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Supplementary Figure 2 from Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion

Supplementary Figure 1 from Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion

Supplementary Table 3 from Telomerase-Specific T-Cell Immunity in Breast Cancer: Effect of Vaccination on Tumor Immunosurveillance

Supplementary Table 2 from Telomerase-Specific T-Cell Immunity in Breast Cancer: Effect of Vaccination on Tumor Immunosurveillance

The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early “elimination phase” of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer. [Cancer Res 2007;67(19):9518–27]

The human telomerase reverse transcriptase (hTERT) is nearly universally overexpressed in human cancer, contributes critically to oncogenesis, and is recognized by cytotoxic T cells that lyse tumors. CD8+ T cells specific for hTERT naturally occur in certain populations of cancer patients in remission, but it remains poorly understood whether such T cells could contribute to tumor immunosurveillance. To address this issue, we induced hTERT-specific T cells in vivo via peptide vaccination in 19 patients with metastatic breast cancer who otherwise had no measurable T-cell responses to hTERT at baseline. Tumor-infiltrating lymphocytes (TIL) were evident after, but not before vaccination, with 4% to 13% of postvaccine CD8+ TIL specific for the immunizing hTERT peptide. Induction of TIL manifested clinically with tumor site pain and pruritus and pathologically with alterations in the tumor microenvironment, featuring histiocytic accumulation and widespread tumor necrosis. hTERT-specific CD8+ T cells were also evident after vaccination in the peripheral blood of patients and exhibited effector functions in vitro including proliferation, IFN-γ production, and tumor lysis. An exploratory landmark analysis revealed that median overall survival was significantly longer in those patients who achieved an immune response to hTERT peptide compared with patients who did not. Immune response to a control cytomegalovirus peptide in the vaccine did not correlate with survival. These results suggest that hTERT-specific T cells could contribute to the immunosurveillance of breast cancer and suggest novel opportunities for both therapeutic and prophylactic vaccine strategies for cancer. [Cancer Res 2007;67(21):1–9]

Supplementary Table 1 from Telomerase-Specific T-Cell Immunity in Breast Cancer: Effect of Vaccination on Tumor Immunosurveillance

Supplementary Table 2 from Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion

Supplementary Table 1 from Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion

BACKGROUND While there are many interventions to support caregivers, text messaging has the capability to be an adjunct to clinical practice on a wide-spread basis. The Department of Veterans Affairs Annie text messaging system was developed to assist Veterans with self-care. OBJECTIVE This paper reports on the first system-wide implementation of a text messaging protocol for caregivers in a national health care system with an Annie stress management protocol for caregivers of Veterans. METHODS After pilot testing, in late 2019, a year-long protocol for caregivers with three messages a week focusing on education, motivation/inspiration, and activities to alleviate stress was begun. An online evaluation occurs at six months. RESULTS As of September 2021, 3807 caregivers had participated in the stress protocol. Caregivers report that the messages have been useful in increasing their confidence, managing their stress, and helping them take care of themselves and their loved one. This success has led to bereavement, taking care of you, COVID-19 precautions and symptoms, and dementia behaviors protocols, with a total of 5643 caregivers enrolled as of September 2021. CONCLUSIONS Caregivers frequently feel overlooked by the health care system but caregivers report that the messages make them feel cared for and less lonely. Text messaging, incorporated into clinical settings and health care systems, represents a seamless, low-cost way to provide useful and meaningful support to caregivers.

Background Although there are many interventions to support caregivers, SMS text messaging has not been used widely. Objective In this paper, we aimed to describe development of the Department of Veterans Affairs (VA) Annie Stress Management SMS text messaging protocol for caregivers of veterans, its pilot test, and subsequent national rollout. Methods The stress management protocol was developed with text messages focusing on education, motivation, and stress-alleviating activities based on the Resources for Enhancing All Caregivers Health (REACH) VA caregiver intervention. This protocol was then tested in a pilot study. On the basis of the pilot study results, a national rollout of the protocol was executed and evaluated. Caregivers were referred from VA facilities nationally for the pilot and national rollout. Pilot caregivers were interviewed by telephone; national rollout caregivers were sent a web-based evaluation link at 6 months. For both evaluations, questions were scored on a Likert scale ranging from completely disagree to completely agree. For both the pilot and national rollout, quantitative data were analyzed with frequencies and means; themes were identified from open-ended qualitative responses. Results Of the 22 caregivers in the pilot study, 18 (82%) provided follow-up data. On a 5-point scale, they reported text messages had been useful in managing stress (mean score 3.8, SD 1.1), helping them take care of themselves (mean score 3.7, SD 1.3), and making them feel cared for (mean score 4.1, SD 1.7). Texts were easy to read (mean score 4.5, SD 1.2), did not come at awkward times (mean score 2.2, SD 1.4), were not confusing (mean score 1.1, SD 0.2), and did not cause problems in responding (mean score 1.9, 1.1); however, 83% (15/18) of caregivers did not want to request an activity when stressed. Consequently, the national protocol did not require caregivers to respond. In the national rollout, 22.17% (781/3522) of the eligible caregivers answered the web-based survey and reported that the messages had been useful in managing stress (mean score 4.3, SD 0.8), helping them take care of themselves (mean score 4.3, SD 0.8) and loved ones (mean score 4.2, SD 0.8), and making them feel cared for (mean score 4.5, SD 0.8). Almost two-thirds (509/778, 65.4%) of the participants tried all or most of the strategies. A total of 5 themes were identified. The messages were appreciated, helped with self-care, and made them feel less alone, looking on Annie as a friend. The caregivers reported that the messages were on target and came when they were most needed and did not want them to stop. This success has led to four additional caregiver texting protocols: bereavement, dementia behaviors and stress management, (posttraumatic stress disorder) PTSD behaviors, and taking care of you, with 7274 caregivers enrolled as of February 2022. Conclusions Caregivers reported the messages made them feel cared for and more confident. SMS text messaging, which is incorporated into clinical settings and health care systems, may represent a low-cost way to provide useful and meaningful support to caregivers.

The secretin receptor is a prototypic class B GPCR with substantial and broad pharmacologic importance. The aim of this project was to develop a high affinity selective antagonist as a new and important pharmacologic tool and to aid stabilization of this receptor in an inactive conformation for ultimate structural characterization. Amino-terminal truncation of the natural 27-residue ligand reduced biological activity, but also markedly reduced binding affinity. This was rationally and experimentally overcome with lactam stabilization of helical structure and with replacement of residues with natural and unnatural amino acids. A key new step in this effort was the replacement of peptide residue Leu(22) with L-cyclohexylalanine (Cha) to enhance potential hydrophobic interactions with receptor residues Leu(31), Val(34), and Phe(92) that were predicted from molecular modeling. Alanine-replacement mutagenesis of these residues markedly affected ligand binding and biological activity. The optimal antagonist ligand, (Y(u)’,c[E(16),K(20)],I(17),Cha(22),R(25))sec(6-27), exhibited high binding affinity (4 nM), similar to natural secretin, and exhibited no demonstrable biological activity to stimulate cAMP accumulation, intracellular calcium mobilization, or P-arrestin-2 translocation. It acts as an orthosteric competitive antagonist, predicted to bind within the peptide-binding groove in the receptor extracellular domain. The analogous peptide that was one residue longer, retaining Thr(5), exhibited partial agonist activity, while further truncation of even a single residue (Phe(6)) reduced binding affinity. This sec(6-27)-based peptide will be an important new tool for pharmacological and structural studies.

Up to 30% of patients diagnosed with breast cancer will develop recurrent disease within their lifetime, and currently this form of the disease is incurable. There are unmet needs to better understand underlying metastatic biology, identify new therapeutic targets and develop better methods for monitoring changes in disease, both to monitor response and elucidate resistance mechanisms. To address these needs, the METAMORPH Study encompasses a comprehensive approach that combines serial molecular tissue profiling at the RNA and DNA level with circulating markers (DTCs, CTCs, plasma tumor DNA), and ongoing assessment of therapeutic response. METAMORPH is a prospective cohort study of women with suspected or confirmed recurrent breast cancer and accessible tumor by standard clinical biopsy, who are enrolled at the University of Pennsylvania prior to starting a new therapy for recurrent metastatic disease. The aims of this trial are to (1) evaluate the mechanisms through which recurrent breast cancer are genetically distinct from the primary tumor, (2) evaluate the circulating tumor biomarker trajectory of recurrent disease, (3) elucidate “escape pathways” of progressing tumors that emerge during the selective pressure of therapy, and (4) explore clinical utility of tumor and blood testing. The study protocol integrates research aims into clinical care, including a standardized approach to disease assessment and biopsy, pathologic confirmation of histology and receptor subtype, panel-based CLIA-approved genomic profiling, collection of research specimens, and standardized reporting of results, which are returned to patients and physicians. Patients are followed for treatment and outcome, and serial samples are collected at progression. A companion protocol, COMET, provides education about genomic testing and assesses patient understanding and impact of results. To date, 155 patients have enrolled, 142 (92%) have been biopsied, 120 (77%) have had sufficient DNA for molecular profiling and 109 (70%) have had genomic panel testing. Accrual is ongoing, with an initial target of 300 patients. Multiple sites within the UPHS Health System are enrolling. Contact information: angela.demichele@uphs.upenn.edu. Key words: Metastatic disease, tumor profiling. Citation Format: DeMichele A, Soucier-Ernst DJ, Clark C, Shih N, Stavropoulos W, Maxwell KN, Feldman M, Lierbamen D, Morrissette JJD, Paul MR, Pan T-C, Wang J, Belka GK, Chen Y, Yee S, Carpenter E, Fox K, Matro J, Clark A, Shah P, Domchek S, Bradbury A, Chodosh L. METAMORPH: METAstatic markers of recurrent tumor PHenotype for breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-06-03.

Undergraduate research is one of the most valuable activities an undergraduate can engage in because of its benefits, and studies have shown that longer experiences are more beneficial. However, prior research has illuminated that undergraduates encounter challenges that may cause them to exit research prematurely. These studies have been almost exclusively conducted at research-intensive (R1) institutions, and it is unclear whether such challenges are generalizable to other institution types. To address this, we extended a study previously conducted at public R1 institutions. In the current study, we analyze data from 1262 students across 25 public R1s, 12 private R1s, 30 master's-granting institutions, and 20 primarily undergraduate institutions (PUIs) to assess 1) to what extent institution type predicts students' decisions to persist in undergraduate research and 2) what factors affect students' decisions to either stay in or consider leaving their undergraduate research experiences (UREs) at different institution types. We found students at public R1s are more likely to leave their UREs compared with students at master's-granting institutions and PUIs. However, there are few differences in why students enrolled at different institution types consider leaving or choose to stay in their UREs. This work highlights the importance of studying undergraduate research across institutions.

Respiratory syncytial virus (RSV) is a global human pathogen responsible for lower respiratory tract infections (LRTI). While RSV infection is innocuous in healthy adults, it is the leading cause of infant hospitalization for respiratory tract infection. Nearly everyone shows evidence of an RSV infection by the age of 3. However, there is still not a vaccine commercially available. This review will provide an update on the clinical and preclinical vaccine studies and different approaches to prevent RSV infection. Novel vaccine approaches that induce protection against RSV without enhancement of respiratory tract disease. Recent technological approaches have led to generation of different strategies to prevent RSV infection, including live attenuated, chimeric, and subunit vaccines, virus-like particles, and nanoparticles. These vaccine approaches represent promising candidates towards an efficient RSV vaccine that effectively protects infants, children, and adults.

The exponential growth of young talented women choosing science and medicine as their professional career over the past decade is substantial. Currently, more than half of the Australian medical doctoral graduates and early career researchers are comprised of women, but less than 20% of all academic professorial staff are women. The loss of female talent in the hierarchical ladder of Australian academia is a considerable waste of government investment, productivity, and scientific innovation. Gender disparity in the professional workforce composition is even more striking within the field of transplantation. Women are grossly underrepresented in leadership roles, with currently no female heads of unit in any of the Australian and New Zealand transplanting centers. At the same time, there is also gender segregation with a greater concentration of women in lower-status academic position compared with their male counterparts. Given the extent and magnitude of the disparity, the Women in Transplantation Committee, a subcommittee of The Transplantation Society of Australia and New Zealand established a workshop comprising 8 female clinicians/scientists in transplantation. The key objectives were to (i) identify potential gender equity issues within the transplantation workforce; (ii) devise and implement potential strategies and interventions to address some of these challenges at a societal level; (iii) set realistic and achievable goals to enhance and facility gender equality, equity, and diversity in transplantation.

Background Many studies have documented lower vaccine efficacy among children in low-income countries, compared with their counterparts in high-income countries. This disparity is especially apparent with respect to oral vaccines such as rotavirus and oral polio vaccines. One potential contributing factor is the presence of maternal antenatal helminth infections, which can modulate the infant's developing immune system. Methods Using a multiplex immunoassay, we tested plasma immunoglobulin A (IgA) or immunoglobulin G (IgG) levels specific for antigens in 9 routinely administered childhood vaccines among 1639 children aged approximately 13 months enrolled in the ECUAVIDA (Ecuador Life) birth cohort study in Ecuador. We compared vaccine responses in 712 children of mothers who tested positive for helminth infections in the last trimester of pregnancy to responses in 927 children of mothers without helminth infection. Results Plasma IgA levels specific for antigens in rotavirus vaccine and oral polio vaccine containing poliovirus serotypes 1 and 3 were all significantly higher in children of helminth-infected mothers, compared with children of uninfected mothers. Plasma IgG levels specific for diphtheria, tetanus, pertussis, measles, rubella, and Haemophilus influenzae type b vaccine antigens were comparable between the 2 groups. Conclusions Antenatal maternal helminth infections were not associated with reduced antibody responses to infant vaccines, but rather with modestly increased IgA responses to oral vaccines.

Exaggerated CD4+ T helper 2–specific cytokine producing memory T cell responses developing concomitantly with a T helper 1 response might have a detrimental role in immunity to infection caused by Mycobacterium tuberculosis. To assess the dynamics of Ag-specific memory T cell compartments in the context of filarial infection, we used multiparameter flow cytometry on PBMCs from 25 microfilaremic filarial-infected (Inf) and 14 filarial-uninfected (Uninf) subjects following stimulation with filarial Ag (BmA) or with the M. tuberculosis–specific Ag culture filtrate protein-10 (CFP-10). Our data demonstrated that the Inf group had a marked increase in BmA-specific CD4+IL-4+ cells (median net frequency compared with baseline [Fo] = 0.09% versus 0.01%; p = 0.038) but also to CFP-10 (Fo = 0.16% versus 0.007%; p = 0.04) and staphylococcal enterotoxin B (Fo = 0.49% versus 0.26%; p = 0.04). The Inf subjects showed a BmA-specific expansion of CD4+CD45RO+IL-4+ producing central memory (TCM, CD45RO+CCR7+CD27+; Fo = 1.1% versus 0.5%; p = 0.04) as well as effector memory (TEM, CD45RO+CCR7−CD27−; Fo = 1.5% versus 0.2%; p = 0.03) with a similar but nonsignificant response to CFP-10. In addition, there was expansion of CD4+IL-4+CD45RA+CCR7+CD27+ (naive-like) in Inf individuals compared with Uninf subjects. Among Inf subjects with definitive latent tuberculosis, there were no differences in frequencies of IL-4–producing cells within any of the memory compartments compared with the Uninf group. Our data suggest that filarial infection induces Ag-specific, exaggerated IL-4 responses in distinct T cell memory compartments to M. tuberculosis–specific Ags, which are attenuated in subjects who are able to mount a delayed type hypersensitivity reaction to M. tuberculosis.

The authors examine the modernist underpinnings of traditional adult learning and development theories and evaluate elements of those theories through more contemporary lenses. Drawing on recent literature focused on “public pedagogy,” the authors argue that much learning takes place outside of formal educational institutions. They look beyond modernist narratives of adult development and consider the possible implications for critical adult learning occurring in and through contemporary fragmented, digital, media-saturated culture.

Eric Brown and colleagues report the mosaic deletion of ATR combined with loss of p53 led to accumulation of highly damaged cells and severe defects in tissue regeneration in adult mice. Trp53 loss of function has previously been shown to rescue tissue maintenance and developmental defects resulting from DNA damage or DNA-repair gene mutations1,2,3,4,5,6,7,8,9,10,11,12. Here, we report that p53 deficiency severely exacerbates tissue degeneration caused by mosaic deletion of the essential genome maintenance regulator Atr. Combined loss of Atr and p53 (Trp53−/−AtrmKO) led to severe defects in hair follicle regeneration, localized inflammation (Mac1+Gr1+ infiltrates), accelerated deterioration of the intestinal epithelium and synthetic lethality in adult mice. Tissue degeneration in Trp53−/−AtrmKO mice was characterized by the accumulation of cells maintaining high levels of DNA damage. Moreover, the elevated frequency of these damaged cells in both progenitor and downstream compartments in Trp53−/−AtrmKO skin coincided with delayed compensatory tissue renewal from residual ATR-expressing cells. Together, our results indicate that the combined loss of Atr and Trp53 in adult mice leads to the accumulation of highly damaged cells, which, consequently, impose a barrier to regeneration from undamaged progenitors.

The resurgent theory of cancer immunosurveillance holds that the immune system plays an important role in the suppression of tumors, particularly in the elimination of early neoplastic lesions. Tumors with reduced immunogenicity or those that have acquired mechanisms to suppress immune effector functions, however, can emerge from this selection pressure and grow progressively. This is an especially important issue in pancreatic cancer, which although inflammatory in vivo is nevertheless highly aggressive and nearly always lethal. Here, we review emerging data obtained from novel genetically defined mouse models of pancreatic adenocarcinoma that suggest that the immune system may be complicit in the inception and progression of pancreatic cancer. Host immune cells with suppressive properties infiltrate the pancreas early during tumorigenesis, even at the earliest stages of neoplasia, preceding and effectively undermining any lymphocytes with potential antitumor function. Thus, in pancreatic adenocarcinoma, the failure of immunosurveillance is likely an early event during tumorigenesis, a concept that carries important implications for the design of novel immunotherapeutics in this disease.

Despite their origin from self-tissue, tumor cells can be immunogenic, triggering immune responses that can profoundly influence tumor biology. The clinical implications are obvious: It may be possible to amplify or induce antitumor immune responses to achieve tumor rejection in patients. Cytotoxic

Background: The majority of deaths from breast cancer are due to distant metastatic disease. Despite this, few systematic genomic analyses have been performed on metastatic tumors. This results from the relative difficulty of performing biopsies on metastatic tumors, as well as the uncertainty regarding genomic determinism, according to which the majority of actionable mutations present in metastases can be discovered in the primary tumor. Methods: “METAMORPH” is an ongoing prospective cohort study of women with suspected or confirmed recurrent breast cancer enrolled prior to starting a new therapy for recurrent metastatic disease. Biopsies of metastatic lesions were performed under radiologic guidance, and archival primary tumors were subsequently obtained. WES and sWGS were performed to determine coding mutations and aberrant copy-number in metastatic tumors from 67 patients, 33 of which were assayed with corresponding matched primary tumors. Results: Using Bayesian approaches, we find that cancers fit one of two patterns: canonical linear evolution (whereby the metastatic tumor arises from one or more advanced primary tumor subclones) vs. branched evolution (whereby both primary and metastatic tumors develop mutations that go on to become clonal within their respective tumors after the time of dissemination). In cases where tumors show evidence of branched evolution or small subclone dissemination, we expect that a large proportion of mutations may not be represented in both the primary and corresponding metastatic tumors. Indeed, primary-metastatic tumor pairs show substantial discordance at the genomic level, sharing only ˜30% of mutations and ˜28% of copy-number alterations on average. Furthermore, we find that metastatic tumors have decreased clonal heterogeneity, suggesting a history of selection. Indeed, we find clinically relevant mutations that are present exclusively in the primary or the corresponding recurrent metastatic tumor, as well as genes that are recurrently altered in metastatic tumors, such as amplification of SRC-1, loss of genes encoding CDK inhibitors, and alterations in JAK1/2/3.Finally, compared to the primary tumors from which they arose, metastatic tumors exhibit increased frequencies of alterations in several discrete pathways, including those involving the extracellular matrix as well as PI3K/AKT/mTOR, estrogen, and HER2 signaling. Conclusions: The low degree of genomic concordance between primary and metastatic tumors due to evolutionary distance, as well as the presence of activating and targetable mutations specifically in metastatic tumors, suggests that there is value in comprehensively characterizing metastatic tumors to inform patient treatment and identify novel targets underlying breast cancer progression. Citation Format: Paul MR, Pan T-C, Pant D, Belka GK, Chen Y, Shih N, Lieberman D, Morrissette JJD, Soucier-Ernst D, Clark C, Stavropoulos W, Maxwell K, Feldman M, DeMichele A, Chodosh LA. Evolutionary history and genomic landscape of metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-04.

Decision-making by elected executives on disaster policy reflects comprehensive vulnerability management, political responsiveness to the media, political negotiation, and intergovernmental conflict. If vulnerability reduction is a significant influence, executive decisions should reflect political and social vulnerability and self-sufficiency. If political responsiveness influences disaster decisions, executive decisions should also reflect media coverage, proximity to elections, and decisions at other levels of government. The data set included 293 major disaster requests between 1974 and 1981. The analysis used multiple regression and logistic regression. Vulnerability reduction had an impact on aid decisions. Political responsiveness affected most decisions on disaster relief. The Ford administration was more sensitive to both responsiveness and vulnerability than the Carter administration. Overall, nationalization of disaster assistance has made the achievement of vulnerability management more difficult. The absence of minimum criteria has increased the discretion of executive choice.

This study examined police reporting behavior in elder mistreatment (abuse, neglect, and exploitation) cases. Relying on a survey of police officers in Alabama, this research investigates a nested model of mandatory reporting using linear regression techniques. Only about half of all elder mistreatment cases are reported to the proper authorities. Job experience, contact with the elderly, understanding of mistreatment laws, and positive attitudes toward reporting should increase detection, reporting, and overall satisfaction with the system. These causal factors, however, increased detection and reporting, but not satisfaction. Improvements in training and knowledge in elder mistreatment can be counterpro-ductive.

Background: While several comprehensive genomic sequencing tests are clinically available for breast cancer(BC), little is known about the spectrum of findings reported in the general population and clinical utility of findings for patients(pts). Here we report tumor sequencing from the METAMORPH study, a comprehensive genomic testing approach in pts with metastatic(met) BC. Methods: Pts with either known or suspected BC mets consented to and clinically underwent concurrent diagnostic and research tumor biopsies(bx). FFPE specimens were profiled via Illumina TruSeq Cancer Panel next generation sequencing platform covering 212 amplicons in 47 cancer genes. Pathology, treatment and outcome data were prospectively collected and tracked. Aside from Her2-directed treatment, therapy was not mutation (mut)-matched. Results: 64 pts enrolled between 11/2013 – 05/2015. Of these, 48 had bx successfully sequenced (75%). Of those without sequencing, 5 had negative/insufficient tissue, 2 had insufficient DNA, remainder no bx/pending. Median age of those sequenced was 56 (range 31-78); 81% Caucasian, 17% African American. 25% (12 pts) presented with de novo stage IV disease. Of those with recurrence (n=36), 83% had prior adjuvant chemotherapy; 81% hormone receptor positive(HR+) had prior endocrine therapy. Median # prior lines of therapy for met disease was 2 (IQR 0 – 8). Tumor characteristics, including mut analyses, are shown in Table 1. # muts did not differ significantly by subtype(p=0.22). Frequency of TP53 and PIK3CA hotspot muts was nearly identical to TCGA. Median # muts was 1 for pts with both de novo mets and recurrence(p=0.79). # of muts was not associated with time to recurrence(p=0.80). Excluding pts found to have TP53 mut only or ERBB2 alterations in known Her2+ disease, 42% of pts were identified as having at least one potentially actionable alteration (PIK3CA mut, AKT1 mut or EGFR amplification). Median time to treatment failure(TTF) on subsequent therapy was 4.1 months for overall group, and 4.1, 6.2, and 1.6 months for HR+/Her2-, any Her2+ and TN, respectively, adjusted for line of therapy(p=0.03). After adjustment for # lines of prior met therapy, TTF was 4.7 vs. 4.1 months for pts with any mut vs. none(p=0.89); 5.7 vs 4.1 months for PIK3CA+ vs. not (p=0.94); 3.3 vs. 6.5 months for TP53+ vs. not (p=0.03). Conclusion: Pts with met BC have frequent and potentially actionable muts.While overall # of muts did not affect response, tumors with TP53 muts had shorter response to subsequent therapy in this cohort. Additional data are needed to determine the clinical utility of mut testing in met BC, for both standard and mut-matched therapy. Total (n=48)HR+/Her2- (n=28)Any HER2+ (n=7)TN (n=13)Receptor concordant with primary 100%78%77%# Mutations Median (Range)1 (0-4)1 (0-3)1 (1-2)1 (0-4)014 (29%)10 (36 %)04 (31%)118 (38%)11 (39%)4 (57%)3 (23%)213 (27%)5 (18%)3 (43%)5 (38%)3+3 (6%)2 (7%)01 (8%)Prevalent Mutations (>20%)TP53 (38%), PIK3CA (35%)PIK3CA (50%), TP53 (25%)TP53 (60%), ERBB2amp (86%)TP53 (62%),PIK3CA (23%)Other Alterations (#)ATM (1), KIT (1), PDGFRA (1), PTEN(1), RB1 (1), SMAD4 (1), SMO (1), STK11 (1)AKT1 (1), ATM VUS (1), ERBB2 (1), PTEN (1), SMAD4 VUS (1), SMO VUS (1)ERBB2 (1), STK11(1)EGFR amp (2), KIT amp (1),PDGFRA amp (1), RB1 VUS (1) Citation Format: Soucier-Ernst D, Colameco C, Troxel AB, Clark C, Shih N, Maxwell KN, Morrissette J, Lieberman D, Feldman M, Goodman N, Bradbury A, Clark A, Domchek S, Fox K, Glick J, Matro J, Nathanson K, Chodosh L, DeMichele A. Mutational spectrum and tumor response in metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-07-05.

A sample of 543 members of Midwest Alliance in Nursing and Midwest Nursing Research Society were surveyed to identify factors encouraging and discouraging research utilization. Lack of time was the factor that most discouraged research utilization. A library containing research journals was available to most service (82 percent) and educator nurses (86 percent). Computer services were more available to educators (85 percent) than service nurses (68 percent). A research newsletter was ranked as more helpful than continuing education or computer networks for keeping abreast of research findings.

To assess the effects of advanced age on the ability of circulating neutrophils to respond to biologically relevant chemoattractants, cells were isolated from the peripheral blood of pathogen and disease-free C57BL/6 mice and evaluated in a microchemotaxis chamber. The responses of granulocytes obtained from senescent mice (26-28 months) to the chemotactic peptide, FMLP, and to leukotriene B4 were similar to those found with cells from the younger animals (8-10 months). In contrast, the migration of neutrophils in response to sonicated type 3 Streptococcus pneumoniae was significantly greater with cells from the older animals. Similarly, the chemotactic response of neutrophils to zymosan-activated serum was greater with cells and serum from the senescent animals; however, the enhanced chemotaxis exhibited by granulocytes from the aged mice was a consequence of serum factors. Following the deposition of viable type 3 S. pneumoniae into the lower respiratory tract, the neutrophil influx at 24 h after challenge was significantly greater in the senescent mice; however, age-related differences in survival rates and LD50 were not detected. Thus, in the C57BL/6 mouse, senescence is not associated with deficiencies in the response of neutrophils in vitro to chemoattractants that contribute to lung host defense against the pneumococcus; further, in this murine strain, advanced age does not result in an attenuation of the pulmonary inflammatory reaction to infection with type 3 S. pneumoniae.

To characterize the factors that contribute to the killing of type 3 S. pneumoniae, human neutrophils were obtained from healthy donors and incubated with viable organisms. In contrast to prior observations with other pneumococcal serotypes, killing was not detected when 10(6) colony forming units (cfu) were incubated at 37 degrees C for 2-4 hours with 10(6) neutrophils in the presence of 20-80% fresh autologous serum; further, pneumococcidal activity was not found when preopsonized bacteria and primed neutrophils were employed in the standard assay. However, when the bacterium to cell ratio was reduced to 1:100 and 1:1000, microbicidal action was detected; a 10-fold reduction in the number of viable bacteria was observed when 2 x 10(3) cfu were incubated with 2 x 10(6) neutrophils and 80% autologous serum at 37 degrees C for 4 hours. To assess the effects of serum factors on killing, bactericidal assays were performed in the presence of normal human serum (NHS), heat-inactivated human serum (HIHS) and absorbed human serum (AHS); heating reduced and absorption eliminated the capacity of serum to support killing. Studies performed with mutanolysin, an enzyme that lyses type 3 pneumococci, demonstrated that the effects of HIHS and AHS on bactericidal activity were highly correlated with alterations in the ability of the sera to support phagocytosis. Studies of neutrophil activation revealed changes in the production of superoxide anion that correlated well with phagocytosis and killing; however, the results of assays of leukotriene B4 generation and degranulation (beta-glucuronidase and lactoferrin release) were more variable. In mixing experiments, the capacity of HIHS to support killing was normalized with NHS; however, the ability of AHS to promote killing was not restored with HIHS or NHS. Thus, these studies demonstrate the relatively limited capacity of human serum to support the killing of type 3 pneumococci, and they emphasize the importance of killing assays in assessing interactions between the bacterium and neutrophils.

The human telomerase reverse transcriptase (hTERT) is nearly universally overexpressed in human cancer, contributes critically to oncogenesis, and is recognized by cytotoxic T cells that lyse tumors. CD8+ T cells specific for hTERT naturally occur in certain populations of cancer patients in remission, but it remains poorly understood whether such T cells could contribute to tumor immunosurveillance. To address this issue, we induced hTERT-specific T cells in vivo via peptide vaccination in 19 patients with metastatic breast cancer who otherwise had no measurable T-cell responses to hTERT at baseline. Tumor-infiltrating lymphocytes (TIL) were evident after, but not before vaccination, with 4% to 13% of postvaccine CD8+ TIL specific for the immunizing hTERT peptide. Induction of TIL manifested clinically with tumor site pain and pruritus and pathologically with alterations in the tumor microenvironment, featuring histiocytic accumulation and widespread tumor necrosis. hTERT-specific CD8+ T cells were also evident after vaccination in the peripheral blood of patients and exhibited effector functions in vitro including proliferation, IFN-γ production, and tumor lysis. An exploratory landmark analysis revealed that median overall survival was significantly longer in those patients who achieved an immune response to hTERT peptide compared with patients who did not. Immune response to a control cytomegalovirus peptide in the vaccine did not correlate with survival. These results suggest that hTERT-specific T cells could contribute to the immunosurveillance of breast cancer and suggest novel opportunities for both therapeutic and prophylactic vaccine strategies for cancer. [Cancer Res 2007;67(21):1–9]

The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early “elimination phase” of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer. [Cancer Res 2007;67(19):9518–27]

In response to its concern for the future of community health centers (CHCs) and those who receive care in these centers, in 1997 the Pfizer Foundation created and funded Community Health Ventures (CHV), a four-year, $3.6 million grant-making program. It was designed to increase the capacity of centers to adjust to a changing health care environment. This descriptive special report discusses the outcomes of the program, including its impact on CHCs and their patients, and offers recommendations for funders on how to establish effective partnerships with CHCs.

Commentary to: Expression of cancer-testis antigens as possible targets for antigen-specific immunotherapy in head and neck squamous cell carcinoma. Atanackovic D, Blum I, Cao Y, Wenzel S, Bartels K, Faltz C, Hossfeld DK, Hegewisch-Becker S, Bokemeyer C, Leuwer R

The Alabama Protective Services Act of 1976 was designed to protect adults over 18 made vulnerable because of age, mental deficiency, or poor health. All practitioners of the healing arts are mandated to report if there is reasonable cause to believe abuse, neglect, or exploitation has occurred.

To assess the effects of purified capsular polysaccharide from type 3 S. pneumoniae (PPS-3) on the capacity of serum to support pneumococcal killing by human neutrophils, varying concentrations of PPS-3 (0.01-100 micrograms/ml) were incubated (4 degrees C) with pooled serum for 30 min, and the resulting preparation, termed absorbed serum, was evaluated in bactericidal and phagocytic assays. The ability of serum to promote the killing of type 3 S. pneumoniae was significantly reduced at greater than or equal to 1.0 micrograms/ml PPS-3; similarly, serum absorbed with greater than or equal to 1.0 micrograms/ml PPS-2 failed to support the killing of type 2 S. penumoniae. However, the impact of these penumococcal polysaccharides was serotype specific, since the killing of type 3 S. pneumoniae was not impaired in serum absorbed with PPS-2, and the killing of type 2 S. pneumoniae was not attenuated in serum treated with PPS-3. The failure of serum absorbed with PPS-3 to promote the killing of type 3 S. pneumoniae was primarily a consequence of impaired bacterial ingestion; the reduction in phagocytosis was associated with parallel changes in superoxide anion release. The defects in phagocytosis and killing induced by PPS-3 were not associated with alterations in classical or alternative complement pathway activity; however, they were highly correlated with changes in serum antibody levels to the polysaccharide. The addition of polyclonal human IgG to serum treated with PPS-3 did not restore its capacity to support killing; however, preopsonization of the bacterium with the IgG preparation did partially correct the deficiency. Finally, neutrophils preincubated with serum containing greater than or equal to 10.0 micrograms/ml PPS-3 exhibited an impaired bactericidal activity against type 3 S. pneumoniae. Thus, these studies demonstrate that the presence of PPS-3 decreases the capacity of serum to support the killing of type 3 S. pneumoniae by absorbing immunoglobulins and by generating factors that interfere with neutrophil function.

Alabama emergency department personnel were surveyed in 1988 concerning elder abuse and Alabama's mandatory reporting and protective services law. Most ED personnel did not understand the requirements of the law. While emergency physicians, registered nurses, and licensed practical nurses had seen cases of elder abuse in their careers, differences existed in their satisfaction with the disposition of cases reported to state authorities. Licensed practical nurses and physicians reported greater satisfaction with the response received; registered nurses were much less satisfied. However, all accepted responsibility for reporting elder abuse. ED registered nurses and emergency physicians were divided on the degree to which they could diagnose elder abuse, did not believe there were sufficient services to care for those who had been abused, and were unsure whether there were procedures for reporting cases of elder abuse. All ED personnel need to know that cases they report will result in protection of abuse victims.