focused on increasing access to antiretroviral therapy (ART). There is growing evidence, however, that treatment availability alone is insufficient to stop the epidemic. In South Africa, only one third of individuals living with HIV are actually on treatment. Treatment refusal has been identified as a phenomenon among people who are asymptomatic, however, factors driving refusal remain poorly understood. We interviewed 50 purposively sampled participants who presented for voluntary counseling and testing in Soweto to elicit a broad range of detailed perspectives on ART refusal. We then integrated our core findings into an explanatory framework. Participants described feeling “too healthy” to start treatment, despite often having a diagnosis of AIDS. This subjective view of wellness was framed within the context of treatment being reserved for the sick. Taking ART could also lead to unintended disclosure and social isolation. These data provide a novel explanatory model of treatment refusal, recognizing perceived risks and social costs incurred when disclosing one’s status through treatment initiation. Our findings suggest that improving engagement in care for people living with HIV in South Africa will require optimizing social integration and connectivity for those who test positive

Rapidly Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in NSCLC Cell Lines through De-Repression of FGFR2 and FGFR3 Expression

Despite initial and sometimes dramatic responses of specific NSCLC tumors to EGFR TKIs, nearly all will develop resistance and relapse. Gene expression analysis of NSCLC cell lines treated with the EGFR TKI, gefitinib, revealed increased levels of FGFR2 and FGFR3 mRNA. Analysis of gefitinib action on a larger panel of NSCLC cell lines verified that FGFR2 and FGFR3 expression is increased at the mRNA and protein level in NSCLC cell lines in which the EGFR is dominant for growth signaling, but not in cell lines where EGFR signaling is absent. A luciferase reporter containing 2.5 kilobases of fgfr2 5′ flanking sequence was activated after gefitinib treatment, indicating transcriptional regulation as a contributing mechanism controlling increased FGFR2 expression. Induction of FGFR2 and FGFR3 protein as well as fgfr2-luc activity was also observed with Erbitux, an EGFR-specific monoclonal antibody. Moreover, inhibitors of c-Src and MEK stimulated fgfr2-luc activity to a similar degree as gefitinib, suggesting that these pathways may mediate EGFR-dependent repression of FGFR2 and FGFR3. Importantly, our studies demonstrate that EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF2 and FGF7 stimulated ERK activation as well as FGF-stimulated transformed growth in the setting of EGFR TKIs. In conclusion, this study highlights EGFR TKI-induced FGFR2 and FGFR3 signaling as a novel and rapid mechanism of acquired resistance to EGFR TKIs and suggests that treatment of NSCLC patients with combinations of EGFR and FGFR specific TKIs may be a strategy to enhance efficacy of single EGFR inhibitors

Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort

Jane Salmon and colleagues studied 250 pregnant patients with SLE and/or antiphospholipid antibodies and found an association of risk variants in complement regulatory proteins in patients who developed preeclampsia, as well as in preeclampsia patients lacking autoimmune disease

Building a sickle cell disease screening program in the Republic of Uganda: the Uganda Sickle Surveillance Study (US3) with 3 years of follow-up screening results.

The prevalence of sickle cell disease (SCD) in the Republic of Uganda is higher than in the United States, but there are no accurate countrywide data and no newborn screening program has been established. The Early Infant Diagnosis (EID) program is well established to analyze dried blood spots (DBSs) collected from HIV-exposed infants (ie, those born to HIV-positive mothers). HIV-positive infants are identified and placed into specialty care. At the request of the Uganda Ministry of Health, a partnership was developed between Cincinnati Children’s Hospital Medical Center, Makerere University, and the Uganda Central Public Health Laboratories (CHPL) to build local laboratory capacity for testing DBSs for sickle cell trait (SCT) and SCD. The Uganda Sickle Surveillance Study (US3) was designed to identify SCT or SCD in DBSs collected throughout the national EID program. After US3, screening commenced in high-burden districts with local capacity built to provide clinical care for affected infants

Trauma history and depression predict incomplete adherence to antiretroviral therapies in a low income country.

As antiretroviral therapy (ART) for HIV becomes increasingly available in low and middle income countries (LMICs), understanding reasons for lack of adherence is critical to stemming the tide of infections and improving health. Understanding the effect of psychosocial experiences and mental health symptomatology on ART adherence can help maximize the benefit of expanded ART programs by indicating types of services, which could be offered in combination with HIV care. The Coping with HIV/AIDS in Tanzania (CHAT) study is a longitudinal cohort study in the Kilimanjaro Region that included randomly selected HIV-infected (HIV+) participants from two local hospital-based HIV clinics and four free-standing voluntary HIV counselling and testing sites. Baseline data were collected in 2008 and 2009; this paper used data from 36 month follow-up interviews (N = 468). Regression analyses were used to predict factors associated with incomplete self-reported adherence to ART. INCOMPLETE ART ADHERENCE WAS SIGNIFICANTLY MORE LIKELY TO BE REPORTED AMONGST PARTICIPANTS WHO EXPERIENCED A GREATER NUMBER OF CHILDHOOD TRAUMATIC EVENTS: sexual abuse prior to puberty and the death in childhood of an immediate family member not from suicide or homicide were significantly more likely in the non-adherent group and other negative childhood events trended toward being more likely. Those with incomplete adherence had higher depressive symptom severity and post-traumatic stress disorder (PTSD). In multivariable analyses, childhood trauma, depression, and financial sacrifice remained associated with incomplete adherence.\ud This is the first study to examine the effect of childhood trauma, depression and PTSD on HIV medication adherence in a low income country facing a significant burden of HIV. Allocating spending on HIV/AIDS toward integrating mental health services with HIV care is essential to the creation of systems that enhance medication adherence and maximize the potential of expanded antiretroviral access to improve health and reduce new infections

A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer

Despite substantial improvements in the treatment landscape of prostate cancer, the evolution of hormone therapy-resistant and metastatic prostate cancer remains a major cause of cancer-related death globally. The mainstay of treatment for advanced prostate cancer is targeting of androgen receptor signaling, including androgen deprivation therapy plus second-generation androgen receptor blockade (e.g., enzalutamide, apalutamide, darolutamide), and/or androgen synthesis inhibition (abiraterone). While these agents have significantly prolonged the lives of patients with advanced prostate cancer, is nearly universal. This therapy resistance is mediated by diverse mechanisms, including both androgen receptor-dependent mechanisms, such as androgen receptor mutations, amplifications, alternative splicing, and amplification, as well as non-androgen receptor-mediated mechanisms, such as lineage plasticity toward neuroendocrine-like or epithelial-mesenchymal transition (EMT)-like lineages. Our prior work identified the EMT transcriptional regulator Snail as critical to hormonal therapy resistance and is commonly detected in human metastatic prostate cancer. In the current study, we sought to interrogate the actionable landscape of EMT-mediated hormone therapy resistant prostate cancer to identify synthetic lethality and collateral sensitivity approaches to treating this aggressive, therapy-resistant disease state. Using a combination of high-throughput drug screens and multi-parameter phenotyping by confluence imaging, ATP production, and phenotypic plasticity reporters of EMT, we identified candidate synthetic lethalities to Snail-mediated EMT in prostate cancer. These analyses identified multiple actionable targets, such as XPO1, PI3K/mTOR, aurora kinases, c-MET, polo-like kinases, and JAK/STAT as synthetic lethalities in Snail+ prostate cancer. We validated these targets in a subsequent validation screen in an LNCaP-derived model of resistance to sequential androgen deprivation and enzalutamide. This follow-up screen provided validation of inhibitors of JAK/STAT and PI3K/mTOR as therapeutic vulnerabilities for both Snail+ and enzalutamide-resistant prostate cancer

Efficacy of manipulation for non-specific neck pain of recent onset: design of a randomised controlled trial

BACKGROUND: Manipulation is a common treatment for non-specific neck pain. Neck manipulation, unlike gentler forms of manual therapy such as mobilisation, is associated with a small risk of serious neurovascular injury and can result in stroke or death. It is thought however, that neck manipulation provides better results than mobilisation where clinically indicated. There is long standing and vigorous debate both within and between the professions that use neck manipulation as well as the wider scientific community as to whether neck manipulation potentially does more harm than good. The primary aim of this study is to determine whether neck manipulation provides more rapid resolution of an episode of neck pain than mobilisation. METHODS/DESIGN: 182 participants with acute and sub-acute neck pain will be recruited from physiotherapy, chiropractic and osteopathy practices in Sydney, Australia. Participants will be randomly allocated to treatment with either manipulation or mobilisation. Randomisation will occur after the treating practitioner decides that manipulation is an appropriate treatment for the individual participant. Both groups will receive at least 4 treatments over 2 weeks. The primary outcome is number of days taken to recover from the episode of neck pain. Cox regression will be used to compare survival curves for time to recovery for the manipulation and mobilisation treatment groups. DISCUSSION: This paper presents the rationale and design of a randomised controlled trial to compare the effectiveness of neck manipulation and neck mobilisation for acute and subacute neck pain

Short and medium-term effects of an education self-management program for individuals with osteoarthritis of the knee, designed and delivered by health professionals: A quality assurance study

<p>Abstract</p> <p>Background</p> <p>Self-management (SM) programs are effective for some chronic conditions, however the evidence for arthritis SM is inconclusive. The aim of this case series project was to determine whether a newly developed specific self-management program for people with osteoarthritis of the knee (OAK), implemented by health professionals could achieve and maintain clinically meaningful improvements.</p> <p>Methods</p> <p><it>Participants: </it>79 participants enrolled; mean age 66, with established osteoarthritis of the knee. People with coexisting inflammatory joint disease or serious co-morbidities were excluded.</p> <p><it>Intervention: </it>6-week disease (OA) and site (knee) specific self-management education program that included disease education, exercise advice, information on healthy lifestyle and relevant information within the constructs of self-management. This program was conducted in a community health care setting and was delivered by health professionals thereby utilising their knowledge and expertise.</p> <p><it>Measurements: </it>Pain, physical function and mental health scales were assessed at baseline, 8 weeks, 6 and 12 months using WOMAC and SF-36 questionnaires. Changes in pain during the 8-week intervention phase were monitored with VAS.</p> <p>Results</p> <p>Pain improved during the intervention phase: mean (95% CI) change 15 (8 to 22) mm. Improvements (0.3 to 0.5 standard deviation units) in indices of pain, mental health and physical functioning, assessed by SF-36 and WOMAC questionnaires were demonstrated from baseline to 12 months.</p> <p>Conclusion</p> <p>This disease and site-specific self-management education program improved health status of people with osteoarthritis of the knee in the short and medium term.</p

Prevalence of inherited blood disorders and associations with malaria and anemia in Malawian children

In sub-Saharan Africa, inherited causes of anemia are common, but data are limited regarding the geographical prevalence and coinheritance of these conditions and their overall contributions to childhood anemia. To address these questions in Malawi, we performed a secondary analysis of the 2015-2016 Malawi Micronutrient Survey, a nationally and regionally representative survey that estimated the prevalence of micronutrient deficiencies and evaluated both inherited and noninherited determinants of anemia. Children age 6 to 59 months were sampled from 105 clusters within the 2015-2016 Malawi Demographic Health Survey. Hemoglobin, ferritin, retinol binding protein, malaria, and inflammatory biomarkers were measured from venous blood. Molecular studies were performed using dried blood spots to determine the presence of sickle cell disease or trait, α-thalassemia trait, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 1279 eligible children, 1071 were included in the final analysis. Anemia, iron deficiency, and malaria were common, affecting 30.9%, 21.5%, and 27.8% of the participating children, respectively. α-Thalassemia trait was common (>40% of children demonstrating deletion of 1 [33.1%] or 2 [10.0%] α-globin genes) and associated with higher prevalence of anemia (P < .001). Approximately 20% of males had G6PD deficiency, which was associated with a 1.0 g/dL protection in hemoglobin decline during malaria infection (P = .02). These data document that inherited blood disorders are common and likely play an important role in the prevalence of anemia and malaria in Malawian children