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Papers by Alejandro Contreras

Echocardiography-a Journal of Cardiovascular Ultrasound and Allied Techniques, 2010

(Echocardiography 2010;27:95-96)

Echocardiography, 2010

A 52-year-old man was referred to our hospital to be evaluated for a heart transplant. He had a h... more A 52-year-old man was referred to our hospital to be evaluated for a heart transplant. He had a history of multiple admissions due to heart failure. His physical examination revealed: jugular distension, hepatomegaly, and peripheral edema. The electrocardiogram showed sinus rhythm with right axis deviation. A chest x-ray revealed cardiomegaly. Transthoracic echocardiography showed an aneurysmal dilatation of the right atrial appendage (RAA) with intracavity thrombus . The right ventricular ejection fraction was impaired, with moderate tricuspid regurgitation, and pulmonary hypertension. A nuclear resonance image confirmed a giant appendage aneurysm with the intracavity thrombus and right ventricular dysfunction (Figs. 2 and 3). A 64-slice multidetector computed tomography ruled out chronic pulmonary Figure 1. Four-chamber echocardiography: RA = right atrial; RV = right ventricle.

Congenital Heart Disease, 2013

ABSTRACT A 2-year-old boy was referred for evaluation of a systolic heart murmur. Two-dimensional... more ABSTRACT A 2-year-old boy was referred for evaluation of a systolic heart murmur. Two-dimensional Doppler echocardiogram showed an abnormal flow through the interventricular septum, directed upward and toward the posterior wall of the main pulmonary artery. Left coronary angiogram showed a normal distribution of the anterior descending and circumflex arteries. The right coronary artery (RCA) was fully filled through collaterals from the left coronary system, and arising from the main pulmonary artery. Successful surgical reimplantation of the RCA was undertaken. Although uncommon, it is important to recognize the anomalous origin of the RCA arising from the pulmonary artery since it can be associated with serious adverse cardiac events.

Catheterization and Cardiovascular Interventions, 2014

Objectives: To evaluate the feasibility, safety, and efficacy of implantation of the new Nit Occl... more Objectives: To evaluate the feasibility, safety, and efficacy of implantation of the new Nit Occlud ASD-RV R (NOASD-R) device for percutaneous closure of ostium secundum atrial septal defects (ASD-OS). Background: Device catheter implantation has become the method of choice for most patients with ASD-OS. No single device has proven to be ideal for this type of procedure. The NOASD-R has a distinct design that may help to overcome limitations of other devices. Methods: A prospective, single arm, observational study including all consecutive patients receiving the NOASD-R device for ASD-OS closure between October 2011 and September 2013 was performed. Patient selection, device design, deployment technique, complications, and procedural outcomes were evaluated. Results: Seventy-four patients underwent attempted transcatheter ASD-OS closure using the NOASD-R device. Implantation of the occluder was successful in 73 patients (98.6%). The majority of patients were female (79.5%) with a median age of 17.2 years (range: 2-74). A 2-D transthoracic color-Doppler echocardiogram (TTE) obtained at the 3 or 6 month follow-up visit showed complete occlusion of the ASD-OS in 72/73 patients (98.6%). At a mean follow-up interval of 11.4 6 6.8 months there have been no episodes of late device embolization, cardiac perforation or erosion, endocarditis, thromboembolism, wire fracture, embolic neurologic events, or death. Conclusions: We report the first worldwide clinical experience using the NOASD-R device for ASD-OS closure. The procedure was feasible, with a high rate of successful implantations, and safe. High ASD-OS closure rates and no complications were encountered during short-term follow-up. V C 2014 Wiley Periodicals, Inc.

International Journal of Gynecological Pathology, 2009

Mature cystic teratoma of the ovary is the most common ovarian tumor. Malignant transformation of... more Mature cystic teratoma of the ovary is the most common ovarian tumor. Malignant transformation of this neoplasm is rare and is mostly represented by squamous carcinoma. Less frequently, malignant transformation is represented by a sarcoma. To date, only 5 cases of angiosarcoma arising in a mature cystic teratoma of the ovary have been reported. Herein, we report the clinicopathologic features of one such case. A review of the literature is also presented.

American Journal of Surgical Pathology, 2009

The development of sarcomatous component (SC) in testicular germ cell tumor (GCT) is an uncommon ... more The development of sarcomatous component (SC) in testicular germ cell tumor (GCT) is an uncommon phenomenon. We searched our surgical pathology files from 1985 to 2007 and identified 33 cases of testicular GCTs with SC. The average age of patients was 31 years. All patients underwent radical orchiectomy, which demonstrated a GCT in all patients except for 3 patients who had received neoadjuvant chemotherapy. All testicular GCTs contained a teratomatous component. The GCTs were pure teratomas in 3 cases, and were mixed GCTs in the other cases. The SC was observed in primary testicular tumor (n=19), in metastasis (n=11), or in both primary testicular tumor and metastasis (n=3). The average percentage of the SC in the primary testicular GCT was 32% (range: 5% to 99%). The most common histologic type of SC was rhabdomyosarcoma (n=24), followed by high-grade unclassified sarcoma (n=5), rhabdomyosarcoma admixed with high-grade unclassified sarcoma (n=2), angiosarcoma (n=1), and low-grade myxoid sarcoma (n=1). Clinical follow-up information was available for 27 patients. Of the 13 patients whose SC was limited to the testicular GCT, 2 patients died of GCT not otherwise specified at 37 and 68 months, respectively; and 11 patients were free of disease at a mean of 46 months. Of the 14 patients with a SC in the metastasis, 7 patients died of GCT not otherwise specified at a mean of 95 months, and 7 patients were free of disease at a mean of 104 months. These results suggest that patients with a SC confined to the primary testicular GCT may not have a higher risk of mortality than those at a comparable stage without a SC. However, patients with a SC in the metastasis have an increased risk of mortality.

2012 9th International Conference on the European Energy Market, 2012

ABSTRACT Modeling competition in the future European Electricity Market (EEM) suggests considerin... more ABSTRACT Modeling competition in the future European Electricity Market (EEM) suggests considering new perspectives of leadership between the participant generators, being this crucial for market concentration or competitiveness analyses. EEM models should be able to represent the possible existence of leaders and followers and Conjectural Stackelberg equilibriums is a powerful approach to do so. These asymmetric equilibriums can represent several types of competitive advantages though generally assume a single-leader-follower game. In addition, their complex resolution methodologies sometimes compromise the applicability, especially if large-scale problems have to be solved. In this paper, a multi-leader-follower conjectural Stackelberg equilibrium model is presented. An easy convex quadratic optimization problem is proposed for its resolution, describing the equilibrium existence conditions. A simple case study is presented to validate the model, and to easily analyze how the market competition changes with the number of leaders or followers. The main conclusion is that if leadership spreads, the policy recommendation of EEM regulators seems to encourage the number of followers, though to a maximum threshold if this type of asymmetric models will be used.

Pathology Case Reviews, 2007

... Contreras, Alejandro Luiña MD; Rossi, Christopher MD; Schwartz, Arnold M. MD, PhD. ... Reprin... more ... Contreras, Alejandro Luiña MD; Rossi, Christopher MD; Schwartz, Arnold M. MD, PhD. ... Reprints: Alejandro Luiña Contreras, MD, Department of Pathology, George Washington University Medical Center, 2300 I Street, NW, Ross Hall, Suite 502, Washington, DC 20037. ...

Human Pathology, 2010

The development of an angiosarcomatous component in germ cell tumors is rare. Here we studied 12 ... more The development of an angiosarcomatous component in germ cell tumors is rare. Here we studied 12 cases of mediastinal germ cell tumors with an angiosarcomatous component. All patients were men with a mean age of 34 years (range, 24-49 years). No patient had a documented testicular germ cell tumor. The mean size of mediastinal tumors was 12.9 cm (range, 5.5-16.0 cm). Grossly, the tumors were cystic with variegated hemorrhagic, mucinous, and fleshy solid areas. Microscopically, all tumors were composed of germ cell tumor. The most common germ cell tumor component was teratoma (n = 10); and other germ cell tumor components included seminoma (n = 3), yolk sac tumor (n = 3), embryonal carcinoma (n = 2), and choriocarcinoma (n = 1). The angiosarcomatous component was present in primary mediastinal tumors (n = 6), metastasis (n = 3), or both primary mediastinal tumor and metastasis (n = 3). The angiosarcomatous component accounted for an average of 30% (range, 5%-95%) of the primary mediastinal tumor. In addition, other non–germ cell components, including rhabdomyosarcoma (n = 3), leiomyosarcoma (n = 1), and poorly differentiated carcinoma (n = 1), were also present in the tumors. Of the 10 patients with follow-up available, all patients developed metastasis (n = 8) or local recurrence (n = 2); 7 died of disease at a mean of 33 months (range, 21-75 months), and 3 patients were alive at a mean of 75 months (range, 5-120 months). Our findings suggest that the presence of an angiosarcomatous component in mediastinal germ cell tumor, even in a small amount, is associated with a poor clinical outcome.

The Journal of biological chemistry, Jan 28, 2005

In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the norm... more In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the normal mammary gland does not occur in the steroid-receptor positive cells but rather in adjacent cells via paracrine signaling involving several local growth factors. To help elucidate the mechanisms involved in the block in proliferation in hormone-receptor positive cells, we have utilized a CCAAT/enhancer binding protein (C/EBP␤)-null mouse model.

Human breast cancers that are estrogen receptor (ER) negative convey a poor prognosis for patient... more Human breast cancers that are estrogen receptor (ER) negative convey a poor prognosis for patient survival. A mouse model that mimics essential biological and genetic attributes of a subset of human breast cancer is the BALB/c p53-null mammary epithelium, in which deletion of the tumor suppressor gene p53 results in enhanced tumorigenic risk. The experiments reported herein examine the hormone dependence of premalignant mammary progression in this model. The p53-null normal mammary epithelium exhibits the same dependence as p53 wild-type mammary epithelium on ovarian hormones for growth. However, in contrast to p53 wild-type epithelium, estrogen and progesterone, singly or in combination, strongly enhance tumorigenesis in p53-null mammary epithelium. The removal of progesterone signaling by deletion of the progesterone receptor eliminates progesterone enhancement of tumorigenesis. The immortalized premalignant outgrowth lines, termed PN, possess different tumorigenic capabilities, but the majority of these lines showed a strong dependence on ovarian hormones for growth and tumorigenesis. Although these lines are highly ER positive, a large number of tumors arising from these lines were ER negative and grew when implanted in ovariectomized mice. As was the case for p53-null normal mammary cells, hormonal stimulation was a strong promoter for tumorigenesis in the premalignant outgrowth lines and, surprisingly, was much stronger than the chemical carcinogen 7,12dimethylbenzanthracene. In summary, these results demonstrate that p53-null mammary cells, which generate a significant percentage of ERnegative tumors, are highly responsive to the absence or presence of ovarian hormones during the normal and premalignant stages. This model would appear an excellent one to test the effects of chemopreventive agents on the development of both ER-negative and ER-positive mammary tumors. TX 77030. 3 The abbreviations used are: MMTV, murine mammary tumor virus; DCIS, ductal carcinoma in situ; DMBA, 7,12-dimethylbenzanthracene; ER, estrogen receptor; PR, progesterone receptor; PRKO, progesterone receptor knockout; TE 50 , time for 50% of the transplants to develop tumors.

Proceedings of The National Academy of Sciences, 2006

PINC is a large, alternatively spliced, developmentally regulated, noncoding RNA expressed in the... more PINC is a large, alternatively spliced, developmentally regulated, noncoding RNA expressed in the regressed terminal ductal lobular unit-like structures of the parous mammary gland. Previous studies have shown that this population of cells possesses not only progenitor-like qualities (the ability to proliferate and repopulate a mammary gland) and the ability to survive developmentally programmed cell death but also the inhibition of carcinogen-induced proliferation. Here we report that PINC expression is temporally and spatially regulated in response to developmental stimuli in vivo and that PINC RNA is localized to distinct foci in either the nucleus or the cytoplasm in a cell-cycle-specific manner. Loss-of-function experiments suggest that PINC performs dual roles in cell survival and regulation of cell-cycle progression, suggesting that PINC may contribute to the developmentally mediated changes previously observed in the terminal ductal lobular unit-like structures of the parous gland. This is one of the first reports describing the functional properties of a large, developmentally regulated, mammalian, noncoding RNA. parity | terminal ductal lobular unit

The Journal of surgical research, 2013

Microdissection and differential display PCR were used to identify genes preferentially expressed... more Microdissection and differential display PCR were used to identify genes preferentially expressed in the highly proliferative terminal end buds (TEBs) in the mammary gland of 45-day-old virgin rats. One clone exhibited 87% homology to the human p190-B gene encoding a novel Rho-Gap. Using in situ hybridization, p190-B was detected in both the TEBs and the terminal ducts, with the highest expression observed in the outer layer of TEBs. During normal mammary gland development, p190-B mRNA expression was highest in the virgin mammary gland and decreased during late pregnancy and lactation. Interestingly, increased levels of p190-B mRNA relative to the normal mammary gland were seen in a subset of murine mammary tumors that appeared to be less well differentiated and potentially more aggressive. Transient transfection of a p190-B expression construct into MCF-10A human mammary epithelial cells resulted in disruption of the actin cytoskeleton, which suggests a role for p190-B in regulating the signaling pathways that influence cell migration and invasion. These results suggest that p190-B may be required for virgin mammary gland development, and its aberrant expression may occur in breast cancer.

Faseb Journal, 2006

Maspin is a tumor-suppressor serpin (serine protease inhibitor), which inhibits cell invasion and... more Maspin is a tumor-suppressor serpin (serine protease inhibitor), which inhibits cell invasion and migration. Here, we analyzed maspin function in cell adhesion in nontransformed mammary epithelial cells and investigated the underlying mechanism involved in this process. We report that maspin acts in the early steps in the cell adhesion process. Addition of recombinant maspin rapidly increased MCF-10A cell adhesion to the endogenously deposited matrix, and conversely both an antimaspin antibody (Ab) and maspin knockdown by RNA interference resulted in decreased cell adhesion. Mutation analyses revealed that a region of 86 amino acids located between aa 139 and aa 225 was responsible for maspin effect on adhesion. In addition, we show that maspin is associated with detergent-insoluble cortical cytoskeleton elements. Collectively, these results suggest that maspin is part of the supramolecular structure of the adhesion plaque and it modulates cell adhesion via a ␤1 integrindependent mechanism.-Cella, N., Contreras, A., Latha, K., Rosen, J. M., and Zhang, M. Maspin is physically and functionally associated with ␤1 integrin regulating cell adhesion in mammary epithelial cells. FASEB J. 20, E721-E731 (2006)

Journal of Cell Biology, 2002

o develop an inducible and progressive model of mammary gland tumorigenesis, transgenic mice were... more o develop an inducible and progressive model of mammary gland tumorigenesis, transgenic mice were generated with a mouse mammary tumor virus-long terminal repeat-driven, conditional, fibroblast growth factor (FGF)-independent FGF receptor (FGFR)1 (iFGFR1) that can be induced to dimerize with the drug AP20187. Treatment of transgenic mice with AP20187 resulted in iFGFR1 tyrosine phosphorylation, increased proliferation, activation of mitogen-activated protein kinase and Akt, and lateral budding. Lateral buds appeared as early as 3 d after T AP20187 treatment and initially consisted of bilayered epithelial cells and displayed apical and basolateral polarity appeared after 13 d of AP20187 treatment. Invasive lesions characterized by multicell-layered lateral buds, decreased myoepithelium, increased vascular branching, and loss of cell polarity were observed after 2-4 wk of treatment. These data indicate that acute iFGFR1 signaling results in increased lateral budding of the mammary ductal epithelium, and that sustained activation induces alveolar hyperplasia and invasive lesions.

Molecular Cell, 2006

Two key components of mammalian heterochromatin that play a structural role in higher order chrom... more Two key components of mammalian heterochromatin that play a structural role in higher order chromatin organization are the heterochromatin protein 1α (HP1α) and the linker histone H1. Here, we show that these proteins interact in vivo and in vitro through their hinge and C-terminal domains, respectively. The phosphorylation of H1 by CDK2, which is required for efficient cell cycle progression, disrupts this interaction. We propose that phosphorylation of H1 provides a signal for the disassembly of higher order chromatin structures during interphase, independent of histone H3-lysine 9 (H3-K9) methylation, by reducing the affinity of HP1α for heterochromatin.

Molecular and Cellular Biology, 2003

The linker histone H1 is involved in maintaining higher-order chromatin structures and displays d... more The linker histone H1 is involved in maintaining higher-order chromatin structures and displays dynamic nuclear mobility, which may be regulated by posttranslational modifications. To analyze the effect of H1 tail phosphorylation on the modulation of the histone's nuclear dynamics, we generated a mutant histone H1, referred to as M1-5, in which the five cyclin-dependent kinase phosphorylation consensus sites were mutated from serine or threonine residues into alanines. Cyclin E/CDK2 or cyclin A/CDK2 cannot phosphorylate the mutant in vitro. Using the technique of fluorescence recovery after photobleaching, we observed that the mobility of a green fluorescent protein (GFP)-M1-5 fusion protein is decreased compared to that of a GFP-wild-type H1 fusion protein. In addition, recovery of H1 correlated with CDK2 activity, as GFP-H1 mobility was decreased in cells with low CDK2 activity. Blocking the activity of CDK2 by p21 expression decreased the mobility of GFP-H1 but not that of GFP-M1-5. Finally, the level and rate of recovery of cyan fluorescent protein (CFP)-M1-5 were lower than those of CFP-H1 specifically in heterochromatic regions. These data suggest that CDK2 phosphorylates histone H1 in vivo, resulting in a more open chromatin structure by destabilizing H1-chromatin interactions.

The Journal of biological chemistry, Jan 28, 2005

In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the norm... more In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the normal mammary gland does not occur in the steroid-receptor positive cells but rather in adjacent cells via paracrine signaling involving several local growth factors. To help elucidate the mechanisms involved in the block in proliferation in hormone-receptor positive cells, we have utilized a CCAAT/enhancer binding protein (C/EBP␤)-null mouse model.

Human breast cancers that are estrogen receptor (ER) negative convey a poor prognosis for patient... more Human breast cancers that are estrogen receptor (ER) negative convey a poor prognosis for patient survival. A mouse model that mimics essential biological and genetic attributes of a subset of human breast cancer is the BALB/c p53-null mammary epithelium, in which deletion of the tumor suppressor gene p53 results in enhanced tumorigenic risk. The experiments reported herein examine the hormone dependence of premalignant mammary progression in this model. The p53-null normal mammary epithelium exhibits the same dependence as p53 wild-type mammary epithelium on ovarian hormones for growth. However, in contrast to p53 wild-type epithelium, estrogen and progesterone, singly or in combination, strongly enhance tumorigenesis in p53-null mammary epithelium. The removal of progesterone signaling by deletion of the progesterone receptor eliminates progesterone enhancement of tumorigenesis. The immortalized premalignant outgrowth lines, termed PN, possess different tumorigenic capabilities, but the majority of these lines showed a strong dependence on ovarian hormones for growth and tumorigenesis. Although these lines are highly ER positive, a large number of tumors arising from these lines were ER negative and grew when implanted in ovariectomized mice. As was the case for p53-null normal mammary cells, hormonal stimulation was a strong promoter for tumorigenesis in the premalignant outgrowth lines and, surprisingly, was much stronger than the chemical carcinogen 7,12dimethylbenzanthracene. In summary, these results demonstrate that p53-null mammary cells, which generate a significant percentage of ERnegative tumors, are highly responsive to the absence or presence of ovarian hormones during the normal and premalignant stages. This model would appear an excellent one to test the effects of chemopreventive agents on the development of both ER-negative and ER-positive mammary tumors. TX 77030. 3 The abbreviations used are: MMTV, murine mammary tumor virus; DCIS, ductal carcinoma in situ; DMBA, 7,12-dimethylbenzanthracene; ER, estrogen receptor; PR, progesterone receptor; PRKO, progesterone receptor knockout; TE 50 , time for 50% of the transplants to develop tumors.

Echocardiography-a Journal of Cardiovascular Ultrasound and Allied Techniques, 2010

(Echocardiography 2010;27:95-96)

Echocardiography, 2010

A 52-year-old man was referred to our hospital to be evaluated for a heart transplant. He had a h... more A 52-year-old man was referred to our hospital to be evaluated for a heart transplant. He had a history of multiple admissions due to heart failure. His physical examination revealed: jugular distension, hepatomegaly, and peripheral edema. The electrocardiogram showed sinus rhythm with right axis deviation. A chest x-ray revealed cardiomegaly. Transthoracic echocardiography showed an aneurysmal dilatation of the right atrial appendage (RAA) with intracavity thrombus . The right ventricular ejection fraction was impaired, with moderate tricuspid regurgitation, and pulmonary hypertension. A nuclear resonance image confirmed a giant appendage aneurysm with the intracavity thrombus and right ventricular dysfunction (Figs. 2 and 3). A 64-slice multidetector computed tomography ruled out chronic pulmonary Figure 1. Four-chamber echocardiography: RA = right atrial; RV = right ventricle.

Congenital Heart Disease, 2013

ABSTRACT A 2-year-old boy was referred for evaluation of a systolic heart murmur. Two-dimensional... more ABSTRACT A 2-year-old boy was referred for evaluation of a systolic heart murmur. Two-dimensional Doppler echocardiogram showed an abnormal flow through the interventricular septum, directed upward and toward the posterior wall of the main pulmonary artery. Left coronary angiogram showed a normal distribution of the anterior descending and circumflex arteries. The right coronary artery (RCA) was fully filled through collaterals from the left coronary system, and arising from the main pulmonary artery. Successful surgical reimplantation of the RCA was undertaken. Although uncommon, it is important to recognize the anomalous origin of the RCA arising from the pulmonary artery since it can be associated with serious adverse cardiac events.

Catheterization and Cardiovascular Interventions, 2014

Objectives: To evaluate the feasibility, safety, and efficacy of implantation of the new Nit Occl... more Objectives: To evaluate the feasibility, safety, and efficacy of implantation of the new Nit Occlud ASD-RV R (NOASD-R) device for percutaneous closure of ostium secundum atrial septal defects (ASD-OS). Background: Device catheter implantation has become the method of choice for most patients with ASD-OS. No single device has proven to be ideal for this type of procedure. The NOASD-R has a distinct design that may help to overcome limitations of other devices. Methods: A prospective, single arm, observational study including all consecutive patients receiving the NOASD-R device for ASD-OS closure between October 2011 and September 2013 was performed. Patient selection, device design, deployment technique, complications, and procedural outcomes were evaluated. Results: Seventy-four patients underwent attempted transcatheter ASD-OS closure using the NOASD-R device. Implantation of the occluder was successful in 73 patients (98.6%). The majority of patients were female (79.5%) with a median age of 17.2 years (range: 2-74). A 2-D transthoracic color-Doppler echocardiogram (TTE) obtained at the 3 or 6 month follow-up visit showed complete occlusion of the ASD-OS in 72/73 patients (98.6%). At a mean follow-up interval of 11.4 6 6.8 months there have been no episodes of late device embolization, cardiac perforation or erosion, endocarditis, thromboembolism, wire fracture, embolic neurologic events, or death. Conclusions: We report the first worldwide clinical experience using the NOASD-R device for ASD-OS closure. The procedure was feasible, with a high rate of successful implantations, and safe. High ASD-OS closure rates and no complications were encountered during short-term follow-up. V C 2014 Wiley Periodicals, Inc.

International Journal of Gynecological Pathology, 2009

Mature cystic teratoma of the ovary is the most common ovarian tumor. Malignant transformation of... more Mature cystic teratoma of the ovary is the most common ovarian tumor. Malignant transformation of this neoplasm is rare and is mostly represented by squamous carcinoma. Less frequently, malignant transformation is represented by a sarcoma. To date, only 5 cases of angiosarcoma arising in a mature cystic teratoma of the ovary have been reported. Herein, we report the clinicopathologic features of one such case. A review of the literature is also presented.

American Journal of Surgical Pathology, 2009

The development of sarcomatous component (SC) in testicular germ cell tumor (GCT) is an uncommon ... more The development of sarcomatous component (SC) in testicular germ cell tumor (GCT) is an uncommon phenomenon. We searched our surgical pathology files from 1985 to 2007 and identified 33 cases of testicular GCTs with SC. The average age of patients was 31 years. All patients underwent radical orchiectomy, which demonstrated a GCT in all patients except for 3 patients who had received neoadjuvant chemotherapy. All testicular GCTs contained a teratomatous component. The GCTs were pure teratomas in 3 cases, and were mixed GCTs in the other cases. The SC was observed in primary testicular tumor (n=19), in metastasis (n=11), or in both primary testicular tumor and metastasis (n=3). The average percentage of the SC in the primary testicular GCT was 32% (range: 5% to 99%). The most common histologic type of SC was rhabdomyosarcoma (n=24), followed by high-grade unclassified sarcoma (n=5), rhabdomyosarcoma admixed with high-grade unclassified sarcoma (n=2), angiosarcoma (n=1), and low-grade myxoid sarcoma (n=1). Clinical follow-up information was available for 27 patients. Of the 13 patients whose SC was limited to the testicular GCT, 2 patients died of GCT not otherwise specified at 37 and 68 months, respectively; and 11 patients were free of disease at a mean of 46 months. Of the 14 patients with a SC in the metastasis, 7 patients died of GCT not otherwise specified at a mean of 95 months, and 7 patients were free of disease at a mean of 104 months. These results suggest that patients with a SC confined to the primary testicular GCT may not have a higher risk of mortality than those at a comparable stage without a SC. However, patients with a SC in the metastasis have an increased risk of mortality.

2012 9th International Conference on the European Energy Market, 2012

ABSTRACT Modeling competition in the future European Electricity Market (EEM) suggests considerin... more ABSTRACT Modeling competition in the future European Electricity Market (EEM) suggests considering new perspectives of leadership between the participant generators, being this crucial for market concentration or competitiveness analyses. EEM models should be able to represent the possible existence of leaders and followers and Conjectural Stackelberg equilibriums is a powerful approach to do so. These asymmetric equilibriums can represent several types of competitive advantages though generally assume a single-leader-follower game. In addition, their complex resolution methodologies sometimes compromise the applicability, especially if large-scale problems have to be solved. In this paper, a multi-leader-follower conjectural Stackelberg equilibrium model is presented. An easy convex quadratic optimization problem is proposed for its resolution, describing the equilibrium existence conditions. A simple case study is presented to validate the model, and to easily analyze how the market competition changes with the number of leaders or followers. The main conclusion is that if leadership spreads, the policy recommendation of EEM regulators seems to encourage the number of followers, though to a maximum threshold if this type of asymmetric models will be used.

Pathology Case Reviews, 2007

... Contreras, Alejandro Luiña MD; Rossi, Christopher MD; Schwartz, Arnold M. MD, PhD. ... Reprin... more ... Contreras, Alejandro Luiña MD; Rossi, Christopher MD; Schwartz, Arnold M. MD, PhD. ... Reprints: Alejandro Luiña Contreras, MD, Department of Pathology, George Washington University Medical Center, 2300 I Street, NW, Ross Hall, Suite 502, Washington, DC 20037. ...

Human Pathology, 2010

The development of an angiosarcomatous component in germ cell tumors is rare. Here we studied 12 ... more The development of an angiosarcomatous component in germ cell tumors is rare. Here we studied 12 cases of mediastinal germ cell tumors with an angiosarcomatous component. All patients were men with a mean age of 34 years (range, 24-49 years). No patient had a documented testicular germ cell tumor. The mean size of mediastinal tumors was 12.9 cm (range, 5.5-16.0 cm). Grossly, the tumors were cystic with variegated hemorrhagic, mucinous, and fleshy solid areas. Microscopically, all tumors were composed of germ cell tumor. The most common germ cell tumor component was teratoma (n = 10); and other germ cell tumor components included seminoma (n = 3), yolk sac tumor (n = 3), embryonal carcinoma (n = 2), and choriocarcinoma (n = 1). The angiosarcomatous component was present in primary mediastinal tumors (n = 6), metastasis (n = 3), or both primary mediastinal tumor and metastasis (n = 3). The angiosarcomatous component accounted for an average of 30% (range, 5%-95%) of the primary mediastinal tumor. In addition, other non–germ cell components, including rhabdomyosarcoma (n = 3), leiomyosarcoma (n = 1), and poorly differentiated carcinoma (n = 1), were also present in the tumors. Of the 10 patients with follow-up available, all patients developed metastasis (n = 8) or local recurrence (n = 2); 7 died of disease at a mean of 33 months (range, 21-75 months), and 3 patients were alive at a mean of 75 months (range, 5-120 months). Our findings suggest that the presence of an angiosarcomatous component in mediastinal germ cell tumor, even in a small amount, is associated with a poor clinical outcome.

The Journal of biological chemistry, Jan 28, 2005

In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the norm... more In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the normal mammary gland does not occur in the steroid-receptor positive cells but rather in adjacent cells via paracrine signaling involving several local growth factors. To help elucidate the mechanisms involved in the block in proliferation in hormone-receptor positive cells, we have utilized a CCAAT/enhancer binding protein (C/EBP␤)-null mouse model.

Human breast cancers that are estrogen receptor (ER) negative convey a poor prognosis for patient... more Human breast cancers that are estrogen receptor (ER) negative convey a poor prognosis for patient survival. A mouse model that mimics essential biological and genetic attributes of a subset of human breast cancer is the BALB/c p53-null mammary epithelium, in which deletion of the tumor suppressor gene p53 results in enhanced tumorigenic risk. The experiments reported herein examine the hormone dependence of premalignant mammary progression in this model. The p53-null normal mammary epithelium exhibits the same dependence as p53 wild-type mammary epithelium on ovarian hormones for growth. However, in contrast to p53 wild-type epithelium, estrogen and progesterone, singly or in combination, strongly enhance tumorigenesis in p53-null mammary epithelium. The removal of progesterone signaling by deletion of the progesterone receptor eliminates progesterone enhancement of tumorigenesis. The immortalized premalignant outgrowth lines, termed PN, possess different tumorigenic capabilities, but the majority of these lines showed a strong dependence on ovarian hormones for growth and tumorigenesis. Although these lines are highly ER positive, a large number of tumors arising from these lines were ER negative and grew when implanted in ovariectomized mice. As was the case for p53-null normal mammary cells, hormonal stimulation was a strong promoter for tumorigenesis in the premalignant outgrowth lines and, surprisingly, was much stronger than the chemical carcinogen 7,12dimethylbenzanthracene. In summary, these results demonstrate that p53-null mammary cells, which generate a significant percentage of ERnegative tumors, are highly responsive to the absence or presence of ovarian hormones during the normal and premalignant stages. This model would appear an excellent one to test the effects of chemopreventive agents on the development of both ER-negative and ER-positive mammary tumors. TX 77030. 3 The abbreviations used are: MMTV, murine mammary tumor virus; DCIS, ductal carcinoma in situ; DMBA, 7,12-dimethylbenzanthracene; ER, estrogen receptor; PR, progesterone receptor; PRKO, progesterone receptor knockout; TE 50 , time for 50% of the transplants to develop tumors.

Proceedings of The National Academy of Sciences, 2006

PINC is a large, alternatively spliced, developmentally regulated, noncoding RNA expressed in the... more PINC is a large, alternatively spliced, developmentally regulated, noncoding RNA expressed in the regressed terminal ductal lobular unit-like structures of the parous mammary gland. Previous studies have shown that this population of cells possesses not only progenitor-like qualities (the ability to proliferate and repopulate a mammary gland) and the ability to survive developmentally programmed cell death but also the inhibition of carcinogen-induced proliferation. Here we report that PINC expression is temporally and spatially regulated in response to developmental stimuli in vivo and that PINC RNA is localized to distinct foci in either the nucleus or the cytoplasm in a cell-cycle-specific manner. Loss-of-function experiments suggest that PINC performs dual roles in cell survival and regulation of cell-cycle progression, suggesting that PINC may contribute to the developmentally mediated changes previously observed in the terminal ductal lobular unit-like structures of the parous gland. This is one of the first reports describing the functional properties of a large, developmentally regulated, mammalian, noncoding RNA. parity | terminal ductal lobular unit

The Journal of surgical research, 2013

Microdissection and differential display PCR were used to identify genes preferentially expressed... more Microdissection and differential display PCR were used to identify genes preferentially expressed in the highly proliferative terminal end buds (TEBs) in the mammary gland of 45-day-old virgin rats. One clone exhibited 87% homology to the human p190-B gene encoding a novel Rho-Gap. Using in situ hybridization, p190-B was detected in both the TEBs and the terminal ducts, with the highest expression observed in the outer layer of TEBs. During normal mammary gland development, p190-B mRNA expression was highest in the virgin mammary gland and decreased during late pregnancy and lactation. Interestingly, increased levels of p190-B mRNA relative to the normal mammary gland were seen in a subset of murine mammary tumors that appeared to be less well differentiated and potentially more aggressive. Transient transfection of a p190-B expression construct into MCF-10A human mammary epithelial cells resulted in disruption of the actin cytoskeleton, which suggests a role for p190-B in regulating the signaling pathways that influence cell migration and invasion. These results suggest that p190-B may be required for virgin mammary gland development, and its aberrant expression may occur in breast cancer.

Faseb Journal, 2006

Maspin is a tumor-suppressor serpin (serine protease inhibitor), which inhibits cell invasion and... more Maspin is a tumor-suppressor serpin (serine protease inhibitor), which inhibits cell invasion and migration. Here, we analyzed maspin function in cell adhesion in nontransformed mammary epithelial cells and investigated the underlying mechanism involved in this process. We report that maspin acts in the early steps in the cell adhesion process. Addition of recombinant maspin rapidly increased MCF-10A cell adhesion to the endogenously deposited matrix, and conversely both an antimaspin antibody (Ab) and maspin knockdown by RNA interference resulted in decreased cell adhesion. Mutation analyses revealed that a region of 86 amino acids located between aa 139 and aa 225 was responsible for maspin effect on adhesion. In addition, we show that maspin is associated with detergent-insoluble cortical cytoskeleton elements. Collectively, these results suggest that maspin is part of the supramolecular structure of the adhesion plaque and it modulates cell adhesion via a ␤1 integrindependent mechanism.-Cella, N., Contreras, A., Latha, K., Rosen, J. M., and Zhang, M. Maspin is physically and functionally associated with ␤1 integrin regulating cell adhesion in mammary epithelial cells. FASEB J. 20, E721-E731 (2006)

Journal of Cell Biology, 2002

o develop an inducible and progressive model of mammary gland tumorigenesis, transgenic mice were... more o develop an inducible and progressive model of mammary gland tumorigenesis, transgenic mice were generated with a mouse mammary tumor virus-long terminal repeat-driven, conditional, fibroblast growth factor (FGF)-independent FGF receptor (FGFR)1 (iFGFR1) that can be induced to dimerize with the drug AP20187. Treatment of transgenic mice with AP20187 resulted in iFGFR1 tyrosine phosphorylation, increased proliferation, activation of mitogen-activated protein kinase and Akt, and lateral budding. Lateral buds appeared as early as 3 d after T AP20187 treatment and initially consisted of bilayered epithelial cells and displayed apical and basolateral polarity appeared after 13 d of AP20187 treatment. Invasive lesions characterized by multicell-layered lateral buds, decreased myoepithelium, increased vascular branching, and loss of cell polarity were observed after 2-4 wk of treatment. These data indicate that acute iFGFR1 signaling results in increased lateral budding of the mammary ductal epithelium, and that sustained activation induces alveolar hyperplasia and invasive lesions.

Molecular Cell, 2006

Two key components of mammalian heterochromatin that play a structural role in higher order chrom... more Two key components of mammalian heterochromatin that play a structural role in higher order chromatin organization are the heterochromatin protein 1α (HP1α) and the linker histone H1. Here, we show that these proteins interact in vivo and in vitro through their hinge and C-terminal domains, respectively. The phosphorylation of H1 by CDK2, which is required for efficient cell cycle progression, disrupts this interaction. We propose that phosphorylation of H1 provides a signal for the disassembly of higher order chromatin structures during interphase, independent of histone H3-lysine 9 (H3-K9) methylation, by reducing the affinity of HP1α for heterochromatin.

Molecular and Cellular Biology, 2003

The linker histone H1 is involved in maintaining higher-order chromatin structures and displays d... more The linker histone H1 is involved in maintaining higher-order chromatin structures and displays dynamic nuclear mobility, which may be regulated by posttranslational modifications. To analyze the effect of H1 tail phosphorylation on the modulation of the histone's nuclear dynamics, we generated a mutant histone H1, referred to as M1-5, in which the five cyclin-dependent kinase phosphorylation consensus sites were mutated from serine or threonine residues into alanines. Cyclin E/CDK2 or cyclin A/CDK2 cannot phosphorylate the mutant in vitro. Using the technique of fluorescence recovery after photobleaching, we observed that the mobility of a green fluorescent protein (GFP)-M1-5 fusion protein is decreased compared to that of a GFP-wild-type H1 fusion protein. In addition, recovery of H1 correlated with CDK2 activity, as GFP-H1 mobility was decreased in cells with low CDK2 activity. Blocking the activity of CDK2 by p21 expression decreased the mobility of GFP-H1 but not that of GFP-M1-5. Finally, the level and rate of recovery of cyan fluorescent protein (CFP)-M1-5 were lower than those of CFP-H1 specifically in heterochromatic regions. These data suggest that CDK2 phosphorylates histone H1 in vivo, resulting in a more open chromatin structure by destabilizing H1-chromatin interactions.

The Journal of biological chemistry, Jan 28, 2005

In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the norm... more In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the normal mammary gland does not occur in the steroid-receptor positive cells but rather in adjacent cells via paracrine signaling involving several local growth factors. To help elucidate the mechanisms involved in the block in proliferation in hormone-receptor positive cells, we have utilized a CCAAT/enhancer binding protein (C/EBP␤)-null mouse model.

Human breast cancers that are estrogen receptor (ER) negative convey a poor prognosis for patient... more Human breast cancers that are estrogen receptor (ER) negative convey a poor prognosis for patient survival. A mouse model that mimics essential biological and genetic attributes of a subset of human breast cancer is the BALB/c p53-null mammary epithelium, in which deletion of the tumor suppressor gene p53 results in enhanced tumorigenic risk. The experiments reported herein examine the hormone dependence of premalignant mammary progression in this model. The p53-null normal mammary epithelium exhibits the same dependence as p53 wild-type mammary epithelium on ovarian hormones for growth. However, in contrast to p53 wild-type epithelium, estrogen and progesterone, singly or in combination, strongly enhance tumorigenesis in p53-null mammary epithelium. The removal of progesterone signaling by deletion of the progesterone receptor eliminates progesterone enhancement of tumorigenesis. The immortalized premalignant outgrowth lines, termed PN, possess different tumorigenic capabilities, but the majority of these lines showed a strong dependence on ovarian hormones for growth and tumorigenesis. Although these lines are highly ER positive, a large number of tumors arising from these lines were ER negative and grew when implanted in ovariectomized mice. As was the case for p53-null normal mammary cells, hormonal stimulation was a strong promoter for tumorigenesis in the premalignant outgrowth lines and, surprisingly, was much stronger than the chemical carcinogen 7,12dimethylbenzanthracene. In summary, these results demonstrate that p53-null mammary cells, which generate a significant percentage of ERnegative tumors, are highly responsive to the absence or presence of ovarian hormones during the normal and premalignant stages. This model would appear an excellent one to test the effects of chemopreventive agents on the development of both ER-negative and ER-positive mammary tumors. TX 77030. 3 The abbreviations used are: MMTV, murine mammary tumor virus; DCIS, ductal carcinoma in situ; DMBA, 7,12-dimethylbenzanthracene; ER, estrogen receptor; PR, progesterone receptor; PRKO, progesterone receptor knockout; TE 50 , time for 50% of the transplants to develop tumors.