Advances in preclinical evaluation of experimental antibody-drug conjugates.

The ability to chemically modify monoclonal antibodies with the attachment of specific functional groups has opened up an enormous range of possibilities for the targeted treatment and diagnosis of cancer in the clinic. As the number of such antibody-based drug candidates has increased, so too has the need for more stringent and robust preclinical evaluation of their in vivo performance to maximize the likelihood that time, research effort, and money are only spent developing the most effective and promising candidate molecules for translation to the clinic. Concurrent with the development of antibody-drug conjugate (ADC) technology, several recent advances in preclinical research stand to greatly increase the experimental rigor by which promising candidate molecules can be evaluated. These include advances in preclinical tumor modeling with the development of patient-derived tumor organoid models that far better recapitulate many aspects of the human disease than conventional subcutaneous xenograft models. Such models are amenable to genetic manipulation, which will greatly improve our understanding of the relationship between ADC and antigen and stringently evaluate mechanisms of therapeutic response. Finally, tumor development is often not visible in these in vivo models. We discuss how the application of several preclinical molecular imaging techniques will greatly enhance the quality of experimental data, enabling quantitative pre- and post-treatment tumor measurements or the precise assessment of ADCs as effective diagnostics. In our opinion, when taken together, these advances in preclinical cancer research will greatly improve the identification of effective candidate ADC molecules with the best chance of clinical translation and cancer patient benefit

Functional Outcomes of Cleft Lip Surgery. Part IV: Between- and Within-Participant Variables Affecting Lip Vermilion Sensory Thresholds

Compare neurosensory assessments for participants with and without a cleft lip; identify between- and within-participant variables affecting sensory thresholds on the vermilion of participants with cleft lip

Functional Outcomes of Cleft Lip Surgery. Part I: Study Design and Surgeon Ratings of Lip Disability and Need for Lip Revision

Objective—Children with a cleft of the upper lip exhibit obvious facial disfigurement. Many require multiple lip surgeries for an optimal esthetic result. However, because the decision for lip revision is based on subjective clinical criteria, clinicians may disagree on whether these surgeries should be performed. To establish more reliable, functionally relevant outcome criteria for evaluation and treatment planning, a clinical trial currently is in progress. In this article, the design of the clinical trial is described and results of a study on subjective evaluations of facial form by surgeons for or against the need for lip revision surgery are presented. Design—Parallel, three-group, nonrandomized clinical trial and subjective evaluations/ratings of facial views by surgeons. Subjects—For the clinical trial, children with repaired cleft lip and palate scheduled for a secondary lip revision, children with repaired cleft lip and palate who did not have lip revision, and noncleft children. For the subjective evaluations, surgeons’ facial ratings of 21 children with repaired cleft lip. Analysis—Descriptive and Kappa statistics assessing the concordance of surgeons’ ratings of (a) repeated facial views and (b) a recommendation of revision on viewing the prerevision and postrevision views. Results—The surgeons’ consistency in rating repeated views was moderate to excellent; however, agreement among the surgeons when rating individual participants was low to moderate. Conclusions—The findings suggest that the agreement among surgeons was poor and support the need for more objective measures to assess the need for revision surgery

A rare case of paediatric astroblastoma with concomitant MN1-GTSE1 and EWSR1-PATZ1 gene fusions altering management

In a case of astroblastoma, methylation analysis was uninformative, with no clustering with known CNS-HGNET-MN1 cases. Whole genome sequencing however identified a novel MN1-GTSE1 gene fusion (image), confirming the diagnosis of astroblastoma, as well as an EWSR1-PATZ1 gene fusion. Whole genome sequencing, alongside methylation profiling and conventional neuropathology, will continue to lead to improved diagnostics and prognostication for children with brain tumours

Functional Outcomes of Cleft Lip Surgery. Part I: Study Design and Surgeon Ratings of Lip Disability and Need for Lip Revision

Objective—Children with a cleft of the upper lip exhibit obvious facial disfigurement. Many require multiple lip surgeries for an optimal esthetic result. However, because the decision for lip revision is based on subjective clinical criteria, clinicians may disagree on whether these surgeries should be performed. To establish more reliable, functionally relevant outcome criteria for evaluation and treatment planning, a clinical trial currently is in progress. In this article, the design of the clinical trial is described and results of a study on subjective evaluations of facial form by surgeons for or against the need for lip revision surgery are presented. Design—Parallel, three-group, nonrandomized clinical trial and subjective evaluations/ratings of facial views by surgeons. Subjects—For the clinical trial, children with repaired cleft lip and palate scheduled for a secondary lip revision, children with repaired cleft lip and palate who did not have lip revision, and noncleft children. For the subjective evaluations, surgeons’ facial ratings of 21 children with repaired cleft lip. Analysis—Descriptive and Kappa statistics assessing the concordance of surgeons’ ratings of (a) repeated facial views and (b) a recommendation of revision on viewing the prerevision and postrevision views. Results—The surgeons’ consistency in rating repeated views was moderate to excellent; however, agreement among the surgeons when rating individual participants was low to moderate. Conclusions—The findings suggest that the agreement among surgeons was poor and support the need for more objective measures to assess the need for revision surgery

The effects of lip revision surgery on nasolabial esthetics in patients with cleft lip

1) To determine the concordance among surgeons on subjective assessments of nasolabial esthetics in children with repaired cleft lip; and 2) to evaluate longitudinal changes in nasolabial esthetics in relation to cleft lip revision surgery.School of Dentistry at University of North Carolina, Chapel Hill. Children with repaired unilateral cleft lip: 32 had lip revision surgery and 27 did not have surgery.Retrospective observational study from a non-randomized clinical trial. Ratings of nasolabial esthetics performed by six surgeons using the Asher-McDade scale at baseline and 12-month follow-up.Concordance among surgeons ranged from poor to acceptable. Nasolabial ratings at follow-up were better in the Revision group than in the Non-Revision group, although differences were small. The most prevalent change in the Revision Group was improvement in one or more units on the scale, while ‘no change’ was most prevalent in the Non-Revision group. Participants in the Revision group were more likely to receive a ‘no’ in relation to the need for lip or nose revision at the follow-up visit.There were mild esthetic improvements observed in relation to lip revision surgery, which should be interpreted with caution given the subjectivity of the rating method used

Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output

Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase. Specifically, we show that nuclear-localized PHLPP suppresses histone phosphorylation and acetylation, in turn suppressing the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a much broader role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: By suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the PI3 kinase/AKT and the Rat sarcoma (RAS)/ERK pathways. Our data are consistent with a model in which PHLPP modifies the histone code to control the transcription of RTKs

Stress exposure and sensitivity in the clinical high-risk syndrome: Initial findings from the North American Prodrome Longitudinal Study (NAPLS)

There is inconsistent evidence for increased stress exposure among individuals at clinical high risk (CHR) for psychosis. Yet similar to patients with a diagnosed psychotic illness, the preponderance of evidence suggests that CHR individuals tend to experience stressful life events (LE) and daily hassles (DH) as more subjectively stressful than healthy individuals. The present study utilizes data from the North American Prodrome Longitudinal Study Phase 2 (NAPLS-2) to test the hypotheses that (1) CHR individuals manifest higher self-reported stress in response to both LE and DH when compared to healthy controls (HC), (2) group differences in self-reported stress increase with age, (3) baseline self-reported stress is associated with follow-up clinical status, and (4) there is a sensitization effect of LE on the response to DH. In contrast to some previous research, the present findings indicate that the CHR group (N = 314) reported exposure to more LE when compared to the HC group (N= 162). As predicted, CHR participants rated events as more stressful, and those who progressed to psychosis reported a greater frequency of LE and greater stress from events compared to those whose prodromal symptoms remitted. There was also some evidence of stress-sensitization; those who experienced more stress from LE rated current DH as more stressful. The results indicate that the prodromal phase is a period of heightened stress and stress sensitivity, and elevated cumulative lifetime exposure to stressful events may increase reactions to current stressors. (C) 2014 Elsevier B.V. All rights reserved

The polaroid image as photo-object

This article is part of a larger project on the cultural history of Polaroid photography and draws on research done at the Polaroid Corporate archive at Harvard and at the Polaroid company itself. It identifies two cultural practices engendered by Polaroid photography, which, at the point of its extinction, has briefly flared into visibility again. It argues that these practices are mistaken as novel but are in fact rediscoveries of practices that stretch back as many as five decades. The first section identifies Polaroid image-making as a photographic equivalent of what Tom Gunning calls the ‘cinema of attractions’. That is, the emphasis in its use is on the display of photographic technologies rather than the resultant image. Equally, the common practice, in both fine art and vernacular circles, of making composite pictures with Polaroid prints, draws attention from image content and redirects it to the photo as object

Report of Altered Sensation in Patients With Cleft Lip

To determine whether patients with cleft lip have normal perioral sensation