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Parity is associated with a short–term increase in breast cancer (BC) risk followed by a long–term decrease in risk. BC diagnosed 5–7 years after a completed pregnancy is associated with worse outcomes. BC is not a single disease. The dual effect of pregnancy could account for the BC characteristics at presentation (i.e. younger age and more advanced disease) and worse outcomes observed among Hispanics, relative to Non–Hispanic Whites. The purpose of this study was to investigate the association of reproductive characteristics by tumor subtype in a case series of women of Mexican–descent. Cases diagnosed ≤10 years following a birth had nearly 3 times the odds of a diagnosis with HER2+ tumors, relative to ER+/PR+ tumors. HER2+ tumors are associated with reduced survival compared to ER+/PR+ tumors. Diagnosis within a recent pregnancy may contribute to the aggressiveness of BC observed among women of Mexican descent ≤50 years of age.

ER positive (ER+) and HER2 negative (HER2-) breast cancers are routinely treated based on estrogen dependence. CDK4/6 inhibitors in combination with endocrine therapy have significantly improved the progression-free survival of patients with ER+/HER2- metastatic breast cancer. Gene expression profiling in ER+/HER2- models was used to define the basis for the efficacy of CDK4/6 inhibitors and develop a gene expression signature of CDK4/6 inhibition. CDK4/6 inhibition robustly suppressed cell cycle progression of ER+/HER2- models and complements the activity of limiting estrogen. Chronic treatment with CDK4/6 inhibitors results in the consistent suppression of genes involved in cell cycle, while eliciting the induction of a comparable number of genes involved in multiple processes. The CDK4/6 inhibitor treatment shifted ER+/HER2- models from a high risk (luminal B) to a low risk (luminal A) molecular-phenotype using established gene expression panels. Consonantly, genes repressed by CDK4/6 inhibition are strongly associated with clinical prognosis in ER+/HER2- cases. This gene repression program was conserved in an aggressive triple negative breast cancer xenograft, indicating that this is a common feature of CDK4/6 inhibition. Interestingly, the genes upregulated as a consequence of CDK4/6 inhibition were more variable, but associated with improved outcome in ER+/HER2- clinical cases, indicating dual and heretofore unknown consequence of CDK4/6 inhibition. Interestingly, CDK4/6 inhibition was also associated with the induction of a collection of genes associated with cell growth; but unlike suppression of cell cycle genes this signaling was antagonized by endocrine therapy. Consistent with the stimulation of a mitogenic pathway, cell size and metabolism were induced with CDK4/6 inhibition but ameliorated with endocrine therapy. Together, the data herein support the basis for profound interaction between CDK4/6 inhibitors and endocrine therapy by cooperating for the suppression of cell cycle progression and limiting compensatory pro-growth processes that could contribute to therapeutic failure.

Children with autism spectrum disorder (ASD) present with a myriad of diagnostic characteristics and associated behaviors. Secondarily, this population is extremely heterogeneous. Efforts have been made by many disciplines to identify more homogenous subgroups in order to improve both research and clinical outcomes. In occupational therapy, the focus has been on establishing sensory-based subtypes. This dissertation is a compilation of three separate research papers related to sensory-based subtypes in children with ASD. The first paper is a systematic review on sensory subtyping systems published in the last 12 years. Findings indicate that the majority of subtyping schemes characterize group differences by patterns of sensory responsivity (i.e., hyperresponsivity, hyporesponsivity and sensory seeking). One subtyping scheme has emerged as the most well researched of these, and includes responses to specific sensory domains for four different subtypes. The subsequent two papers presents additional research examining this subtyping system. The second paper examined neurophysiological response to sensory stimuli between the four subtypes. Salivary cortisol, skin conductance level (SCL) and respiratory sinus arrhythmia (RSA) were used examine neuroendocrine function, parasympathetic and sympathetic nervous system responses. Results indicate that parasympathetic response (as indexed by RSA) may best distinguish subtypes with typical sensory processing versus those with atypical sensory processing. More discrete differences between each of the subtypes hallmarked by different sensory processing differences were less substantial. The third paper examined functional and adaptive behaviors, in addition to clinical behaviors (psychopathology) in relationship to subtype membership. Subtypes with greater sensory processing dysfunction were found to have poorer communication, socialization and performance of daily living skills. In addition, subtypes with atypical sensory processing characteristics had higher levels of internalizing and externalizing behaviors. Again, certain subtypes were not found to differ significantly from each other on these measures. Overall findings suggest that current sensory-based subtyping schemes may not fully explain sensory processing differences or the variety of behavioral traits observed in this population. In addition, neurological reactivity patterns may not completely align with these subtype divisions. Stronger statistical differences found between certain subtypes indicates particular sensory processing characteristics may be more impairing and have more clinical relevance than others.

Therapeutic alliance is a robust predictor of future therapeutic outcomes. While treatment of normal children and adolescents is often hard, treating antisocial youth is especially difficult because of the social, cognitive, and emotional deficits experienced by these youth. This study investigated whether differing levels of callous-unemotional (CU) traits influenced the formation of therapeutic alliance in a sample of 51 adjudicated youth in juvenile institutions. Also, we tested whether therapeutic alliance influenced success in the institution and whether this association differed based on levels of CU traits. Results revealed that CU traits and selfreported delinquency were both modestly related to institutional infractions. Children low on both dimensions showed the lowest levels of institutional infractions. Additionally, these findings suggest that children high on both CU traits and delinquency reported better therapeutic alliance, but that youth with high CU traits committed more institutional infractions, despite their level of therapeutic alliance.

The purpose of this study was to examine the potential moderating effects of CU traits on the relationship between self-reported social intelligence and aggression in a community sample of boys and girls (ages 14-18). Four subtypes of aggression were measured: reactive overt, reactive relational, proactive overt, and proactive relational. Results indicated that there was not a significant association between social intelligence and any of the aggression subtypes. Neither CU traits nor empathy moderated the association between social intelligence and any of the four subtypes of aggression. Supplementary analyses were conducted to investigate whether level and type of aggression was related to levels of social intelligence and CU traits (or an interaction between the two). Results indicated that at high levels of CU traits, youth exhibited significantly higher levels of proactive overt and reactive overt aggression (t(113.06) than at low levels of CU traits.

The central scientific objective of the current dissertation was to take a multidisciplinary approach to make use of the full potential information, both scientific and clinical to aid prevention and treatment of EDs. In our studies we assessed a.) social and individual risk factors in EDs (Study 1), b.) empirical ED subtypes based on drive for thinness (DT) and depression (Study 2) and c.) the classification based on these four different empirical ED subtypes without cluster analysis and based on the use of clinical cutoff scores of DT and depression. Finally, we assessed the predictive validity for this subtyping scheme with regard to dropout from CBT in an unselected BN-P population seeking treatment. Our first line of investigation (Study 1) assessed social and self-standards in EDs. The results of the study suggest that compared to healthy controls, standards for physical appearance, family standards and self-achievements were higher in individuals with EDs, that ED patients show higher self-discrepancy between their personal and social values and confidence to attain them and that the conflict with their significant others over these issues was higher. Furthermore, high social and self-standards was associated with developing an ED, which emphasize the importance of assessing risk factors in ED. Finally we also observed differences in the ED subtypes; physical appearance a greater risk factor in BN and EDNOS while social-other standards were more associated with AN. The second research area (Study 2 and 3) explored new empirical ED subtypes along DT and depression. In our initial study (Study 2) we found four new ED subtypes through cluster analysis; “DT”, “DT-Depressive”, “mild DT” and “depressive-moderate DT”. This result indicates that dieting and depression are useful for analyzing and identifying ED subtypes. Study 3 further assessed these empirical subtypes and found that the same subtypes emerged when basing them on scores from clinical well-validated questionnaires and moreover that attrition rates differed between subtypes and that the dropout rate was highest for the “DT-Depressive” subtype. Our findings agree with the growing body of research indicating the importance of dieting and comorbid depression as contributing factors in ED diagnoses. Finally, these findings will hopefully aid in resolving the current controversy surrounding current DSM-ED classifications. / El objetivo central de esta tesis ha sido, desde una perspectiva multidisciplinar, integrar los conocimientos clínicos y científicos para contribuir en el avance de la prevención y tratamiento de los Trastornos de la Conducta Alimentaria (TCA). En estos estudios, se han explorado una serie de aspectos como a) factores de riesgo sociales e individuales en los TCA (estudio 1), b) identificación de subtipos empíricos de los TCA, basados en el impulso a la delgadez y la realización de dietas y la depresión (estudio 2), y c) asociación entre los cuatro subtipos de TCA, basados en los factores descritos, y respuesta a un abordaje cognitivo-conductual, en una población con diagnóstico de bulimia nerviosa purgativa (BN-P), que solicitaron tratamiento por su trastorno (estudio 3). Nuestra primera línea de investigación (estudio 1) analizó la implicación de las expectativas sociales e individuales en los TCA. Los resultados de este trabajo sugirieron que las expectativas familiares, individuales y las relacionadas con la apariencia física, eran superiores en pacientes con TCA que en sujetos control. Asimismo, los pacientes con diagnóstico de TCA mostraban mayor discrepancia entre sus valores personales y sociales, menor confianza en poder alcanzarlos y mayor conflicto con sus familiares por estas cuestiones. Por otra parte, la presencia de elevadas expectativas sociales y personales se asociaba al desarrollo de un TCA, lo que enfatizaba la importancia de evaluar estos factores de riesgo. Finalmente, se observaron diferencias significativas entre los subtipos de TCA, siendo la apariencia física un factor de riesgo más presente en BN y en trastornos de la conducta alimentaria no especificados (TCANE), mientras que otras expectativas sociales se asociaban más a la anorexia nerviosa (AN). La segunda línea de investigación (estudios 2 y 3) exploraba nuevos subtipos empíricos de TCA, teniendo en cuenta las variables de impulso a la delgadez y realización de dietas (ID) y la depresión (D). En el primer trabajo (estudio 2), se obtuvieron cuatro nuevos subtipos a través de un análisis de cluster. Los subgrupos fueron “ID”, “IDDepresivo”, “ID moderado” y “D-ID moderado”. Estos resultados mostraban que la realización de dietas y la depresión eran útiles en el análisis e identificación de subtipos en los TCA. En el estudio 3 se exploraban estos subtipos con mayor profundidad, observando que se obtenían los mismos subgrupos, cuando nos basábamos en las puntuaciones de diversos cuestionarios clínicos validados. Asimismo, la respuesta al tratamiento era distinta en función de los subtipos de TCA, presentando tasas de abandonos más elevadas el subtipo “ID-Depresivo”. De este modo, los resultados estaban en concordancia con las evidencias empíricas, cada vez mayores, que indican la importancia de la realización de dietas y la depresión comórbida como factores que contribuyen a explicar características diagnósticas en los TCA. Finalmente, estos hallazgos podrían tener una relevancia destacada en la controversia actual sobre las clasificaciones diagnósticas en el próximo DSM. / L’objectiu central d’aquesta tesi ha estat, des d’una perspectiva multidisciplinar, integrar els coneixements clínics i científics per a contribuir a l’avenç de la prevenció i tractament dels trastorns de la conducta alimentària (TCA). En aquests estudis, s’han explorat una sèrie d’aspectes com a) factors de risc socials i individuals en els TCA (estudi 1), b) identificació de subtipus empírics dels TCA, i c) associació entre els quatre subtipus de TCA, basats en els factors descrits, i resposta a un abordatge cognitivoconductual, en una població amb diagnòstic de bulímia nerviosa purgativa (BN-P), que varen sol•licitar tractament pel seu trastorn (estudi 3). La nostra primera línia de recerca (estudi 1) va analitzar la implicació de les expectatives socials i individuals en els TCA. Els resultats d’aquest treball varen suggerir que les expectatives familiars, individuals i les relacionades amb l’aparença física, eren superiors en pacients amb TCA que en subjectes control. Alhora, els pacients amb diagnòstic de TCA mostraven major discrepància entre els seus valors personals i socials, menor confiança en poder aconseguir-los i major conflicte amb els seus familiars per aquestes qüestions. Per altra banda, la presència d’elevades expectatives socials i personals s’associava al desenvolupament d’un TCA, fet que emfatitzava la importància d’avaluar aquests factors de risc. Finalment, es varen observar diferències significatives entre els subtipus de TCA, sent l’aparença física un factor de risc més present en BN i en trastorns de la conducta alimentària no especificats (TCANE), mentre que altres expectatives socials s’associaven més a l’anorèxia nerviosa (AN). La segona línia de recerca (estudis 2 i 3) explorava nous subtipus empírics de TCA, tenint en compte les variables d’impuls a estar prim i realització de dietes (ID) i la depressió (D). En el primer treball (estudi 2), es varen obtenir quatre nous subtipus a través d’una anàlisi de cluster. Els subgrups foren “ID”, “ID-Depressiu”,“ID moderat” i “D-ID moderat”. Aquests resultants mostraven que la realització de dietes i la depressió eren útils en l’anàlisi i identificació de subtipus en els TCA. En l’estudi 3 s’exploraven aquests subtipus amb major profunditat, observant que s’obtenien els mateixos subgrups, quan ens basàvem en les puntuacions de diversos qüestionaris clínics validats. Alhora, la resposta al tractament era diferent en funció dels subtipus de TCA, presentant taxes d’abandonament més elevades el subtipus “IDDepressiu”. D’aquesta manera, els resultats estaven en concordança amb les evidències empíriques, cada vegada més grans, que indiquen la importància de la realització de dietes i la depressió comòrbida, com a factors que contribueixen a explicar les característiques diagnòstiques en els TCA. Finalment, aquestes troballes podrien tenir una rellevància destacada en la controvèrsia actual sobre les classificacions diagnòstiques en el proper DSM.

We investigated the role of muscarinic receptor subtypes at the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic neurogenic vasomotor tone, in mevinphos (Mev) intoxication. Adult Sprague-Dawley rats anesthetized by pentobarbital (45 mg/kg) and maintained by propofol (30 mg/kg/h) were used. Co-microinjection bilaterally of Mev (10 nmol) and artificial cerebrospinal fluid (aCSF) into the RVLM resulted in an increase (Phase I) followed by a decrease (Phase II) in the power density of the vasomotor components of systemic arterial pressure spectrum, our experimental index for sympathetic vasomotor tone. These changes in sympathetic vasomotor outflow in both phases of Mev intoxication were significantly and dose-dependently reduced on co-microinjection of Mev and the M2 subtype of muscarinic receptor (M2R) antagonist methoctramine (0.5 or 1 nmol) or M4R antagonist tropicamide (0.5 or 1 nmol). On the other hand, the M1R antagonist pirenzepine (0.5 or 1 nmol) or M3R antagonist 4-DAMP (0.5 or 1 nmol) was ineffective. Western blot analysis further revealed that the increase in NOS I protein levels at the RVLM during Phase I Mev intoxication or the augmented level of NOS II during both phases were significantly blunted on co-microinjection bilaterally of Mev and methoctramine (1 nmol) or tropicamide (1 nmol) into the RVLM. Pirenzepine (1 nmol) or 4-DMAP (1 nmol) was again ineffective. We conclude that both M2R and M4R subtypes in the RVLM may be involved in Mev intoxication. Whereas the prevalence of NOS I over NOS II at the RVLM during Phase I results in sympathoexcitation, sympathoinhibition induced by NO from NOS II in the RVLM is primarily involved in Phase II Mev intoxication.

Serotonergic neurons modulate a wide range of behaviors and functions, from mood and aggression to vital autonomic processes like heart rate, respiratory dynamics, and body temperature. We hypothesize that this broad scope reflects the collective actions of many functionally and molecularly distinct subtypes of serotonergic neurons, each with specialized roles in different neural processes. Supporting this idea are examples of heterogeneity among serotonergic neurons with respect to developmental origin, biophysical properties, and molecular expression; yet deciphering the functional and behavioral relevance of these differences has been challenging. In order to better understand serotonergic system organization, we have developed and applied a set of mouse genetic tools to subdivide serotonergic neurons into groups based on molecular criteria, and then to query these subtypes for differences with respect to biophysical properties, hodology, gene expression, and whole animal function. We applied these tools in a stage-wise fashion, from neural system en masse, as reference, and then to specific serotonergic neuron subtypes. From this, we have established that serotonergic neurons play key roles in at least two life-sustaining reflexes - the respiratory chemoreflex (breathing modulation to keep tissue PCO2/pH within physiological limits) and body temperature regulation. We found that chemoreflex modulation, but not body temperature regulation, maps to a specific serotonergic neuron subtype - that subtype with a developmental history of Egr2 gene expression. Further, in brain slice preparations, we found that this subtype is chemosensitive, increasing firing rate in response to conditions of hypercapnic acidosis. Thus, in vivo, Egr2-serotonergic neurons likely transduce chemosensory information into action potential firing to increase respiratory drive and ultimately breathing. Further, we found that Egr2-serotonergic neurons project selectively to respiratory nuclei involved in PCO2/pH sensory signal transduction, but not primary respiratory motor nuclei. This indicates that the serotonergic system has distinct sensory and motor divisions - another unexpected finding. In summary, these results establish a previously unappreciated functional modularity and organization to the serotonergic system, and open up potential for tailored function-specific therapeutic strategies, for example here as relates to disorders of respiratory homeostasis or thermoregulation.

Borderline personality disorder (BPD) is a complex psychiatric condition whose severity is compounded by the heterogeneous psychological functioning of those who suffer from the disorder. This heterogeneity has made the identification of a unified treatment strategy difficult and attempts to resolve this variation within the disorder by investigating subtypes of BPD have been made. However, the clinical utility of this approach has not been examined. The major object of this research project was to investigate the presence of subtypes of BPD and to examine whether treatment effectiveness varied as a function of subtype. Data from 61, predominantly female, participants with BPD were entered into a cluster analysis. Using variables that are central to cognitive behavioural models of BPD and have been shown to be heterogeneously distributed in previous BPD samples, two subgroups were identified and defined on the basis of whether participants attributed the causes o f negative events as being themselves or other people. Consistent with hypotheses, the subgroup with a tendency to blame others for negative events showed far lower levels of change between admission and discharge than the subgroup who blamed themselves for negative events, on both measures of statistical and clinical significance. Alternate means of identifying participants who optimally responded to the intervention were explored and a cluster analysis identified two groups of participants that were separated on the basis of whether they had shown clinically significant change on a range of variables. It was found that data from admission to the program could successfully predict which participants would belong in the optimal or mixed response groups upon discharge. Taken together, the findings of this research project suggest that not only can theoretically valid subgroups of BPD be identified, but that they have clinical utility in understanding participants' response to intervention. Further, the findi ngs suggest that profiles of clinical change can be identified and predicted. The findings of this research project are discussed with respect to their methodological limitations, suggestions for future research, and their implications for both theory and practice.