Objective assessment of tumor infiltrating lymphocytes as a prognostic marker in melanoma using machine learning algorithms

BACKGROUND The prognostic value of tumor-infiltrating lymphocytes (TILs) assessed by machine learning algorithms in melanoma patients has been previously demonstrated but has not been widely adopted in the clinic. We evaluated the prognostic value of objective automated electronic TILs (eTILs) quantification to define a subset of melanoma patients with a low risk of relapse after surgical treatment. METHODS We analyzed data for 785 patients from 5 independent cohorts from multiple institutions to validate our previous finding that automated TIL score is prognostic in clinically-localized primary melanoma patients. Using serial tissue sections of the Yale TMA-76 melanoma cohort, both immunofluorescence and Hematoxylin-and-Eosin (H&E) staining were performed to understand the molecular characteristics of each TIL phenotype and their associations with survival outcomes. FINDINGS Five previously-described TIL variables were each significantly associated with overall survival (p<0.0001). Assessing the receiver operating characteristic (ROC) curves by comparing the clinical impact of two models suggests that etTILs (electronic total TILs) (AUC: 0.793, specificity: 0.627, sensitivity: 0.938) outperformed eTILs (AUC: 0.77, specificity: 0.51, sensitivity: 0.938). We also found that the specific molecular subtype of cells representing TILs includes predominantly cells that are CD3+ and CD8+ or CD4+ T cells. INTERPRETATION eTIL% and etTILs scores are robust prognostic markers in patients with primary melanoma and may identify a subgroup of stage II patients at high risk of recurrence who may benefit from adjuvant therapy. We also show the molecular correlates behind these scores. Our data support the need for prospective testing of this algorithm in a clinical trial. FUNDING This work was also supported by a sponsored research agreements from Navigate Biopharma and NextCure and by grants from the NIH including the Yale SPORE in in Skin Cancer, P50 CA121974, the Yale SPORE in Lung Cancer, P50 CA196530, NYU SPORE in Skin Cancer P50CA225450 and the Yale Cancer Center Support Grant, P30CA016359

VR.net: A Real-world Dataset for Virtual Reality Motion Sickness Research

Researchers have used machine learning approaches to identify motion sickness in VR experience. These approaches demand an accurately-labeled, real-world, and diverse dataset for high accuracy and generalizability. As a starting point to address this need, we introduce `VR.net', a dataset offering approximately 12-hour gameplay videos from ten real-world games in 10 diverse genres. For each video frame, a rich set of motion sickness-related labels, such as camera/object movement, depth field, and motion flow, are accurately assigned. Building such a dataset is challenging since manual labeling would require an infeasible amount of time. Instead, we utilize a tool to automatically and precisely extract ground truth data from 3D engines' rendering pipelines without accessing VR games' source code. We illustrate the utility of VR.net through several applications, such as risk factor detection and sickness level prediction. We continuously expand VR.net and envision its next version offering 10X more data than the current form. We believe that the scale, accuracy, and diversity of VR.net can offer unparalleled opportunities for VR motion sickness research and beyond

The effect of Staphylococcus aureus carriage in late pregnancy on antibody levels to staphylococcal toxins in cord blood and breast milk.

We investigated the effect of carriage of Staphylococcus aureus in the later stages of pregnancy on levels of antibody specific to the S. aureus toxins, staphylococcal enterotoxin B (SEB), staphylococcal enterotoxin C (SEC) and toxic shock syndrome toxin-1 (TSST-1), in cord blood and breast milk and also explored the relationship between levels of antibody in antenatal serum and cord blood. Nasopharyngeal swabs and stool samples were collected on two occasions, from 96 women, during the last 6 weeks of pregnancy. Samples were cultured and S. aureus isolates were identified. Antenatal and cord blood samples from the same women and their infants were analysed for IgG antibody to SEB, SEC and TSST-1 by enzyme-linked immunosorbent assay. Breast milk samples were analysed for IgA antibody to the same toxins. We found that S. aureus carriage in pregnancy is common and exposure to a toxin-producing isolate boosts immunity. Over 89% of women and infants have some protective antibody to the toxins, and antitoxin IgG levels are higher in cord blood samples compared with antenatal samples. Levels of cord blood IgG and breast milk IgA specific for the staphylococcal toxins vary. Some infants lack protection and could be at risk of toxin-induced disease

The prognostic value of tumor mitotic rate in children and adolescents with cutaneous melanoma:A retrospective cohort study

Background: Mitotic rate is a strong predictor of outcome in adult patients with primary cutaneous melanoma, but for children and adolescent patients this is unknown. Objective: We sought to assess the prognostic value of primary tumor mitotic rate in children and adolescents with primary melanoma. Methods: This was a cohort study of 156 patients who were <20 years of age and who had clinically localized cutaneous melanoma. Patients <12 years of age were classified as children and those 12 to 19 years of age as adolescents. Clinicopathologic and outcome data were collected. Recurrence-free and melanoma-specific survival were calculated. Univariable and multivariable analyses were performed using Cox proportional hazard models. Results: Thirteen of 156 patients (8%) were children. The mitotic rate was ≥1/mm2 in 104 patients (67%) and correlated with increasing Breslow thickness. A positive sentinel node was found in 23 of 61 patients (38%) in whom a sentinel lymph node biopsy specimen was obtained. The median follow-up was 61 months. Five-year melanoma-specific and recurrence-free survival rates were 91% and 84%, respectively. Mitotic rate was a stronger predictor of outcome than tumor thickness and was the only factor independently associated with recurrence-free survival. Limitations: This research was conducted at a single institution and the sample size was small. Conclusion: Mitotic rate is an independent predictor of recurrence-free survival in children and adolescents with clinically localized melanoma

LNK suppresses interferon signaling in melanoma.

LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy

Rendering an Account: An Open-State Archive in Postgraduate Supervision

The paper begins with a brief account of the transformation of research degree studies under the pressures of global capitalism and neo-liberal governmentality. A parallel transformation is occurring in the conduct of research through the use of information and communication technologies. Yet the potential of ICTs to shape practices of surveillance or to produce new student-supervisor relations and enhance the processes of developing the dissertation has received almost no critical attention. As doctoral supervisor and student, we then describe the features and uses of a web-based open state archive of the student's work-in-progress, developed by the student and accessible to his supervisor. Our intention was to encourage more open conversations between data and theorising, student and supervisor, and ultimately between the student and professional community. However, we recognise that relations of accountability, as these have developed within a contemporary "audit revolution" (Power, 1994, 1997) in universities, create particular "lines of visibility" (Munro, 1996). Thus while the open-state archive may help to redefine in less managerial terms notions of quality, transparency, flexibility and accountability, it might also make possible greater supervisory surveillance. How should we think about the panoptical potential of this archive? We argue that the diverse kinds of interactional patterns and pedagogical intervention it encourages help to create shifting subjectivities. Moreover, the archive itself is multiple, in bringing together an array of diverse materials that can be read in various ways, by following multiple paths. It therefore constitutes a collage, which we identify as a mode of cognition and of accounting distinct from but related to argument and narrative. As a more "open" text (Iser, 1978) it has an indeterminacy which may render it less open to abuse for the technologies of managerial accountability

Multiparameter analysis of naevi and primary melanomas identifies a subset of naevi with elevated markers of transformation

Here we have carried out a multiparameter analysis using a panel of 28 immunohistochemical markers to identify markers of transformation from benign and dysplastic naevus to primary melanoma in three separate cohorts totalling 279 lesions. We have identified a set of eight markers that distinguish naevi from melanoma. None of markers or parameters assessed differentiated benign from dysplastic naevi. Indeed, the naevi clustered tightly in terms of their immunostaining patterns whereas primary melanomas showed more diverse staining patterns. A small subset of histopathologically benign lesions had elevated levels of multiple markers associated with melanoma, suggesting that these represent naevi with an increased potential for transformation to melanoma

The influence of lateral advection on the residual estuarine circulation : a numerical modeling study of the Hudson River Estuary

Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 39 (2009): 107-124, doi:10.1175/2008JPO3952.1.In most estuarine systems it is assumed that the dominant along-channel momentum balance is between the integrated pressure gradient and bed stress. Scaling the amplitude of the estuarine circulation based on this balance has been shown to have predictive skill. However, a number of authors recently highlighted important nonlinear processes that contribute to the subtidal dynamics at leading order. In this study, a previously validated numerical model of the Hudson River estuary is used to examine the forces driving the residual estuarine circulation and to test the predictive skill of two linear scaling relationships. Results demonstrate that the nonlinear advective acceleration terms contribute to the subtidal along-channel momentum balance at leading order. The contribution of these nonlinear terms is driven largely by secondary lateral flows. Under a range of forcing conditions in the model runs, the advective acceleration terms nearly always act in concert with the baroclinic pressure gradient, reinforcing the residual circulation. Despite the strong contribution of the nonlinear advective terms to the subtidal dynamical balance, a linear scaling accurately predicts the strength of the observed residual circulation in the model. However, this result is largely fortuitous, as this scaling does not account for two processes that are fundamental to the estuarine circulation. The skill of this scaling results because of the compensatory relationship between the contribution of the advective acceleration terms and the suppression of turbulence due to density stratification. Both of these processes, neither of which is accounted for in the linear scaling, increase the residual estuarine circulation but have an opposite dependence on tidal amplitude and, consequently, strength of stratification.This research was supported by the Beacon Institute for Rivers and Estuaries—Woods Hole Oceanographic Institution postdoctoral fellowship program, as well as NSF Grants OCE-0452054 and OCE-0451740