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The high dose conformity and healthy tissue sparing achievable in Particle Therapy when using C ions calls for safety factors in treatment planning, to prevent the tumor under-dosage related to the possible occurrence of inter-fractional morphological changes during a treatment. This limitation could be overcome by a range monitor, still missing in clinical routine, capable of providing on-line feedback. The Dose Profiler (DP) is a detector developed within the INnovative Solution for In-beam Dosimetry in hadronthErapy (INSIDE) collaboration for the monitoring of carbon ion treatments at the CNAO facility (Centro Nazionale di Adroterapia Oncologica) exploiting the detection of charged secondary fragments that escape from the patient. The DP capability to detect inter-fractional changes is demonstrated by comparing the obtained fragment emission maps in different fractions of the treatments enrolled in the first ever clinical trial of such a monitoring system, performed at CNAO. The case of a CNAO patient that underwent a significant morphological change is presented in detail, focusing on the implications that can be drawn for the achievable inter-fractional monitoring DP sensitivity in real clinical conditions. The results have been cross-checked against a simulation study.

Purpose: Sexual minority women (SMW) may have a different distribution of breast cancer risk factors than their heterosexual peers. Epidemiologic studies of breast cancer in SMW have been limited, and many use only proxy variables to identify SMW in data sets, introducing selection bias. We utilized National Health Interview Survey (NHIS) data to compare breast cancer risk factors, screening, and prevalence between SMW and non-SMW. Methods: We identified female respondents to the NHIS from 2013 to 2017, selected women ≥40 years old and stratified by sexual orientation. We compared demographics and health maintenance variables and prevalence of breast cancer diagnosis between groups and performed a multivariable analysis of breast cancer risk. Results: Of 58,378 women ≥40 years old, 1162 (2.0%) were identified as SMW. SMW were younger and more likely to use tobacco and alcohol, be younger at menarche, and be nulliparous. SMW also reported less preventive care, and despite reporting equivalent rates of mammography, were more likely to obtain mammograms due to an identifiable problem and not simply for screening purposes. Prevalence of breast cancer was similar between SMW and non-SMW (4.7% vs. 5.0%, p = 0.67), and SMW status was not associated with breast cancer diagnosis on univariate and multivariable logistic regression (p = 0.14 and p = 0.07, respectively). Conclusion: Despite finding no difference in breast cancer prevalence between SMW and non-SMW, there was evidence for differences in the utilization of breast care. Further studies of breast cancer incidence, characteristics (including subtype and stage), treatment, and survival for SMW are needed.

The aim of this work was the investigation of the ion recombination and polarity factors (k

Many studies have demonstrated disparities in breast cancer (BC) incidence and mortality among Black women. We hypothesized that in Pennsylvania (PA), a large economically diverse state, BC diagnosis and mortality would be similar among races when stratified by a municipality's median income.We collected the frequencies of BC diagnosis and mortality for years 2011-2015 from the Pennsylvania Cancer Registry and demographics from the 2010 US Census. We analyzed BC diagnoses and mortalities after stratifying by median income, municipality size, and race with univariable and multivariable logistic regression models.In this cohort, of 5,353,875 women there were 54,038 BC diagnoses (1.01% diagnosis rate) and 9,828 BC mortalities (0.18% mortality rate). Unadjusted diagnosis rate was highest among white women (1.06%) but Black women had a higher age-adjusted diagnosis rate (1.06%) than white women (1.02%). Race, age and income were all significantly associated with BC diagnosis, but there were no differences in BC diagnosis between white and Black women across all levels of income in the multivariable model. BC mortality was highest in Black women, a difference which persisted when adjusted for age. Black women 35 years and older had a higher mortality rate in all income quartiles.We found that in PA, age, race and income are all associated with BC diagnosis and mortality with noteworthy disparities for Black women. Continued surveillance of differences in both breast cancer diagnosis and mortality, and targeted interventions related to education, screening and treatment may help to eliminate these socioeconomic and racial disparities.

Background: Breast cancers are traditionally viewed as immunologically silent. However, recent research has demonstrated that the triple-negative breast cancer (TNBC) and HER-2 positive (HER2) are capable of stimulating the immune system. In contrast, the most commonly diagnosed subtype, the luminal A (hormone receptor positive (HR+)/HER-2 negative), is associated with a lower degree of tumor infiltrating lymphocytes (TILs) and low expression level of immune checkpoint regulators such as programmed death-ligand-1 (PD-L1). Cryoablation, the destruction of cells by ultra-low temperatures, has been used to treat benign breast disease and clinical trials have been conducted to determine its utility for invasive breast cancers. The primary endpoint has been the rate of complete tumor ablation with no assessment of immunological responses. We hypothesized that neoantigens released during cryoablation might be sufficient to trigger immune responses that could aid in the prevention/reduction of metastatic spread and relapse of breast cancers.In this pilot study we evaluated biopsy material, cryoablated specimens and sentinel lymph nodes (SLN) from patients enrolled in the ACOSOG Z1072 trial at Lankenau Medical Center (LMC) [N=18] with cancers < 2 cm. Responses were compared to patients treated with surgical resection.Methods: After obtaining IRB approval for retrospective analyses of specimens from the ACOSOG Z1072 trial, immunohistochemical staining of archival specimens was performed. An on-going biomarker study protocol was amended to include immune markers and used to select control patients of similar age and tumor characteristics. Per trial protocol, tumors had to be be surgically removed within 28 days of cryoablation, but the exact time was left to the surgeons discretion. Participating surgeons at LMC preferred to remove tumors on average 24.7 days after ablation resulting in an average time from diagnosis to surgical removal of 43.3 days (range 25- 56 days). Although most breast surgeries are performed within two weeks of diagnosis; some patients defer their surgery for personal reasons. This allowed us to identify patients (N=26) with a comparable average time from diagnosis to surgery of 37 days (range 21 - 66 days). Sections were stained for CD4, CD8, CD20, CD21, and CD1c to assess possible changes in immune repertoire due to cryoablation. We also evaluated presence of immune check-point regulators such as PD-L1 and CTLA-4 in biopsy, surgical material and SLN together with the immune modulator IDO1 using commercially available antibodies and standard techniques. Results: Cryoablation transformed tumors in patients into a gelatinous mass surrounded by a fibrotic capsule. The ACOSOG trial demonstrated an effective cryoablation-induced destruction of ER+ invasive ductal carcinoma lesions in 92% of patients (N=86). Sections from cryoablation patients displayed a necrotic core and infiltrating lymphocytes in the microenvironment. These masses had a slightly higher presence of CD8+ lymphocytes compared to CD4+. The inverse relation was observed in non-cryoblated specimens. SLNs from cryoablated patients had an elevated presence of CD20+ B cells compared to patients treated by surgery. Follicular dendritic cells (CD21+) were also present at higher numbers in SLNs from cryoablated patients. We detected positive staining for both PD-L1 and IDO1 among surgical and cryoablated patients. Sporadic presence of CTLA-4 was identified with a slight preference for cryoabalted patients. Conclusion: Cryoablation of breast cancer lesions can induce immune responses in vivo with possible anti-tumor activity in immunologically silent tumors such as HR+ breast cancers. All local cryo patients in the clinical trial are currently disease-free (F/U 5 - 13years), while 1 surgical patient is alive with late recurrence (11 years post-surgery). Citation Format: Margaretha Wallon, Jonah D Klein, Zachary Aukers, Nolan Metz, Vibha Ahudja, Laura Mandik-Nayak, Vincenzo Ciocca, Vlasta Zemba-Palko, Robin M Ciocca, Jennifer L Sabol, Ned Z Carp. Development of unique immune responses triggered by cryoablation of breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-05.

Background: Breast cancer is traditionally not considered as a highly immunogenic disease. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with reported high genomic instability and high mutation rate, indicating the possible presence of neoantigens. Cryoablation, the destruction of cells by ultra-low temperatures, can release these neoantigens and induce a tumor specific immune response. We hypothesized these neoantigens might be sufficient to trigger a robust immune response to prevent and/or reduce spread and relapse of TNBC. In this pilot study we cryoablated orthotopical 4T1 tumors in immune competent Balb/c mice and compared the results to surgery to evaluate 1) possible induction of immune responses and 2) effects on metastases formation. Methods: We used 4T1 mammary carcinoma cells to initiate tumor growth in the mammary fatpad. Tumors were treated by cryoablation, cryoablation followed by surgery (cryo-surgery), or surgery alone. Tumor growth was followed and allowed to reach 3-4mm in largest dimension. Animals were euthanized 7 days post-treatment and tissues were collected to assess cytokine levels and presence of dissociated 4T1 cells. Single-cell suspensions of tumor, tumor-draining lymph node [TDLN], and spleen were tested for secretion of mouse Th1/Th2 cytokines using a bead array and measured by flow cytometery. Possible metastatic spread was assessed by a clonogenic assay using cells from venous blood, lung, and brain. Cell suspensions were seeded in growth medium supplemented with the selection agent 6-thioguanine, allowing only resistant 4T1 cells to form colonies. Results: Cryoablation transformed tumors into a gelatinous mass surrounded by a fibrotic capsule, as typically seen in the clinic. Frozen sections of tumors revealed a necrotic core and infiltrating lymphocytes in the microenvironment. These animals displayed robust increases of Th1 and Th2 cytokines in both spleen and TDLN compared to animals with cryo-surgery treatment. TDLN of animals with surgically excised tumors secreted only IL-2. Circulating tumor cells were found in animals prior to treatment, while no 4T1 colonies formed from cell suspensions of lung and brain tissue [N=8]. At end-point, the surgery alone group had more 4T1 foci formed from lung and brain [mean foci /animal = 6.25 and 0.75, respectively; N=6] than the other two groups. Two animals in this group progressed and were euthanized early due to numerous lung metastases. The cryoablated group had the lowest number of foci formed in the lung and brain [2.25 and 0 respectively; N=8], and all animals were healthy at the predetermined end-point. Mean foci formation in the cryo-surgery group [N=7] was in-between the two other groups and one animal was euthanized early due to metastatic burden 5 days after surgery. Conclusion: Cryoablation of TNBC can induce stimulatory immune responses in vivo. These immune responses might explain why animals treated with cryoablation, though having circulating tumor cells at the time of treatment, exhibited fewer micro metastatic growths compared to surgery alone and the cryo-surgery combination. On-going experiments aim to identify long-term effects of cryoablation on the formation of metastatic foci and growth. Citation Format: Klein JD, Aukers Z, Kennedy J, Ciocca RM, Sabol JL, Carp NZ, Wallon UM. Cryoablation of murine mammary tumors induce robust immune response [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-11.

Background: Cryoablation, the destruction of cells by ultra-low temperatures, has been used to treat benign breast disease and two clinical trials (ACOSOG Z1072 and FROST) have been conducted to determine its utility in invasive breast cancers. The focus of the trials has been the rate of complete tumor ablation with no assessment of immunological responses. We hypothesize that neoantigens released during cryoablation might be sufficient to trigger a robust immune response to prevent and/or reduce spread and relapse of breast cancers. In this pilot study we 1) evaluated biopsy material, cryoablated specimens and axillary lymph nodes from patients with cancers smaller than 2cm enrolled in the ACOSOG Z1072 trial at Lankenau Medical Center [N=18] and 2) assessed immune responses and effects on metastases formation in the classical mouse mammary tumor model 4T1 in immune competent Balb/c mice. In both settings responses were compared to patients/mice treated with surgical resection alone. Methods: After obtaining IRB approval for retrospective analyses of specimens from the ACOSOG Z1072 trial, immunohistochemical staining of surgical specimens was performed. Sections were stained for CD4, CD8, CD20, CD21, and CD1c. In the IACUC approved animal experiments, 4T1 cells were injected orthotopically in the mammary fatpad to initiate tumor growth. Small tumors were treated by cryoablation or surgery alone. Animals were euthanized 7 days post-treatment and tissues were collected to assess cytokine levels and presence of dissociated 4T1 cells. Single-cell suspensions of tumor, tumor-draining lymph node [TDLN], and spleen were tested for secretion of mouse Th1/Th2 cytokines using a bead array and measured by flow cytometry. Possible metastatic spread was assessed by a clonogenic assay using cells from venous blood, lung and brain. Cell suspensions were seeded in growth medium with the selection agent 6-thioguanine, allowing only resistant 4T1 cells to form colonies. Results: Cryoablation transformed tumors in both patients and mice into a gelatinous mass surrounded by a fibrotic capsule. Sections of tumors from both humans and mice displayed a necrotic core and infiltrating lymphocytes in the microenvironment. The cryoablated human tumors had slightly higher presence of lymphocytes positive for CD8+ compared to CD4+. The inverse relation was observed in non-cryoblated specimens. No significant difference was observed for CD20+ lymphocytes. Tumor-draining lymph nodes from cryoablated patients had an elevated presence of CD20+ B cells compared to patients treated by surgery alone. Follicular dendritic cells (CD21+) were also present at higher numbers in TDLN from cryoablated patients. Animals treated with cryoablation displayed robust increases of Th1 and Th2 cytokines in both spleen and TDLN compared to animals with surgery treatment. In the animals, circulating tumor cells were found prior to treatment, while no 4T1 colonies formed from cell suspensions of lung and brain tissue [N=8]. At end-point, the surgery group had more 4T1 foci formed from lung and brain [mean foci /animal = 6.25 and 0.75, respectively; N=6] than the cryo group that had 2.25 and 0 foci in lung and brain, respectively [N=8]. Conclusion: Cryoablation of breast cancer lesions can induce stimulatory immune responses in vivo. These immune responses might explain why animals treated with cryoablation, though having circulating tumor cells at the time of treatment, exhibited fewer micro metastatic growths compared to surgery alone. The presence of elevated numbers of CD20+ in TDLN has been associated with improved disease-free survival. All local patients in the clinical trial are currently disease-free (5 to 9-year F/U) which is higher than expected recurrence rate at ~15% at 9 years post treatment. Citation Format: Allison A Campoverde, Jonah D Klein, Zachary Aukers, John Kennedy, Vlasta Zemba-Palko, Vincenzo Ciocca, Robin M Ciocca, Jennifer L Sabol, Ned Z Carp, Margaretha Wallon. Immune responses triggered by cryoablation of breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-22.

Studies of the beam broadening and in-depth dose profiles in water for a pencil beams of protons and carbon ions, with energies in the range of interest for Hadron Therapy, have been carried out. Transversal images of absorbed dose have been attained and fitted with Gaussian approximation. The area of the section at half height of the fitting surface was evaluated to quantify the beam broadening. The radius R of the section was taken to describe the beam broadening and a mathematical function giving R versus depth in water, for whichever PB energy, was attained, both for protons and for carbon ions.

The Italian National Centre for Oncological Hadrontherapy (CNAO) has been treating patients since 2011 with carbon-ion beams using the active-scanning modality. In such irradiation modality, the beam spot, which scans the treatment area, is characterised by very high particle-fluence rates (more than 105 s-1 mm-2). Moreover, the Bragg-peak is only ~1 mm-FWHM. Commercial tissue-equivalent proportional counters (TEPC), like the Far West Technologies LET-½, are large, hence they have limited capability to measure at high counting fluence rates. In this study we have used two home-made detectors, a mini-TEPC 0.81 mm2 in sensitive area and a silicon telescope 0.125 mm2 in sensitive area, to perform microdosimetric measurements in the therapeutic carbon-ion beam of CNAO. A monoenergetic carbon-ion beam of 189.5 ± 0.3 MeV/u scanning a 3 × 3 cm2 area has been used. Spectral differences are visible in the low y-value region, but the mean microdosimetric values, measured with the two detectors, result to be pretty consistent, as well as the microdosimetric spectra in the high y-value region.

Observations of thermospheric neutral winds and temperatures obtained during a geomagnetic storm on 2 October 2013 from a network of six Fabry-Perot interferometers (FPIs) deployed in the Midwest United States are presented. Coincident with the commencement of the storm, the apparent horizontal wind is observed to surge westward and southward (toward the equator). Simultaneous to this surge in the apparent horizontal winds, an apparent downward wind of approximately 100 m/s lasting for 6 h is observed. The apparent neutral temperature is observed to increase by approximately 400 K over all of the sites. Observations from an all-sky imaging system operated at the Millstone Hill observatory indicate the presence of a stable auroral red (SAR) arc and diffuse red aurora during this time. We suggest that the large sustained apparent downward winds arise from contamination of the spectral profile of the nominal thermospheric 630.0 nm emission by 630.0 nm emission from a different (nonthermospheric) source. Modeling demonstrates that the effect of an additional population of 630.0 nm photons, with a distinct velocity and temperature distribution, introduces an apparent Doppler shift when the combined emissions from the two sources are analyzed as a single population. Thus, the apparent Doppler shifts should not be interpreted as the bulk motion of the thermosphere, calling into question results from previous FPI studies of midlatitude storm time thermospheric winds. One possible source of contamination could be fast O related to the infusion of low-energy O+ ions from the magnetosphere. The presence of low-energy O+ is supported by observations made by the Helium, Oxygen, Proton, and Electron spectrometer instruments on the twin Van Allen Probes spacecraft, which show an influx of low-energy ions during this period. These results emphasize the importance of distributed networks of instruments in understanding the complex dynamics that occur in the upper atmosphere during disturbed conditions.

We searched the light curves of over 40000 stars in the 2 Micron All Sky Survey (2MASS) calibration database, spanning approximately 4 years, for objects that have significant day long dimming events. We also searched the multi-color light curves for red dimming events that could be due to transient extinction. In the color independent sigma-limited search, we found 46 previously unknown eclipsing binaries, 6 periodic variable stars likely to be intrinsic pulsators and 21 young stellar objects in the ρ Ophiucus star formation region previously studied by Parks et al. 2013. An additional 11 objects exhibited dimming events and most of these are unclassified. The search for red dimming events primarily reveals a population of low luminosity active galaxies that become bluer when they are brighter, and variable young stellar objects exhibiting high cross-correlation coefficients between color and brightness. The young stellar objects exhibit brightness and color variations in the direction of interstellar extinction whereas the active galaxies can have a bowed distribution in color and magnitude with reduced variation in color when the object is brightest. Among the objects that are usually quiescent (not strongly variable), we failed to find any dimming events deeper than 0.2 magnitude and lasting longer than a day. Two of the least embedded young stellar objects, however, dimmed by 0.2 mag for longer than a day without strong color variation. Having failed to find new exotic objects, we explored ways to eliminate commonly found objects so that a larger number of objects may be searched. We find that all but one eclipsing binary are excluded by requiring moderate color variation during a dimming event and most of the active galaxies are excluded by placing a limit on the standard deviation of the magnitude distribution in the light curve.

BACKGROUND – Tissue inhibitor of metalloproteinase-4 (TIMP-4) is a secreted multi-functional protein associated with poor survival prognosis among early-stage triple-negative breast cancers (TNBC). TNBC represent a highly aggressive form of this disease with an unmet need for effective predictive markers and targeted therapy. Extracellular TIMP-4 binds to the membrane bound tetraspanin CD63 and induces the activation of the tumor promoting PI3K/AKT/mTOR pathway. Here we report that TIMP-4 induced aggressive tumor growth and metastasis can be adverted by directly targeting TIMP-4 using a newly developed monoclonal antibody (mAb) to sequester TIMP-4 and the varied responses to common chemotherapy (CTX) regimen. METHODS – The role of elevated TIMP-4 in TNBC cell behavior was tested in cell culture and animal experiments using the human breast cancer line MDA-MB-468. Cells with or without TIMP-4 added to the medium were used to determine the effects on growth, clonogenic survival and response to chemotherapeutic agents such as adriamycin, Taxol, and the new TIMP-4 mAb. The same cell-line was used to induce tumor growth in nude mice with or without TIMP-4 containing slow-release pellets implanted into the mammary fatpad (mfp). Tumor growth and response to therapy was followed over a six-week period. Lungs, liver, spleen and mfp were collected and analyzed for presence of human cells using a specific anti-human MHC I mAb. Prospectively collected patient samples, in accordance with the IRB approved protocol, were tested for circulating levels of TIMP-4 using a commercially available ELISA assay in samples collected prior to chemotherapy and at each treatment cycle. The medical oncology staff recommended therapy without knowledge of TIMP-4 status. RESULTS – Augmentation of TIMP-4 levels in cell culture medium or the mfp of mice resulted in similar tumor phenotype as in the clinic; fast growing tumors with accelerated disease progression. Elevated TIMP-4 levels in the tumor environment resulted in a 1.5-fold increased growth rate with liver and/or lung metastasis in 25% of animals (N=16). No metastases were found in animals with normal TIMP-4 levels. Treating cell cultures or tumor-bearing mice (i.p. injections) with our TIMP-4 mAb resulted in decelerated growth rate and no detectable metastatic disease in the animals. Results from patient samples demonstrated that circulating TIMP-4 levels in breast cancer patients remain elevated after definitive surgery, indicating that TIMP-4 might continuously stimulate any remaining disseminated tumor cells. Adriamycin containing regiments was the only CTX to suppress the TIMP-4 levels independent of primary tumor size and nodal status. CONCLUSIONS – Based on these clinical and experimental data we suggest that TIMP-4 may represent a prognostic and predictive marker, and a therapeutic target for TNBC patients at highest risk. The presence of TIMP-4 identifies a patient population likely to recur quickly due to continuous activation of the PI3K/AKT/mTOR pathway. Though adriamycin therapy can reduce the TIMP-4 levels, the toxicity of this agent suggests that targeted therapy of the PI3K/AKT pathway and/or a biological therapeutic approach directed against TIMP-4 may be of benefit in this subset of pts and should be further explored. Citation Format: U Margaretha Wallon, Jennifer L Sabol, Vlasta Zemba-Palko, James S DuHadaway, Erica Sutanto-Ward, Zonera A Ali, Paul B Gilman, Robin M Ciocca, Ned Z Carp, George C Prendergast. TIMP-4 is a prognostic and predictive marker in triple-negative breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-54.

Although the evolutionarily acquired role by cellular senescence as a powerful tumour suppressor is well acknowledged, ectopically senescing cells may exert deleterious effects on the tissue microenvironment, the most prominent of which is the so-called senescence-associated secretory phenotype (SASP), by which senescing cells may promote tumour progression. Chromosome aberrations, on the other hand, are the most validated biomarker for cancer risk and provide useful insights on mechanistical modes of ionising radiation action. The recently operational National Centre for Oncological Hadrontherapy (Centro Nazionale di Adroterapia Oncologica, CNAO) is the first Italian facility for cancer treatment with carbon ions. The main justification for the medical use of high –LET radiations rely on their greater effectiveness at tumour cell killing compared to low-LET radiations or lighter charged particles such as protons. Despite encouraging results on local tumour control from other centres worldwide that have adopted this therapeutic strategy, there still exists uncertainties surrounding late effects in the normal tissue. These can be brought about by sublethally damaged cells, such as those that enter senescence prematurely or those carrying transmissible genetic damage, which may lead to organ dysfunction/tissue disruption and secondary cancers. Therefore, we have studied the onset of premature cellular senescence by -galactosidase expression in post-irradiation serially cultivated cells as well as the induction of structural chromosome aberrations detected by FISH techniques in chemically-induced (calyculin A) metaphases 24 h after radiation exposure. Normal endothelial and epithelial cells were exposed to a 6-cm Spread Out Bragg Peak (SOBP) carbon ion beam (E = 246-312 MeV/n) at CNAO. Two doses (0.5 and 2 Gy) were delivered at various depths along the beam, with LET values ranging from 14 keV/m at the entrance to 100 keV/m at the distal SOBP position. Results will be illustrated and their implications for carbon-ion radiotherapy discussed.

Usefulness of Urine as a Sample for Detection of Brucella Spp in Male Canines Urine was used as a sample and Sensitivity (S), Specificity (Sp) and the positive Likelihood Ratio (LR+) of molecular and serological methods, combined with epidemiology and the clinical symptoms for detection of Brucella spp., were compared in blood and urine samples from 241 male canines. The rapid slide agglutination test together with 2- mercaptoethanol (2-ME RSAT) were used as a screening test, followed by confirmation using an indirect immunoenzymatic assay (iELISA) and bacteriological culture. Results were as follows: Test a) PCR (Polymerase Chain Reaction) of blood compared to blood culture: S 80%, Sp 92%, LR+ 10.32% (CI 5.27-19.20) test b) iELISA compared to blood culture: S 100%, Sp 94%, LR+: 16.57%) (CI 9.97-27.53), test c) PCR of urine compared to urine culture: S 100%, Sp 93% (CI 8.36-21.56), LR+: 13.64 test d) iELISA compared to urine culture: S 100%, Sp 93%, RV+: 14.5 (CI 9.03-23.26). We conclude that molecular and serological tests in conjunction with epidemiology are both useful for diagnosis and that both blood and urine samples should be assayed together.

The North American Thermosphere Ionosphere Observing Network (NATION), comprising a new network of Fabry-Perot interferometers (FPIs), to be deployed in the Midwest of the United States of America is described. FPIs will initially be deployed to four sites to make coordinated measurements of the neutral winds and temperature in the Earth's thermosphere using measurements of the 630 nm redline emission. The observing strategy of the network will take into account local observing conditions, and common volume measurements from multiple sites will be made in order to estimate local vector wind quantities. The network described is expandable, and as additional FPI sites are installed in North America, or elsewhere, the goal of providing the upper atmospheric research community with a robust dataset of neutral winds and temperatures can be achieved.

BACKGROUND: Triple-negative breast cancers (TNBC) represent a highly aggressive form of this disease with few treatment options available. Currently, even the smallest node negative cancers are considered by many to warrant treatment with chemotherapy (CTX). While many recur early (within 2–3 years), there is a subset of long-term survivors illustrating the heterogeneity within this group. Here we report our ongoing effort to establish tissue inhibitor of metalloproteinase-4 (TIMP-4) as a prognostic marker in all early breast cancers a. While the canonical function of TIMPs is to inhibit tissue degradation, numerous reports have established that TIMPs exert tumor promoting activity. In our prospective study, we evaluated TIMP-4 as prognostic marker for TNBC and its role in disease progression. METHODS: Specimens from our retrospective and prospective cohorts were assessed by immunohistochemical staining using standard techniques and a monoclonal antibody for TIMP-4b in accordance with the IRB approved protocol. Staining intensity was documented on a scale of 0–3. No data was released to the treating physicians at the time of collection. Outcome data from a total of 240 pts was obtained through tumor registry and clinician practices. Staining intensity was then correlated with outcome to calculate sensitivity and specificity of the marker. To determine the role of TIMP-4 in TNBC cell behavior we have performed microarray analyses. The effects of TIMP-4-induced signaling were tested using invasion and clonogenic survival assays under normal growth conditions and after exposure to gamma radiation. RESULTS: Elevated TIMP-4 expression identified a high risk of relapse and short survival time with 75% sensitivity and 80% specificity. No discernable differences were noted between retrospective and prospective cohorts. Array analyses revealed activation of the PI3K/AKT pathway in the presence of TIMP-4. Furthermore, elevated TIMP-4 increased the invasive behavior of breast cancer cells in Matrigel™-coated invasion chambers and reduced sensitivity to gamma irradiation. These effects were reversible by addition of either a PI3K inhibitor or an anti-TIMP-4 antibody, suggesting their use as potential therapeutic strategies. CONCLUSIONS: On the basis of these clinical data we suggest that TIMP-4 may offer a simple prognostic marker for TNBC patients at highest risk. The presence of TIMP-4 identifies a patient population likely to recur quickly despite standard CTX treatment. Our research suggests that targeted therapy of the PI3K/AKT pathway and/or a biological therapeutic approach directed against TIMP-4 may be of benefit in this subset of pts and should be explored. Therefore, TIMP-4 testing of TNBC patients could aid in the selection of a treatment regimen to improve survival outcome. a Liss, M et.al. Am. J. Pathol. 2009 b Donover, P et.al. J. Cell. Biochem. 2010 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-21.

The neural control of the cardiovascular system is a complex process that involves many structures at different levels of nervous system. Several cortical areas are involved in the control of systemic blood pressure, such as the sensorimotor cortex, the medial prefrontal cortex and the insular cortex. Non-invasive brain stimulation techniques - repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) - induce sustained and prolonged functional changes of the human cerebral cortex. rTMS and tDCS has led to positive results in the treatment of some neurological and psychiatric disorders. Because experiments in animals show that cortical modulation can be an effective method to regulate the cardiovascular system, non-invasive brain stimulation might be a novel tool in the therapeutics of human arterial hypertension. We here review the experimental evidence that non-invasive brain stimulation can influence the autonomic nervous system and discuss the hypothesis that focal modulation of cortical excitability by rTMS or tDCS can influence sympathetic outflow and, eventually, blood pressure, thus providing a novel therapeutic tool for human arterial hypertension.

GATA3 is a transcription factor closely associated with estrogen receptor alpha in breast carcinoma, with a potential prognostic utility. This study investigated the immunohistochemical expression of GATA3 in estrogen receptor alpha-positive and estrogen receptor alpha-negative breast carcinomas. One hundred sixty-six cases of invasive breast carcinomas with 10-year follow-up information were analyzed. Positive GATA3 and estrogen receptor alpha cases were defined as greater than 20% of cells staining. Time to cancer recurrence and time to death were analyzed with survival methods. Of 166 patients, 40 were estrogen receptor alpha negative and 121 estrogen receptor alpha positive. Thirty-eight (23%) recurrences and 51 (31%) deaths were observed. In final multivariable analyses, GATA3-positive tumors had about two thirds the recurrence risk of GATA3-negative tumors (hazard ratio = 0.65, P = .395) and comparable mortality risk (hazard ratio = 0.86, P = .730). In prespecified subgroup analyses, the protective effect of GATA3 expression was most pronounced among estrogen receptor alpha-positive patients who received tamoxifen (hazard ratio = 0.57 for recurrence and 0.68 for death). We found no statistically significant differences in recurrence or survival rates between GATA3-positive and GATA3-negative tumors. However, there was a suggestion of a modest-to-strong protective effect of GATA3 expression among estrogen receptor alpha-positive patients receiving hormone therapy.

To describe the dosimetric commissioning and quality assurance (QA) of the actively scanned proton and carbon ion beams at the Italian National Center for Oncological Hadrontherapy.The laterally integrated depth-dose-distributions (IDDs) were acquired with the PTW Peakfinder, a variable depth water column, equipped with two Bragg peak ionization chambers. fluka Monte Carlo code was used to generate the energy libraries, the IDDs in water, and the fragment spectra for carbon beams. EBT3 films were used for spot size measurements, beam position over the scan field, and homogeneity in 2D-fields. Beam monitor calibration was performed in terms of number of particles per monitor unit using both a Farmer-type and an Advanced Markus ionization chamber. The beam position at the isocenter, beam monitor calibration curve, dose constancy in the center of the spread-out-Bragg-peak, dose homogeneity in 2D-fields, beam energy, spot size, and spot position over the scan field are all checked on a daily basis for both protons and carbon ions and on all beam lines.The simulated IDDs showed an excellent agreement with the measured experimental curves. The measured full width at half maximum (FWHM) of the pencil beam in air at the isocenter was energy-dependent for both particle species: in particular, for protons, the spot size ranged from 0.7 to 2.2 cm. For carbon ions, two sets of spot size are available: FWHM ranged from 0.4 to 0.8 cm (for the smaller spot size) and from 0.8 to 1.1 cm (for the larger one). The spot position was accurate to within ± 1 mm over the whole 20 × 20 cm(2) scan field; homogeneity in a uniform squared field was within ± 5% for both particle types at any energy. QA results exceeding tolerance levels were rarely found. In the reporting period, the machine downtime was around 6%, of which 4.5% was due to planned maintenance shutdowns.After successful dosimetric beam commissioning, quality assurance measurements performed during a 24-month period show very stable beam characteristics, which are therefore suitable for performing safe and accurate patient treatments.

A high-resolution, 33 mA (FWHM), optically thin emission study of the N2 c' 1Σ(0)-X 1Σ(0) band transition has been performed with electron impact at 100 eV. Recently measured line oscillator strengths and lifetimes have been examined by comparing model spectra with the observed emission. Good agreement between model and data indicates consistency between the measured lifetimes and oscillator strengths. Predissociation yields for various Jj levels are estimated. The calculated predissociation yield is in the range 0.2-0.5 for Jj = 4-23 and negligible for Jj = 0-2.

Introduction: To investigate the main physical properties of low-energy X-ray beams produced by a Plasma Focus (PF) device and to carry out dosimetric and radiobiological characterization, in view of a possible clinical application to IORT treatments. Materials and Methods: PF is a device designed to generate a plasma sheet between two co-axial electrodes by means of a high voltage difference. The energy of a bank of capacitors (typically between a few and a few tens of kJ) is instantly transferred to the electrodes producing a plasma sheet, which is pushed towards the open end of the electrodes by the self-generated IxB force. The sheet implodes into a very dense magnetized plasma pinch, in a region called focus. Under such a condition, thermo-nuclear reactions may take place and charged particles are emitted. Apart from neutron production, ions and electrons are accelerated as well by the strong electromagnetic field following the focus decay. The charged particles emission can be described as follows: a) ion beam forward peaked; b) relativistic electron beam emitted with a narrow cone of aperture. When the filling gas is hydrogen or some other pure inert gas, as in our case, the reactions are neutron-free, while an ion beam plus an electron one are generated in opposite directions. A dedicated PF device has been designed and is currently under advanced status of construction and testing by the research groups of the Universities of Bologna and Ferrara, coordinated by the Alma Mater s.r.l. of the University of Bologna and with the financial support of ABO Project (Biotechnology Applications for Oncology). It can be used to produce an electron beam to be extracted from the PF vacuum chamber through a dedicated channel. The electron beam can be directly used for the irradiation of small targets or to generate X-rays by interaction with appropriate targets (Bremsstrahlung and/or characteristic emission). The system can deliver up to 5 Gy/pulse and each pulse lasts about 10-20 ns. Absorbed dose to water determination, as well as relative dosimetry (PDD curves and transversal dose profiles), will be performed mainly using calibrated radiochromic films (ISP MD-55) in a water-equivalent phantom. TLD-100 detectors, in form of micro-rods, will also be investigated. The biological endpoint for RBE calculation will be also evaluated, through an in-situ approach of apoptosis induction and gamma-H2AX foci expression. Results: With the present asymmetric PF configuration, an electron beam of about 1 kA was extracted by means of an electron pipe 25 cm long and converted into X-rays in the interval 10–50 keV from impact with a Cu or W target. The X-ray spectra were assessed through an original spectrometer made of LiF dosimeters staked together. The preliminary dosimetric results using radiochromic films revealed doses higher than 1 Gy/shot, uniformly distributed over a surface of 7 cm2, 5 mm away from the target. One order of magnitude higher results are expected with an appropriate symmetric assembly. Conclusion: Preliminary results on the prototype device seem encouraging, although deeper investigation is warranted in the perspective of a potential clinical application.

La Fondazione CNAO ha tra i suoi scopi anche lo svolgimento di attività di ricerca. Il centro CNAO è stato concepito sin dall'inizio con tre sale di trattamento, espandibili fino a cinque, ed una 'sala sperimentale' nella quale le attività di ricerca possano venire svolte senza intralciare e senza essere intralciate dalla attività clinica.Tale sala sperimentale deve essere progettata per essere 'multi-uso', cioè tale da poter venire utilizzata per attività di ricerca nei campi più disparati e non specializzata in un tipo di attività particolare. Possibili argomenti di ricerca sono radiobiologia, sviluppo di monitor di fascio, sviluppo di dosimetri, studi di radiation hardness e molti altri ancora.Lo studio di tale facility ed in particolare lo studio degli aspetti tecnici legati all'ampliamento del complesso dell'acceleratore è stato portato avanti congiuntamente da CNAO e INFN, nell'ambito dell'accordo quadro approvato nel 2009 e del nuovo accordo quadro stipulato nel 2013. Per meglio identificare le necessità dei possibili utenti è stato svolto un sondaggio i cui risultati sono stati considerati nella definizione delle specifiche funzionali della linea e della sala sperimentale. Tale sondaggio è illustrato più avanti in questo documento. In questo documento viene descritto il progetto della sala sperimentale e delle linee di alta e di bassa energie coinvolte. Nella prima parte del documento viene data una descrizione generale del progetto, mentre i dettagli sono generalmente riportati nelle appendici e nei documenti allegati.

A high resolution 36 mA (FWHM), optically thin emission study of the and (3, 2) Rydberg bands excited by electron impact at 100 eV has been completed in the extreme ultraviolet (EUV). A model of the perturbed rotational line intensity distribution of the bands shows the effects of electronic state mixing between the Rydberg state and the valence state. By normalizing the model to the published predissociation yield for the laboratory spectrum can be used to determine the predissociation yields for each rotational level of and 4. Based on a 25% accuracy of the model fit to the measured signal intensities it is found that the predissociation yields of the rotational levels increase as the percentage of character increases. On the other hand, the predissociation yields of the rotational levels reach a maximum for . The mean predissociation yields for and 4 levels are a function of temperature and are found to be 0.41 and 0.58, respectively at 300 K. The -dependent predissociation yields indicate that the emission cross section is a function of temperature. The remainder of the bands forming the progressions -5) from and -6) from were studied at 64 mA (FWHM) resolution. Using this composite spectrum of the two progressions the electron impact emission cross sections of the and 4 levels at 300 K were determined and compared with previous results.

Using Floquet spectroscopy, we have measured the scalar and tensor polarizabilities of a nominally hydrogenic state of a multielectron atom. We obtain ${\mathrm{\ensuremath{\alpha}}}_{0}$=426.1\ifmmode\pm\else\textpm\fi{}16 MHz/(V/cm${)}^{2}$ and ${\mathrm{\ensuremath{\alpha}}}_{2}$=-66.3\ifmmode\pm\else\textpm\fi{}22 MHz/(V/${\mathrm{cm}}^{2}$) for the Stark states linked to the 30${\mathit{d}}^{2}$D zero-field states of sodium, which we compare with the results of several theoretical treatments. We have also mapped the important transition from quadratic to linear behavior, thus measuring the hyperpolarizability as well. The measurements are discussed within the framework of a semiclassical model for the atomic response to the external field. \textcopyright{} 1996 The American Physical Society.

The Doppler profiles of one of the fine structure lines of the N I (1200 A) g (sup 4)S(sup 0)-(sup 4)P multiplet and of the N II (1085 A) g (sup 3)p(sup O)-(sup 3)D multiplet have been measured. Excitation of the multiplets is produced by electron impact dissociative excitation of N2. The experimental line profiles are evaluated by fast Fourier transform (FFT) techniques and analysis of the profiles yields the kinetic energy distribution of fragments. The full width at half maximum (FWHM) of N I (1200 A) increases from 27+/-6 mA at 30 eV to 37+/-4 mA at 100 eV as the emission cross section of the dissociative ionization excitation process becomes more important relative to the dissociative excitation process. The FWHM of the N II (1085 A) line is 36+/-4 mA at 100 eV. For each multiplet the kinetic energy distribution function of each of the two fragment N atoms (ions) is much broader than thermal with a mean energy above 1.0 eV. The dissociation process with the largest cross section is predissociation and predominantly produces N atoms with kinetic energy distributions having mean energies above 0.5 eV. Dissociative processes can lead to a substantial escape flux of N I atoms from the satellites, Titan and Triton of the outer planets.

The next generation of high resolution UV imaging spacecraft are being prepared for studying the airglow and aurora of the Earth, the other terrestrial planets and the Jovian planets. To keep pace with these technological improvements we have developed a laboratory program to provide electron impact collision cross sections of the major molecular planetary gases (H2, N2, CO2, O2, and CO). Spectra under optically thin conditions have been measured with a high resolution (lambda/delta(lambda) = 50000) UV spectrometer in tandem with electron impact collision chamber. High resolution spectra of the Lyman and Wemer band systems of H2 have been obtained and modeled. Synthetic spectral intensities based on the J-dependent transition probabilities that include ro-vibronic perturbations are in very good agreement with experimental intensities. The kinetic energy distribution of H(2p,3p) atoms resulting from electron impact dissociation of H2 has been measured. The distribution is based on the first measurement of the H Lyman-alpha (H L(alpha)) and H Lyman-beta (H L(beta)) emission line Doppler profiles. Electron impact dissociation of H2 is believed to be one of the major mechanisms leading to the observed wide profile of H L-alpha from Jupiter aurora by the Hubble Space Telescope (HST). Analysis of the deconvolved line profile of H L-alpha reveals the existence of a narrow line peak (40 mA FWHM) and a broad pedestal base (240 mA FWHM). The band strengths of the electron excited N2 (C(sup 3) Pi(sub(upsilon) - B(sup 3)Pi(sub g)) second positive system have been measured in the middle ultraviolet. We report a quantitative measurement of the predissociation fraction 0.15 +/- 01(sup .045, sub .01) at 300 K in the N2 c'(sub )4 (1)sigma(sup +, sub g) - x(1)sigma(sup +, sub g)(00) band, with an experimental determination of rotational line strengths to be used to understand N2 EUV emission from Titan, Triton and the Earth.