Reverse Engineering Tumor Invasion and Resistance using Micro/Nano Technologies

Tumor invasion and metastasis, as well as the emergence of drug resistance, confound existing anti-cancer therapies and result in over 9 out of 10 cancer-related fatalities. However, this complex and emergent phenomenon remains poorly understood, particularly from a physical and mechanical perspective. Engineering approaches based on micro/nano technologies may enable new insights into cancer biology and their translation for preclinical drug testing. Here, I describe the use of engineered microenvironments to profile single cell invasion and drug resistance. These behaviors can be comprehensively analyzed in space and time using computer vision, revealing an unexpected analogy with phase transitions during binary mixture solidification. Finally, we describe ongoing efforts to evolve towards three-dimensional tissue architectures based on soft materials patterned with integrated microfluidics

Nutritional Supplement Use and Age-Related Macular Degeneration

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Nanotechnology: emerging tools for biology and medicine

Historically, biomedical research has been based on two paradigms. First, measurements of biological behaviors have been based on bulk assays that average over large populations. Second, these behaviors have then been crudely perturbed by systemic administration of therapeutic treatments. Nanotechnology has the potential to transform these paradigms by enabling exquisite structures comparable in size with biomolecules as well as unprecedented chemical and physical functionality at small length scales. Here, we review nanotechnology-based approaches for precisely measuring and perturbing living systems. Remarkably, nanotechnology can be used to characterize single molecules or cells at extraordinarily high throughput and deliver therapeutic payloads to specific locations as well as exhibit dynamic biomimetic behavior. These advances enable multimodal interfaces that may yield unexpected insights into systems biology as well as new therapeutic strategies for personalized medicineDamon Runyon Cancer Research Foundation (Merck Fellow, DRG-2065-10)Howard Hughes Medical Institute (Investigator)Lustgarten FoundationNational Institutes of Health (U.S.) (U54CA151884, , Massachusetts Institute of Technology-Harvard Center of Cancer Nanotechnology Excellence)National Institutes of Health (U.S.) (P41- EB002503, BIoMEMS Resource Center

Reemergence of Syphilitic Uveitis Masquerading as Other Diseases: A Report of Two Cases

During a 6-month period in 2010, 2 patients with uveitis were examined at our department and diagnosed with ocular syphilis. They initially presented with symptoms and signs resembling Harada's disease and Behçet's disease and were therefore treated with systemic steroids with suboptimal responses. When laboratory workup revealed neurosyphilis, they were given a course of intravenous penicillin G, which led to significant clinical and visual improvement. Epidemiological data indicates a worldwide reemergence of syphilis and a high degree of suspicion is necessary in view of its multitude of presenting ocular signs without pathognomonic features

Evaluation of the risk of cardiovascular events with clarithromycin using both propensity score and self-controlled study designs

Aim: Some previous studies suggest a long term association between clarithromycin use and cardiovascular events. This study investigates this association for clarithromycin given as part of Helicobacter pylori treatment (HPT). Methods: Our source population was the Clinical Practice Research Datalink (CPRD), a UK primary care database. We conducted a self-controlled case series (SCCS), a case–time–control study (CTC) and a propensity score adjusted cohort study comparing the rate of cardiovascular events in the 3 years after exposure to HPT containing clarithromycin with exposure to clarithromycin free HPT. Outcomes were first incident diagnosis of myocardial infarction (MI), arrhythmia and stroke. For the cohort analysis we included secondary outcomes all cause and cardiovascular mortality. Results: Twenty-eight thousand five hundred and fifty-two patients were included in the cohort. The incidence rate ratio of first MI within 1 year of exposure to HPT containing clarithromycin was 1.07 (95% CI 0.85, 1.34, P = 0.58) and within 90 days was 1.43 (95% CI 0.99, 2.09 P = 0.057) in the SCCS analysis. CTC and cohort results were consistent with these findings. Conclusions There was some evidence for a short term association for first MI but none for a long term association for any outcome

Cosmic-Enu: An emulator for the non-linear neutrino power spectrum

Cosmology is poised to measure the neutrino mass sum $M_\nu$ and has identified several smaller-scale observables sensitive to neutrinos, necessitating accurate predictions of neutrino clustering over a wide range of length scales. The FlowsForTheMasses non-linear perturbation theory for the massive neutrino power spectrum, $\Delta^2_\nu(k)$, agrees with its companion N-body simulation at the $10\%-15\%$ level for $k \leq 1~h/$Mpc. Building upon the Mira-Titan IV emulator for the cold matter, we use FlowsForTheMasses to construct an emulator for $\Delta^2_\nu(k)$ covering a large range of cosmological parameters and neutrino fractions $\Omega_{\nu,0} h^2 \leq 0.01$, which corresponds to $M_\nu \leq 0.93$~eV. Consistent with FlowsForTheMasses at the $3.5\%$ level, it returns a power spectrum in milliseconds. Ranking the neutrinos by initial momenta, we also emulate the power spectra of momentum deciles, providing information about their perturbed distribution function. Comparing a $M_\nu=0.15$~eV model to a wide range of N-body simulation methods, we find agreement to $3\%$ for $k \leq 3 k_\mathrm{FS} = 0.17~h/$Mpc and to $19\%$ for $k \leq 0.4~h/$Mpc. We find that the enhancement factor, the ratio of $\Delta^2_\nu(k)$ to its linear-response equivalent, is most strongly correlated with $\Omega_{\nu,0} h^2$, and also with the clustering amplitude $\sigma_8$. Furthermore, non-linearities enhance the free-streaming-limit scaling $\partial \log(\Delta^2_\nu / \Delta^2_{\rm m}) / \partial \log(M_\nu)$ beyond its linear value of 4, increasing the $M_\nu$-sensitivity of the small-scale neutrino density.Comment: 17 pages, 14 figures, 3 tables. Emulator code available at: https://github.com/upadhye/Cosmic-En

Risk stratification of cardiac arrhythmias and sudden cardiac death in type 2 diabetes mellitus patients receiving insulin therapy: A population-based cohort study

Introduction Metabolic abnormalities may exacerbate the risk of adverse outcomes in patients with type 2 diabetes mellitus. The present study aims to assess the predictive value of HbA1c and lipid variability on the risks of sudden cardiac death (SCD) and incident atrial fibrillation (AF). Methods The retrospective observational study consists of type 2 diabetic patients prescribed with insulin, who went to publicly funded clinics and hospitals in Hong Kong between January 1, 2009 and December 31, 2009. Variability in total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, and HbA1c were assessed through their SD and coefficient of variation. The primary outcomes were incident (1) ventricular tachycardia/ventricular fibrillation, actual or aborted SCD and (2) AF. Results A total of 23 329 patients (mean ± SD age: 64 ± 14 years old; 51% male; mean HbA1c 8.6 ± 1.3%) were included. On multivariable analysis, HbA1c, total cholesterol, LDL-C and triglyceride variability were found to be predictors of SCD (p < .05). Conclusion HbA1c and lipid variability were predictive of SCD. Therefore, poor glucose control and variability in lipid parameters in diabetic patients are associated with aborted or actual SCD. These observations suggest the need to re-evaluate the extent of glycemic control required for outcome optimization

Concurrent Use of Oral Anticoagulants and Sulfonylureas in Individuals With Type 2 Diabetes and Risk of Hypoglycemia: A UK Population-Based Cohort Study

OBJECTIVE: To investigate the association of concurrent use of oral anticoagulants (OACs) and sulfonylureas and the risk of hypoglycemia in individuals with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: A retrospective cohort study was conducted between 2001 and 2017 using electronic primary healthcare data from the IQVIA Medical Research Data (IMRD) that incorporates data supplied by The Health Improvement Network (THIN), a propriety database of Cegedim SA. Individuals with T2DM who received OAC prescription and sulfonylureas were included. We compared the risk of hypoglycemia with sulfonylureas and OACs using propensity score matching and Cox regression. RESULTS: 109,040 individuals using warfarin and sulfonylureas and 77,296 using direct oral anticoagulants (DOACs) and sulfonylureas were identified and included. There were 285 hypoglycemia events in the warfarin with sulfonylureas group (incidence rate = 17.8 per 1,000 person-years), while in the sulfonylureas only, 304 hypoglycemia events were observed (incidence rate = 14.4 per 1,000 person-years). There were 14 hypoglycemic events in the DOACs with sulfonylureas group (incidence rates = 14.8 per 1,000 person-years), while in the sulfonylureas alone group, 60 hypoglycemia events were observed (incidence rate =23.7 per 1,000 person-years). Concurrent use of warfarin and sulfonylureas was associated with increased risk of hypoglycemia compared with sulfonylureas alone (HR 1.38; 95% CI 1.10–1.75). However, we found no evidence of an association between concurrent use of DOACs and sulfonylureas and risk of hypoglycemia (HR 0.54; 95% CI, 0.27–1.10) when compared with sulfonylureas only. CONCLUSIONS: We provide real-world evidence of possible drug-drug interactions between warfarin and sulfonylureas. The decision to prescribe warfarin with coexistent sulfonylureas to individuals with T2DM should be carefully evaluated in the context of other risk factors of hypoglycemia, and availability of alternative medications

Is Routine Pupil Dilation Safe among Asian Patients with Diabetes?

PURPOSE. To investigate the risk of acute angle closure (AAC), changes in intraocular pressure (IOP), and factors associated with these outcomes after routine pupil dilation in a cohort of Asian subjects with diabetes mellitus. METHODS. The study was a prospective observational case series of 1910 consecutive Asian subjects newly referred for assessment of diabetic retinopathy at a tertiary clinic. All subjects underwent routine pupil dilation unless there was a prior history of angle-closure glaucoma. Noncontact air-puff tonometry was used to assess IOP, which was measured by the same observer before and 1 hour after pupil dilation. Subjects were assessed for signs and symptoms of AAC before leaving the clinic, and their charts were also subsequently reviewed for revisits with AAC. RESULTS. Of the 1910 subjects who participated, none developed AAC. Sixty-nine subjects (3.6%, 95% CI: 2.8%-4.5%) showed an increase in IOP of Ն5 mm Hg in the either eye, 37 subjects (1.9%, 95% CI: 1.4%-2.6%) had a postdilation IOP Ͼ25 mm Hg in either eye, and only 10 subjects (0.52%, 95% CI: 0.25%-0.96%) had an increase in IOP Ն5 mm Hg and had a postdilation IOP Ͼ25 mm Hg in either eye. The level of predilation IOP and a known history of glaucoma were significant risk factors for a postdilation IOP Ն25 mm Hg. CONCLUSIONS. In this cohort of Asian persons with diabetes, the risk of AAC was insignificant after routine dilation of pupils for fundus examination. These data substantiate the safety of routine dilation of pupils in Asian patients with diabetes. (Invest Ophthalmol Vis Sci. 2009;50:4110 -4113