Search

Supplementary Figure S4. Anti-PD-1 blockade partially restores IFNγ secretion by TILs against CD44+ SCCHN cells.

Background: Despite the growing popularity of mobile app interventions, specific engagement components of mobile apps have not been well studied. Methods: The objectives of this scoping review are ...

Background Approximately 6.1 million adults in the United States serve as care partners for cancer survivors. Studies have demonstrated that engaging cancer survivors and their care partners through technology-enabled structured symptom collection has several benefits. Given the high utilization of mobile technologies, even among underserved populations and in low resource areas, mobile apps may provide a meaningful access point for all stakeholders for symptom management. Objective We aimed to develop a mobile app incorporating user preferences to enable cancer survivors’ care partners to monitor the survivors’ health and to provide care partner resources. Methods An iterative information gathering process was conducted that included (1) discussions with 138 stakeholders to identify challenges and gaps in survivor home care; (2) semistructured interviews with clinicians (n=3), cancer survivors (n=3), and care partners (n=3) to identify specific needs; and (3) a 28-day feasibility field test with seven care partners. Results Health professionals noted the importance of identifying early symptoms of adverse events. Survivors requested modules on medication, diet, self-care, reminders, and a version in Spanish. Care partners preferred to focus primarily on the patient’s health and not their own. The app was developed incorporating quality-of-life surveys and symptom reporting, as well as resources on home survivor care. Early user testing demonstrated ease of use and app feasibility. Conclusions TOGETHERCare, a novel mobile app, was developed with user input to track the care partner’s health and report on survivor symptoms during home care. The following two clinical benefits emerged: (1) reduced anxiety among care partners who use the app and (2) the potential for identifying survivor symptoms noted by the care partner, which might prevent adverse events. Trial Registration ClinicalTrials.gov NCT04018677; https://clinicaltrials.gov/ct2/show/NCT04018677

BACKGROUND Approximately 6.1 million adults in the United States serve as care partners for cancer survivors. Studies have demonstrated that engaging cancer survivors and their care partners through technology-enabled structured symptom collection has several benefits. Given the high utilization of mobile technologies, even among underserved populations and in low resource areas, mobile apps may provide a meaningful access point for all stakeholders for symptom management. OBJECTIVE We aimed to develop a mobile app incorporating user preferences to enable cancer survivors’ care partners to monitor the survivors’ health and to provide care partner resources. METHODS An iterative information gathering process was conducted that included (1) discussions with 138 stakeholders to identify challenges and gaps in survivor home care; (2) semistructured interviews with clinicians (n=3), cancer survivors (n=3), and care partners (n=3) to identify specific needs; and (3) a 28-day feasibility field test with seven care partners. RESULTS Health professionals noted the importance of identifying early symptoms of adverse events. Survivors requested modules on medication, diet, self-care, reminders, and a version in Spanish. Care partners preferred to focus primarily on the patient’s health and not their own. The app was developed incorporating quality-of-life surveys and symptom reporting, as well as resources on home survivor care. Early user testing demonstrated ease of use and app feasibility. CONCLUSIONS TOGETHERCare, a novel mobile app, was developed with user input to track the care partner’s health and report on survivor symptoms during home care. The following two clinical benefits emerged: (1) reduced anxiety among care partners who use the app and (2) the potential for identifying survivor symptoms noted by the care partner, which might prevent adverse events. CLINICALTRIAL ClinicalTrials.gov NCT04018677; https://clinicaltrials.gov/ct2/show/NCT04018677

157 Background: There is increasing appreciation for the insight provided by combining low-burden home-based remote digital measurements with patient and observer reported outcomes. In this study, we assessed perspectives of cancer patients and their caregivers on the utility of a mobile app combined with a smartwatch for collection of specific outcomes and to provide clinically actionable data. Methods: In a decentralized clinical trial we consented and enrolled (10/12/2020-4/30/2021) dyads that consisted of a cancer patient and their informal caregiver. All participants had to own an Apple iPhone 6 or higher. Patients were provided with an Apple watch 3 or 4 and downloaded a patient informed mobile app (DigiBioMarC). Caregivers only download a caregiver informed mobile app (TOGETHERCare). Participants were asked to use their respective app for 28 days during which time specific surveys and activity requests were delivered through the mobile app; digital measures of physical activity were collected via the smartwatch. At the end of the app usage period, questions were asked in a video interview about the patient and caregiver perspectives on use of their respective apps and what they believed could be impacted if their doctor were to receive the app information. Respondents could select Strongly Agree, Agree, Neutral, Disagree, or Strongly Disagree. Results: Fifty-four dyads were enrolled; four were unable to continue due to a decline in health. Questions were drafted and IRB approved in time to be asked of 45 dyads. The Table lists some results and the percent of respondents that selected Strongly Agree or Agree. Conclusions: Patients and caregivers reported that both apps would encourage them to take better care of themselves/be more physically active and would improve emotional wellbeing. A high proportion of respondents also felt the apps would improve communication with their doctor and provide early important information for the doctor to act upon compared to usual care. Additional work in a large randomized trial is planned to evaluate specific care outcomes. [Table: see text]

Purpose: Human tumors consist of heterogeneous populations of cells with distinct marker expression and functional properties. In squamous cell carcinoma of the head and neck (SCCHN), CD44 is a well-characterized marker of a resilient subpopulation of cells associated with increased tumorigenesis, radioresistance, and chemoresistance. Evidence indicates that these cells have an immunosuppressive phenotype; however, mechanisms have been elusive. Experimental Design: Using primary human SCCHN tumor samples and patient-derived xenografts, we examined the phenotypes of subsets of tumor cells and investigated mechanisms regulating their immunogenicity. Results: CD44+ cells in primary human SCCHN were found to have an epithelial-to-mesenchymal (EMT) phenotype and were less immunogenic than CD44− cells when cultured with autologous CD8+ tumor-infiltrating T cells. Selective expression of the programmed death-ligand 1 (PD-L1) was observed on CD44+ cells compared with CD44− cells and was associated with constitutive phosphorylation of STAT3 on CD44+ cells. Importantly, inhibition of STAT3 decreased expression of PD-L1 on CD44+ cells. IFNγ treatment preferentially induced even further PD-L1 expression on CD44+ cells and was associated with enhanced IFNγ receptor expression and phosphorylation of STAT1. Finally, the decreased immunogenicity of CD44+ cells was partially reversed by antibody blockade of the programmed death 1 (PD-1) receptor, indicating that the differences in PD-L1 expression between CD44+ and CD44− cells are biologically and clinically relevant. Conclusions: Our findings provide a mechanism by which long-lived CD44+ tumor-initiating cells can selectively evade host immune responses and provide rationale for targeting the PD-1 pathway in the adjuvant therapy setting of SCCHN. Clin Cancer Res; 22(14); 3571–81. ©2016 AACR.

Background: Informal cancer caregivers are being asked to provide more extensive home care for cancer patients. It is well documented that caregivers frequently experience psychological and behavioral effects that impact their overall well-being. Digital solutions can support informal caregivers by providing key information on the patient's care and nudging them to focus on their own mental and physical health. Objective: In this paper, we describe a user-centered design approach to build a digital solution by engaging with stakeholders that include clinical staff, health care decision makers, cancer patients and survivors, and informal caregivers. The NIH funded digital solution, TOGETHERCareTM, (Track Outcomes & Guidance, Technology for Health & Effective Resources for Care) is a smart phone mobile app to provide support and resources to informal caregivers while enabling them to monitor the cancer survivor's health for potential adverse events, thereby preventing unnecessary emergency care and reducing daily caregiver worries. Methods: An iterative information gathering process was conducted that included a) key-informant (n=139) and semi-structured interviews (n=11) with stakeholders to assess health care value propositions and corresponding modules of benefit; b) prototype review, evaluation and feedback by a Patient Advisory Council and Clinical Advisory Team and; c) a 28-day beta user-testing with feasibility and acceptability feedback from 15 stakeholders in two geographically diverse academic cancer centers (Duke and Stanford). This study was registered on clinicaltrials.gov (NCT04018677). Results: The interviews conducted prior to developing the mHealth app prototype identified consistency in responses between different stakeholder groups in terms of how the mobile app should work, and areas of difference. Clinical teams focused on app usage efficiency and features that would improve information sharing and follow-up visits with survivors. Survivors and caregivers were more focused on features that would provide assistance with at-home medical tasks and activities of daily living. The interviews and data analysis following the Beta test of the prototype indicated satisfaction with the app's usability, that caregivers preferred to focus primarily on the patient's health and not their own, and that regular surveys on the patient's symptoms educated and reduced anxiety among caregivers. Conclusions: This study describes the user-centered design process and demonstrates the feasibility and acceptability of TOGETHERCareTM, an iOS smart phone app for informal cancer caregivers. Larger studies, in various oncology populations, are needed to further evaluate efficacy of the app across health metrics that matter to the different stakeholders. Citation Format: Ingrid Oakley-Girvan, Vasu Divi, Oxana Palesh, Jena Daniels, Lisa G. Rosas, Dale O'Brien, Sharon W. Davis, Arif H. Kamal, Allison W. Kurian, Michelle R. Longmire. Reducing cancer caregiver burden: A user-centered design approach for an mHealth app [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2033.

Background: Machine learning has been used to successfully develop biomarkers from data collected from a wide range of commodity and specialized sensor devices. Typical machine learning algorithms, such as deep learning, require several thousand to on the order of millions of samples of data to work most effectively. However, in many studies with limited numbers of patients and data samples, such methods cannot be used. Objective: To solve this problem, we have developed a specialized algorithm that can convert time series signals into a set of histogram signatures that can then be used with unsupervised methods such as clustering to create biomarkers. Methods: Our methods decompose the time series data into time windows and analyze aggregate mean and variance and other statistical qualities over these windows. Results: We will describe our approach and show how we have applied it along with genetic algorithms to perform auto-tuning for novel biomarkers and endpoints. Conclusions: We will be able to develop a highly accurate biomarker to detect gate imbalance and impairment from limited accelerometer data. Citation Format: Nick Moss, Ingrid Oakley-Girvan, Michelle R. Longmire. A method to create aggregate histogram representations for machine learning from small sample size medical sensor time series [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 862.

BACKGROUND Both the National Cancer Institute (NCI) and the National Academy of Medicine have stressed the importance of survivorship care plans (SCP) for cancer survivors and discussed the significance of input from survivors and their advocates. However, there are many barriers to cancer care coordination and the creation of SCPs, including oncology staff time required to write them. Although survivors valued SCPs and liked them, few survivors or care partners report receiving survivorship information. Digital platforms can support cancer survivorship care by integrating with the existing Electronic Health Record and presenting information in a dynamic and user-friendly format that improves coordination and communication. OBJECTIVE In this paper, we describe including medical staff, survivors, and informal care partners in developing a user-centered design for TOGETHERCareTM, (Track Outcomes & Guidance, Technology for Health & Effective Resources for Care) a smartphone mobile app envisioned to provide critical functionality, including planning and sharing the SCP among survivors, physicians, and informal care partners. METHODS Two interviewers conducted a total of nine semi-structured interviews, including a convenience sample of three clinical staff who work with cancer survivors, three cancer survivors, and three informal care partners currently caring for cancer survivors. The interviews with Spanish-speaking survivors and care partners were conducted with a translator. Notes from the interviews were transcribed into a prepared template. The results were compiled and coded by two members of the team. RESULTS We identified areas of consistency in responses between the three different groups in terms of how the mobile app should work, as well as areas of difference. Additional suggestions for features for the mobile app are also presented. Clinical teams focused on the efficiency of using the app, and features that would improve follow-up visits with survivors. Survivors and care partners were more focused on features that would provide assistance with at-home medical tasks and activities of daily living. Although all three groups agreed that there is currently no systematic way for specialists to keep in touch with survivors once they have moved to community care, and that SCPs would be useful, they currently do not receive or provide a SCP. Survivors, care partners, and clinical staff all agreed that they have smartphones and that a mobile app including the ability to communicate between the different groups, along with other features would be welcome and useful. CONCLUSIONS The ubiquity of smartphones and mobile app use provides an opportunity to incorporate patient outcomes and make information and survivorship plans more readily available to informal care partners and cancer survivors. Clinical teams, cancer survivors, and informal care partners all responded positively to a variety of features that could improve the efficiency of cancer care coordination and rapidly improve SCP provision. CLINICALTRIAL None.

From response to vaccinations to autoimmune disease, gender differences in immunity have been long recognized in clinical medicine. The primary genetic difference between males and females is the complement of sex chromosomes. The X chromosome contains a far higher number of genes than the Y chromosome, and it has long been thought that the second X in females was effectively silenced to provide genetic equity or dosage compensation. Emerging technologies are telling an increasingly fascinating story and calling to question long held assumptions about the silenced X chromosome, suggesting that the X may be a regulator of immune system function in health and disease. It has been long postulated that epigenetic or regulatory differences between male and female immune cells may underlie immune difference and autoimmune susceptibility and emerging science suggests that sex-chromosome and autosomal gene regulation may contribute to immune variation and provide insight into gender differences in health and disease. Herein we review recent findings on gender differences in immunity, with a focus on gene regulation and T cells.

Background: Both the National Cancer Institute (NCI) and Institute of Medicine have stressed the importance of survivorship care plans (SCP) for cancer patients/survivors and discussed the significance and importance of required input from survivors and advocates. However, there are many barriers to cancer care coordination and the creation of SCPs, including oncology staff time required to write them. Although survivors valued SCPs and liked them, few survivors or caregivers report receiving survivorship information and in some studies, reported no receipt of an SCP. Digital platforms can support cancer survivorship care by integrating with the existing Electronic Health Record and presenting information in a dynamic and user-friendly format that improves coordination and communication. Objective: In this paper, we describe our involvement of stakeholders, including medical staff, patients/survivors and informal caregivers in developing a user-centered design for TOGETHERCARE, a smartphone app envisioned to provide critical functionality including planning and sharing of the SCP among survivors, physicians, and informal caregivers. Methods: Two interviewers conducted a total of nine semi-structured interviews, including a convenience sample of three health care providers who work with cancer patients, three cancer patients/survivors, and three informal caregivers currently caring for cancer patients/survivors. The interviews with Spanish-speaking patients/survivors and caregivers were conducted with a translator. Notes from the interviews were transcribed into a prepared template. The results were compiled and coded by two members of the core team. Results: We identified areas of consistency in responses between the three different groups in terms of how the application should work, as well as areas of difference. Additional suggestions for features for the application are also presented. Health care providers focused on the efficiency of using the application, features that would improve follow-up visits with patients and reduce the nursing triage, ER visits and readmissions. Survivors and caregivers were more focused on features that would provide assistance with patient appointment schedules, at-home medical tasks and activities of daily living. Although all three groups agreed that there is currently no systematic way for specialists to keep in touch with patients once they have moved to community care, and that SCPs would be useful, the practice of providing SCPs is rarely implemented. Survivors, caregivers, and providers all agreed that they have smartphones and that an app that includes the ability to communicate between the different groups, along with other features such as guidance on assisting with daily medical tasks and activities of daily living would be useful. Conclusions: The pervasiveness of mobile devices and mobile app use provides an opportunity to make survivorship information and plans more readily available to caregivers and survivors, and to incorporate patient outcome reporting. Health care providers, cancer survivors, and informal caregivers all responded positively to a variety of features that could improve the efficiency of cancer care coordination and dynamic SCP provision.

SummaryHere, we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws from 12 healthy volunteers over time, from cancer patients, and during T-cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.

Cutaneous small vessel vasculitis (CSVV) is a nonspecific finding with an extensive differential diagnosis. It is critically important to distinguish skin-limited presentations of CSVV from severe life-threatening systemic vasculitides presenting with CSVV as an initial manifestation. It can be challenging to determine which patients presenting with CSVV are at risk for systemic disease. Standard histopathologic evaluation, direct immunofluorescence, and serologic evaluation is typically required to exclude a systemic vasculitis. Type 1 cryoglobulinemia may rarely present with CSVV. Herein, we report a case of type 1 cryoglobulinemia in the setting of occult multiple myeloma. CSVV with prominent intravascular crystal formation was noted. The presence of intravascular crystals in the setting of CSVV may represent an important early clue to the diagnosis of type 1 cryoglobulinemic vasculitis.

Background: Nerve involvement developed in a patient with granuloma annulare, as evidenced by a perineural infiltrate of histiocytes in the dermis. The histopathologic pattern was suggestive of leprosy. No mycobacteria were observed, and neurologic testing was normal. Objective: To determine whether inflammation of the nerves or perineural tissue is common in granuloma annulare, we studied the cutaneous nerves in skin biopsy specimens from 14 patients with granuloma annulare. Methods: Sections were stained with hematoxylin-eosin to highlight inflammatory cells and with S-100 to identify cutaneous nerves. Results: No inflammation around nerves was found in 12 specimens, abutting granulomatous inflammation was found in 1 specimen, and enveloping granulomatous inflammation was found in 1 specimen. No nerves were infiltrated by inflammatory cells. Conclusion: Perineural granulomatous inflammation resembling the perineural infiltrate of leprosy appears to be an uncommon characteristic of granuloma annulare. Clinical correlation and acid-fast stains can assist in establishing the correct diagnosis. Contexte: Une atteinte nerveuse est apparue chez un patient atteint de granulome annulaire, comme en témoignait un infiltrat périneural d'histiocytes dans le derme. Les signes histopathologiques étaient évocateurs de la lèpre, mais aucune mycobactérie n'a été observée, et l'examen neurologique était normal. Objectif: L'étude visait à déterminer si l'inflammation des nerfs ou du tissu périneural est fréquente dans le granulome annulaire; pour ce faire, nous avons examiné les nerfs cutanés dans des prélèvements biopsiques de la peau, effectués sur 14 patients atteints de granulome annulaire. Méthodes: Les coupes ont été colorées à l'hématoxyline-éosine pour mettre en évidence des cellules inflammatoires, ainsi qu'au S-100 pour repérer les nerfs cutanés. Résultats: Aucune inflammation autour des nerfs n'a été observée sur 12 prélèvements, mais il y avait présence d'inflammation granulomateuse contiguë sur un prélèvement et d'inflammation granulomateuse enveloppante, sur un autre prélèvement. Les nerfs n'ont pas été infiltrés par les cellules inflammatoires. Conclusion: L'inflammation granulomateuse périneurale qui ressemble à l'infiltration périneurale observée dans la lèpre semble un signe peu fréquent du granulome annulaire. L'établissement de corrélations cliniques et des colorations résistantes à l'acide peuvent faciliter la pose du bon diagnostic.

The Centers for Disease Control and Prevention's (CDC) Category C consists of biological agents not presently considered public health threats in terms of bioterrorism but which could emerge in this capacity as the scientific understanding of them grows in the future. Category C agents include Nipah virus, the hantaviruses, and multiple drug-resistant (MDR) Mycobacterium tuberculosis. Each is discussed, with special attention paid to weapons application. Keywords: biological weapons; Category C agents; CDC; Centers for Disease Control and Prevention; hantaviruses; HFRS; HPS; multiple drug-resistant Mycobacterium tuberculosis; natural host; Nipah virus; pathogenesis; tuberculosis

A 9-year-old girl presented with a choroidal tumor 6 years after remission of Burkitt lymphoma with no evidence of systemic recurrence. The tumor regressed after plaque radiotherapy. The second tumor could have been related to previous chemotherapy, caused by Epstein-Barr virus infection, or the result of independent lymphoma cell growth.

We present a method to reintroduce ophthalmic training into the medical school curriculum.To evaluate knowledge and skills acquired when participating in a service project, the Community Vision Project, and to develop a quantitative method for testing skills with the direct ophthalmoscope in patients.Second-year medical students participated in the study. After 1 month, their knowledge was compared with that of peers and graduates (internal medicine residents). Also at 1 month, their direct ophthalmoscope skills were compared with those of upperclassmen who had completed all core clerkships. One year later, after the participants had completed their core clerkships, long-term ophthalmoscope skills retention was tested, and their performance was compared with that of their classmates.Training occurred in mobile eye clinics. Knowledge and skills assessments were performed in the hospital eye clinic among students and residents at The University of New Mexico School of Medicine. Patients were recruited from the hospital eye clinic. Participants attended a 3-hour training session held by an attending physician in the hospital eye clinic and took part in at least 1 mobile eye clinic.A knowledge assessment quiz was administered to participants (n = 12), their classmates (n = 18), and internal medicine residents (n = 33). Skills assessment with the direct ophthalmoscope was performed at 1 month and at 1 year in 5 participants and 5 nonparticipants. Tonometer skills were assessed by comparing participants' readings with those of an ophthalmologist's obtained in patients at the mobile eye clinics. RESULTS Participants' median knowledge assessment scores were 48% higher than those of their classmates and 37% higher than those of internal medicine residents (P .001 for both). Short-term (1 month) direct ophthalmoscopy median scores were 60% (quartile 1 to quartile 3 range, 40%-80%) for participants and 40% (quartile 1 to quartile 3 range, 20%-60%) for nonparticipating upperclassmen (P = .24). Long-term direct ophthalmoscopy median scores were 100% (quartile 1 to quartile 3 range, 75%-100%) for participants and 0% (quartile 1 to quartile 3 range, 0%-25%) for nonparticipating classmates (P = .11). Participants' tonometer readings were similar to those of the ophthalmologist's; their median reading was 2 mm Hg (quartile 1 to quartile 3 range, 0-4 mm Hg) higher than that of the ophthalmologist's (P = .05, sign test).Service-based learning offered an efficient model for incorporating ophthalmic training into the medical school curriculum. A viable tool for quantitatively testing ophthalmoscope skills is presented.

Filamentous phage display has been extensively used to select proteins with binding properties of specific interest. Although many different display platforms using filamentous phage have been described, no comprehensive comparison of their abilities to display similar proteins has been conducted. This is particularly important for the display of cytoplasmic proteins, which are often poorly displayed with standard filamentous phage vectors. In this article, we have analyzed the ability of filamentous phage to display a stable form of green fluorescent protein and modified variants in nine different display vectors, a number of which have been previously proposed as being suitable for cytoplasmic protein display. Correct folding and display were assessed by phagemid particle fluorescence, and with anti-GFP antibodies. The poor correlation between phagemid particle fluorescence and recognition of GFP by antibodies, indicates that proteins may fold correctly without being accessible for display. The best vector used a twin arginine transporter leader to transport the displayed protein to the periplasm, and a coil-coil arrangement to link the displayed protein to g3p. This vector was able to display less robust forms of GFP, including ones with inserted epitopes, as well as fluorescent proteins of the Azami green series. It was also functional in mock selection experiments.