Antagonizing CD105 and androgen receptor to target stromal-epithelial interactions for clinical benefit.

Androgen receptor signaling inhibitors (ARSIs) are standard of care for advanced prostate cancer (PCa) patients. Eventual resistance to ARSIs can include the expression of androgen receptor (AR) splice variant, AR-V7, expression as a recognized means of ligand-independent androgen signaling. We demonstrated that interleukin (IL)-6-mediated AR-V7 expression requires bone morphogenic protein (BMP) and CD105 receptor activity in both PCa and associated fibroblasts. Chromatin immunoprecipitation supported CD105-dependent ID1- and E2F-mediated expression of RBM38. Further, RNA immune precipitation demonstrated RBM38 binds the AR-cryptic exon 3 to enable AR-V7 generation. The forced expression of AR-V7 by primary prostatic fibroblasts diminished PCa sensitivity to ARSI. Conversely, downregulation of AR-V7 expression in cancer epithelia and associated fibroblasts was achieved by a CD105-neutralizing antibody, carotuximab. These compelling pre-clinical findings initiated an interventional study in PCa patients developing ARSI resistance. The combination of carotuximab and ARSI (i.e., enzalutamide or abiraterone) provided disease stabilization in four of nine assessable ARSI-refractory patients. Circulating tumor cell evaluation showed AR-V7 downregulation in the responsive subjects on combination treatment and revealed a three-gene panel that was predictive of response. The systemic antagonism of BMP/CD105 signaling can support ARSI re-sensitization in pre-clinical models and subjects that have otherwise developed resistance due to AR-V7 expression.

The book is just being written: The enduring journey of parents of children with emerging- ultrarare disorders.

Ultra rare disorders are being diagnosed at an unprecedented rate, due to genomic sequencing. These diagnoses are often a new gene association, for which little is known, and few share the diagnosis. For these diagnoses, we use the term emerging-ultrarare disorder (E-URD), defined as <100 diagnosed individuals. We contacted 20 parents of children diagnosed with an E-URD through the Duke University Research Sequencing Clinic. Seventeen completed semi-structured interviews exploring parental perspectives (7/17 had children in publications describing the phenotype; 4/17 had children in the first publication establishing a new disorder). Data were analyzed using a directed content approach informed by an empowerment framework. Parents reported a range of responses, including benefits of a diagnosis and challenges of facing the unknown, some described feeling lost and confused, while others expressed empowerment. Empowerment characteristics were hope for the future, positive emotions, engagement, and confidence/self-efficacy to connect with similar others, partner with healthcare providers, and seek new knowledge. We identified a subset of parents who proactively engaged researchers, supported research and publications, and created patient advocacy and support organizations to connect with and bolster similarly diagnosed families. Other parents reported challenges of low social support, low tolerance for uncertainty, limited knowledge about their child's disorder, as well as difficulty partnering with HCPs and connecting to an E-URD community. An overarching classification was developed to describe parental actions taken after an E-URD diagnosis: adjusting, managing, and pioneering. These classifications may help genetic counselors identify and facilitate positive steps with parents of a child with an E-URD.

The disequilibrium of hope: A grounded theory analysis of parents' experiences of receiving a "no primary finding" result from genome sequencing.

Genome sequencing (GS) has the potential to reduce the "diagnostic odyssey" that many parents of children with rare undiagnosed conditions experience. While much research has considered the impact of receiving a diagnostic result, research has rarely focused solely on the impact of receiving a "no primary finding" (NPF) result. This study aimed to investigate the experience of parents of children with rare and undiagnosed conditions following an NPF result from GS. Nine parents whose child had an NPF result from GS were recruited through the social media platform of the charity SWAN (Syndromes Without A Name) UK. Semi-structured telephone interviews were conducted, transcribed verbatim, and analyzed using grounded theory. Analysis led to the emergence of two main themes. The first theme "Striving to Solve the Unsolved Puzzle" concerned the experience of striving to end the "diagnostic odyssey." The second theme "Navigating Hope, Lost then Found" plots the trajectory of hope raised by the promise of a new technology, dashed by the NPF, and the eventual return of small and distant hope for the future. Taken together, these themes allowed for a proposed theory: "The Disequilibrium of Hope," which highlights the dynamic and modifiable experience of hope participants experience in their GS journey. These results suggest GS can be an emotional rollercoaster for parents. While hope plays an important role in coping with the day-to-day life of living with a rare disease, careful management of expectations from GS is important during pre-test counseling, and continued follow-up and support are needed beyond result disclosure. An understanding of the disappointment and distress caused by an NPF result is valuable for healthcare professionals in this field to ensure counseling can be tailored. Further research should consider how to support parents after an NPF result.

Facile bottom-up synthesis of partially oxidized black phosphorus nanosheets as metal-free photocatalyst for hydrogen evolution.

Few-layer black phosphorus (BP) nanosheets were first reported as a 2D material for the application of field-effect transistors in 2014 and have stimulated intense activity among physicists, chemists, and material and biomedical scientists, driving research into novel synthetic techniques to produce BP nanosheets. At present, exfoliation is the main route toward few-layer BP nanosheets via employing bulk BP as raw material. However, this is a complicated and time-consuming process, which is difficult for the large-scale synthesis of BP nanosheets. Moreover, BP degrades rapidly when exfoliated to nanoscale dimensions, resulting in the rapid loss of semiconducting properties. Here, we report the direct wet-chemical synthesis of few-layer BP nanosheets in gram-scale quantities in a bottom-up approach based on common laboratory reagents at low temperature, showing excellent stability due to partial oxidation of surface. Solvent and temperature are two critical factors, controlling not only the formation of BP nanosheets but also the thickness. The as-prepared BP nanosheets can extract hydrogen from pure water (pH = 6.8), exhibiting more than 24-fold higher activity than the well-known C3N4 nanosheets. Our results reporting the ability to prepare few-layer BP nanosheets with a facile, scalable, low-cost approach take us a step closer to real-world applications of phosphorene including next-generation metal-free photocatalysts for photosynthesis.

Extreme pacemaker reel syndrome in an elderly patient with cognitive impairment.

Twiddler's syndrome is a rare cause of pacemaker failure, where patient manipulation of the pulse generator results in lead dislodgement or retraction. Variations in manifestation have been identified including reel syndrome, where rotation occurs around the transverse axis resulting in coiling of the leads, and ratchet syndrome where arm movement results in lead displacement. Device manipulation leading to device failure has been documented in up to 1.7% of implants, particularly in patients with large pockets or mental disorders. Such complications have serious consequences, particularly in pacing-dependent patients where loss of capture may result in asystole. This article reviews the case of an 84-year-old patient presenting at 8-month pacemaker follow-up in complete heart block with no evidence of pacemaker function.

The impact of rehabilitation on quality of life after hearing loss: a systematic review.

PURPOSE: Hearing loss is a major health problem and is associated with several negative outcomes such as difficulties in communicating and poor quality of life. The aim of this study was to conduct a systematic literature review to evaluate the impact of different types of hearing rehabilitation after hearing loss and their impact on quality of life. METHODS: A systematic literature search was conducted on Pubmed which retrieved 549 articles. Of these, 29 articles regarding cochlear implants, bone anchored hearing devices and traditional amplification hearing aids have been systematically reviewed. The search was limited to articles published from 1960/01/01 to 2017/05/22, included human participants and available in English. RESULTS: The main finding was that hearing rehabilitation is beneficial in all types of hearing loss and treatment regarding quality of life. However, bone-anchored hearing devices and cochlear implants were shown to produce greater improvements in terms of quality of life than conventional hearing aids. CONCLUSION: From these findings, we concluded that hearing rehabilitation does have a positive impact on quality of life after hearing loss.

Right-ear precedence and vocal emotion contagion: The role of the left hemisphere.

Much evidence suggests that the processing of emotions is lateralized to the right hemisphere of the brain. However, under some circumstances the left hemisphere might play a role, particularly for positive emotions and emotional experiences. We explored whether emotion contagion was right-lateralized, lateralized valence-specifically, or potentially left-lateralized. In two experiments, right-handed female listeners rated to what extent emotionally intoned pseudo-sentences evoked target emotions in them. These sound stimuli had a 7 ms ear lead in the left or right channel, leading to stronger stimulation of the contralateral hemisphere. In both experiments, the results revealed that right ear lead stimuli received subtly but significantly higher evocation scores, suggesting a left hemisphere dominance for emotion contagion. A control experiment using an emotion identification task showed no effect of ear lead. The findings are discussed in relation to prior findings that have linked the processing of emotional prosody to left-hemisphere brain regions that regulate emotions, control orofacial musculature, are involved in affective empathy processing areas, or have an affinity for processing emotions socially. Future work is needed to eliminate alternative interpretations and understand the mechanisms involved. Our novel binaural asynchrony method may be useful in future work in auditory laterality.

Muscadine grape skin extract can antagonize Snail-cathepsin L-mediated invasion, migration and osteoclastogenesis in prostate and breast cancer cells.

To develop new and effective chemopreventive agents against bone metastasis, we assessed the effects of muscadine grape skin extract (MSKE), whose main bioactive component is anthocyanin, on bone turnover, using prostate and breast cancer cell models overexpressing Snail transcription factor. MSKE has been shown previously to promote apoptosis in prostate cancer cells without affecting normal prostate epithelial cells. Snail is overexpressed in prostate and breast cancer, and is associated with increased invasion, migration and bone turnover/osteoclastogenesis. Cathepsin L (CatL) is a cysteine cathepsin protease that is overexpressed in cancer and involved in bone turnover. Snail overexpression in prostate (LNCaP, ARCaP-E) and breast (MCF-7) cancer cells led to increased CatL expression/activity and phosphorylated STAT-3 (pSTAT-3), compared to Neo vector controls, while the reverse was observed in C4-2 (the aggressive subline of LNCaP) cells with Snail knockdown. Moreover, CatL expression was higher in prostate and breast tumor tissue compared to normal tissue. MSKE decreased Snail and pSTAT3 expression, and abrogated Snail-mediated CatL activity, migration and invasion. Additionally, Snail overexpression promoted osteoclastogenesis, which was significantly inhibited by the MSKE as effectively as Z-FY-CHO, a CatL-specific inhibitor, or osteoprotegerin, a receptor activator of nuclear factor kappa B ligand (RANKL) antagonist. Overall, these novel findings suggest that Snail regulation of CatL may occur via STAT-3 signaling and can be antagonized by MSKE, leading to decreased cell invasion, migration and bone turnover. Therefore, inhibition using a natural product such as MSKE could potentially be a promising bioactive compound for bone metastatic cancer.

Folding paper-based lithium-ion batteries for higher areal energy densities.

Paper folding techniques are used in order to compact a Li-ion battery and increase its energy per footprint area. Full cells were prepared using Li4Ti5O12 and LiCoO2 powders deposited onto current collectors consisting of paper coated with carbon nanotubes. Folded cells showed higher areal capacities compared to the planar versions with a 5 × 5 cell folded using the Miura-ori pattern displaying a ~14× increase in areal energy density.

Experimental evidence for adaptive divergence in response to a warmed habitat reveals roles for morphology, allometry and parasite resistance.

Ectotherms are expected to be particularly vulnerable to climate change-driven increases in temperature. Understanding how populations adapt to novel thermal environments will be key for informing mitigation plans. We took advantage of threespine stickleback (Gasterosteus aculeatus) populations inhabiting adjacent geothermal (warm) and ambient (cold) habitats to test for adaptive evolutionary divergence using a field reciprocal transplant experiment. We found evidence for adaptive morphological divergence, as growth (length change) in non-native habitats related to head, posterior and total body shape. Higher growth in fish transplanted to a non-native habitat was associated with morphological shape closer to native fish. The consequences of transplantation were asymmetric with cold sourced fish transplanted to the warm habitat suffering from lower survival rates and greater parasite prevalence than warm sourced fish transplanted to the cold habitat. We also found divergent shape allometries that related to growth. Our findings suggest that wild populations can adapt quickly to thermal conditions, but immediate transitions to warmer conditions may be particularly difficult.

May-Thurner Syndrome: An Interesting Presentation of Recurrent, Unprovoked Deep Vein Thrombosis.

May-Thurner Syndrome (MTS) is a unique condition characterized by the compression of the left iliac vein by the right common iliac artery, which causes venous outflow obstruction and a high risk of venous sequelae. May-Thurner Syndrome is a condition that is primarily observed in females and is an uncommon cause of deep vein thrombosis (DVT). The more common presentation of DVT is in the lower left extremity, although there have been cases of right-sided formation. In this case report, we present a patient with unprovoked, recurrent, left-sided deep vein thrombosis in a 70-year-old woman. The aim of this case report is to highlight this uncommon condition and to suggest consideration of MTS in the setting of a patient with recurrent unprovoked DVTs of the same extremity.

Testing the predictability of morphological evolution in contrasting thermal environments.

Gaining the ability to predict population responses to climate change is a pressing concern. Using a "natural experiment," we show that testing for divergent evolution in wild populations from contrasting thermal environments provides a powerful approach, and likely an enhanced predictive power for responses to climate change. Specifically, we used a unique study system in Iceland, where freshwater populations of threespine sticklebacks (Gasterosteus aculeatus) are found in waters warmed by geothermal activity, adjacent to populations in ambient-temperature water. We focused on morphological traits across six pairs from warm and cold habitats. We found that fish from warm habitats tended to have a deeper mid-body, a subterminally orientated jaw, steeper craniofacial profile, and deeper caudal region relative to fish from cold habitats. Our common garden experiment showed that most of these differences were heritable. Population age did not appear to influence the magnitude or type of thermal divergence, but similar types of divergence between thermal habitats were more prevalent across allopatric than sympatric population pairs. These findings suggest that morphological divergence in response to thermal habitat, despite being relatively complex and multivariate, are predictable to a degree. Our data also suggest that the potential for migration of individuals between different thermal habitats may enhance nonparallel evolution and reduce our ability to predict responses to climate change.

Supraphysiological glutamine as a means of depleting intracellular amino acids to enhance pancreatic cancer chemosensitivity.

Limited efficacy of systemic therapy for pancreatic ductal adenocarcinoma (PDAC) patients contributes to high mortality. Cancer cells develop strategies to secure nutrients in nutrient-deprived conditions and chemotherapy treatment. Despite the dependency of PDAC on glutamine (Gln) for growth and survival, strategies designed to suppress Gln metabolism have limited effects. Here, we demonstrated that supraphysiological concentrations of glutamine (SPG) could produce paradoxical responses leading to tumor growth inhibition alone and in combination with chemotherapy. Integrated metabolic and transcriptomic analysis revealed that the growth inhibitory effect of SPG was the result of a decrease in intracellular amino acid and nucleotide pools. Mechanistically, disruption of the sodium gradient, plasma membrane depolarization, and competitive inhibition of amino acid transport mediated amino acid deprivation. Among standard chemotherapies given to PDAC patients, gemcitabine treatment resulted in a significant enrichment of amino acid and nucleoside pools, exposing a metabolic vulnerability to SPG-induced metabolic alterations. Further analysis highlighted a superior anticancer effect of D-glutamine, a non-metabolizable enantiomer of the L-glutamine, by suppressing both amino acid uptake and glutaminolysis, in gemcitabine-treated preclinical models with no apparent toxicity. Our study suggests supraphysiological glutamine could be a means of inhibiting amino acid uptake and nucleotide biosynthesis, potentiating gemcitabine sensitivity in PDAC.

Genetic and biological drivers of prostate cancer disparities in Black men.

Black men with prostate cancer have historically had worse outcomes than white men with prostate cancer. The causes of this disparity in outcomes are multi-factorial, but a potential basis is that prostate cancers in Black men are biologically distinct from prostate cancers in white men. Evidence suggests that genetic and ancestral factors, molecular pathways involving androgen and non-androgen receptor signalling, inflammation, epigenetics, the tumour microenvironment and tumour metabolism are contributing factors to the racial disparities observed. Key genetic and molecular pathways linked to prostate cancer risk and aggressiveness have potential clinical relevance. Describing biological drivers of prostate cancer disparities could inform efforts to improve outcomes for Black men with prostate cancer.

Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms.

Neural sites that interact with the suprachiasmatic nuclei (SCN) to generate rhythms of unrestricted feeding remain unknown. We used the targeted toxin, leptin conjugated to saporin (Lep-SAP), to examine the importance of leptin receptor-B (LepR-B)-expressing neurons in the arcuate nucleus (Arc) for generation of circadian feeding rhythms. Rats given Arc Lep-SAP injections were initially hyperphagic and rapidly became obese (the "dynamic phase" of weight gain). During this phase, Lep-SAP rats were arrhythmic under 12:12-h light-dark (LD) conditions, consuming 59% of their total daily intake during the daytime, compared with 36% in blank-SAP (B-SAP) controls. Lep-SAP rats were also arrhythmic in continuous dark (DD), while significant circadian feeding rhythms were detected in all B-SAP controls. Approximately 8 wk after injection, Lep-SAP rats remained obese but transitioned into a "static phase" of weight gain marked by attenuation of their hyperphagia and rate of weight gain. In this phase, Arc Lep-SAP rats exhibited circadian feeding rhythms under LD conditions, but were arrhythmic in continuous light (LL) and DD. Lep-SAP injections into the ventromedial hypothalamic nucleus did not cause hyperphagia, obesity, or arrhythmic feeding in either LD or DD. Electrolytic lesion of the SCN produced feeding arrhythmia in DD but not hyperphagia or obesity. Results suggest that both Arc Lep-SAP neurons and SCN are required for generation of feeding rhythms entrained to photic cues, while also revealing an essential role for the Arc in maintaining circadian rhythms of ad libitum feeding independent of light entrainment.

Snail transcription factor negatively regulates maspin tumor suppressor in human prostate cancer cells.

BACKGROUND: Maspin, a putative tumor suppressor that is down-regulated in breast and prostate cancer, has been associated with decreased cell motility. Snail transcription factor is a zinc finger protein that is increased in breast cancer and is associated with increased tumor motility and invasion by induction of epithelial-mesenchymal transition (EMT). We investigated the molecular mechanisms by which Snail increases tumor motility and invasion utilizing prostate cancer cells. METHODS: Expression levels were analyzed by RT-PCR and western blot analyses. Cell motility and invasion assays were performed, while Snail regulation and binding to maspin promoter was analyzed by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RESULTS: Snail protein expression was higher in different prostate cancer cells lines as compared to normal prostate epithelial cells, which correlated inversely with maspin expression. Snail overexpression in 22Rv1 prostate cancer cells inhibited maspin expression and led to increased migration and invasion. Knockdown of Snail in DU145 and C4-2 cancer cells resulted in up-regulation of maspin expression, concomitant with decreased migration. Transfection of Snail into 22Rv1 or LNCaP cells inhibited maspin promoter activity, while stable knockdown of Snail in C4-2 cells increased promoter activity. ChIP analysis showed that Snail is recruited to the maspin promoter in 22Rv1 cells. CONCLUSIONS: Overall, this is the first report showing that Snail can negatively regulate maspin expression by directly repressing maspin promoter activity, leading to increased cell migration and invasion. Therefore, therapeutic targeting of Snail may be useful to re-induce expression of maspin tumor suppressor and prevent prostate cancer tumor progression.

NHS 111 Clinical Assessment Services: paediatric consultations.

Around the UK, commissioners have different models for delivering NHS 111, General Practice (GP) out-of-hours and urgent care services, focusing on telephony to help deliver urgent and emergency care. During the (early phases of the) COVID-19 pandemic, NHS 111 experienced an unprecedented volume of calls. At any time, 25%-30% of calls relate to children and young people (CYP). In response, the CYP's Transformation and Integrated Urgent Care teams at NHS England and NHS Improvement (NHSE/I) assisted in redeploying volunteer paediatricians into the integrated urgent care NHS 111 Clinical Assessment Services (CAS), taking calls about CYP. From this work, key stakeholders developed a paediatric 111 consultation framework, as well as learning outcomes, key capabilities and illustrations mapped against the Royal College of Paediatrics and Child Health (RCPCH) Progress curriculum domains, to aid paediatricians in training to undertake NHS 111 activities. These learning outcomes and key capabilities have been endorsed by the RCPCH Curriculum Review Group and are recommended to form part of the integrated urgent care service specification and workforce blueprint to improve outcomes for CYP.

Fatty Acid Signaling Impacts Prostate Cancer Lineage Plasticity in an Autocrine and Paracrine Manner.

Prostate cancer (PCa) affects an estimated 250,000 men every year and causes 34,000 deaths annually. A high-fat diet and obesity are associated with PCa progression and mortality. This study's premise was the novel observation of crosstalk between PCa epithelia and cancer-associated fibroblasts (CAF) in response to palmitate-mediated lineage plasticity. We found that cholesterol activated canonical Hedgehog (Hh) signaling by increasing cilium Gli activity in PCa cells, while palmitate activated Hh independent of Gli. Exogenous palmitate activated SOX2, a known mediator of lineage plasticity, in PCa cells cocultured with CAF. Stroma-derived Wnt5a was upregulated in CAF while cocultured with PCa cells and treated with palmitate. Wnt5a knockdown in CAF inhibited Hh and SOX2 expression in PCa cells from cocultures. These findings supported our proposed mechanism of a high-fat diet promoting Hh signaling-mediated transformation within the tumor microenvironment. SOX2 and Wnt5a expression were limited by the CD36 neutralizing antibody. Mice xenografted with PCa epithelia and CAF tumors were fed a high-fat diet, leading to elevated SOX2 expression and lineage plasticity reprogramming compared to mice fed an isocaloric rodent diet. CD36 inhibition with enzalutamide elevated apoptosis by TUNEL, but limited proliferation and SOX2 expression compared to enzalutamide alone. This study revealed a mechanism for a high-fat diet to affect prostate cancer progression. We found that saturated fat induced lineage plasticity reprogramming of PCa by interaction with CAF through Wnt5a and Hh signaling.

The mass-specific energy cost of human walking is set by stature.

The metabolic and mechanical requirements of walking are considered to be of fundamental importance to the health, physiological function and even the evolution of modern humans. Although walking energy expenditure and gait mechanics are clearly linked, a direct quantitative relationship has not emerged in more than a century of formal investigation. Here, on the basis of previous observations that children and smaller adult walkers expend more energy on a per kilogram basis than larger ones do, and the theory of dynamic similarity, we hypothesized that body length (or stature, L(b)) explains the apparent body-size dependency of human walking economy. We measured metabolic rates and gait mechanics at six speeds from 0.4 to 1.9 m s(-1) in 48 human subjects who varied by a factor of 1.5 in stature and approximately six in both age and body mass. In accordance with theoretical expectation, we found the most economical walking speeds measured (J kg(-1) m(-1)) to be dynamically equivalent (i.e. similar U, where U=velocity(2)/gravity · leg length) among smaller and larger individuals. At these speeds, stride lengths were directly proportional to stature whereas the metabolic cost per stride was largely invariant (2.74±0.12 J kg(-1) stride(-1)). The tight coupling of stature, gait mechanics and metabolic energy expenditure resulted in an inverse relationship between mass-specific transport costs and stature (E(trans)/M(b)∝L(b)(-0.95), J kg(-1) m(-1)). We conclude that humans spanning a broad range of ages, statures and masses incur the same mass-specific metabolic cost to walk a horizontal distance equal to their stature.