Cloud-Integrated Smart Nanomembrane Wearables for Remote Wireless Continuous Health Monitoring of Postpartum Women.

Noncommunicable diseases (NCD), such as obesity, diabetes, and cardiovascular disease, are defining healthcare challenges of the 21st century. Medical infrastructure, which for decades sought to reduce the incidence and severity of communicable diseases, has proven insufficient in meeting the intensive, long-term monitoring needs of many NCD disease patient groups. In addition, existing portable devices with rigid electronics are still limited in clinical use due to unreliable data, limited functionality, and lack of continuous measurement ability. Here, a wearable system for at-home cardiovascular monitoring of postpartum women-a group with urgently unmet NCD needs in the United States-using a cloud-integrated soft sternal device with conformal nanomembrane sensors is introduced. A supporting mobile application provides device data to a custom cloud architecture for real-time waveform analytics, including medical device-grade blood pressure prediction via deep learning, and shares the results with both patient and clinician to complete a robust and highly scalable remote monitoring ecosystem. Validated in a month-long clinical study with 20 postpartum Black women, the system demonstrates its ability to remotely monitor existing disease progression, stratify patient risk, and augment clinical decision-making by informing interventions for groups whose healthcare needs otherwise remain unmet in standard clinical practice.

Intrinsic resistance to ROS1 inhibition in a patient with CD74-ROS1 mediated by AXL overexpression.

BACKGROUND: The vast majority of patients with ROS1 positive non-small cell lung cancer (NSCLC) derive clinical benefit from currently approved ROS1 therapies, including crizotinib and entrectinib. However, a small proportion of patients treated with ROS1 inhibitors fail to derive any clinical benefit and demonstrate rapid disease progression. The biological mechanisms underpinning intrinsic resistance remain poorly understood for oncogene-driven cancers. METHODS: We generated a patient-derived cell line, CUTO33, from a ROS1 therapy naive patient with CD74-ROS1+ NSCLC, who ultimately did not respond to a ROS1 inhibitor. We evaluated a panel of ROS1+ patient-derived NSCLC cell lines and used cell-based assays to determine the mechanism of intrinsic resistance to ROS1 therapy. RESULTS: The CUTO33 cell line expressed the CD74-ROS1 gene fusion at the RNA and protein level. The ROS1 fusion protein was phosphorylated at baseline consistent with the known intrinsic activity of this oncogene. ROS1 phosphorylation could be inhibited using a wide array of ROS1 inhibitors, however these inhibitors did not block cell proliferation, confirming intrinsic resistance in this model and consistent with the patient's lack of response to a ROS1 inhibitor. CUTO33 expressed high levels of AXL, which has been associated with drug resistance. Combination of an AXL inhibitor or AXL knockdown with a ROS1 inhibitor partially reversed resistance. CONCLUSIONS: In summary, we demonstrate that AXL overexpression is a mechanism of intrinsic resistance to ROS1 inhibitors.

Therapy for insomnia with chronic obstructive pulmonary disease: a randomized trial of components.

STUDY OBJECTIVES: To determine efficacy and mechanisms of cognitive behavioral therapy for insomnia (CBT-I) and chronic obstructive pulmonary disease (COPD) education (COPD-ED) on clinical outcomes in adults with concurrent COPD and insomnia. METHODS: We conducted a 2 × 2 factorial study to test the impact of CBT-I and COPD-ED delivered alone or in combination on severity of insomnia and fatigue, sleep, and dyspnea. Participants were randomized to 1 of 4 groups-group 1: CBT-I + attention control (AC; health videos, n = 27); group 2: COPD-ED + AC, n = 28; group 3: CBT-I + COPD-ED, n = 27; and group 4, AC only, n = 27. Participants received six 75-minute weekly sessions. Dependent variables included insomnia severity, sleep by actigraphy, fatigue, and dyspnea measured at baseline, immediately postintervention, and at 3 months postintervention. Presumed mediators of intervention effects included beliefs and attitudes about sleep, self-efficacy for sleep and COPD, and emotional function. RESULTS: COPD patients (percent predicted forced expiratory volume in 1 second [FEV1pp] 67% ± 24% [mean ± standard deviation]), aged 65 ± 8 years, with insomnia participated in the study. Insomnia and sleep improved more in patients who received CBT-I than in those who did not, an effect that was sustained at 3 months postintervention and mediated by beliefs and attitudes about sleep. CBT-I was associated with clinically important improvements in fatigue and dyspnea. When CBT-I and COPD-ED were concurrently administered, effects on insomnia, fatigue, and dyspnea were attenuated. CONCLUSIONS: CBT-I produced significant and sustained decreases in insomnia improved sleep and clinically important improvement in fatigue, and dyspnea. The combination of CBT-I and COPD-ED reduced CBT-I's effectiveness. Further research is needed to understand the mechanisms associated with effects of insomnia therapy on multiple symptoms in COPD. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Behavioral Therapy for Insomnia Co-existing with COPD; URL: https://clinicaltrials.gov/ct2/show/NCT01973647; Identifier: NCT01973647. CITATION: Kapella M, Steffen A, Prasad B, et al. Therapy for insomnia with chronic obstructive pulmonary disease: a randomized trial of components. J Clin Sleep Med. 2022;18(12):2763-2774.

Reasons Why Pregnant Women Participate in Ultrasound Research Involving Transvaginal Scans.

OBJECTIVES: The aim of this study was to explore the motivations of pregnant women in participating in an ultrasound study and the acceptability of vaginal ultrasound examinations. METHODS: A prospective sample of 270 women were asked one question: "Can you tell me what motivated you to participate in the study?" The data were then analyzed through a qualitative thematic analysis with an inductive approach. In addition to the thematic analysis, quantification of the data was performed to enhance the qualitative result. RESULTS: Through the thematic analysis, 5 themes emerged from the responses of the participants: altruism, research, personal experience, personal benefit, and finding out. All responses were relatively short, and some responses included more than one theme. CONCLUSIONS: Vaginal ultrasound examinations were acceptable to the participants, and pregnant women had many motivations to participate. Regardless of race, ethnicity, or insurance status, the women in our study were altruistic and curious about our research.

The effects of repeated binge drinking on arterial stiffness and urinary norepinephrine levels in young adults.

OBJECTIVES: The aim of this study was to investigate the effect of repeated binge drinking and moderate alcohol consumption in young adults on arterial stiffness and sympathetic activity. METHODS: We enrolled 49 healthy young adults, free of cardiovascular diseases (25 men; age: 23.5 ±â€Š0.4 years; BMI: 23.4 ±â€Š0.4 kg/m; mean ±â€ŠS.E). Individuals included were those with a history of repeated binge drinking (>2 years duration; n = 20), drank at moderate levels (MODs, >5 years duration; n = 16) and abstained from alcohol (last 2-3 years; n = 13). Arterial stiffness was assessed using carotid to femoral pulse wave velocity (cfPWV) and sympathetic activity was assessed using 24-h urinary norepinephrine levels. Also measured was aortic SBP and augmentation index (AIx), a measure of wave reflection. RESULTS: Binge drinkers and MODs had higher cfPWV than alcohol abstainers (0.6 and 0.5 m/s, respectively; P ≤ 0.04). In addition, binge drinkers had higher urinary norepinephrine levels than MODs and alcohol abstainers (P < 0.05). Higher cfPWV were correlated with higher norepinephrine levels (r = 0.35. P = 0.02). Aortic SBP (P = 0.2) and AIx (P = 0.96) were similar among binge drinkers, MODs and alcohol abstainers. CONCLUSION: Our findings suggest that repeated exposure to alcohol, regardless of drinking pattern, may increase aortic arterial stiffness in healthy young adults. In addition, sympathetic activation, reflected by increased 24-h urinary norepinephrine levels, may contribute to alcohol-induced arterial stiffening in young adults.

Tetrahydrobiopterin Restores Microvascular Dysfunction in Young Adult Binge Drinkers.

BACKGROUND: Repeated binge drinking is associated with reduced microvascular function. However, microvascular responses to pathophysiological stimulus such as high pressure as well as potential mechanisms that underlie binge-induced microvascular dysfunction are unknown. Therefore, using an ex vivo experimental model, we examined microvascular responses following a brief period of high intraluminal pressure in isolated arterioles from young adults who have a history of repeated binge drinking. In addition, we examined whether the application of the endothelial nitric oxide synthase cofactor, tetrahydrobiopterin, would restore microvascular function in response to flow and high intraluminal pressure in young adult binge drinkers. METHODS: Isolated subcutaneous adipose arterioles were obtained from young adult binge drinkers (BD; n = 14), moderate drinkers (MODs; n = 10), and alcohol abstainers (ABs; n = 12; mean age: 23.7 ± 0.5 years; and body mass index: 23.4 ± 0.4 kg/m2 ). Arteriolar flow-induced dilation (FID, pressure gradient: ∆10 to 100 cm H2 O) was measured before and after acute high intraluminal pressure with and without tetrahydrobiopterin. RESULTS: Before high pressure, FID at Δ60 and Δ100 cm H2 O pressure gradient in BDs was 14% lower and 18% lower, respectively, than ABs (p < 0.05), while MODs and ABs had similar FID across all pressure gradients (p ≥ 0.2). After high pressure, FID in BDs was further reduced by 10% (p < 0.0005) and this impairment was ameliorated by the treatment of tetrahydrobiopterin (4 to 26% higher, p < 0.005). In contrast, FID after high pressure did not change in MODs and ABs (p ≥ 0.5). CONCLUSIONS: Microvascular dysfunction in young adult binge drinkers may be exacerbated with acute pathophysiological stimulus. These binge-induced dysfunctions may be reversed by tetrahydrobiopterin, which suggests a role of oxidative stress and/or uncoupled endothelial nitric oxide synthase in binge drinking.

A Phantom-Based Assessment of Repeatability and Reproducibility of Transvaginal Quantitative Ultrasound.

This article evaluated the repeatability and reproducibility (R&R) of quantitative ultrasound (QUS) biomarkers attenuation coefficient (AC) and backscatter coefficient (BSC) in transvaginal QUS reference phantoms for obstetric applications. Five phantoms were scanned by three sonographers according to the scanning protocol. Each sonographer scanned each phantom with four transvaginal transducers of the same model (MC9-4) and three probe cover types (latex cover, nonlatex cover, and no cover). The AC and BSC were estimated by using a reference phantom method. The R&R analysis was performed for the frequency-averaged AC and logBSC (= 10log10BSC) (5.4-5.8 MHz) by using three-factor random effects Analysis of Variance with interaction. The total R&R variabilities for AC and logBSC are small (AC: 0.042-0.065 dB/cm-MHz; logBSC: 0.50-0.68 dB), indicating high measurement precision. These values are small compared to the ranges of AC (0.28-0.99 dB/cm-MHz) and logBSC (-33.16 to -20.35 dB) of the five phantoms. The AC and logBSC biomarkers measured on transvaginal QUS phantoms using the reference phantom method are repeatable, and reproducible between sonographers, transducers, and probe covers.

Target-Based Screening against eIF4A1 Reveals the Marine Natural Product Elatol as a Novel Inhibitor of Translation Initiation with In Vivo Antitumor Activity.

Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors.Experimental Design: We tested potency and specificity of the marine compound elatol versus eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding site mutagenesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors.Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at approximately 100× relative dosing, leading to significant activity against lymphoma xenografts.Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo antitumor activities provides proof of principle for target-based screening against this highly promising target for cancer therapy. Clin Cancer Res; 24(17); 4256-70. ©2018 AACR.

Steps to Enhance Early Recovery After Hematopoietic Stem Cell Transplantation: Lessons Learned From a Physical Activity Feasibility Study.

AIMS: This pilot study tested and refined a free-living physical activity intervention. The investigators evaluated the acceptability and feasibility of the intervention after hematopoietic stem cell transplantation and determined preliminary effects on physical activity, fatigue, muscle strength, functional ability, and quality of life. DESIGN: This pilot study used a 1-group, pretest-posttest design. METHODS: The free-living physical activity intervention consisted of an education component and 6 weeks of gradually increasing physical activity after discharge from the hospital. The intervention was designed to increase steps by 10% weekly. Subjects were assessed before transplantation and during the seventh week after discharge from the hospital after completing the intervention. Pretest-posttest scores were analyzed with paired t tests. RESULTS: Subject wore the physical activity tracker for an average of 38 of 42 days and met their physical activity goals 57% of the time. Subjects reported significantly less physical fatigue after the free-living physical activity intervention compared with baseline (P = .05). Improvements in quality of life approached significance (P = .06). CONCLUSION: The findings demonstrate that the free-living physical activity intervention implemented during the very early recovery period after transplantation is feasible and acceptable. The intervention potentially reduces fatigue and improves quality of life. The positive results must be interpreted cautiously given the pilot nature of the study. The evidence supports continued investigation.

Exercise Intervention: Attrition, Compliance, Adherence, and Progression Following Hematopoietic Stem Cell Transplantation
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BACKGROUND: Exercise is widely touted as an effective intervention to optimize health and well-being after high-dose chemotherapy and hematopoietic stem cell transplantation. 
. OBJECTIVES: This article reports attrition, compliance, adherence, and progression from the strength training arm of the single-blind randomized, controlled trial Strength Training to Enhance Early Recovery (STEER). 
. METHODS: 37 patients were randomized to the intervention and participated in a structured strength training program introduced during hospitalization and continued for six weeks after release. Research staff and patients maintained exercise logs to document compliance, adherence, and progression. 
. FINDINGS: No patients left the study because of burden. Patients were compliant with completion of exercise sessions, and their adherence was high; they also progressed on their exercise prescription. Because STEER balances intervention effectiveness with patient burden, the findings support the likelihood of successful translation into clinical practice.

ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A.

Activation of translation initiation is a common trait of cancer cells. Formation of the heterotrimeric eukaryotic initiation factor F (eIF4F) complex is the rate-limiting step in 5' m7GpppN cap-dependent translation. This trimeric complex includes the eIF4E cap binding protein, the eIF4G scaffolding protein, and the DEAD box RNA helicase eIF4A. eIF4A is an ATP-dependent helicase and because it is the only enzyme in the eIF4F complex, it has been shown to be a potential therapeutic target for a variety of malignancies. To this end, we have used a simple ATPase biochemical screen to survey several hundred marine and terrestrial derived natural products. Herein, we report the discovery of two natural products from marine sources, elisabatin A (1) and allolaurinterol (2), which show low µM inhibition of eIF4A ATPase activity. Enzymological analyses revealed 1 and 2 to be ATP-competitive, and cellular evaluations showed reasonable cytotoxicity against A549 (lung cancer) and MDA-MA-468 (breast cancer) cell lines. However, only compound 2 showed potent inhibition of helicase activity congruent with its ATPase inhibitory activity.

Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?

Gene-expression profiling and next-generation sequencing have defined diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis, as a heterogeneous group of subentities. Despite ongoing explosions of data illuminating disparate pathogenic mechanisms, however, the five-drug chemoimmunotherapy combination R-CHOP remains the frontline standard treatment. This has not changed in 15 years, since the anti-CD20 monoclonal antibody rituximab was added to the CHOP backbone, which first entered use in the 1970s. At least a third of patients are not cured by R-CHOP, and relapsed or refractory DLBCL is fatal in ∼90%. Targeted small-molecule inhibitors against distinct molecular pathways activated in different subgroups of DLBCL have so far translated poorly into the clinic, justifying the ongoing reliance on R-CHOP and other long-established chemotherapy-driven combinations. New drugs and improved identification of biomarkers in real time, however, show potential to change the situation eventually, despite some recent setbacks. Here, we review established and putative molecular drivers of DLBCL identified through large-scale genomics, highlighting among other things the care that must be taken when differentiating drivers from passengers, which is influenced by the promiscuity of activation-induced cytidine deaminase. Furthermore, we discuss why, despite having so much genomic data available, it has been difficult to move toward personalized medicine for this umbrella disorder and some steps that may be taken to hasten the process.

Strength Training to Enhance Early Recovery after Hematopoietic Stem Cell Transplantation.

Intensive cancer treatment followed by hematopoietic stem cell transplantation (HCT) results in moderate to severe fatigue and physical inactivity, leading to diminished functional ability. The purpose of this study was to determine the efficacy of an exercise intervention, strength training to enhance early recovery (STEER), on physical activity, fatigue, muscle strength, functional ability, and quality of life after HCT. This single-blind, randomized clinical trial compared strength training (n = 33) to usual care plus attention control with health education (UC + AC with HE) (n = 34). Subjects were stratified by type of transplantation and age. STEER consisted of a comprehensive program of progressive resistance introduced during hospitalization and continued for 6 weeks after hospital discharge. Fatigue, physical activity, muscle strength, functional ability, and quality of life were assessed before HCT hospital admission and after intervention completion. Data were analyzed using split-plot analysis of variance. Significant time × group interactions effects were noted for fatigue (P = .04). The STEER group reported improvement in fatigue from baseline to after intervention whereas the UC + AC with HE group reported worsened fatigue from baseline to after intervention. Time (P < .001) and group effects (P = .05) were observed for physical activity. Physical activity declined from baseline to 6 weeks after hospitalization. The STEER group was more physically active. Functional ability tests (timed stair climb and timed up and go) resulted in a significant interaction effect (P = .03 and P = .05, respectively). Subjects in the UC + AC with HE group were significantly slower on both tests baseline to after intervention, whereas the STEER group's time remained stable. The STEER group completed both tests faster than the UC + AC with HE group after intervention. Study findings support the use of STEER after intensive cancer treatment and HCT. Strength training demonstrated positive effects on fatigue, physical activity, muscle strength, and functional ability. The exact recovery patterns between groups and over time varied; the STEER group either improved or maintained their status from baseline to after intervention (6 weeks after hospital discharge) whereas the health education group generally declined over time or did not change.

Persistent Fatigue in Hematopoietic Stem Cell Transplantation Survivors.

BACKGROUND: Fatigue is highly prevalent after hematopoietic stem cell transplantation (HCT). It has been described as intense and may last for years following treatment. OBJECTIVE: The aim of this study is to compare fatigue, physical activity, sleep, emotional distress, cognitive function, and biological measures in HCT survivors with persistent fatigue (n = 25) with age- and gender-matched healthy controls with occasional tiredness (n = 25). METHODS: Data were collected using (a) objective, real-time assessments of physical activity and sleep over 7 days; (b) patient-reported fatigue assessments; (c) computerized objective testing of cognitive functioning; and (d) biological measures. Differences between groups were examined using multivariate analysis of variance. RESULTS: Survivors of HCT reported increased physical (P < .001), mental (P < .001), and overall (P < .001) fatigue as well as increased anxiety (P < .05) and depression (P < .01) compared with healthy controls. Red blood cell (RBC) levels were significantly lower in HCT survivors (P < .001). Levels of RBC for both groups, however, were in the normal range. Tumor necrosis factor-α (P < .001) and interleukin-6 (P < .05) levels were significantly higher in HCT survivors. CONCLUSIONS: Persistent fatigue in HCT survivors compared with healthy controls with occasional tiredness is accompanied by increased anxiety and depression along with decreased RBC counts. Elevated tumor necrosis factor-α and interleukin-6 levels may be important biomarkers. IMPLICATIONS FOR PRACTICE: This study provides preliminary support for the conceptualization of fatigue as existing on a continuum, with tiredness anchoring one end and exhaustion the other. Persistent fatigue experienced by HCT survivors is more severe than the occasional tiredness of everyday life.

Real-time Fatigue and Free-Living Physical Activity in Hematopoietic Stem Cell Transplantation Cancer Survivors and Healthy Controls: A Preliminary Examination of the Temporal, Dynamic Relationship.

BACKGROUND: Fatigue and physical inactivity, critical problems facing cancer survivors, impact overall health and functioning. Our group designed a novel methodology to evaluate the temporal, dynamic patterns in real-world settings. OBJECTIVE: Using real-time technology, the temporal, dynamic relationship between real-time fatigue and free-living is described and compared in cancer survivors who were treated with hematopoietic stem cell transplantation (n = 25) and age- and gender-matched healthy controls (n = 25). METHODS: Subjects wore wrist actigraphs on their nondominant hand to assess free-living physical activity, measured in 1-minute epochs, over 7 days. Subjects entered real-time fatigue assessments directly into the subjective event marker of the actigraph 5 times per day. Running averages of mean 1-minute activity counts 30, 60, and 120 minutes before and after each real-time fatigue score were correlated with real-time fatigue using generalized estimating equations, RESULTS:: A strong inverse relationship exists between real-time fatigue and subsequent free-living physical activity. This inverse relationship suggests that increasing real-time fatigue limits subsequent physical activity (B range= -0.002 to -0.004; P < .001). No significant differences in the dynamic patterns of real-time fatigue and free-living physical activity were found between groups. CONCLUSIONS: To our knowledge, this is the first study to document the temporal and potentially causal relationship between real-time fatigue and free-living physical activity in real-world setting. These findings suggest that fatigue drives the subsequent physical activity and the relationship may not be bidirectional. IMPLICATIONS FOR PRACTICE: Understanding the temporal, dynamic relationship may have important health implications for developing interventions to address fatigue in cancer survivors.

Control of translational activation by PIM kinase in activated B-cell diffuse large B-cell lymphoma confers sensitivity to inhibition by PIM447.

The PIM family kinases promote growth and survival of tumor cells and are expressed in a wide variety of human cancers. Their potential as therapeutic targets, however, is complicated by overlapping activities with multiple other pathways and remains poorly defined in most clinical scenarios. Here we explore activity of the new pan-PIM inhibitor PIM447 in a variety of lymphoid-derived tumors. We find strong activity in cell lines derived from the activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Sensitive lines show lost activation of the mTORC1 signaling complex and subsequent lost activation of cap-dependent protein translation. In addition, we characterize recurrent PIM1 protein-coding mutations found in DLBCL clinical samples and find most preserve the wild-type protein's ability to protect cells from apoptosis but do not bypass activity of PIM447. Pan-PIM inhibition therefore may have an important role to play in the therapy of selected ABC-DLBCL cases.

Ultrasound Assessment of the Rectus Femoris Cross-Sectional Area: Subject Position Implications.

Ultrasonic measurement of the rectus femoris (RF) is a novel, proxy measure for muscle strength. The impact of hip flexion/head of bed positioning on RF cross-sectional area (CSA) has not been fully explored. This study describes and compares differences in RF CSA across four degrees of hip flexion. This repeated-measures, comparative study enrolled healthy, pre-menopausal women (n = 20). RF CSA of the dominant leg was measured using the SonoSite M-Turbo ultrasound system with the head of bed at 0°, 20°, 30°, and 60°. One-way repeated measures indicated significant differences in RF CSA, F(3, 17) = 14.18, p < .001, with variation in hip flexion/head of bed elevation and significant RF CSA differences between: (a) 0° and 20°, (b) 0° and 30°, (c) 0° and 60°, and (d) 20° and 60°. Standardizing patient positioning when conducting ultrasonic measurement of RF CSA is vital for researchers who assess muscle mass.

Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors.

The anaplastic lymphoma kinase (ALK) is chromosomally rearranged in a subset of certain cancers, including 2% to 7% of non-small cell lung cancers (NSCLC) and ∼70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors crizotinib and ceritinib are approved for relapsed ALK(+) NSCLC, but acquired resistance to these drugs limits median progression-free survival on average to ∼10 months. Kinase domain mutations are detectable in 25% to 37% of resistant NSCLC samples, with activation of bypass signaling pathways detected frequently with or without concurrent ALK mutations. Here we report that, in contrast to NSCLC cells, drug-resistant ALCL cells show no evidence of bypassing ALK by activating alternate signaling pathways. Instead, drug resistance selected in this setting reflects upregulation of ALK itself. Notably, in the absence of crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested or killed cells, allowing a prolonged control of drug-resistant tumors in vivo with the administration of discontinuous rather than continuous regimens of drug dosing. Furthermore, even when drug resistance mutations were detected in the kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We confirmed these findings derived from human ALCL cells in murine pro-B cells that were transformed to cytokine independence by ectopic expression of an activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK activation functions as a double-edged sword for tumor cell viability, with potential therapeutic implications.

How informed is online informed consent?

We examined participants' reading and recall of informed consent documents presented via paper or computer. Within each presentation medium, we presented the document as a continuous or paginated document to simulate common computer and paper presentation formats. Participants took slightly longer to read paginated and computer informed consent documents and recalled slightly more information from the paginated documents. We concluded that obtaining informed consent online is not substantially different than obtaining it via paper presentation. We also provide suggestions for improving informed consent--in both face-to-face and online experiments.