VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300.

Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEAD. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2, recently identified in spindle cell rhabdomyosarcoma. We demonstrate that, in contrast to VGLL2 and TEAD1, the fusion proteins are strong activators of TEAD-dependent transcription, and their function does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase p300 to control TEAD-mediated transcriptional and epigenetic landscapes. We showed that small molecule p300 inhibition can suppress fusion proteins-induced oncogenic transformation both in vitro and in vivo. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL, TEAD, or NCOA translocations.

Integrating a self-directed ultrasound curriculum for the internal medicine clerkship.

BACKGROUND: Incorporating ultrasound into the clinical curriculum of undergraduate medical education has been limited by a need for faculty support. Without integration into the clinical learning environment, ultrasound skills become a stand-alone skill and may decline by the time of matriculation into residency. A less time intensive ultrasound curriculum is needed to preserve skills acquired in preclinical years. We aimed to create a self-directed ultrasound curriculum to support and assess students' ability to acquire ultrasound images and to utilize ultrasound to inform clinical decision-making. METHODS: Third year students completed the self-directed ultrasound curriculum during their required internal medicine clerkship. Students used Butterfly iQ+ portable ultrasound probes. The curriculum included online modules that focused on clinical application of ultrasound as well as image acquisition technique. Students were graded on image acquisition quality and setting, a patient write-up focused on clinical decision-making, and a multiple-choice quiz. Student feedback was gathered with an end-of-course survey. Faculty time was tracked. RESULTS: One hundred and ten students participated. Students averaged 1.79 (scale 0-2; SD = 0.21) on image acquisition, 78% (SD = 15%) on the quiz, and all students passed the patient write-up. Most reported the curriculum improved their clinical reasoning (72%), learning of pathophysiology (69%), and patient care (55%). Faculty time to create the curriculum was approximately 45 h. Faculty time to grade student assignments was 38.5 h per year. CONCLUSIONS: Students were able to demonstrate adequate image acquisition, use of ultrasound to aid in clinical decision-making, and interpretation of ultrasound pathology with no in-person faculty instruction. Additionally, students reported improved learning of pathophysiology, clinical reasoning, and rapport with patients. The self-directed curriculum required less faculty time than prior descriptions of ultrasound curricula in the clinical years and could be considered at institutions that have limited faculty support.

The lateral approach water bath: A novel method of ultrasound imaging of the hand.

BACKGROUND: Traditional water baths for ultrasound exams place a hand into a pan of water and submerge an ultrasound probe into the water. While this improves ultrasound transmission and moves structures into the focal zone to make higher resolution images, this method does have limitations. Patients must be manipulated directly under the probe, which can be limited by pain or normal movement restrictions. The probe must also be held very still in water to minimize motion artifact. The lateral approach water bath method addresses such limitations by imaging through the side of a thin-walled plastic container without submerging the probe. This reduces much need for patient manipulation by imaging through the side of a column-shaped bath, which has 360 degrees of imaging freedom. It also stabilizes the probe directly against the flat, firm container to reduce image degrading motion artifact. We hypothesized that because of these improvements the lateral approach water bath might create higher quality images than traditional water baths. METHODS: We compared twenty images from each method, which were obtained with the same model and ultrasound operator at the same time. Two ultrasound fellowship trained blinded reviewers rated the images for quality and adequacy for clinical decision making on a scale from 1 to 5. RESULTS: Image quality was better for the lateral water bath, with an average rating of 4.2 compared to the traditional bath's 2.6 (p < 0.001). Adequacy to aid clinical decision making was better for the lateral approach bath with an average rating of 4.0 compared to the traditional bath's 2.6 (p < 0.001). The lateral bath also had a smaller range for image quality and thus greater consistency. CONCLUSIONS: The lateral approach water bath is a method of hand imaging that produces higher quality, more consistent, and more clinically useful images than traditional water bath imaging.

Subcostal versus right lateral ultrasound measurements of inferior vena cava: Measurements obtained from these two views are not equivalent in non-ICU patients.

Objective: The objective of this study is to assess concordance between the subcostal and right lateral view for ultrasonographic inferior vena cava measurements including the end-inspiratory diameter, end-expiratory diameter and respiratory variation represented by the caval index in spontaneously breathing healthy adults. Methods: We recruited a convenience sample of 33 healthy adults. A phased array ultrasound probe was used to obtain inferior vena cava measurements from a subcostal view in the sagittal plane and from a right lateral view in the coronal plane with B-mode ultrasound. End-inspiratory diameter, end-expiratory diameter and caval index were obtained for each view. A two-tailed t-test was performed to compare the caval indices obtained by the two views. Bland-Altman analysis was used to obtain the limits of agreement for the inferior vena cava diameter and caval index across the two views. Results: Subcostal and right lateral caval indices across all participants were significantly different according to a paired t-test (p < 0.0001). The Bland-Altman analysis showed wide limits of agreement in end-inspiratory diameter (-0.97 and 0.50 cm) and in end-expiratory diameter (-0.94 and 0.90 cm). The right lateral view underestimated the inferior vena cava caval index relative to the subcostal view. Conclusions: The subcostal and right lateral views are not equivalent in obtaining inferior vena cava measurements in spontaneously breathing healthy adults. Current cut-off values for measurement-based applications of inferior vena cava ultrasound, including fluid responsiveness using caval indices, may not be accurate when values are obtained from the right lateral view in the coronal plane of the inferior vena cava in patients.

Expressed Barcoding Enables High-Resolution Tracking of the Evolution of Drug Tolerance.

For a majority of patients with non-small cell lung cancer with EGFR mutations, treatment with EGFR inhibitors (EGFRi) induces a clinical response. Despite this initial reduction in tumor size, residual disease persists that leads to disease relapse. Elucidating the preexisting biological differences between sensitive cells and surviving drug-tolerant persister cells and deciphering how drug-tolerant cells evolve in response to treatment could help identify strategies to improve the efficacy of EGFRi. In this study, we tracked the origins and clonal evolution of drug-tolerant cells at a high resolution by using an expressed barcoding system coupled with single-cell RNA sequencing. This platform enabled longitudinal profiling of gene expression and drug sensitivity in response to EGFRi across a large number of clones. Drug-tolerant cells had higher expression of key survival pathways such as YAP and EMT at baseline and could also differentially adapt their gene expression following EGFRi treatment compared with sensitive cells. In addition, drug combinations targeting common downstream components (MAPK) or orthogonal factors (chemotherapy) showed greater efficacy than EGFRi alone, which is attributable to broader targeting of the heterogeneous EGFRi-tolerance mechanisms present in tumors. Overall, this approach facilitates thorough examination of clonal evolution in response to therapy that could inform the development of improved diagnostic approaches and treatment strategies for targeting drug-tolerant cells. SIGNIFICANCE: The evolution and heterogeneity of EGFR inhibitor tolerance are identified in a large number of clones at enhanced cellular and temporal resolution using an expressed barcode technology coupled with single-cell RNA sequencing.

Pharmacological blockade of TEAD-YAP reveals its therapeutic limitation in cancer cells.

Targeting TEAD autopalmitoylation has been proposed as a therapeutic approach for YAP-dependent cancers. Here we show that TEAD palmitoylation inhibitor MGH-CP1 and analogues block cancer cell "stemness", organ overgrowth and tumor initiation in vitro and in vivo. MGH-CP1 sensitivity correlates significantly with YAP-dependency in a large panel of cancer cell lines. However, TEAD inhibition or YAP/TAZ knockdown leads to transient inhibition of cell cycle progression without inducing cell death, undermining their potential therapeutic utilities. We further reveal that TEAD inhibition or YAP/TAZ silencing leads to VGLL3-mediated transcriptional activation of SOX4/PI3K/AKT signaling axis, which contributes to cancer cell survival and confers therapeutic resistance to TEAD inhibitors. Consistently, combination of TEAD and AKT inhibitors exhibits strong synergy in inducing cancer cell death. Our work characterizes the therapeutic opportunities and limitations of TEAD palmitoylation inhibitors in cancers, and uncovers an intrinsic molecular mechanism, which confers potential therapeutic resistance.

PTEN and LKB1 are differentially required in Gli1-expressing mesenchymal cells to suppress gastrointestinal polyposis.

PTEN and LKB1 are intimately associated with gastrointestinal tumorigenesis. Mutations of PTEN or LKB1 lead to Cowden syndrome and Peutz-Jeghers syndrome characterized by development of gastrointestinal polyps. However, the cells of origin of these polyps and underlying mechanism remain unclear. Here, we reveal that PTEN or LKB1 deficiency in Gli1+ gut mesenchymal cells, but not intestinal epithelium, drives polyp formation histologically resembling polyposis in human patients. Mechanistically, although PTEN and LKB1 converge to regulate mTOR/AKT signaling in various tumor contexts, we find that mTOR is essential for PTEN-deletion-induced polyp formation but is largely dispensable for polyposis induced by mesenchymal LKB1 deficiency. Altogether, our studies identify Gli1-expressing mesenchymal cells as a common cell of origin for polyposis associated with PTEN and LKB1 and reveal their engagement of different downstream pathways in gut mesenchyme to suppress gastrointestinal tumorigenesis.

Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription.

Intestinal homeostasis is tightly regulated by complex yet poorly understood signaling networks. Here, we demonstrate that Lats1/2, the core Hippo kinases, are essential to maintain Wnt pathway activity and intestinal stem cells. Lats1/2 deletion leads to loss of intestinal stem cells but drives Wnt-uncoupled crypt expansion. To explore the function of downstream transcriptional enhanced associate domain (TEAD) transcription factors, we identified a selective small-molecule reversible inhibitor of TEAD auto-palmitoylation that directly occupies its lipid-binding site and inhibits TEAD-mediated transcription in vivo. Combining this chemical tool with genetic and proteomics approaches, we show that intestinal Wnt inhibition by Lats deletion is Yes-associated protein (YAP)/transcriptional activator with PDZ-binding domain (TAZ) dependent but TEAD independent. Mechanistically, nuclear YAP/TAZ interact with Groucho/Transducin-Like Enhancer of Split (TLE) to block Wnt/T-cell factor (TCF)-mediated transcription, and dual inhibition of TEAD and Lats suppresses Wnt-uncoupled Myc upregulation and epithelial over-proliferation in Adenomatous polyposis coli (APC)-mutated intestine. Our studies highlight a pharmacological approach to inhibit TEAD palmitoylation and have important implications for targeting Wnt and Hippo signaling in human malignancies.

YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression.

Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GαQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM.

Surgery for epilepsy.

BACKGROUND: This is an updated version of the original Cochrane review, published in 2015.Focal epilepsies are caused by a malfunction of nerve cells localised in one part of one cerebral hemisphere. In studies, estimates of the number of individuals with focal epilepsy who do not become seizure-free despite optimal drug therapy vary between at least 20% and up to 70%. If the epileptogenic zone can be located, surgical resection offers the chance of a cure with a corresponding increase in quality of life. OBJECTIVES: The primary objective is to assess the overall outcome of epilepsy surgery according to evidence from randomised controlled trials.Secondary objectives are to assess the overall outcome of epilepsy surgery according to non-randomised evidence, and to identify the factors that correlate with remission of seizures postoperatively. SEARCH METHODS: For the latest update, we searched the following databases on 11 March 2019: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to March 08, 2019), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs) that included at least 30 participants in a well-defined population (age, sex, seizure type/frequency, duration of epilepsy, aetiology, magnetic resonance imaging (MRI) diagnosis, surgical findings), with an MRI performed in at least 90% of cases and an expected duration of follow-up of at least one year, and reporting an outcome related to postoperative seizure control. Cohort studies or case series were included in the previous version of this review. DATA COLLECTION AND ANALYSIS: Three groups of two review authors independently screened all references for eligibility, assessed study quality and risk of bias, and extracted data. Outcomes were proportions of participants achieving a good outcome according to the presence or absence of each prognostic factor of interest. We intended to combine data with risk ratios (RRs) and 95% confidence intervals (95% CIs). MAIN RESULTS: We identified 182 studies with a total of 16,855 included participants investigating outcomes of surgery for epilepsy. Nine studies were RCTs (including two that randomised participants to surgery or medical treatment (99 participants included in the two trials received medical treatment)). Risk of bias in these RCTs was unclear or high. Most of the remaining 173 non-randomised studies followed a retrospective design. We assessed study quality using the Effective Public Health Practice Project (EPHPP) tool and determined that most studies provided moderate or weak evidence. For 29 studies reporting multivariate analyses, we used the Quality in Prognostic Studies (QUIPS) tool and determined that very few studies were at low risk of bias across domains.In terms of freedom from seizures, two RCTs found surgery (n = 97) to be superior to medical treatment (n = 99); four found no statistically significant differences between anterior temporal lobectomy (ATL) with or without corpus callosotomy (n = 60), between subtemporal or transsylvian approach to selective amygdalohippocampectomy (SAH) (n = 47); between ATL, SAH and parahippocampectomy (n = 43) or between 2.5 cm and 3.5 cm ATL resection (n = 207). One RCT found total hippocampectomy to be superior to partial hippocampectomy (n = 70) and one found ATL to be superior to stereotactic radiosurgery (n = 58); and another provided data to show that for Lennox-Gastaut syndrome, no significant differences in seizure outcomes were evident between those treated with resection of the epileptogenic zone and those treated with resection of the epileptogenic zone plus corpus callosotomy (n = 43). We judged evidence from the nine RCTs to be of moderate to very low quality due to lack of information reported about the randomised trial design and the restricted study populations.Of the 16,756 participants included in this review who underwent a surgical procedure, 10,696 (64%) achieved a good outcome from surgery; this ranged across studies from 13.5% to 92.5%. Overall, we found the quality of data in relation to recording of adverse events to be very poor.In total, 120 studies examined between one and eight prognostic factors in univariate analysis. We found the following prognostic factors to be associated with a better post-surgical seizure outcome: abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography, history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection, and presence of unilateral interictal spikes. We found no evidence that history of head injury, presence of encephalomalacia, presence of vascular malformation, and presence of postoperative discharges were prognostic factors of outcome.Twenty-nine studies reported multi-variable models of prognostic factors, and showed that the direction of association of factors with outcomes was generally the same as that found in univariate analyses.We observed variability in many of our analyses, likely due to small study sizes with unbalanced group sizes and variation in the definition of seizure outcome, the definition of prognostic factors, and the influence of the site of surgery AUTHORS' CONCLUSIONS: Study design issues and limited information presented in the included studies mean that our results provide limited evidence to aid patient selection for surgery and prediction of likely surgical outcomes. Future research should be of high quality, follow a prospective design, be appropriately powered, and focus on specific issues related to diagnostic tools, the site-specific surgical approach, and other issues such as extent of resection. Researchers should investigate prognostic factors related to the outcome of surgery via multi-variable statistical regression modelling, where variables are selected for modelling according to clinical relevance, and all numerical results of the prognostic models are fully reported. Journal editors should not accept papers for which study authors did not record adverse events from a medical intervention. Researchers have achieved improvements in cancer care over the past three to four decades by answering well-defined questions through the conduct of focused RCTs in a step-wise fashion. The same approach to surgery for epilepsy is required.

YAP drives cutaneous squamous cell carcinoma formation and progression.

Squamous cell carcinoma (SCC) can progress to malignant metastatic cancer, including an aggressive subtype known as spindle cell carcinoma (spSCC). spSCC formation involves epithelial-to-mesenchymal transition (EMT), yet the molecular basis of this event remains unknown. The transcriptional co-activator YAP undergoes recurrent amplification in human SCC and overexpression of YAP drives SCC formation in mice. Here, we show that human spSCC tumours also feature strong nuclear localisation of YAP and overexpression of activated YAP (NLS-YAP-5SA) with Keratin-5 (K5-CreERt) is sufficient to induce rapid formation of both SCC and spSCC in mice. spSCC tumours arise at sites of epithelial scratch wounding, where tumour-initiating epithelial cells undergo EMT to generate spSCC. Expression of the EMT transcription factor ZEB1 arises upon wounding and is a defining characteristic of spSCC in mice and humans. Thus, the wound healing response synergises with YAP to drive metaplastic transformation of SCC to spSCC.

YAP/TAZ and Hedgehog Coordinate Growth and Patterning in Gastrointestinal Mesenchyme.

YAP/TAZ are the major mediators of mammalian Hippo signaling; however, their precise function in the gastrointestinal tract remains poorly understood. Here we dissect the distinct roles of YAP/TAZ in endodermal epithelium and mesenchyme and find that, although dispensable for gastrointestinal epithelial development and homeostasis, YAP/TAZ function as the critical molecular switch to coordinate growth and patterning in gut mesenchyme. Our genetic analyses reveal that Lats1/2 kinases suppress expansion of the primitive mesenchymal progenitors, where YAP activation also prevents induction of the smooth muscle lineage through transcriptional repression of Myocardin. During later development, zone-restricted downregulation of YAP/TAZ provides the positional cue and allows smooth muscle cell differentiation induced by Hedgehog signaling. Taken together, our studies identify the mesenchymal requirement of YAP/TAZ in the gastrointestinal tract and highlight the functional interplays between Hippo and Hedgehog signaling underlying temporal and spatial control of tissue growth and specification in developing gut.

Climate, CO2, and the history of North American grasses since the Last Glacial Maximum.

The spread of C4 grasses in the late Neogene is one of the most important ecological transitions of the Cenozoic, but the primary driver of this global expansion is widely debated. We use the stable carbon isotopic composition (δ(13)C) of bison and mammoth tissues as a proxy for the relative abundance of C3 and C4 vegetation in their grazing habitat to determine climatic and atmospheric CO2 controls on C4 grass distributions from the Last Glacial Maximum (LGM) to the present. We predict the spatial variability of grass δ(13)C in North America using a mean of three different methods of classification and regression tree (CART) machine learning techniques and nine climatic variables. We show that growing season precipitation and temperature are the strongest predictors of all single climate variables. We apply this CART analysis to high-resolution gridded climate data and Coupled Model Intercomparison Project (CMIP5) mean paleoclimate model outputs to produce predictive isotope landscape models ("isoscapes") for the current, mid-Holocene, and LGM average δ(13)C of grass-dominated areas across North America. From the LGM to the present, C4 grass abundances substantially increased in the Great Plains despite concurrent increases in atmospheric CO2. These results suggest that changes in growing season precipitation rather than atmospheric CO2 were critically important in the Neogene expansion of C4 grasses.

Tead and AP1 Coordinate Transcription and Motility.

The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription. We find that Tead-AP1 interaction is JNK independent but engages the SRC1-3 co-activators to promote downstream transcription. Furthermore, we show that Tead-AP1 cooperation regulates the activity of the Dock-Rac/CDC42 module and drives the expression of a unique core set of target genes, thereby directing cell migration and invasion. Together, our data unveil a critical regulatory mechanism underlying Tead- and AP1-controlled transcriptional and functional outputs in cancer cells.

Surgery for epilepsy.

BACKGROUND: Focal epilepsies are caused by a malfunction of nerve cells localised in one part of one cerebral hemisphere. In studies, estimates of the number of individuals with focal epilepsy who do not become seizure-free despite optimal drug therapy vary according to the age of the participants and which focal epilepsies are included, but have been reported as at least 20% and in some studies up to 70%. If the epileptogenic zone can be located surgical resection offers the chance of a cure with a corresponding increase in quality of life. OBJECTIVES: The primary objective is to assess the overall outcome of epilepsy surgery according to evidence from randomised controlled trials.The secondary objectives are to assess the overall outcome of epilepsy surgery according to non-randomised evidence and to identify the factors that correlate to remission of seizures postoperatively. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), MEDLINE (Ovid) (2001 to 4 July 2013), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for relevant trials up to 4 July 2013. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs), cohort studies or case series, with either a prospective and/or retrospective design, including at least 30 participants, a well-defined population (age, sex, seizure type/frequency, duration of epilepsy, aetiology, magnetic resonance imaging (MRI) diagnosis, surgical findings), an MRI performed in at least 90% of cases and an expected duration of follow-up of at least one year, and reporting an outcome relating to postoperative seizure control. DATA COLLECTION AND ANALYSIS: Three groups of two review authors independently screened all references for eligibility, assessed study quality and risk of bias, and extracted data. Outcomes were proportion of participants achieving a good outcome according to the presence or absence of each prognostic factor of interest. We intended to combine data with risk ratios (RR) and 95% confidence intervals. MAIN RESULTS: We identified 177 studies (16,253 participants) investigating the outcome of surgery for epilepsy. Four studies were RCTs (including one that randomised participants to surgery or medical treatment). The risk of bias in the RCTs was unclear or high, limiting our confidence in the evidence that addressed the primary review objective. Most of the remaining 173 non-randomised studies had a retrospective design; they were of variable size, were conducted in a range of countries, recruited a wide demographic range of participants, used a wide range of surgical techniques and used different scales used to measure outcomes. We performed quality assessment using the Effective Public Health Practice Project (EPHPP) tool and determined that most studies provided moderate or weak evidence. For 29 studies reporting multivariate analyses we used the Quality in Prognostic Studies (QUIPS) tool and determined that very few studies were at low risk of bias across the domains.In terms of freedom from seizures, one RCT found surgery to be superior to medical treatment, two RCTs found no statistically significant difference between anterior temporal lobectomy (ATL) with or without corpus callosotomy or between 2.5 cm or 3.5 cm ATL resection, and one RCT found total hippocampectomy to be superior to partial hippocampectomy. We judged the evidence from the four RCTs to be of moderate to very low quality due to the lack of information reported about the randomised trial design and the restricted study populations.Of the 16,253 participants included in this review, 10,518 (65%) achieved a good outcome from surgery; this ranged across studies from 13.5% to 92.5%. Overall, we found the quality of data in relation to the recording of adverse events to be very poor.In total, 118 studies examined between one and eight prognostic factors in univariate analysis. We found the following prognostic factors to be associated with a better post-surgical seizure outcome: an abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography (EEG), history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection and presence of unilateral interictal spikes. We found no evidence that history of head injury, presence of encephalomalacia, presence of vascular malformation or presence of postoperative discharges were prognostic factors of outcome. We observed variability between studies for many of our analyses, likely due to the small study sizes with unbalanced group sizes, variation in the definition of seizure outcome, definition of the prognostic factor and the influence of the site of surgery, all of which we observed to be related to postoperative seizure outcome. Twenty-nine studies reported multivariable models of prognostic factors and the direction of association of factors with outcome was generally the same as found in the univariate analyses. However, due to the different multivariable analysis approaches and selective reporting of results, meaningful comparison of multivariate analysis with univariate meta-analysis is difficult. AUTHORS' CONCLUSIONS: The study design issues and limited information presented in the included studies mean that our results provide limited evidence to aid patient selection for surgery and prediction of likely surgical outcome. Future research should be of high quality, have a prospective design, be appropriately powered and focus on specific issues related to diagnostic tools, the site-specific surgical approach and other issues such as the extent of resection. Prognostic factors related to the outcome of surgery should be investigated via multivariable statistical regression modelling, where variables are selected for modelling according to clinical relevance and all numerical results of the prognostic models are fully reported. Protocols should include pre- and postoperative measures of speech and language function, cognition and social functioning along with a mental state assessment. Journal editors should not accept papers where adverse events from a medical intervention are not recorded. Improvements in the development of cancer care over the past three to four decades have been achieved by answering well-defined questions through the conduct of focused RCTs in a step-wise fashion. The same approach to surgery for epilepsy is required.

The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila.

Similar to the mammalian intestine, the Drosophila adult midgut has resident stem cells that support growth and regeneration. How the niche regulates intestinal stem cell activity in both mammals and flies is not well understood. Here, we show that the conserved germinal center protein kinase Misshapen restricts intestinal stem cell division by repressing the expression of the JAK-STAT pathway ligand Upd3 in differentiating enteroblasts. Misshapen, a distant relative to the prototypic Warts activating kinase Hippo, interacts with and activates Warts to negatively regulate the activity of Yorkie and the expression of Upd3. The mammalian Misshapen homolog MAP4K4 similarly interacts with LATS (Warts homolog) and promotes inhibition of YAP (Yorkie homolog). Together, this work reveals that the Misshapen-Warts-Yorkie pathway acts in enteroblasts to control niche signaling to intestinal stem cells. These findings also provide a model in which to study requirements for MAP4K4-related kinases in MST1/2-independent regulation of LATS and YAP.

First "glass" education: telementored cardiac ultrasonography using Google Glass- a pilot study.

OBJECTIVES: The objective of this study was to determine the feasibility of telementored instruction in bedside ultrasonography (US) using Google Glass. The authors sought to examine whether first-time US users could obtain adequate parasternal long axis (PSLA) views to approximate ejection fraction (EF) using Google Glass telementoring. METHODS: This was a prospective, randomized, single-blinded study. Eighteen second-year medical students were randomized into three groups and tasked with obtaining PSLA cardiac imaging. Group A received real-time telementored education through Google Glass via Google Hangout from a remotely located expert. Group B received bedside education from the same expert. Group C represented the control and received no instruction. Each subject was given 3 minutes to obtain a best PSLA cardiac imaging using a portable GE Vscan. Image clips obtained by each subject were stored. A second expert, blinded to instructional mode, evaluated images for adequacy and assigned an image quality rating on a 0 to 10 scale. RESULTS: Group A was able to obtain adequate images six out of six times (100%) with a median image quality rating of 7.5 (interquartile range [IQR] = 6 to 10) out of 10. Group B was also able to obtain adequate views six out of six times (100%), with a median image quality rating of 8 (IQR = 7 to 9). Group C was able to obtain adequate views one out of six times (17%), with a median image quality of 0 (IQR = 0 to 2). There were no statistically significant differences between Group A and Group B in the achievement of adequate images for E-point septal separation measurement or in image quality. CONCLUSIONS: In this pilot/feasibility study, novice US users were able to obtain adequate imaging to determine a healthy patient's EF through telementored education using Google Glass. These preliminary data suggest telementoring as an adequate means of medical education in bedside US. This conclusion will need to be validated with larger, more powerful studies including evaluation of pathologic findings and varying body habitus among models.