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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.

Herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2) are prototypical alphaherpesviruses that are characterized by their unique properties to infect trigeminal and dorsal root ganglionic neurons, respectively, and establish life-long latent infections. These viruses initially infect mucosal epithelial tissues and subsequently spread to neurons. They are associated with a significant disease spectrum, including orofacial and ocular infections for HSV-1 and genital and neonatal infections for HSV-2. Viral glycoproteins within the virion envelope bind to specific cellular receptors to mediate virus entry into cells. This is achieved by the fusion of the viral envelope with the plasma membrane. Similarly, viral glycoproteins expressed on cell surfaces mediate cell-to-cell fusion and facilitate virus spread. An interactive complex of viral glycoproteins gB, gD/gH/gL, and gK and other proteins mediate these membrane fusion phenomena with glycoprotein B (gB), the principal membrane fusogen. The requirement for the virion to enter neuronal axons suggests that the heterodimeric protein complex of gK and membrane protein UL20, found only in alphaherpesviruses, constitute a critical determinant for neuronal entry. This hypothesis was substantiated by the observation that a small deletion in the amino terminus of gK prevents entry into neuronal axons while allowing entry into other cells via endocytosis. Cellular receptors and receptor-mediated signaling synergize with the viral membrane fusion machinery to facilitate virus entry and intercellular spread. Unraveling the underlying interactions among viral glycoproteins, envelope proteins, and cellular receptors will provide new innovative approaches for antiviral therapy against herpesviruses and other neurotropic viruses.

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.

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.

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.

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.

We evaluated physicians' responses to state elder abuse reporting statutes. Most statutes require reporting without providing for adequate investigation and service delivery. The Alabama Protective Services Act of 1976 is typical. Survey responses by Alabama physicians suggest that they have reservations about their ability to diagnose abuse, the operation of the law, and their willingness to report abuse. It appears that, in Alabama, mandatory reporting by itself is counterproductive because the statute fails to provide for adequate investigation and service delivery or to command knowledgeable compliance. Language: en

A survey of Alabama physicians in the fields of internal medicine, family practice and general practice and a survey of nurses in the areas of home health and community health care were conducted in 1987 and 1988 concerning elder abuse and Alabma's thirteen-year-old mandatory reporting/protective services law. The authors found that phyisicans did not understand the law but nurses did. Physicians' attitudes toward the law were ambivalent. Nurses had more negative attitudes toward the law. These attitudes appeared to be based on poor response by authorities to earlier reports.

In order to assess the influence of the protease inhibitor eglin-c on superoxide anion (O-2) release by human polymorphonuclear leukocytes (PMN), cells were secured from normal donors and stimulated with phorbol myristate acetate (PMA), opsonized zymosan, or n-formyl-methionyl-leucyl-phenylalanine (FMLP). In the presence of 100 micrograms/ml eglin-c, the activation time was prolonged and the maximum linear rate of O-2 formation was depressed following stimulation with PMA; a concentration of 1000 micrograms/ml eglin-c was required to produce a similar effect with opsonized zymosan. Eglin-c did not influence the activation time following stimulation with FMLP, but at 2000 micrograms/ml, the protease inhibitor attenuated the rate of O-2 production in response to the chemotactic peptide. In the presence of cytochalasin B, the inhibitory effect of eglin-c on O-2 release following stimulation with FMLP became more pronounced. In spite of these alterations in O-2 formation, the protease inhibitor did not impair the bactericidal activity of PMN against Staphylococcus aureus. Therefore, we conclude that although eglin-c can disrupt the activation and the activity of the superoxide-generating system of human PMN, the effect is stimulus dependent and is not associated with an alteration in the microbicidal capacity of neutrophils against S. aureus.

A positive‐reinforcement procedure was used to determine hearing sensitivity and noise‐induced hearing loss in the chinchilla. The animals were reinforced with 45‐mg pellets (Noyes) for depressing and holding a key for 1–6 sec and either releasing it during a 2‐sec tone presentation or not releasing it during a 2‐sec catch trial. Using a tracking procedure, thresholds were determined at 9–15 frequencies during each daily 1‐h session. Following threshold determinations, two animals were exposed to a 123‐dB‐SPL band of noise (710–2800 Hz) for 15 min. Threshold shifts were measured daily after the exposure and the animals were sacrificed at 7 and 28 days post‐exposure, respectively. Their cochleas were examined under the light microscope and the number of hair cells missing was compared with the hearing loss present. Contrary to previous findings, both animals showed a considerable permanent threshold shift that agreed closely with the degree of change seen in the cochlea. The advantages and disadvantages of the new behavioral procedure are discussed.

Cancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1(+) CD11b(+) cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1(+) CD11b(+) cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1(+) CD11b(+) cells to the tumor microenvironment and blocked tumor development-a finding that was dependent on CD8(+) T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment.

Normal CD-1 mice were administered digoxin (4 micrograms/kg/24 h) and infected with type 3 Streptococcus pneumoniae in order to assess the effects of the cardiac glycoside on the chemotactic responsiveness of peripheral blood neutrophils and the mobilization of granulocytes from storage pools. The chemotactic responses to autologous zymosan-activated serum (C5a) by neutrophils obtained from uninfected digoxin-treated and control animals were similar; comparable observations were made with circulating granulocytes isolated from animals at 24 or 48 h after intratracheal challenge with 5 x 10(5) colony-forming units (cfu) of bacteria. However, at 4 and 6 h after intratracheal pneumococcal challenge, the number of immature neutrophils in the peripheral blood was significantly lower in the glycoside-treated animals versus controls; at 24 and 48 h, these differences were not apparent. Following the intravenous inoculation of pneumococci, the number of circulating immature neutrophils was also found to be significantly lower at 4 and 24 h in animals given the cardiac glycoside versus controls. We conclude that digoxin disrupts host defense in experimental pneumococcal pneumonia and bacteremia by impairing the mobilization of neutrophils.

To assess the effects of advanced age on the release of neutrophil chemoattractant activity by resident bronchoalveolar macrophages (BAM), cells from three strains of pathogen- and disease-free mice were secured by lung lavage and stimulated in vitro with unopsonized zymosan or the calcium ionophore, A23187. Chemoattractant release by BAM from adult (5-8 mos) and senescent (19-26 mos) C57BL/6 and DBA/2 mice in response to both stimulants was comparable; however, the generation of chemoattractant activity by BAM from senescent (18-20 mos) BALB/c mice was greater than that observed with cells from younger (4-6 mos) animals with both zymosan and A23187. In the presence of 50 microM piriprost potassium, a 5-lipoxygenase inhibitor, the release of chemoattractant activity and leukotriene B4 (LTB4) in response to zymosan and A23187 by BAM from both groups of C57BL/6 mice was significantly impaired. With BAM from BALB/c mice, 100 microM piriprost potassium was required to produce changes in A23187-stimulated chemoattractant and LTB4 release; of note, the generation of LTB4 in response to A23187 by BAM from aged BALB/c mice was significantly greater than that observed with cells from the younger animals under all conditions studied. Finally, with BAM from DBA/2 mice, 50 microM piriprost potassium significantly reduced chemoattractant activity in both groups of animals, but the lipoxygenase inhibitor had no effect on LTB4 production. Thus, although these studies revealed substantial age and strain-related differences in the release of neutrophil chemoattractant activity by murine BAM, they did not demonstrate deficiencies that might enhance the susceptibility of the senescent host to infection of the lower respiratory tract.

The volumes in this popular series provide nurse educators with material to help them plan, conduct, and evaluate their instructional goals and accomplishments. The series addresses a broad spectrum of teaching situations, classroom settings, and clinical instruction-supervision.New to this edition are chapters on working with the elderly in groups, and in working with groups with specific problems, such as eating disorders, rape, or depression.

To the Editor.— In 1976, Alabama passed a statute (the Adult Protective Services Act) to prohibit the abuse, neglect, and exploitation of adults and mandate the reporting of mistreatment. Alabama focused its mandatory reporting requirements on all "practitioners of the healing arts." To evaluate the efficacy of the statute, the Center for the Study of Aging at the University of Alabama conducted in July 1987 a three-wave mail survey of Alabama physicians to assess their knowledge of the law and their responses to elder abuse. The random sample consisted of 336 internists, family practitioners, and general practitioners in Alabama stratified by specialty and city size. The response rate was 46%. The physicians responded to a series of statements concerning abuse using a five-point Likert scale ranging from "definitely not true" to "definitely true." The results show that after 12 years, Alabama physicians are confused about the law and about the

Old World monkeys were exposed to octave‐band or wide‐band noise at 117–120 dB SPL, 8 hours daily, five days per week for four weeks. The octave bands were centered at 500, 2000, 4000, or 8000 Hz. Thresholds for frequencies 63–40 000 Hz were measured daily before, during, and for one month after exposure, by the staircase method, using operant conditioning procedures with positive reinforcement. After the final threshold measurements the temporal bones were fixed and the inner ears examined by microdissection and phase‐contrast microscopy. Maximum TTS, usually attained on the first day of exposure, ranged from 60 to 100 dB; PTS, from 40 to 60 dB. Both temporary and permanent loss involved at least two or three octaves and for the most part were greatest at, or within the octave above, the center of the exposure band. Hair cell counts showed reasonable correspondence between the location, severity, and extent (5–12 mm) of outer hair cell loss and the degree of PTS, in accordance with the place principle. I...

Absolute thresholds were determined in the chinchilla using a new behavioral procedure. The animal was reinforced with a 45‐mg pellet (Noyes) for depressing and holding a key 1–7 sec and either releasing it during a 2‐sec tone presentation or not releasing it during a 2‐sec catch trial. Using a tracking procedure, thresholds were determined at 9 to 15 frequencies during each daily 1‐hour session. Thresholds are compared to those obtained by conventional shock‐avoidance techniques, and the advantages and disadvantages of the procedure are considered. Following threshold determinations, two of the animals were exposed to a 123‐dB two‐octave band of noise (710–2800 Hz) for 15 minutes. The animals were sacrificed 7 and 28 days post exposure, respectively and their cochleas prepared for examination under the light microscope by the surface preparation technique. The correlation between the amount of hearing loss present and the cochlear pathology is examined, and these results are compared to those obtained by Ward and Duvall [Ann. Otol. 80, 881 (1971)]. [Research supported by NIH research and training grants.]