CUZD1 is a critical mediator of the JAK/STAT5 signaling pathway that controls mammary gland development during pregnancy.

In the mammary gland, genetic circuits controlled by estrogen, progesterone, and prolactin, act in concert with pathways regulated by members of the epidermal growth factor family to orchestrate growth and morphogenesis during puberty, pregnancy and lactation. However, the precise mechanisms underlying the crosstalk between the hormonal and growth factor pathways remain poorly understood. We have identified the CUB and zona pellucida-like domain-containing protein 1 (CUZD1), expressed in mammary ductal and alveolar epithelium, as a novel mediator of mammary gland proliferation and differentiation during pregnancy and lactation. Cuzd1-null mice exhibited a striking impairment in mammary ductal branching and alveolar development during pregnancy, resulting in a subsequent defect in lactation. Gene expression profiling of mammary epithelium revealed that CUZD1 regulates the expression of a subset of the EGF family growth factors, epiregulin, neuregulin-1, and epigen, which act in an autocrine fashion to activate ErbB1 and ErbB4 receptors. Proteomic studies further revealed that CUZD1 interacts with a complex containing JAK1/JAK2 and STAT5, downstream transducers of prolactin signaling in the mammary gland. In the absence of CUZD1, STAT5 phosphorylation in the mammary epithelium during alveologenesis was abolished. Conversely, elevated expression of Cuzd1 in mammary epithelial cells stimulated prolactin-induced phosphorylation and nuclear translocation of STAT5. Chromatin immunoprecipitation confirmed co-occupancy of phosphorylated STAT5 and CUZD1 in the regulatory regions of epiregulin, a potential regulator of epithelial proliferation, and whey acidic protein, a marker of epithelial differentiation. Collectively, these findings suggest that CUZD1 plays a critical role in prolactin-induced JAK/STAT5 signaling that controls the expression of key STAT5 target genes involved in mammary epithelial proliferation and differentiation during alveolar development.

Aberrantly high expression of the CUB and zona pellucida-like domain-containing protein 1 (CUZD1) in mammary epithelium leads to breast tumorigenesis.

The peptide hormone prolactin (PRL) and certain members of the epidermal growth factor (EGF) family play central roles in mammary gland development and physiology, and their dysregulation has been implicated in mammary tumorigenesis. Our recent studies have revealed that the CUB and zona pellucida-like domain-containing protein 1 (CUZD1) is a critical factor for PRL-mediated activation of the transcription factor STAT5 in mouse mammary epithelium. Of note, CUZD1 controls production of a specific subset of the EGF family growth factors and consequent activation of their receptors. Here, we found that consistent with this finding, CUZD1 overexpression in non-transformed mammary epithelial HC11 cells increases their proliferation and induces tumorigenic characteristics in these cells. When introduced orthotopically in mouse mammary glands, these cells formed adenocarcinomas, exhibiting elevated levels of STAT5 phosphorylation and activation of the EGF signaling pathway. Selective blockade of STAT5 phosphorylation by pimozide, a small-molecule inhibitor, markedly reduced the production of the EGF family growth factors and inhibited PRL-induced tumor cell proliferation in vitro Pimozide administration to mice also suppressed CUZD1-driven mammary tumorigenesis in vivo Analysis of human MCF7 breast cancer cells indicated that CUZD1 controls the production of the same subset of EGF family members in these cells as in the mouse. Moreover, pimozide treatment reduced the proliferation of these cancer cells. Collectively, these findings indicate that overexpression of CUZD1, a regulator of growth factor pathways controlled by PRL and STAT5, promotes mammary tumorigenesis. Blockade of the STAT5 signaling pathway downstream of CUZD1 may offer a therapeutic strategy for managing these breast tumors.

Efficacy of Percutaneous Posterior Tibial Nerve Stimulation for the Management of Fecal Incontinence in Multiple Sclerosis: A Pilot Study.

BACKGROUND: Fecal incontinence is a debilitating and highly prevalent problem among multiple sclerosis patients. Conservative therapies often fail to provide benefit. Posterior tibial nerve stimulation is a minimally invasive neuromodulatory therapy with proven efficacy for fecal incontinence in non-neurological settings. OBJECTIVE: To evaluate the efficacy of posterior tibial nerve stimulation in treating multiple sclerosis-related fecal incontinence. METHODS: Consecutive multiple sclerosis patients with fecal incontinence that had failed conservative therapy received posterior tibial nerve stimulation between 2012 and 2015. All patients had previously undergone anorectal physiology tests and endoanal ultrasound. Patients whose Wexner incontinence score reduced below 10 post-therapy or halved from baseline were deemed responders. RESULTS: Thirty-three patients (25 female, median age 43 years) were included. Twenty-three (70%) had urge, 4 (12%) passive, and 9 (27%) mixed fecal incontinence. Twenty-six (79%) were classified as responders. The majority of subjects had relapsing-remitting multiple sclerosis (67%); those had a significantly higher response rate (95% vs. 67% and 50% in primary and secondary progressive respectively, P < 0.05). Responders tended to be more symptomatic at baseline and had greater improvements in bowel symptom scores and quality of life scores with therapy. CONCLUSION: Posterior tibial nerve stimulation demonstrates potential as an effective therapy for fecal incontinence in multiple sclerosis. These findings provide the basis for future more definitive controlled studies.

What you need to know about: organising pneumonia.

Organising pneumonia was first described in the context of respiratory infection, but over time has become established as its own entity. It is an area of diagnostic complexity because of the non-specific presenting symptoms and signs that can often mimic other respiratory pathology. Multidisciplinary review to correlate clinical, radiological and histopathological features can aid timely and effective diagnosis. This article discusses the epidemiology, aetiology, clinical, radiological and histopathological features, investigation and management of organising pneumonia.

Symptomatic, biochemical and radiographic recovery in patients with COVID-19.

BACKGROUND: The symptoms, radiography, biochemistry and healthcare utilisation of patients with COVID-19 following discharge from hospital have not been well described. METHODS: Retrospective analysis of 401 adult patients attending a clinic following an index hospital admission or emergency department attendance with COVID-19. Regression models were used to assess the association between characteristics and persistent abnormal chest radiographs or breathlessness. RESULTS: 75.1% of patients were symptomatic at a median of 53 days post discharge and 72 days after symptom onset and chest radiographs were abnormal in 47.4%. Symptoms and radiographic abnormalities were similar in PCR-positive and PCR-negative patients. Severity of COVID-19 was significantly associated with persistent radiographic abnormalities and breathlessness. 18.5% of patients had unscheduled healthcare visits in the 30 days post discharge. CONCLUSIONS: Patients with COVID-19 experience persistent symptoms and abnormal blood biomarkers with a gradual resolution of radiological abnormalities over time. These findings can inform patients and clinicians about expected recovery times and plan services for follow-up of patients with COVID-19.

Surgical management of buried penis in adults.

INTRODUCTION: Buried penis is a condition that causes the penis to become hidden beneath the skin. It has a significant impact on quality of life and can present in a variety of ways, with lower urinary tract symptoms and erectile dysfunction being common. Whilst there are several causes, obesity is the most common in adults. Due to the burden that obesity is increasingly presenting to healthcare, buried penis may become more common in the future.The purpose of this article is to provide an overview of the causes, presentation and surgical management of this condition in adults. MATERIAL AND METHOD: A literature review was conducted using urological and plastic surgery articles from PubMed, Embase and Medline. Eighteen studies, published between 1982 and 2016, were included. RESULTS: Original research trials discussed the treatment of buried penis in lymphoedema and balanitis xerotica obliterans (BXO), new techniques for fat removal, comparison of grafts and postoperative dressings. Several studies provided broad overviews, although focused on management rather than cause and presentation. Overall, studies suggest that, whilst some causes can only be treated with surgery, others can be modified by lifestyle changes and medical management. CONCLUSIONS: Buried penis is a complex condition that may take years to treat. Several surgical techniques are available, with patients likely requiring a combination of techniques to treat this problem. This review aims to provide a comprehensive overview of the causes, presentation and surgical management of this condition, in order to further the understanding of clinicians who may be faced with this problem more commonly in the future.

Misexpression screen for genes altering the olfactory map in Drosophila.

Despite the identification of a number of guidance molecules, a comprehensive picture has yet to emerge to explain the precise anatomy of the olfactory map. From a misexpression screen of 1,515 P{GS} lines, we identified 23 genes that, when forcibly expressed in the olfactory receptor neurons, disrupted the stereotyped anatomy of the Drosophila antennal lobes. These genes, which have not been shown previously to control olfactory map development, encode novel proteins as well as proteins with known roles in axonal outgrowth and cytoskeletal remodeling. We analyzed Akap200, which encodes a Protein Kinase A-binding protein. Overexpression of Akap200 resulted in fusion of the glomeruli, while its loss resulted in misshapen and ectopic glomeruli. The requirement of Akap200 validates our screen as an effective approach for recovering genes controlling glomerular map patterning. Our finding of diverse classes of genes reveals the complexity of the mechanisms that underlie olfactory map development.