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1.  A role for PAX8 in the tumorigenic phenotype of ovarian cancer cells 
BMC Cancer  2014;14:292.
Background
PAX8 is a member of the paired box (Pax) multigene family of transcription factors, which are involved in the developmental and tissue-specific control of the expression of several genes in both vertebrates and invertebrates. Previously, several studies reported that PAX8 is expressed at high levels in specific types of tumors. In particular, PAX8 has been recently reported to be conspicuously expressed in human ovarian cancer, but the functional role of PAX8 in the carcinogenesis of this type of tumor has not been addressed. In this study, we investigated the contribution of PAX8 in ovarian cancer progression.
Methods
Stable PAX8 depleted ovarian cancer cells were generated using short hairpin RNA (shRNA) constructs. PAX8 mRNA and protein were detected by RT-PCR, immunoblot and immunofluorescence. Cell proliferation, motility and invasion potential of PAX8 silenced cells were analyzed by means of growth curves, wound healing and Matrigel assays. In addition, PAX8 knockdown and control cells were injected into nude mice for xenograft tumorigenicity assays. Finally, qPCR was used to detect the expression levels of EMT markers in PAX8-overexpressing and control cells.
Results
Here, we show that PAX8 plays a critical role in the migration, invasion and tumorigenic ability of ovarian cancer cells. Our results show that RNA interference-mediated knockdown of PAX8 expression in SKOV-3 ovarian cancer cells produces a significant reduction of cell proliferation, migration ability and invasion activity compared with control parental SKOV-3 cells. Moreover, PAX8 silencing strongly suppresses anchorage-independent growth in vitro. Notably, tumorigenesis in vivo in a nude mouse xenograft model is also significantly inhibited.
Conclusions
Overall, our results indicate that PAX8 plays an important role in the tumorigenic phenotype of ovarian cancer cells and identifies PAX8 as a potential new target for the treatment of ovarian cancer.
doi:10.1186/1471-2407-14-292
PMCID: PMC4005813  PMID: 24766781
PAX8; Ovarian cancer; shRNA; Gene silencing
2.  Cortisol and Inflammatory Processes in Ovarian Cancer Patients Following Primary Treatment: Relationships with Depression, Fatigue, and Disability 
Brain, behavior, and immunity  2012;30(0):S126-S134.
Elevations in the pro-inflammatory cytokine interleukin-6 (IL-6) and alterations in the anti-inflammatory hormone cortisol have been reported in a variety of cancers. IL-6 has prognostic significance in ovarian cancer and cortisol has been associated with fatigue, disability, and vegetative depression in ovarian cancer patients prior to surgery. Ovarian cancer patients undergoing primary treatment completed psychological self-report measures and collected salivary cortisol and plasma IL-6 prior to surgery, at six months, and at one year. Patients included in this study had completed chemotherapy and had no evidence of disease recurrence. At six months, patients showed significant reductions in nocturnal cortisol secretion, plasma IL-6, and a more normalized diurnal cortisol rhythm, changes that were maintained at one year. The reductions in IL-6 and nocturnal cortisol were associated with declines in self-reported fatigue, vegetative depression, and disability. These findings suggest that primary treatment for ovarian cancer reduces the inflammatory response. Moreover, patients who have not developed recurrent disease by one year appear to maintain more normalized levels of cortisol and IL-6. Improvement in fatigue and vegetative depression is associated with the normalization of IL-6 and cortisol, a pattern which may be relevant for improvements in overall quality of life for ovarian cancer patients.
doi:10.1016/j.bbi.2012.07.022
PMCID: PMC3697797  PMID: 22884960
ovarian cancer; fatigue; depression; disability; cortisol; IL-6; inflammation
3.  Production traits in F1 and F2 crosses with naturalized hair breed Santa Inês ewes 
SpringerPlus  2014;3:66.
The once bred ewe slaughter method proposes the use of female lamb to produce a lamb and then both are slaughtered, increasing income and high quality meat production. Thus, this study evaluated the growth and reproduction performance of ewe lamb from Santa Inês (SI), a naturalized genetic resource, and their crosses (Dorper x Santa Inês (DOR), Texel x Santa Inês (TEX), Ile de France x Santa Inês (ILE)), as well as the survivability and development of their offspring. The animals were weighed monthly from birth to 12-months age. Samples of milk were collected on approximately 30 days of lactation. The physical-chemical analysis of milk was performed. SI females (2.94 kg) had significantly lower birth weight than DOR (3.80 kg) and TEX (3.87 kg). ILE females had higher weaning weight and weight at 12 months than SI females, which reflected in higher daily weight gain (ADG) (108.46 g/day) than TEX and SI. The pregnancy rates at 12 months were ILE (57.14%), TEX (25%), DOR (50%), and SI (28.57%), with TEX and SI differing of ILE and DOR (p = 0.03). Therefore, in semi-confinement and in a once-bred ewe production system using crossbreeding and allying meat production and reproduction, we recommend the use of Dorper and Ile de France breeds for crossbreeding with Santa Inês females. These results demonstrated the useful of a local genetic resource in productive system aiming a low cost meat production.
doi:10.1186/2193-1801-3-66
PMCID: PMC3921340  PMID: 24555173
Sheep production; Milk; Females; Performance; Fertility; Genetic resource
4.  Benefits of Physical Exercise on Basic Visuo-Motor Functions Across Age 
Motor performance deficits of older adults are due to dysfunction at multiple levels. Age-related differences have been documented on executive functions; motor control becomes more reliant on cognitive control mechanisms, including the engagement of the prefrontal cortex (PFC), possibly compensating for age-related sensorimotor declines. Since at functional level the PFC showed the largest age-related differences during discriminative response task, we wonder whether those effects are mainly due to the cognitive difficulty in stimulus discrimination or they could be also detected in a much easier task. In the present study, we measured the association of physical exercise with the PFC activation and response times (RTs) using a simple response task (SRT), in which the participants were asked to respond as quickly as possible by manual key-press to visual stimuli. Simultaneous behavioral (RTs) and electroencephalographic (EEG) recordings were performed on 84 healthy participants aged 19–86 years. The whole sample was divided into three cohorts (young, middle-aged, and older); each cohort was further divided into two equal sub-cohorts (exercise and not-exercise) based on a self-report questionnaire measuring physical exercise. The EEG signal was segmented in epochs starting 1100 prior to stimulus onset and lasting 2 s. Behavioral results showed age effects, indicating a slowing of RTs with increasing age. The EEG results showed a significant interaction between age and exercise on the activities recorded on the PFC. The results indicates that: (a) the brain of older adults needs the PFC engagement also to perform elementary task, such as the SRT, while this activity is not necessary in younger adults, (b) physical exercise could reduce this age-related reliance on extra cognitive control also during the performance of a SRT, and (c) the activity of the PFC is a sensitive index of the benefits of physical exercise on sensorimotor decline.
doi:10.3389/fnagi.2014.00048
PMCID: PMC3955899  PMID: 24672482
simple response task; response time; event-related potential; prefrontal cortex; lifespan
5.  Aldehyde Dehydrogenase1 Immunohistochemical Staining in Primary Breast Cancer Cells Independently Predicted Overall Survival But Did Not Correlate with the Presence of Circulating or Disseminated Tumors Cells 
Journal of Cancer  2014;5(5):360-367.
Purpose: We hypothesized that aldehyde dehydrogenase 1 (ALDH1) staining in breast cancer tumor cells might be a simple surrogate for the presence of circulating tumor cells (CTCs) or disseminated tumor cells (DTCs).
Experimental Design: Whole tissue primary tumor sections from 121 patients enrolled in a clinical trial assessing CTCs and DTCs at the time of surgery were stained for ALDH1 and scored by a dedicated breast pathologist blinded to outcome. Clinical data was extracted and staining was correlated to clinical variables and outcome by Fisher's exact test, the Log rank test and Cox proportional hazards regression analysis respectively. P < 0.05 was considered significant.
Results: ALDH1 staining in tumor cells was present in 12% of cases (15/121). In univariate analysis, ALDH1 tumor staining predicted worse overall survival (71% vs. 91% at 5 years P = 0.0074) and was an independent predictor on multivariable analysis of worse overall survival, (HR 4.93) after adjusting for stage, ER, grade, LVI, age and neoadjuvant chemotherapy (P = 0.04).
ALDH1 was significantly associated with estrogen receptor (ER) negative (P value = 0.029) primary tumors but not the presence of CTCs or DTCs by multivariate logistic regression. Positive ALDH staining in non-tumor cells of any pattern or morphology was common but did not correlate with CTCs or DTCs, other clinical variables, or outcome.
Conclusion: ALDH1 tumor staining was associated with ER -negative breast cancer and was an independent predictor of OS. However, it did not correlate to putative cancer stem cell surrogates CTCs and/or DTCs.
doi:10.7150/jca.7885
PMCID: PMC4007524  PMID: 24799954
ALDH1; breast cancer; cancer stem cells; circulating tumor cells; disseminated tumor cells; micrometastatic disease.
6.  Getting ready for an emotion: specific premotor brain activities for self-administered emotional pictures 
Emotional perception has been extensively studied, but only a few studies have investigated the brain activity preceding exposure to emotional stimuli, especially when they are triggered by the subject himself. Here, we sought to investigate the emotional expectancy by means of movement related cortical potentials (MRCPs) in a self-paced task, in which the subjects begin the affective experience by pressing a key. In this experiment, participants had to alternatively press two keys to concomitantly display positive, negative, neutral, and scrambled images extracted from the International Affective Pictures System (IAPS). Each key press corresponded to a specific emotional category, and the experimenter communicated the coupling before each trial so that the subjects always knew the valence of the forthcoming picture. The main results of the present study included a bilateral positive activity in prefrontal areas during expectancy of more arousing pictures (positive and negative) and an early and sustained positivity over occipital areas, especially during negative expectancy. In addition, we observed more pronounced and anteriorly distributed Late Positive Potential (LPPs) components in the emotional conditions. In conclusion, these results show that emotional expectancy can influence brain activity in both motor preparation and stimulus perception, suggesting enhanced pre-processing in the to-be-stimulated areas. We propose that before a predictable emotional stimulus, both appetitive and defensive motivational systems act to facilitate the forthcoming processing of survival-relevant contents by means of an enhancement of attention toward more arousing pictures.
doi:10.3389/fnbeh.2014.00197
PMCID: PMC4035832  PMID: 24904344
emotions; expectancy; Movement Related Cortical Potentials (MRCPs); Event Related Potentials (ERPs); Late Positive Potentials (LPPs)
7.  Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients 
Purpose
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response.
Experimental Design
Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined.
Results
Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified.
Conclusion
These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.
doi:10.1158/1078-0432.CCR-12-1177
PMCID: PMC3525747  PMID: 23032743
melanoma; tumor-infiltrating lymphocytes; adoptive cell therapy
8.  Variability in melanoma post-treatment surveillance practices by country and physician specialty: A systematic review 
Melanoma research  2012;22(5):10.1097/CMR.0b013e328357d796.
Background
There are no evidence-based guidelines for surveillance of patients with melanoma following surgical treatment. We performed a systematic review to identify current stage-specific surveillance practices for patients with melanoma by country and physician specialty.
Methods
Three major medical indices, MEDLINE, the Cochrane Library database, and Scopus, were reviewed to identify articles published in January 1970 to October 2011 that included detailed information about surveillance of patients with melanoma after initial surgical treatment. Data on surveillance intervals and recommended evaluation were extracted and categorized by country and, when reported, physician specialty.
Results
One hundred four articles from 10 countries and 4 physician specialties (dermatology, surgical oncology, medical oncology, and general practice) met the inclusion criteria, including 43 providing specific patient-level data. The articles showed wide variation with respect to surveillance intervals and recommended evaluations. Variation was greatest for patients with stage I disease, for whom follow-up frequency ranged from 1 to 6 visits per year during years 1 and 2 after treatment. All 4 physician specialties agreed that for years 1–3, the follow-up frequency should be 4 times per year for all patients. For years 4 and 5, surgical oncologists recommended 2 follow-up visits per year, whereas general practitioners, dermatologists, and medical oncologists recommended 4 visits per year. Recommended imaging and laboratory evaluations were most intense in the United Kingdom and most minimalist in The Netherlands. While general practitioners did not recommend routine laboratory or imaging tests for surveillance, all other specialties utilized both in their surveillance practice. Self skin-examination was recommended for surveillance in all countries and by all practitioner specialties.
Conclusions
There is significant intercountry and interspecialty variation in surveillance of patients with melanoma. As the number of melanoma survivors increases, it will be critical to examine the benefits and costs of various follow-up strategies to establish consensus guidelines for melanoma post-treatment surveillance.
doi:10.1097/CMR.0b013e328357d796
PMCID: PMC3858181  PMID: 22914178
melanoma; post-treatment surveillance; patient care; systematic review
9.  Biology, Treatment, and Outcome in Very Young and Older Women with DCIS 
Annals of surgical oncology  2012;19(12):10.1245/s10434-012-2413-4.
Background
This study examines a modern cohort of women with ductal carcinoma-in-situ (DCIS) in order to identify potential differences in clinical presentation, treatments, and outcome based on age.
Methods
From 1996 to 2009, a total of 2037 patients with pure DCIS were treated. Clinical presentation, pathologic factors, type of surgery and adjuvant therapy, and local recurrence rates among age groups were compared and analyzed. Median follow-up was 5.2 years.
Results
There were 132 patients (6.5 %) aged <40, 1,690 (83 %) aged 40–70, and 215 (10.5 %) aged >70. Younger patients (<40) were significantly more likely to have a family history of breast cancer, present with clinical symptoms, undergo mastectomy with immediate reconstruction, and have a contralateral prophylactic mastectomy (P < 0.05). Older patients (>70) were significantly less likely to use adjuvant radiotherapy and tamoxifen (P <0.05). No significant differences were found in DCIS size, estrogen receptor status, necrosis, or contralateral breast cancer based on age. Among women <40, 29.3 % had evidence of multicentric disease versus 17.7 and 13.3 % in the women aged 40–70 and those >70, respectively (P = 0.004). On multivariate analysis, younger age (<40), larger-size DCIS (≥1.5 cm), and no use of radiotherapy were significant independent predictors of locoregional recurrence. The 5 year rates of local recurrence were 10.1 % in women <40 compared with 3.2 % in older women (P = 0.005).
Conclusions
Younger patients with DCIS more often have multicentric disease, present with clinical findings, and opt for or require mastectomy with immediate reconstruction. Conservative surgery is only appropriate for younger patients if adjuvant radiotherapy is delivered.
doi:10.1245/s10434-012-2413-4
PMCID: PMC3854959  PMID: 22622473
10.  Biologic features and prognosis of ductal carcinoma in situ are not adversely impacted by initial large body mass 
Breast cancer research and treatment  2012;133(3):10.1007/s10549-012-1999-3.
Obesity is associated with adverse biologic features and poor outcome in patients with invasive breast cancer, yet this relationship has not been evaluated in patients with ductal carcinoma in situ (DCIS). From 1996 to 2009, body mass index (BMI) was recorded at initial diagnosis for 1,885 patients with DCIS treated at our institution. Patients were categorized as obese (BMI ≥ 30 kg/m2), overweight (BMI 25 to<30 kg/m2), or of normal weight or underweight (BMI <25 kg/m2). Logistic regression was used to examine associations between BMI and patient, clinical, and pathologic features and treatment. Local–regional recurrence was calculated using the Kaplan–Meier method. All statistical tests were two-sided. Of the 1,885 patients, 514 (27.7%) were obese, 510 (27.5%) were overweight, and 831 (44.8%) were normal/underweight. In multivariate analysis, overweight and obese patients were significantly more likely to be African American (odds ratio [OR], 3.93; 95% confidence interval [CI], 2.66–5.80) or Hispanic (OR, 1.44; CI, 1.02–2.04), be postmenopausal (OR, 1.63; CI, 1.28–2.07), have diabetes (OR, 4.60; CI, 2.60–8.12), have estrogen-receptor-positive DCIS (OR, 1.39; CI, 1.00–192), and present with a radiologic abnormality rather than clinical symptoms (OR, 1.35; CI, 1.01–1.80). At a median follow-up time of 4.96 years (range, 1.0–14.34 years), no significant differences in local recurrence rates were detected based on patients’ initial BMI category. Furthermore, there was no significant difference in risk of recurrence between diabetic patients receiving metformin or not. In conclusion, higher BMI is not associated with adverse biologic features or prognosis in patients with DCIS.
doi:10.1007/s10549-012-1999-3
PMCID: PMC3855009  PMID: 22392043
DCIS; Obesity; Breast cancer; Body mass index; Metformin
11.  The “Taygetis ypthima species group” (Lepidoptera, Nymphalidae, Satyrinae): taxonomy, variation and description of a new species 
ZooKeys  2013;11-29.
A new species of Taygetis Hübner, [1819] (Lepidoptera, Nymphalidae, Satyrinae) from southeastern Brazil is described: Taygetis drogoni sp. n. In addition, T. servius Weymer, 1910 and T. fulginia d’Almeida, 1922 are resurrected from synonymy and a taxonomic discussion on the species T. ypthima Hübner, [1821] and T. rectifascia Weymer, 1907 is provided. A dichotomous key for the species is also provided.
doi:10.3897/zookeys.356.6481
PMCID: PMC3867108  PMID: 24363572
Atlantic Forest; Euptychiina; Neotropical; Pseudodebis; Taygetis rectifascia
12.  Symptoms, CA125 and HE4 for the preoperative prediction of ovarian malignancy in Brazilian women with ovarian masses 
BMC Cancer  2013;13:423.
Background
This manuscript evaluates whether specific symptoms, a symptom index (SI), CA125 and HE4 can help identify women with malignant tumors in the group of women with adnexal masses previously diagnosed with ultrasound.
Methods
This was a cross-sectional study with data collection between January 2010 and January 2012. We invited 176 women with adnexal masses of suspected ovarian origin, attending the hospital of the Department of Obstetrics and Gynecology of the Unicamp School of Medicine. A control group of 150 healthy women was also enrolled. Symptoms were assessed with a questionnaire tested previously. Women with adnexal masses were interviewed before surgery to avoid recall bias. The Ward Agglomerative Method was used to define symptom clusters. Serum measurements of CA125 and HE4 were made. The Risk of Ovarian Malignancy Algorithm (ROMA) was calculated using standard formulae.
Results
Sixty women had ovarian cancer and 116 benign ovarian tumors. Six symptom clusters were formed and three specific symptoms (back pain, leg swelling and able to feel abdominal mass) did not agglomerate. A symptom index (SI) using clusters abdomen, pain and eating was formed. The sensitivity of the SI in discriminating women with malignant from those with benign ovarian tumors was 78.3%, with a specificity of 60.3%. Positive SI was more frequent in women with malignant than in women with benign tumors (OR 5.5; 95% CI 2.7 to 11.3). Elevated CA125 (OR 11.8; 95% CI 5.6 to 24.6) or HE4 (OR 7.6; 95% CI 3.7 to 15.6) or positive ROMA (OR 9.5; 95% CI 4.4 to 20.3) were found in women with malignant tumors compared with women with benign tumors. The AUC-ROC for CA125 was not different from that for HE4 or ROMA. The best specificity and negative predictive values were obtained using CA125 in women with negative SI.
Conclusion
Women diagnosed with an adnexal mass could benefit from a short enquiry about presence, frequency and onset of six symptoms, and CA125 measurements. Primary care physicians can be thereby assisted in deciding as to whether or not reference the woman to often busy, congested specialized oncology centers.
doi:10.1186/1471-2407-13-423
PMCID: PMC3848801  PMID: 24044637
Specific symptoms; Ovarian tumors; CA125; HE4; ROMA; Prediction of malignancy
13.  Invasive Lobular Carcinoma Predicts Micrometastasis in Breast Cancer 
The Journal of surgical research  2012;177(1):93-96.
Background
Invasive lobular carcinomas (ILCs) are almost always estrogen receptor (ER) positive. Most delayed breast cancer recurrences occur in ER positive patients. Disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) have been implicated in recurrence. The study purpose was to determine if DTCs and CTCs are associated with ILCs in stage I-III breast cancer.
Materials and Methods
Clinical stage I-III breast cancer patients consented to participate in an IRB-approved study involving collection of bone marrow and blood at surgery for their primary breast cancer. DTCs were assessed by anti-CK antibody cocktail following cytospin. CTCs were detected using CellSearchTM. CTCs were defined as nucleated cells lacking CD45 but expressing cytokeratin. One or more cells per 5 ml of bone marrow or 7.5 ml of blood was considered positive. Statistical analyses used chi-square and Fischer’s exact tests.
Results
We prospectively enrolled 422 patients, 64 with ILC and 358 with invasive ductal carcinoma (IDC). ER positivity was higher in ILCs (92.2% vs. 66.2%). {P=0.0001} DTCs were identified 43.4% with ILC compared to 28.9% with IDC. {P = 0.03} CTC rates were similar. Either DTCs or CTCs were identified in 75.6% with ILC compared to 51.7% with IDC. {P = 0.002} No correlation was observed between presence of DTCs and CTCs in ILC patients and tumor size, grade, hormone receptor status, stage, lymph node status, or administration of NACT.
Conclusions
ILC independently predicted micrometastatic disease. Since most late recurrences are ER positive, this raises the question of whether DTCs and CTCs are indeed responsible for late breast cancer recurrence.
doi:10.1016/j.jss.2012.03.014
PMCID: PMC3419792  PMID: 22482764
14.  Status of the anaplastic lymphoma kinase (ALK) gene in inflammatory breast carcinoma 
SpringerPlus  2013;2:409.
Background
Although preliminary reports suggest that ALK gene amplification may occur in inflammatory breast cancer (IBC), data are limited. We performed a comprehensive investigation of the status of ALK gene in IBC.
Methods
We used core biopsy (CB) samples from 30 IBC patients for immunohistochemistry (IHC), 25 of these samples for fluorescence in situ hybridization (FISH) of ALK gene rearrangement, 8 for chromosome 2 aneusomy, and 20 microdissected frozen CBs for array comparative genomic hybridization (CGH) and mRNA analysis.
Results
All 30 samples were negative for ALK protein expression by IHC. FISH analysis showed no EML4-ALK gene rearrangement in any samples, although 16 of the 25 samples (64%) contained 3 to 4 extra copies of the ALK gene, and chromosome 2 aneusomy was found in 7 of 8 samples that had extra copies of the ALK gene. Only 3 of the 20 samples showed evidence of mild ALK gene amplification by array CGH. mRNA analysis revealed that mRNA expression of ALK was not significantly higher in these samples compared with samples that showed no evidence of ALK gene amplification in CGH analysis, nor was mRNA expression of ALK significantly different in tumor compared with 5 normal breast samples (P > 0.05, t test).
Conclusion
Our comprehensive evaluation suggests that ALK gene rearrangement did not occur in the IBC patients studied. The significance of our finding of mildly increased copy numbers of the ALK gene resulting from chromosome 2 aneusomy rather than mild amplification of the ALK gene requires further investigation.
doi:10.1186/2193-1801-2-409
PMCID: PMC3797914  PMID: 24156086
15.  Limb immobilization alters functional electrophysiological parameters of sciatic nerve 
Immobilization, used in clinical practice to treat traumatologic problems, causes changes in muscle, but it is not known whether changes also occur in nerves. We investigated the effects of immobilization on excitability and compound action potential (CAP) and the ultrastructure of the rat sciatic nerve. Fourteen days after immobilization of the right leg of adult male Wistar rats (n=34), animals were killed and the right sciatic nerve was dissected and mounted in a moist chamber. Nerves were stimulated at a baseline frequency of 0.2 Hz and tested for 2 min at 20, 50, and 100 Hz. Immobilization altered nerve excitability. Rheobase and chronaxy changed from 3.13±0.05 V and 52.31±1.95 µs (control group, n=13) to 2.84±0.06 V and 59.71±2.79 µs (immobilized group, n=15), respectively. Immobilization altered the amplitude of CAP waves and decreased the conduction velocity of the first CAP wave (from 93.63±7.49 to 79.14±5.59 m/s) but not of the second wave. Transmission electron microscopy showed fragmentation of the myelin sheath of the sciatic nerve of immobilized limbs and degeneration of the axon. In conclusion, we demonstrated that long-lasting leg immobilization can induce alterations in nerve function.
doi:10.1590/1414-431X20132626
PMCID: PMC3854417  PMID: 23969978
Immobilization; Sciatic nerve; Compound action potential; Conduction velocity; Rheobase; Chronaxy
16.  Social Influences on Clinical Outcomes of Patients With Ovarian Cancer  
Journal of Clinical Oncology  2012;30(23):2885-2890.
Purpose
Previous research has demonstrated relationships of social support with disease-related biomarkers in patients with ovarian cancer. However, the clinical relevance of these findings to patient outcomes has not been established. This prospective study examined how social support relates to long-term survival among consecutive patients with ovarian cancer. We focused on two types of social support: social attachment, a type of emotional social support reflecting connections with others, and instrumental social support reflecting the availability of tangible assistance.
Patients and Methods
Patients were prospectively recruited during a presurgical clinic visit and completed surveys before surgery. One hundred sixty-eight patients with histologically confirmed epithelial ovarian cancer were observed from the date of surgery until death or December 2010. Clinical information was obtained from medical records.
Results
In a Cox regression model, adjusting for disease stage, grade, histology, residual disease, and age, greater social attachment was associated with a lower likelihood of death (hazard ratio [HR], 0.87; 95% CI, 0.77 to 0.98; P = .018). The median survival time for patients with low social attachment categorized on a median split of 15 was 3.35 years (95% CI, 2.56 to 4.15 years). In contrast, by study completion, 59% of patients with high social attachment were still alive after 4.70 years. No significant association was found between instrumental social support and survival, even after adjustment for covariates.
Conclusion
Social attachment is associated with a survival advantage for patients with ovarian cancer. Clinical implications include the importance of screening for deficits in the social environment and consideration of support activities during adjuvant treatment.
doi:10.1200/JCO.2011.39.4411
PMCID: PMC3410403  PMID: 22802321
17.  Benefits of Physical Exercise on the Aging Brain: The Role of the Prefrontal Cortex 
Motor planning in older adults likely relies on the overengagement of the prefrontal cortex (PFC) and is associated with slowness of movement and responses. Does a physically active lifestyle counteract the overrecruitment of the PFC during action preparation? This study used high-resolution electroencephalography to measure the effect of physical exercise on the executive functions of the PFC preceding a visuomotor discriminative task. A total of 130 participants aged 15–86 were divided into two groups based on physical exercise participation. The response times and accuracy and the premotor activity of the PFC were separately correlated with age for the two groups. The data were first fit with a linear function and then a higher order polynomial function. We observed that after 35–40 years of age, physically active individuals have faster response times than their less active peers and showed no signs of PFC hyperactivity during motor planning. The present findings show that physical exercise could speed up the response of older people and reveal that also in middle-aged people, moderate-to-high levels of physical exercise benefits the planning/execution of a response and the executive functions mediated by the PFC, counteracting the neural overactivity often observed in the elderly adults.
doi:10.1093/gerona/glt094
PMCID: PMC3805300  PMID: 23833198
Physical exercise; Middle aged; Prefrontal cortex; Movement-related cortical potential.
18.  Inflammatory Breast Cancer: What We Know and What We Need to Learn 
The Oncologist  2012;17(7):891-899.
This article reviews the current status of multidisciplinary care for patients with inflammatory breast cancer. Future avenues of research to advance the care of patients with this disease are also presented.
Purpose.
We review the current status of multidisciplinary care for patients with inflammatory breast cancer (IBC) and discuss what further research is needed to advance the care of patients with this disease.
Design.
We performed a comprehensive review of the English-language literature on IBC through computerized literature searches.
Results.
Significant advances in imaging, including digital mammography, high-resolution ultrasonography with Doppler capabilities, magnetic resonance imaging, and positron emission tomography–computed tomography, have improved the diagnosis and staging of IBC. There are currently no established molecular criteria for distinguishing IBC from noninflammatory breast cancer. Such criteria would be helpful for the diagnosis and development of novel targeted therapies. Combinations of neoadjuvant systemic chemotherapy, surgery, and radiation therapy have led to an improved prognosis; however, the overall 5-year survival rate for patients with IBC remains very low (∼30%). Sentinel lymph node biopsy and skin-sparing mastectomy are not recommended for patients with IBC.
Conclusion.
Optimal management of IBC requires close coordination among medical, surgical, and radiation oncologists, as well as radiologists and pathologists. There is a need to identify molecular changes that define the pathogenesis of IBC to enable eradication of IBC with the use of IBC-specific targeted therapies.
doi:10.1634/theoncologist.2012-0039
PMCID: PMC3399643  PMID: 22584436
Inflammatory breast cancer; Systemic therapy; Targeted therapy
19.  Knee and hip sagittal and transverse plane changes after two fatigue protocols 
Fatigue has been shown to alter the biomechanics of lower extremity during landing tasks. To date, no study has examined the effects of two types of fatigue on kinetics and kinematics.
Objectives
This study was conducted to assess biomechanical differences between two fatigue protocols [Slow Linear Oxidative Fatigue Protocol (SLO-FP) and Functional Agility Short-Term Fatigue Protocol (FAST-FP)].
Design
Single-group repeated measures design.
Methods
Fifteen female collegiate soccer players had to perform five successful trials of unanticipated sidestep cutting (SS) pre- and post-fatigue protocols. The SLO-FP consisted of an initial VO2peak test followed by 5-min rest, and a 30-min interval run. The FAST-FP consisted of 4 sets of a functional circuit. Biomechanical measures of the hip and knee were obtained at different instants while performing SS pre- and post-fatigue. Repeated 2 × 2 ANOVAs were conducted to examine task and fatigue differences. Alpha level set a priori at 0.05.
Results
During the FAST-FP, participants had increased knee internal rotation at initial contact (IC) (12.5 ± 5.9°) when compared to the SLO-FP (7.9 ± 5.4°, p < 0.001). For hip flexion at IC, pre-fatigue had increased angles (36.4 ± 8.4°) compared to post-fatigue (30.4 ± 9.3°, p = 0.003), also greater knee flexion during pre-fatigue (25.6 ± 6.8°) than post-fatigue (22.4 ± 8.4°, p = 0.022).
Conclusion
The results of this study showed that hip and knee mechanics were substantially altered during both fatigue conditions.
doi:10.1016/j.jsams.2011.05.001
PMCID: PMC3591478  PMID: 21636322
Fatigue; SLO-FP; FAST-FP; Biomechanics; Lower extremity
20.  Management of patients with acute coronary syndromes in real-world practice in Italy: an outcome research study focused on the use of ANTithRombotic Agents: the MANTRA registry 
Background:
Although outcomes of acute coronary syndromes (ACS) have greatly improved, bleeding is still an issue. Thus, this study aims to evaluate in-hospital management and outcomes of unselected patients with ACS focusing on antithrombotic therapies and bleeding.
Methods and results:
From 22 April 2009 to 29 December 2010, 6394 consecutive Italian patients were prospectively enrolled and followed for 6 months. Most patients (55.3%) had non-ST-elevation (NSTE) ACS. Of the ST-elevation (STE) ACS patients, 79.8% received reperfusion (mainly mechanical). In-hospital and 6-month unadjusted total mortality rates were 4.2 and 7.8% for STE-ACS and 2.5 and 6.4% for NSTE-ACS, respectively. During hospitalization, TIMI major bleeding rate was 1.2% (1.4% STE-ACS and 1.1% NSTE-ACS, respectively) and TIMI minor bleeding was 3.1%. In-hospital and 6-month unadjusted total mortality rates were 3.1 and 6.7% for patients without bleeding, 1.5 and 8.6% for minor bleeding, and 19.0 and 26.6% for TIMI major bleeding, respectively (p<0.0001). Notably, TIMI major bleeding was one of the strongest predictors of the 6-month composite end point (death or reinfarction) (STE-ACS hazard ratio, HR, 2.86, 95% confidence interval, 95% CI, 1.57−5.23; NSTE-ACS HR, 2.71, 95% CI 1.52−4.80). Predictors of in-hospital TIMI major bleeding were weight (odds ratio, OR, 0.97, 95% CI 0.95−0.99), female gender (OR 1.80, 95% CI 1.09−2.96), history of peripheral vasculopathy (OR 2.95, 95% CI 1.83−4.78), switching anticoagulant therapy (OR 2.62, 95% CI 1.36−5.05), intra-aortic balloon pump implantation (OR 4.44, 95% CI 1.85−10.69), and creatinine ≥2 mg/dl on admission (OR 3.68, 95% CI 1.84−7.33).
Conclusions:
Despite aggressive management, the rate of bleeding remains relatively low in an unselected ACS population. However, major bleeding adversely affects prognosis and physicians should tailor treatments to reduce it.
doi:10.1177/2048872612471213
PMCID: PMC3760574  PMID: 24062931
Acute coronary syndromes; bleeding; outcome research
21.  Evaluation of a Breast Cancer Nomogram for Predicting Risk of Ipsilateral Breast Tumor Recurrences in Patients With Ductal Carcinoma in Situ After Local Excision 
Journal of Clinical Oncology  2012;30(6):600-607.
Purpose
Prediction of patients at highest risk for ipsilateral breast tumor recurrence (IBTR) after local excision of ductal carcinoma in situ (DCIS) remains a clinical concern. The aim of our study was to evaluate a published nomogram from Memorial Sloan-Kettering Cancer Center to predict for risk of IBTR in patients with DCIS from our institution.
Patients and Methods
We retrospectively identified 794 patients with a diagnosis of DCIS who had undergone local excision from 1990 through 2007 at the MD Anderson Cancer Center (MDACC). Clinicopathologic factors and the performance of the Memorial Sloan-Kettering Cancer Center nomogram for prediction of IBTR were assessed for 734 patients who had complete data.
Results
There was a marked difference with respect to tumor grade, prevalence of necrosis, initial presentation, final margins, and receipt of endocrine therapy between the two cohorts. The biggest difference was that more patients received radiation in the MDACC cohort (75% at MDACC v 49% at MSKCC; P < .001). Follow-up time in the MDACC cohort was longer than in the MSKCC cohort (median 7.1 years v 5.6 years), and the recurrence rate was lower in the MDACC cohort (7.9% v 11%). The median 5-year probability of recurrence was 5%, and the median 10-year probability of recurrence was 7%. The nomogram for prediction of 5- and 10-year IBTR probabilities demonstrated imperfect calibration and discrimination, with a concordance index of 0.63.
Conclusion
Predictive models for IBTR in patients with DCIS who were treated with local excision are imperfect. Our current ability to accurately predict recurrence on the basis of clinical parameters alone is limited.
doi:10.1200/JCO.2011.36.4976
PMCID: PMC3295558  PMID: 22253459
22.  Expression of Epithelial-Mesenchymal Transition-Inducing Transcription Factors in Primary Breast Cancer: The Effect of Neoadjuvant Therapy 
Epithelial cancer cells are likely to undergo epithelial mesenchymal transition (EMT) prior to entering the peripheral circulation. By undergoing EMT, circulating tumor cells (CTCs) lose epithelial markers and may escape detection by conventional methods. Therefore, we conducted a pilot study to investigate mRNA transcripts of EMT-inducing transcription factors (TFs) in tumor cells from the peripheral blood (PB) of primary breast cancer (PBC) patients.
Peripheral blood mononuclear cells were isolated from 52 stages I–III PBC patients and 30 healthy donors (HD) and sequentially depleted of EpCAM+ cells and CD45+ leukocytes, henceforth referred to as CD45−. The expression levels of EMT-inducing TFs (TWIST1, SNAIL1, SLUG, ZEB1, and FOXC2) in the CD45− cells were determined using qRT-PCR. The highest level of expression by the CD45− cell fraction of HD was used as “cut off” to determine if samples from PBC patients overexpressed any EMT-inducing TFs. In total, 15.4% of PBC patients overexpressed at least one of the EMT-inducing TF transcripts. Overexpression of any EMT-inducing TF transcripts was more likely to be detected in PBC patients who received neoadjuvant therapies (NAT) than patients who received no NAT (P = 0.003). Concurrently, CTCs were detected in 7 out of 38 (18.4%) patients by CellSearch® and 15 out of 42 (35.7%) patients by AdnaTest™. There was no association between the presence of CTCs measured by CellSearch® or AdnaTest™.
In summary, our results demonstrate that CTCs with EMT phenotype may occur in the peripheral circulation of PBC patients and NAT is unable to eliminate CTCs undergoing EMT.
doi:10.1002/ijc.26037
PMCID: PMC3169728  PMID: 21387303
circulating tumor cells; epithelial-mesenchymal transition; primary breast cancer; neoadjuvant therapy
23.  The Effects of Aging on Conflict Detection 
PLoS ONE  2013;8(2):e56566.
Several cognitive changes characterize normal aging; one change regards inhibitory processing and includes both conflict monitoring and response suppression. We attempted to segregate these two aspects within a Go/No-go task, investigating three age categories. Accuracy, response times and event-related potentials (ERPs) were recorded. The ERP data were analyzed, and the Go and No-go trials were separated; in addition, the trials were organized in repeat trials (in which the subjects repeated the action delivered in the previous trial) and switch trials (in which the subjects produced a response opposite to the previous response). We assumed that the switch trials conveyed more conflict than the repeat trials. In general, the behavioral data and slower P3 latencies confirmed the well-known age-related speed/accuracy trade-off. The novel analyses of the repeat vs. switch trials indicated that the age-related P3 slowing was significant only for the high conflict condition; the switch-P3 amplitude increased only in the two older groups. The ‘aging switch effect’ on the P3 component suggests a failure in the conflict conditions and likely contributes to a generalized dysfunction. The absence of either a switch effect in the young group and the P3 slowing in middle-aged group indicate that switching was not particularly demanding for these participants. The N2 component was less sensitive to the repeat/switch manipulation; however, the subtractive waves also enhanced the age effects in this earlier time window. The topographic maps showed other notable age effects: the frontal No-go N2 was nearly undetectable in the elderly; in the identical time window, a large activity in the posterior and prefrontal scalp regions was observed. Moreover, the prefrontal activity showed a negative correlation with false alarms. These results suggest that the frontal involvement during action suppression becomes progressively dysfunctional with aging, and additional activity was required to reach a good level of accuracy.
doi:10.1371/journal.pone.0056566
PMCID: PMC3572012  PMID: 23418584
24.  Two Different Fatigue Protocols and Lower Extremity Motion Patterns During a Stop-Jump Task 
Journal of Athletic Training  2012;47(1):32-41.
Context:
Altered neuromuscular control strategies during fatigue probably contribute to the increased incidence of non-contact anterior cruciate ligament injuries in female athletes.
Objective:
To determine biomechanical differences between 2 fatigue protocols (slow linear oxidative fatigue protocol [SLO-FP] and functional agility short-term fatigue protocol [FAST-FP]) when performing a running-stop-jump task.
Design:
Controlled laboratory study.
Setting:
Laboratory.
Patients or Other Participants:
A convenience sample of 15 female soccer players (age = 19.2 ±0.8 years, height = 1.67±0.05m, mass = 61.7 + 8.1 kg) without injury participated.
Intervention(s):
Five successful trials of a running–stop-jump task were obtained prefatigue and postfatigue during the 2 protocols. For the SLO-FP, a peak oxygen consumption (V˙o2peak) test was conducted before the fatigue protocol. Five minutes after the conclusion of the V˙o2peak test, participants started the fatigue protocol by performing a 30-minute interval run. The FAST-FP consisted of 4 sets of a functional circuit. Repeated 2 (fatigue protocol) × 2 (time) analyses of variance were conducted to assess differences between the 2 protocols and time (prefatigue, postfatigue).
Main Outcome Measure(s):
Kinematic and kinetic measures of the hip and knee were obtained at different times while participants performed both protocols during prefatigue and postfatigue.
Results:
Internal adduction moment at initial contact (IC) was greater during FAST-FP (0.064 ±0.09 Nm/kgm) than SLO-FP (0.024±0.06 Nm/kgm) (F1,14 = 5.610, P=.03). At IC, participants had less hip flexion postfatigue (44.7°±8.1°) than prefatigue (50.1°±9.5°) (F1,14 = 16.229, P=.001). At peak vertical ground reaction force, participants had less hip flexion postfatigue (44.7°±8.4°) than prefatigue (50.4°±10.3°) (F1,14 = 17.026, P=.001). At peak vertical ground reaction force, participants had less knee flexion postfatigue (−35.9°±6.5°) than prefatigue (−38.8°±5.03°) (F1,14 = 11.537, P=.001).
Conclusions:
Our results demonstrated a more erect landing posture due to a decrease in hip and knee flexion angles in the postfatigue condition. The changes were similar between protocols; however, the FAST-FP was a clinically applicable 5-minute protocol, whereas the SLO-FP lasted approximately 45 minutes.
PMCID: PMC3418112  PMID: 22488228
anterior cruciate ligament; hip; knee; biomechanics
25.  Time, Self, and Intertemporal Choice 
Neuroscientific studies of intertemporal choice (IC) have focused mainly on the neural representation of self-control mechanisms and valuation. This reflects what has been considered as the core of the IC phenomenon. The claim of this paper is that deviations from exponential reward discounting as a function of time might be fully accounted for by the deviation of subjective time from calendar time. This claim is based on evidence that specificities of time perception can modulate discounting. Consequently, time perception is fundamental to IC and it is crucial to understand the mechanisms underlying time processing in different situations; to investigate when human time perception differs from time as represented by the calendar metric system; and to study how time perception predicts choices. This paper surveys the recent literature on time perception in order to discuss the measuring of IC through time-perception specificities. The notion of self is also discussed within this temporal perspective. If time perception modulates discounting, and time perception is related to self, the relationship between self and time perception becomes a new path to be explored in the IC studies.
doi:10.3389/fnins.2013.00040
PMCID: PMC3664308  PMID: 23750125
human time perception; discounting; self-referential processing

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