Optical diffraction for measurements of nano-mechanical bending

Micromechanical transducers such as cantilevers for AFM often rely on optical readout methods that require illumination of a specific region of the microstructure. Here we explore and exploit the diffraction effects that have been previously neglected when modeling cantilever bending measurement techniques. The illumination of a cantilever end causes an asymmetric diffraction pattern at the photodetector that significantly affects the calibration of the signal in the popular optical beam deflection technique (OBDT). Conditions for optimized linear signals that avoid detection artifacts conflict with small numerical aperture illumination and narrow cantilevers which are softer and therefore more sensitive. Embracing diffraction patterns as a physical measurable allows a richer detection technique that decouples measurements of tilt and curvature and simultaneously relaxes the requirements on the alignment of illumination and detector. We show analytical results, numerical simulations and physiologically relevant experimental data demonstrating the usefulness of these diffraction features. We offer experimental design guidelines and identify and quantify possible sources of systematic error of up to 10% in OBDT. We demonstrate a new nanometre resolution detection method that can replace OBDT, where Frauenhofer and Bragg diffraction effects from finite sized and patterned cantilevers are exploited. Such effects are readily generalized to arrays, and allow transmission detection of mechanical curvature, enabling in-line instruments. In particular, a cantilever with a periodic array of slots produces Bragg peaks which can be analyzed to deduce the cantilever curvature. We highlight the comparative advantages over OBDT by detecting molecular activity of antibiotic Vancomycin, with an RMS noise equivalent to less than $2.5 \mu M$ (1.5 nm), as example of possible multi-maker bio-assays.Comment: 9 pages, 8 figure

Model-based detection of alternative splicing signals

Motivation: Transcripts from ∼95% of human multi-exon genes are subject to alternative splicing (AS). The growing interest in AS is propelled by its prominent contribution to transcriptome and proteome complexity and the role of aberrant AS in numerous diseases. Recent technological advances enable thousands of exons to be simultaneously profiled across diverse cell types and cellular conditions, but require accurate identification of condition-specific splicing changes. It is necessary to accurately identify such splicing changes to elucidate the underlying regulatory programs or link the splicing changes to specific diseases

The establishment of the GENEQOL consortium to investigate the genetic disposition of patient-reported quality-of-life outcomes

To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported quality-of-life outcomes. The overall objective of this paper is to describe the establishment of an international and interdisciplinary consortium, the GENEQOL Consortium, which intends to investigate the genetic disposition of patient-reported quality-of-life outcomes. We have identified five primary patient-reported quality-of-life outcomes as initial targets: negative psychological affect, positive psychological affect, self-rated physical health, pain, and fatigue. The first tangible objective of the GENEQOL Consortium is to develop a list of potential biological pathways, genes and genetic variants involved in these quality-of-life outcomes, by reviewing current genetic knowledge. The second objective is to design a research agenda to investigate and validate those genes and genetic variants of patient-reported quality-of-life outcomes, by creating large datasets. During its first meeting, the Consortium has discussed draft summary documents addressing these questions for each patient-reported quality-of-life outcome. A summary of the primary pathways and robust findings of the genetic variants involved is presented here. The research agenda outlines possible research objectives and approaches to examine these and new quality-of-life domains. Intriguing questions arising from this endeavor are discussed. Insight into the genetic versus environmental components of patient-reported quality-of-life outcomes will ultimately allow us to explore new pathways for improving patient care. If we can identify patients who are susceptible to poor quality of life, we will be able to better target specific clinical interventions to enhance their quality of life and treatment outcome

Enter the Matrix: What the new brain-computer interfaces teach us about agency, privacy, and human subjectivity

Within the last decade, the global brain-computer interface (BCI) industry has experienced significant economic growth and captured the public’s imagination through enthusiastic coverage in the popular media. Responding dialectically to this growing public discourse, this paper overviews the social, ethical, and philosophical aspects of BCIs that pose the greatest concern for information policymakers. By reading the industry’s techno-economic trends against contemporary critical philosophy, I argue that these technologies enable new “posthuman” forms of surveillance and control that challenge democratic notions of freedom, privacy, and equality

Measuring Ion Channels on Solid Supported Membranes

Application of solid supported membranes (SSMs) for the functional investigation of ion channels is presented. SSM-based electrophysiology, which has been introduced previously for the investigation of active transport systems, is expanded for the analysis of ion channels. Membranes or liposomes containing ion channels are adsorbed to an SSM and a concentration gradient of a permeant ion is applied. Transient currents representing ion channel transport activity are recorded via capacitive coupling. We demonstrate the application of the technique to liposomes reconstituted with the peptide cation channel gramicidin, vesicles from native tissue containing the nicotinic acetylcholine receptor, and membranes from a recombinant cell line expressing the ionotropic P2X2 receptor. It is shown that stable ion gradients, both inside as well as outside directed, can be applied and currents are recorded with an excellent signal/noise ratio. For the nicotinic acetylcholine receptor and the P2X2 receptor excellent assay quality factors of Z′ = 0.55 and Z′ = 0.67, respectively, are obtained. This technique opens up new possibilities in cases where conventional electrophysiology fails like the functional characterization of ion channels from intracellular compartments. It also allows for robust fully automatic assays for drug screening

The Impact of Concomitant Medication Use on Patient Eligibility for Phase I Cancer Clinical Trials

<p>Concomitant medication (CM) use may result in Phase I cancer clinical trial ineligibility due to concern for potential CM-investigational drug interactions or alteration of investigational drug absorption. Few studies have examined the impact of CM use on trial eligibility. <b>Methods:</b> We reviewed records of 274 patients on Phase I trials at a single academic institution. Demographics, CM identities and classes, CM discontinuation, reasons, and incidence of CM substitution were recorded. CM-investigational drug cytochrome P450 (CYP) enzyme interactions were documented. Statistical analysis was performed using descriptive statistics. <b>Results: </b>273 of 274 patients (99.6%, 95% confidence interval [CI] 98.9-100%) took CM, with a median of 8 CM per patient (range 0 - 42). CM discontinuation occurred in 67 cases (25%, 95% CI 19-30%). The most common CM classes discontinued were herbal (17 cases, 25%, 95% CI 16-37%) and proton pump inhibitors (15 cases, 22%, 95% CI 12-32%). CM discontinuation reasons were: protocol prohibition (32 cases, 48%, 95% CI 36-60%); potential CM-investigational drug interaction (25 cases, 37%, 95% CI 26-49%); other (10 cases, 15%, 95% CI 6-23%). A potential CM-investigational drug CYP interaction was noted in 122 cases (45%, 95% CI 39-50%). CM potentially weakly decreased investigational drug metabolism in 52 cases (43%, 95% CI 34-51%), and potentially strongly decreased investigational drug metabolism in 17 cases (14%, 95% CI 8-20%). Investigational drug potentially weakly decreased CM metabolism in 39 cases (32%, 95% CI 24-40%), and potentially strongly decreased CM metabolism in 28 cases (23%, 95% CI 15-30%). CM substitution occurred in 36/67 cases (54%, 95% CI 41-66%) where CM were discontinued to allow for eventual participation in clinical trials. Overall in 2 cases (0.7%, 95% CI 0.1-2.6%), patients were protocol ineligible because CM could not be discontinued or substituted. <b>Conclusions: </b>This study highlights the high prevalence of concomitant medication use among cancer patients enrolled in phase I clinical trials. Most patients did meet trial eligibility criteria with careful substitution and discontinuation of CM. The most common reason for discontinuation of CM was protocol prohibition. The most common medications discontinued were herbal, proton pump inhibitors, selective serotonin reuptake inhibitor anti-depressants, and non-steroidal anti-inflammatory drugs.</p

Preoperative Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by RESULTS: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.)