Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras‐driven lung tumours

A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision‐cut slices from Kras‐driven non‐small‐cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen‐activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short‐term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3‐kinase–mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology‐associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Nano-opto-mechanical characterization of neuron membrane mechanics under cellular growth and differentiation

We designed and fabricated silicon probe with nanophotonic force sensor to directly stimulate neurons (PC12) and measured its effect on neurite initiation and elongation. A single-layer pitch-variable diffractive nanogratings was fabricated on silicon nitride probe using e-beam lithography, reactive ion etching and wet-etching techniques. The nanogratings consist of flexure folding beams suspended between two parallel cantilevers of known stiffness. The probe displacement, therefore the force, can be measured through grating transmission spectrum. We measured the mechanical membrane characteristics of PC12 cells using the force sensors with displacement range of 10 mum and force sensitivity 8 muN/mum. Young's moduli of 425 +/- 30 Pa are measured with membrane deflection of 1% for PC12 cells cultured on polydimethylsiloxane (PDMS) substrate coated with collagen or laminin in Ham's F-12K medium. In a series of measurements, we have also observed stimulation of directed neurite contraction up to 6 mum on extended probing for a time period of 30 min. This method is applicable to measure central neurons mechanics under subtle tensions for studies on development and morphogenesis. The close synergy between the nano-photonic measurements and neurological verification can improve our understanding of the effect of external conditions on the mechanical properties of cells during growth and differentiation.     

Breast milk feeding rates of mothers of multiples compared to mothers of singletons.

OBJECTIVE: Over 3% of infants born annually in the United States are from a multiple gestation pregnancy, yet there is little data published about the feeding practices of their mothers. The objectives of this study were to determine and compare the rates of breast milk feeding of mothers of multiples and mothers of singletons. METHODS: Stratified random sampling (n = 686) on the basis of plurality of pregnancy and gestational age at delivery was performed on a 1999 birth certificate database in the greater Cincinnati area. We collected information about infant feeding during the first 6 months of life using a retrospective, self-administered questionnaire and phone interview from mothers of term singletons (TS), preterm singletons (PS), term multiples (TM), and preterm multiples (PM). Data were analyzed using chi-square and logistic or multiple regression. RESULTS: We obtained feeding information from 346 mothers (n = 81 TS, 80 PS, 90 TM, and 95 PM). By 3 days postpartum, PM provided breast milk less often than all other groups: TS = 69%, PS = 66%, TM = 73%, PM = 57% (P =.035). Among mothers who initiated breast milk feeding, the geometric mean duration of at least some breast milk feeding was significantly shorter for PM than for all other groups: TS = 23 weeks, PS = 19 weeks, TM = 24 weeks, and PM = 12 weeks (P =.002). CONCLUSIONS: Further evaluation of the potential causes for the lower breast milk feeding rates among PM is needed to develop effective intervention strategies and increase the number of preterm multiple gestation infants receiving breast milk.     

Prognostic significance of soluble fas and soluble fas ligand in serum of patients with complete hydatidiform moles

Citation Soni S, Rath G, Deval R, Salhan S, Mishra AKumar, Saxena S. Prognostic significance of soluble Fas and soluble Fas ligand in serum of patients with complete hydatidiform moles. Am J Reprod Immunol 2011; 66: 230–236 Problem Despite of advances in diagnosis and staging, the prognosis of hydatidiform mole (HM) remains intricate. HM possesses the substantial risk of developing persistent trophoblastic disease (PTD), which is considerably high for complete hydatidiform moles (CHMs). Significance of serum soluble Fas (sFas) and soluble FasL (sFasL) has been observed in various malignancies; however, there is no report till date on HM. Method of study The serum levels of sFas and sFasL were measured using enzyme‐linked immunosorbent assay in 62 patients with CHMs and 64 healthy controls. The protein concentrations were also correlated with clinicopathological parameters, β‐hCG level, and clinical outcome. Results The serum sFas and sFasL levels in patients with CHM were significantly higher than those in control group (mean ± SD: 703.497 ± 491.759 versus 348.141 ± 175.24; P < 0.004 and 31.17 ± 18.758 versus 18.802 ± 6.775; P < 0.0001, respectively). Patients who progressed to PTD demonstrated higher sFas and sFasL concentrations than those who regressed spontaneously (794.211 ± 415.892 versus 446.69 ± 161.382; P < 0.046 and 37.55 ± 20.337 versus 22.763 ± 6.52; P < 0.011, respectively). Furthermore, significant associations were observed among sFas, sFasL, and β‐hCG levels (P < 0.0001 for all associations). Conclusion Production of sFas and sFasL may play a crucial role in progression of CHM and may serve both as prognostic tool and therapeutic target in improving the clinical outcome.     

Comparison of Vascular Smooth Muscle Cell Apoptosis and Fibrous Cap Morphology in Symptomatic and Asymptomatic Carotid Artery Disease

The biological cascades that lead to carotid plaque disruptions and symptoms are largely unknown. Certain cellular events within the plaque might be responsible for destabilizing the plaque, though the popular belief is that the plaque size is directly related to symptoms. The aim of our study was to assess the morphology of the fibrous cap and apoptosis in the plaque and compare these two pathological features in symptomatic and asymptomatic carotid artery disease. Our work was carried out in plaques obtained following carotid endarterectomy performed for symptomatic disease (including hemispheric transient ischemic attacks, amaurosis fugax, or stroke) or asymptomatic high-grade severe stenosis. Scion images of Gomori's stained sections were used to measure fibrous cap thickness and area. TUNEL assay was performed to assess the extent of apoptosis. The results indicated that the area of the fibrous cap did not significantly correlate with the presence of symptoms. There was a higher percentage of apoptotic nuclei and the thinner fibrous cap in symptomatic plaques than in asymptomatic plaques. This finding suggests that these factors might be involved in destabilizing plaque, causing rupture and leading to symptomatic carotid disease.     

Airway pressure release ventilation for in-vivo donor lung management and lung transplant outcomes

Background:Airway pressure release ventilation (APRV) can be used for cadaveric donor lung recruitment. APRV elevates PaO₂ in donor lungs; however, reported outcomes in recipients with APRV-managed donor lungs are limited. Methods:We retrospectively reviewed patients who underwent lung transplantation (LTx) from 2012 to 2013 and divided them into two groups based on mode of ventilation used during donor management and organ extraction (A: non-APRV; B: APRV). Kaplan-Meier method and multivariate Cox regression were used for analysis. Results:We found 126 LTx recipients (LTxRs); 9 were excluded for use of portable ventilation perfusion systems. Of the remaining 117 patients, 81 (69%) were in Group A; 36 (31%) were in Group B. Preoperative LTxR characteristics (age, sex, lung allocation score, end-stage lung disease type) were comparable between groups. Donors for Group B were older (P=0.03) and had higher body mass index (BMI) (P<0.001), higher incidence of death from chest trauma (P=0.008), longer ventilation duration after brain death (P<0.001), and higher pre-explant PaO₂/FiO₂ ratios (P<0.001). Post-LTx duration of mechanical ventilation, hospital stay, and median survival were similar in both groups. Risk of death was comparable between the two groups at the end of follow-up (HR =1.42; 95% CI: 0.57-3.56; P=0.45). Conclusions:APRV is a safe and effective pre-LTx donor lung management strategy. Short- and long-term survival outcomes were comparable in LTx recipients, irrespective of donor ventilation mode. APRV may help recruit lungs from older donors with higher BMI who die from chest trauma and have anticipated longer ventilation duration.     

Survival prediction of glioblastoma patients—are we there yet? A systematic review of prognostic modeling for glioblastoma and its clinical potential

Glioblastoma is associated with a poor prognosis. Even though survival statistics are well-described at the population level, it remains challenging to predict the prognosis of an individual patient despite the increasing number of prognostic models. The aim of this study is to systematically review the literature on prognostic modeling in glioblastoma patients. A systematic literature search was performed to identify all relevant studies that developed a prognostic model for predicting overall survival in glioblastoma patients following the PRISMA guidelines. Participants, type of input, algorithm type, validation, and testing procedures were reviewed per prognostic model. Among 595 citations, 27 studies were included for qualitative review. The included studies developed and evaluated a total of 59 models, of which only seven were externally validated in a different patient cohort. The predictive performance among these studies varied widely according to the AUC (0.58–0.98), accuracy (0.69–0.98), and C-index (0.66–0.70). Three studies deployed their model as an online prediction tool, all of which were based on a statistical algorithm. The increasing performance of survival prediction models will aid personalized clinical decision-making in glioblastoma patients. The scientific realm is gravitating towards the use of machine learning models developed on high-dimensional data, often with promising results. However, none of these models has been implemented into clinical care. To facilitate the clinical implementation of high-performing survival prediction models, future efforts should focus on harmonizing data acquisition methods, improving model interpretability, and externally validating these models in multicentered, prospective fashion.