University of Puerto Rico at Ponce

Although the role of the amygdala in acquisition of conditioned fear is well established, there is debate concerning the intra-amygdala circuits involved. The lateral nucleus of the amygdala (LA) is thought to be an essential site of plasticity in fear conditioning. The LA has both direct and indirect [via the basal nuclei; basal amygdala (BA)] projections to the central nucleus (Ce) of the amygdala, an essential output for fear behaviors. Lesions of the LA or Ce prevent acquisition of conditioned freezing to a conditioned stimulus, but BA lesions do not, suggesting that the BA is not normally involved in fear conditioning. If true, posttraining BA lesions should also have no effect. Replicating previous studies, we found that rats given electrolytic BA lesions before training acquired conditioned fear normally. They also showed normal long-term retention and extinction of conditioned fear. Unexpectedly, BA lesions made after training completely blocked expression of conditioned fear. Despite this deficit, lesioned rats were able to learn a new tone-shock association. Thus, although the LA-Ce system is sufficient for fear acquisition in the absence of the BA, it is not sufficient when the BA is present, suggesting that the BA is an important site of plasticity in fear conditioning. The pattern of lesion deficits we observed (after but not before training) might be explained by homeostatic mechanisms that balance plasticity over multiple inputs, regulating the influence of the BA and LA onto Ce output neurons.

This is a one-year prospective study of one hundred and five 2 to 17 year old children of a consecutive sample of young widows and widowers in the community and of the children of controls. The children's reactions to the parental death were recorded at one month and thirteen months after the event in a structured interview with the surviving parent. The interview included items of general adaption to the death, school performance, behaviour problems, symptoms relevant to psychopathological manifestations (depression, anxiety, etc.) and general health. The results indicate a significant increase of dysphoria which disappears over time (P less than 0.0001), the persistence of a minor form of depression (P less than 0.03), an increase in bedwetting (P less than 0.03), and a significant degree of impairment in school performance (P less than 0.0001). There were no significant increases in behaviour problems and severe forms of depression. The children's general health was not affected. Those results are compared to currently available data on childhood bereavement and discussed in the light of conflicting reports relating parental loss to adult psychopathology.

High rates of genetic gain can be achieved through (1) accurate predictions of breeding values (2) high intensities of selection and (3) shorter generation intervals. Reliabilities of ~60% are currently achievable using genomic selection in dairy cattle. This breakthrough means that selection of animals can happen at a very early age (i.e. as soon as a DNA sample is available) and has opened opportunities to radically redesign breeding schemes. Most research over the past decade has focussed on the feasibility of genomic selection, especially how to increase the accuracy of genomic breeding values. More recently, how to apply genomic technology to breeding schemes has generated a lot of interest. Some of this research remains the intellectual property of breeding companies, but there are examples in the public domain. Here we review published research into breeding scheme design using genomic selection and evaluate which designs appear to be promising (in terms of rates of genetic gain) and those that may have unfavourable side-effects (i.e. increasing the rate of inbreeding). The schemes range from fairly conservative designs where bulls are screened genomically to reduce numbers entering progeny testing, to schemes where very large numbers of bull calves are screened and used as sires as soon as they reach sexual maturity. More radical schemes that incorporate the use of reproductive technologies (in juveniles) and genomic selection in nucleus herds are also described. The models used are either deterministic and more recently tend to be stochastic, simulating populations of cattle. A key driver of the rate of genetic gain is the generation interval, which could range from being similar to that in conventional testing (~5 years), down to as little as 1.5 years. Generally, the rate of genetic gain is between 12% and 100% more than in conventional progeny testing, while the rate of inbreeding tends to be lower per generation than in progeny testing because Mendelian sampling terms can be estimated more accurately. However, short generation intervals can lead to higher rates of inbreeding per year in genomic breeding programs.

A general response of plants to high soil salinity relies on the cellular accumulation of osmolytes, which help the plant to maintain osmotic balance under salt stress condition and/or act as 'osmoprotectants' with chaperon or reactive oxygen species (ROS) scavenging activities. Yet the ecological relevance of this response for the salt tolerance mechanisms of halophytes in their natural habitats remains largely unknown. In this review, we describe and discuss published data supporting the participation of compatible solutes in those mechanisms, with especial focus on soluble carbohydrates. Evidence for a functional role of carbohydrates in salt tolerance include: (i) relatively high levels of specific sugars and polyols have been detected in many halophytic taxa; (ii) an increase in salt tolerance has often been observed in parallel with increased intracellular levels of particular soluble carbohydrates, in transgenic plants overexpressing the corresponding biosynthetic enzymes; (iii) there are several examples of genes involved in carbohydrate metabolism which are induced under salt stress conditions; (iv) specific sugars or polyols have been shown to accumulate in different halophytes upon controlled salt treatments; and (v) although very few field studies on environmentally induced carbohydrate changes in halophytes exist, in general they also support the involvement of this type of osmolytes in salt stress tolerance mechanisms. We also highlight the complexities of unequivocally attributing carbohydrates a biological role in salt tolerance mechanisms of a given tolerant species. It is proposed that research on halophytes in their natural ecosystems should be intensified, correlating seasonal changes in carbohydrate contents with the degree of environmental stress affecting the plants. This could be an important complement to experiments made under more controlled (but artificial) conditions, such as laboratory set-ups.

Abstract Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications. Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233–42. ©2018 AACR.

BACKGROUND: Previous epidemiological studies have suggested that the incidence of inflammatory bowel disease (IBD) is lower in Latin American populations. The aim of this study was to estimate the incidence of IBD in Puerto Rico, a predominantly Hispanic population. METHODS: A nonconcurrent prospective study was conducted in collaboration with private gastroenterologists in southwest Puerto Rico. Basic medical history and demographics were extracted from the medical records of patients for which a new diagnosis of IBD (Crohn's disease, CD; ulcerative colitis, UC; or nonspecified IBD) was made during each of the years 1996-2000. RESULTS: A total of 202 eligible cases of IBD were identified (95 male, 107 female). Forty-eight patients were diagnosed with CD, 102 with UC, and 52 with nonspecified IBD. The total incidence of IBD increased significantly between 1996 and 2000 (3.07/100,000 to 7.74/100,000; p < 0.001), being significantly higher for CD (four-fold increase, p < 0.01) and nonspecified IBD (fourfold increase, p < 0.005), but not UC (1.7-fold increase). The prevalence of CD was higher in males with an earlier age of onset (p < 0.05). CONCLUSIONS: This study demonstrates that the incidence of IBD within the Puerto Rican population is increasing and may be higher than previously reported for other Latin American populations.

In the budding yeast Saccharomyces cerevisiae, loss of mitochondrial DNA (rho(0)) can induce the retrograde response under appropriate conditions, resulting in increased replicative lifespan (RLS). Although the retrograde pathway has been extensively elaborated, the nature of the mitochondrial signal triggering this response has not been clear. Mitochondrial membrane potential (MMP) was severely reduced in rho(0) compared to rho(+) cells, and RLS was concomitantly extended. To examine the role of MMP in the retrograde response, MMP was increased in the rho(0) strain by introducing a mutation in the ATP1 gene, and it was decreased in rho(+) cells by deletion of COX4. The ATP1-111 mutation in rho(0) cells partially restored the MMP and reduced mean RLS to that of rho(+) cells. COX4 deletion decreased MMP in rho(+) cells to a value intermediate between rho(+) and rho(0) cells and similarly increased RLS. The increase in expression of CIT2, the diagnostic gene for the retrograde response, seen in rho(0) cells, was substantially suppressed in the presence of the ATP1-111 mutation. In contrast, CIT2 expression increased in rho(+) cells on deletion of COX4. Activation of the retrograde response results in the translocation of the transcription factor Rtg3 from the cytoplasm to the nucleus. Rtg3-GFP translocation to the nucleus was directly observed in rho(0) and rho(+)cox4Δ cells, but it was blunted in rho(0) cells with the ATP1-111 mutation. We conclude that a decrease in MMP is the signal that initiates the retrograde response and leads to increased RLS.

N-Acetylcystelne (NAC) is highly nontoxic for peripheral blood T cells and immunostimulatory enhancing T cell functions such as mitogenesis, interleukin-2 (IL-2) production, and growth in culture. NAC has been proposed for the treatment of AIDS based on its inhibition of human immunodeficiency virus (HIV) replication in cultured cells. Therefore its effect on normal T cells from 10 young donors and one elderly donor has been investigated as a prelude to clinical consideration. T cell function was evaluated in the presence and absence of accessory cells. With concanavalin A and anti-CD3 activation, NAC enhanced mitogenesis by ˜2- to 2.5-fold at 5–10 mM. Mitogenesis of purified T cells with anti-CD2 was not affected by NAC; in the presence of accessory cells, NAC enhanced mitogenesis by ˜2-fold at 1 – 10 mM. Importantly, NAC levels above 10 mM completely inhibited activation of peripheral blood mononuclear cells by anti-CD2. IL-2 secreted by T cells was also enhanced by NAC, ˜1.5-fold, but IL-2 secreted by cells from old donors was enhanced by 3-fold. In cultures of peripheral blood T cells, NAC (10 mM) stimulated growth by at least 4- to 6-fold after two passages. These results show that NAC, nontoxic even at 20 mM, is an effective enhancer of T cell function and a remarkable enhancer of growth. Results from other laboratories show that NAC, which increases glutathione levels, suppresses HIV replication presumably via suppression of the activation of transcriptional factor NF-kappa B. For normal T cells, however, this mechanism does not appear applicable because IL-2 production, regulated by several factors including NF-kappa B, Is enhanced by NAC. Rather, glutathione may enhance the activity of other transcriptional factors modulating IL-2 expression. NAC did exhibit one inhibitory characteristic, however, towards T cell adhesion. Slow cluster formation, induced by PMA, was moderately Inhibited (0–30%) by 5–10 mM NAC in cells from most donors studied.

Angiotensin-converting enzyme (ACE) inhibitors ameliorate the progression of renal disease. In combination with vitamin D receptor activators, they provide additional benefits. In the present study, uremic (U) rats were treated as follows: U+vehicle (UC), U+enalapril (UE; 25 mg/l in drinking water), U+paricalcitol (UP; 0.8 μg/kg ip, 3 × wk), or U+enalapril+paricalcitol (UEP). Despite hypertension in UP rats, proteinuria decreased by 32% vs. UC rats. Enalapril alone, or in combination with paricalcitol, further decreased proteinuria (≈70%). Glomerulosclerosis and interstitial infiltration increased in UC rats. Paricalcitol and enalapril inhibited this. The increase in cardiac atrial natriuretic peptide (ANP) seen in UC rats was significantly decreased by paricalcitol. Enalapril produced a more dramatic reduction in ANP. Renal oxidative stress plays a critical role in inflammation and progression of sclerosis. The marked increase in p22(phox), a subunit of NADPH oxidase, and decrease in endothelial nitric oxide synthase were inhibited in all treated groups. Cotreatment with both compounds inhibited the uremia-induced increase in proinflammatory inducible nitric oxide synthase (iNOS) and glutathione peroxidase activity better than either compound alone. Glutathione reductase was also increased in UE and UP rats vs. UC. Kidney 4-hydroxynonenal was significantly increased in the UC group compared with the normal group. Combined treatment with both compounds significantly blunted this increase, P < 0.05, while either compound alone had no effect. Additionally, the expression of Mn-SOD was increased and CuZn-SOD decreased by uremia. This was ameliorated in all treatment groups. Cotreatment with enalapril and paricalcitol had an additive effect in increasing CuZn-SOD expression. In conclusion, like enalapril, paricalcitol alone can improve proteinuria, glomerulosclerosis, and interstitial infiltration and reduce renal oxidative stress. The effects of paricalcitol may be amplified when an ACE inhibitor is added since cotreatment with both compounds seems to have an additive effect on ameliorating uremia-induced changes in iNOS and CuZn-SOD expression, peroxidase activity, and renal histomorphometry.

BACKGROUND: Late capsular contraction around breast implants is one of the most difficult complications to prevent or resolve. The authors studied the mechanisms that control the fibrotic process in an animal model. Using angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonist, the authors previously described a significant reduction in fibrosis in different experimental models. METHODS: Four groups of six rats each had a mini breast implant, 12 with a smooth surface and 12 with a textured surface. In two groups, the angiotensin-converting enzyme inhibitor enalapril was administered in drinking water, ad libitum, to determine its effect on both implant types. Two control groups were given plain drinking water. Three months postoperatively, all of the rats were killed and the capsule sections were cut and stained with hematoxylin and eosin and Masson's trichrome. Immunolabeling of collagen III and transforming growth factor (TGF)-beta1 was performed using monoclonal antibodies. RESULTS: Significant differences were found between smooth and textured implants, with a uniformly low inflammatory response found on textured implants. For both surfaces, the enalapril-treated group had a significant reduction of the inflammatory process that was especially marked in the textured implants. Immunostaining for collagen III and TGF-beta1 showed a consistent reduction in both fibrous tissue and cytokine mediator. CONCLUSIONS: Enalapril lowers the expression of fibrotic mediators, TGF-beta1, inflammatory markers, anti-ED1, anti-collagen III monoclonals, and the periprosthetic fibrosis process. The reduction of TGF-beta1 indicates that the probable main cytokine mediator of the fibrotic cascade is attenuated. This hypothesis may provide the basis for a safe and cheap therapeutic strategy with which to modify the capsular contracture that sometimes affects women with mammary implants.

The viral kinetics of HERV-K in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) is not unknown. HERV-K kinetic modeling may provide insight into factors altering the effectiveness of HAART in suppressing HIV-1 burden. We conducted a longitudinal study measuring the HERV-K RNA titers in four patients with successful HIV-1-suppressive HAART and in six patients undergoing HAART failure. HERV-K titers were usually undetectable in patients with successful HAART, and when detected, HERV-K titers remained below 5000 copies/ml. On the other hand, HERV-K RNA was consistently detected in patients who failed to respond to HAART before and after HIV-1 rebounds (p < 0.001). Elevated HERV-K RNA titers frequently preceded HIV-1 rebounds. These results suggest that HERV-K viral load may predict HIV-1 reactivation. HERV-K RNA testing might be clinically useful in predicting the onset of HIV-1 resistance due to suboptimal antiretroviral drug levels and/or poor adherence to treatment.

Comparative studies on the responses to salinity and drought were carried out in three Juncus species, two halophytes (Juncus maritimus Lam. and Juncus acutus L.) and one more salt-sensitive (Juncus articulatus L.). Salt tolerance in Juncus depends on the inhibition of transport of toxic ions to the aerial part. In the three taxa studied Na+ and Cl- accumulated to the same extent in the roots of salt treated plants; however, ion contents were lower in the shoots and correlated with the relative salt sensitivity of the species, with the lowest levels measured in the halophytes. Activation of K+ transport at high salt concentration could also contribute to salt tolerance in the halophytes. Maintenance of cellular osmotic balance is mostly based on the accumulation of sucrose in the three species. Yet, neither the relative salt-induced increase in sugar content nor the absolute concentrations reached can explain the observed differences in salt tolerance. In contrast, proline increased significantly in the presence of salt only in the salt-tolerant J. maritimus and J. acutus, but not in J. articulatus. Similar patterns of osmolyte accumulation were observed in response to water stress, supporting a functional role of proline in stress tolerance mechanisms in Juncus.

Penman's revised evapotranspiration formula tested under grassland conditions with a high water table by means of weighable lysimeters gave satisfactory results. (Abstract retrieved from CAB Abstracts by CABI’s permission)

Severe pulmonary hypertension (PH) associated with vascular remodeling is a long-term complication of HIV infection (HIV-PH) affecting 1/200 infected individuals vs. 1/200,000 frequency in the uninfected population. Factors accounting for increased PH susceptibility in HIV-infected individuals are unknown. Rhesus macaques infected with chimeric SHIVnef virions but not with SIV display PH-like pulmonary vascular remodeling suggesting that HIV-Nef is associated with PH; these monkeys showed changes in nef sequences that correlated with pathogenesis after passage in vivo. We further examined whether HIV-nef alleles in HIV-PH subjects have signature sequences associated with the disease phenotype. We evaluated specimens from participants with and without HIV-PH from European Registries and validated results with samples collected as part of the Lung-HIV Studies in San Francisco. We found that 10 polymorphisms in nef were overrepresented in blood cells or lung tissue specimens from European HIV-PH individuals but significantly less frequent in HIV-infected individuals without PH. These polymorphisms mapped to known functional domains in Nef. In the validation cohort, 7/10 polymorphisms in the HIV-nef gene were confirmed; these polymorphisms arose independently from viral load, CD4(+) T cell counts, length of infection, and antiretroviral therapy status. Two out of 10 polymorphisms were previously reported in macaques with PH-like pulmonary vascular remodeling. Cloned recombinant Nef proteins from clinical samples down-regulated CD4, suggesting that these primary isolates are functional. This study offers new insights into the association between Nef polymorphisms in functional domains and the HIV-PH phenotype. The utility of these polymorphisms as predictors of PH should be examined in a larger population.

OBJECTIVE: To determine the prevalence of endometriosis and its symptoms in a Puerto Rican cohort, and to describe the menstrual, obstetric, and clinical profiles of the women. METHODS: A self-administered questionnaire was given to 1285 Puerto Rican women. Categorical variables were compared using chi2 analysis or Fisher exact test. RESULTS: There were 57 self-reported cases of endometriosis (48 surgically confirmed) among 1193 valid questionnaires, for a point prevalence of 4.0%. A diagnosis of endometriosis was significantly associated with dysmenorrhea, dyspareunia, and chronic pelvic pain, but not with menstrual cycle characteristics. Undiagnosed women commonly reported signs and symptoms of endometriosis. CONCLUSIONS: The estimated prevalence of endometriosis in Puerto Rico is 4.0%, comparable to what has been reported in other populations. Endometriosis symptoms were common in the population surveyed, indicating the need for increased awareness and development of public health policies leading to early diagnosis and appropriate management.

Dengue often presents with non-specific clinical signs, and given the current paucity of accurate, rapid diagnostic laboratory tests, identifying easily obtainable bedside markers of dengue remains a priority. Previous studies in febrile Asian children have suggested that the combination of a positive tourniquet test (TT) and leucopenia can distinguish dengue from other febrile illnesses, but little data exists on the usefulness of these tests in adults or in the Americas. We evaluated the diagnostic accuracy of the TT and leucopenia (white blood cell count <5000/mm(3)) in identifying dengue as part of an acute febrile illness (AFI) surveillance study conducted in the Emergency Department of Saint Luke's Hospital in Ponce, Puerto Rico. From September to December 2009, 284 patients presenting to the ED with fever for 2-7 days and no identified source were enrolled. Participants were tested for influenza, dengue, leptospirosis and enteroviruses. Thirty-three (12%) patients were confirmed as having dengue; 2 had dengue co-infection with influenza and leptospirosis, respectively. An infectious etiology was determined for 141 others (136 influenza, 3 enterovirus, 2 urinary tract infections), and 110 patients had no infectious etiology identified. Fifty-two percent of laboratory-positive dengue cases had a positive TT versus 18% of patients without dengue (P<0.001), 87% of dengue cases compared to 28% of non-dengue cases had leucopenia (P<0.001). The presence of either a positive TT or leucopenia correctly identified 94% of dengue patients. The specificity and positive predictive values of these tests was significantly higher in the subset of patients without pandemic influenza A H1N1, suggesting improved discriminatory performance of these tests in the absence of concurrent dengue and influenza outbreaks. However, even during simultaneous AFI outbreaks, the absence of leucopenia combined with a negative tourniquet test may be useful to rule out dengue.

As the number of persons living with HIV continues to increase in Jamaica, attitudes and values become more important. This study aimed to examine the attitudes of university students in Jamaica toward persons living with HIV, including homosexual men, heterosexual men, women sex workers, other women, and children. One thousand two hundred and fifty‐two students were surveyed between June 2001 and February 2002 using a 193‐item questionnaire measuring a variety of HIV‐related knowledge, attitudinal and behavioural items. Less than half of students reported sympathetic attitudes toward homosexual men or women sex workers living with HIV while a majority reported generally sympathetic attitudes toward heterosexual men and non‐sex worker women living with the disease. Predictors of sympathy varied by target group. Male students were significantly less likely to report sympathy for homosexual men than for any other group. Spirituality was associated with sympathy for homosexual men and women sex workers, but not for the remaining two groups. Findings suggest that levels of negative attitudes are high in Jamaica and warrant attention to both individual and societal‐level actions and interventions. In addition, messages and interventions must be targeted, recognizing both the differences in level of sympathy expressed toward different groups and predictors of sympathy across the groups. Résumé Alors que le nombre de personnes vivant avec le VIH continue d’augmenter en Jamaïque, les attitudes et les valeurs ont une importance croissante. Cette étude avait pour objectif d’examiner les attitudes d’étudiants en Jamaïque, à l’égard des personnes vivant avec le VIH, parmi lesquelles les hommes homosexuels, les hommes hétérosexuels, les professionnelles du sexe, les autres femmes et les enfants. 1252 étudiants ont été interrogés entre juin 2001 et février 2002, à l’aide d’un questionnaire en 193 points pour évaluer les connaissances, les attitudes et les comportements relatifs au VIH. Moins de la moitié des étudiants a déclaré des attitudes de sympathie à l’égard des hommes homosexuels ou des professionnelles du sexe vivant avec le VIH, alors qu’une majorité d’entre eux a déclaré des attitudes générales de sympathie à l’égard des hommes hétérosexuels et des femmes, autres que les professionnelles du sexe, qui vivent avec le VIH. Les facteurs prédictifs de sympathie varient selon les groupes ciblés. Les étudiants de sexe masculin déclarent significativement avoir moins de sympathie pour les hommes homosexuels que pour les autres groupes. La spiritualité est associée à la sympathie pour les hommes homosexuels et les travailleuses du sexe, mais pas pour les deux autres groupes. Les résultats suggèrent que les niveaux d’attitudes négatives sont élevés en Jamaïque et qu’ils incitent à une attention particulière pour des interventions aussi bien au niveau individuel que sociétal. De plus, les messages et les interventions doivent être ciblés, en reconnaissant à la fois les différences des niveaux de sympathie exprimés vis‐à‐vis des différents groupes et les facteurs prédictifs de sympathie à travers les groupes. Resumen Ante el continuo aumento de personas contagiadas con el VIH en Jamaica, las actitudes y los valores de la sociedad adquieren más importancia. El objetivo de este estudio es analizar la actitud de los estudiantes universitarios en Jamaica hacia las personas infectadas con el VIH, entre ellas hombres homosexuales y heterosexuales, trabajadoras sexuales, otras mujeres y niños. Entre junio de 2001 y febrero de 2002, 1252 estudiantes participaron en un estudio en el que completaron un cuestionario de 193 puntos para medir toda una serie de conocimientos, actitudes y conductas en torno al tema del sida. Menos de la mitad de los estudiantes mostraron una actitud de compasión hacia los homosexuales y las trabajadoras sexuales contagiados con el VIH/sida, pero una mayoría mostraron compasión en general hacia los seropositivos como hombres heterosexuales y mujeres no relacionadas con el comercio sexual. Los pronósticos de compasión variaban según el grupo objetivo. Los estudiantes masculinos eran mucho menos propensos a mostrar simpatía hacia los homosexuales que ningún otro grupo. La espiritualidad se relacionaba con la compasión hacia los homosexuales y las trabajadoras sexuales pero no para los otros dos grupos. Los resultados indican que en Jamaica existen actitudes muy negativas y, por tanto, habría que prestar más atención a las intervenciones dirigidas a los individuos y a la sociedad. Asimismo hay que establecer objetivos en los mensajes y las intervenciones reconociendo las diferencias en el nivel de compasión expresada hacia los diferentes grupos y los pronósticos de compasión en todos los grupos.

Abstract Nek2 (NIMA‐related kinase 2) is a serine/threonine-protein kinase that localizes to centrosomes and kinetochores, controlling centrosome separation, chromosome attachments to kinetochores, and the spindle assembly checkpoint. These processes prevent centrosome amplification (CA), mitotic dysfunction, and chromosome instability (CIN). Our group and others have suggested that Nek2 maintains high levels of CA/CIN, tumor growth, and drug resistance. We identified that Nek2 overexpression correlates with poor survival of breast cancer. However, the mechanisms driving these phenotypes are unknown. We now report that overexpression of Nek2 in MCF10A cells drives CA/CIN and aneuploidy. Besides, enhanced levels of Nek2 results in larger 3D acinar structures, but could not initiate tumors in a p53 +/+ or a p53 −/− xenograft model. Nek2 overexpression induced the epithelial-to-mesenchymal transition (EMT) while its downregulation reduced the expression of the mesenchymal marker vimentin. Furthermore, either siRNA-mediated downregulation or INH6’s chemical inhibition of Nek2 in MDA-MB-231 and Hs578t cells showed important EMT changes and decreased invasion and migration. We also showed that Slug and Zeb1 are involved in Nek2 mediated EMT, invasion, and migration. Besides its role in CA/CIN, Nek2 contributes to breast cancer progression through a novel EMT mediated mechanism.

AIM: We endeavored to create a folate-targeted liposome (Fol-liposome) that could selectively target areas of inflammation. MATERIALS & METHODS: Fol-liposomes were prepared with encapsulated DiD fluorophore or betamethasone (BM) to image and treat an adjuvant-induced rat model of rheumatoid arthritis. RESULTS: Fol-liposomes selectively accumulated in arthritic rat paws to a greater extent than nontargeted liposomes. When these Fol-liposomes were used to encapsulate BM and administered to arthritic rats, animals exhibited less paw swelling, lower arthritis scores, a reduction in bone erosion, less splenomegaly and better maintenance of body weight when compared with nontreated or nontargeted BM-containing liposome groups. CONCLUSION: Fol-liposomes can selectively deliver imaging and therapeutic agents to sites of inflammation in a rat model of rheumatoid arthritis.

Multiple studies have shown that psychological distress in epithelial ovarian cancer (EOC) patients is associated with worse quality of life and poor treatment adherence. This may influence chemotherapy response and prognosis. Moreover, although stress hormones can reduce cisplatin efficacy in EOC treatment, their effect on the integrity of DNA remains poorly understood. In this study, we investigated whether norepinephrine and epinephrine can induce DNA damage and modulate cisplatin-induced DNA damage in three EOC cell lines. Our data show that norepinephrine and epinephrine exposure led to increased nuclear γ-H2AX foci formation in EOC cells, a marker of double-strand DNA breaks. We further characterized norepinephrine-induced DNA damage by subjecting EOC cells to alkaline and neutral comet assays. Norepinephrine exposure caused DNA double-strand breaks, but not single-strand breaks. Interestingly, pre-treatment with propranolol abrogated norepinephrine-induced DNA damage indicating that its effects may be mediated by β-adrenergic receptors. Lastly, we determined the effects of norepinephrine on cisplatin-induced DNA damage. Our data suggest that norepinephrine reduced cisplatin-induced DNA damage in EOC cells and that this effect may be mediated independently of β-adrenergic receptors. Taken together, these results suggest that stress hormones can affect DNA integrity and modulate cisplatin resistance in EOC cells.