STAT5 Represses a STAT3-Independent Th17-like Program during Th9 Cell Differentiation.

IL-9-producing Th cells, termed Th9 cells, contribute to immunity against parasites and cancers but have detrimental roles in allergic disease and colitis. Th9 cells differentiate in response to IL-4 and TGF-ß, but these signals are insufficient to drive Th9 differentiation in the absence of IL-2. IL-2-induced STAT5 activation is required for chromatin accessibility within Il9 enhancer and promoter regions and directly transactivates the Il9 locus. STAT5 also suppresses gene expression during Th9 cell development, but these roles are less well defined. In this study, we demonstrate that human allergy-associated Th9 cells exhibited a signature of STAT5-mediated gene repression that is associated with the silencing of a Th17-like transcriptional signature. In murine Th9 cell differentiation, blockade of IL-2/STAT5 signaling induced the expression of IL-17 and the Th17-associated transcription factor Rorγt. However, IL-2-deprived Th9 cells did not exhibit a significant Th17- or STAT3-associated transcriptional signature. Consistent with these observations, differentiation of IL-17-producing cells under these conditions was STAT3-independent but did require Rorγt and BATF. Furthermore, ectopic expression of Rorγt and BATF partially rescued IL-17 production in STAT3-deficient Th17 cells, highlighting the importance of these factors in this process. Although STAT3 was not required for the differentiation of IL-17-producing cells under IL-2-deprived Th9 conditions, their prolonged survival was STAT3-dependent, potentially explaining why STAT3-independent IL-17 production is not commonly observed in vivo. Together, our data suggest that IL-2/STAT5 signaling plays an important role in controlling the balance of a Th9 versus a Th17-like differentiation program in vitro and in allergic disease.

What are the views of three key stakeholder groups on extending the breast screening interval for low-risk women? A secondary qualitative analysis.

INTRODUCTION: There is increasing interest in risk-stratified breast screening, whereby the prevention and early detection offers vary by a woman's estimated risk of breast cancer. To date, more focus has been directed towards high-risk screening pathways rather than considering women at lower risk, who may be eligible for extended screening intervals. This secondary data analysis aimed to compare the views of three key stakeholder groups on how extending screening intervals for low-risk women should be implemented and communicated as part of a national breast screening programme. METHODS: Secondary data analysis of three qualitative studies exploring the views of distinct stakeholder groups was conducted. Interviews took place with 23 low-risk women (identified from the BC-Predict study) and 17 national screening figures, who were involved in policy-making and implementation. In addition, three focus groups and two interviews were conducted with 26 healthcare professionals. A multiperspective thematic analysis was conducted to identify similarities and differences between stakeholders. FINDINGS: Three themes were produced: Questionable assumptions about negative consequences, highlighting how other stakeholders lack trust in how women are likely to understand extended screening intervals; Preserving the integrity of the programme, centring on decision-making and maintaining a positive reputation of breast screening and Negotiating a communication pathway highlighting communication expectations and public campaign importance. CONCLUSIONS: A risk-stratified screening programme should consider how best to engage women assessed as having a low risk of breast cancer to ensure mutual trust, balance the practicality of change whilst ensuring acceptability, and carefully develop multilevel inclusive communication strategies. PATIENT AND PUBLIC CONTRIBUTION: The research within this paper involved patient/public contributors throughout including study design and materials input.

Micropatterned mammalian cells exhibit phenotype-specific left-right asymmetry.

Left-right (LR) asymmetry (handedness, chirality) is a well-conserved biological property of critical importance to normal development. Changes in orientation of the LR axis due to genetic or environmental factors can lead to malformations and disease. While the LR asymmetry of organs and whole organisms has been extensively studied, little is known about the LR asymmetry at cellular and multicellular levels. Here we show that the cultivation of cell populations on micropatterns with defined boundaries reveals intrinsic cell chirality that can be readily determined by image analysis of cell alignment and directional motion. By patterning 11 different types of cells on ring-shaped micropatterns of various sizes, we found that each cell type exhibited definite LR asymmetry (p value down to 10(-185)) that was different between normal and cancer cells of the same type, and not dependent on surface chemistry, protein coating, or the orientation of the gravitational field. Interestingly, drugs interfering with actin but not microtubule function reversed the LR asymmetry in some cell types. Our results show that micropatterned cell populations exhibit phenotype-specific LR asymmetry that is dependent on the functionality of the actin cytoskeleton. We propose that micropatterning could potentially be used as an effective in vitro tool to study the initiation of LR asymmetry in cell populations, to diagnose disease, and to study factors involved with birth defects in laterality.

"Find Out What They Lack, Try to Provide": A Qualitative Investigation of Palliative Care Services Adapted to Local Need in a Low-Resource Setting.

Background: People in low- and middle-income countries with serious health problems rarely have access to palliative care. Promising models of palliative care delivery have emerged in India despite widespread poverty and poor health care infrastructure. Objective: To explore structural and philosophical aspects of palliative care delivery in a low-resource setting. Design: One author spent six months as a participant observer at Pallium India (PI), a nongovernmental organization recognized for leadership in palliative care delivery in Kerala, India. We collected administrative data, conducted semistructured interviews with key stakeholders, and observed clinical encounters and other organization-led events. Results: We performed 73 interviews with patients, families, clinicians, staff, and volunteers, and observed 180 patient encounters. The majority of palliative care patients did not have cancer. Many had chronic diseases that were not immediately life threatening. Services addressed a broad range of patients' medical, psychological, social, and/or financial needs. PI's care delivery maximizes accessibility. Conclusions: PI employs an expansive definition of palliative care and adapts services to respond to patients' diverse needs. This accessible, people-centered care is necessary in low-resource settings to alleviate multifaceted suffering caused by gaps in the health care system, poor social support, and poverty.

The successful use of dronabinol for failure to thrive secondary to intestinal dysmotility.

INTRODUCTION: Symptoms of severe intestinal dysmotility decrease patients' quality of life and may prevent them from sustaining adequate oral intake. Dronabinol is a synthetic cannabinoid that is labeled for use in AIDS-related anorexia and chemotherapy-associated nausea and vomiting that has additional efficacy in patients with other etiologies of nausea, vomiting, and anorexia. PRESENTATION OF CASE: We present a 58-year-old female with a history of nausea, vomiting, abdominal pain, and inability to maintain oral intake after multiple laparotomies for ectopic pregnancy, recurrent caecal volvulus, and cholecystitis. After eight years of unsuccessful trials of medicines, dietary modifications, and a partial colectomy, she began a trial of dronabinol, which caused almost complete remission of her symptoms. When this medication was discontinued by her payer, she was unable to maintain oral intake and therefore, was admitted to the hospital for fluid resuscitation and resumption of dronabinol. DISCUSSION: The use of dronabinol in this patient with severe intestinal dysmotility allowed her to maintain her nutritional status orally and obviated the need for enteral or parenteral feeding. Unfortunately, it was not covered by her insurance company for this indication. CONCLUSION: Dronabinol has the potential to improve quality of life for patients beyond those undergoing chemotherapy or suffering from AIDS. Lack of access to this medicine for patients with intestinal dysmotility after all other modalities have been tried can lead to morbid and expensive complications, such as inpatient admission and surgery for enteral access.