Objectives: High frequency left-sided (HFL) and low frequency right-sided (LFR) unilateral repetitive transcranial magnetic stimulation (rTMS) are efficacious in treatment-resistant major depression (TRD). Similar benefit has been suggested for sequential bilateral rTMS (LFR then HFL). Therefore, this study evaluated the efficacy of HFL and sequential bilateral rTMS compared to sham in TRD. Methods: Seventy-four subjects between the ages of 18 and 85 with TRD and a 17-item Hamilton Depression Rating Scale (HDRS) greater than 21 were randomized to receive unilateral, bilateral, or sham rTMS. Remission rates were compared among the three groups. Results: Remission rates differed significantly among the three groups. The remission rate was significantly higher in the bilateral group (34.6%) than the unilateral (4.5%) and sham (5.0%) groups. The remission rate in the unilateral group did not differ from sham group. Conclusion: These findings warrant larger controlled studies that compare the efficacy of sequential bilateral rTMS and HFL rTMS in TRD.

Objectives: High frequency left-sided (HFL) and low frequency right-sided (LFR) unilateral repetitive transcranial magnetic stimulation (rTMS) are efficacious in treatment-resistant major depression (TRD). Similar benefit has been suggested for sequential bilateral rTMS (LFR then HFL). Therefore, this study evaluated the efficacy of HFL and sequential bilateral rTMS compared to sham in TRD. Methods: Seventy-four subjects between the ages of 18 and 85 with TRD and a 17-item Hamilton Depression Rating Scale (HDRS) greater than 21 were randomized to receive unilateral, bilateral, or sham rTMS. Remission rates were compared among the three groups. Results: Remission rates differed significantly among the three groups. The remission rate was significantly higher in the bilateral group (34.6%) than the unilateral (4.5%) and sham (5.0%) groups. The remission rate in the unilateral group did not differ from sham group. Conclusion: These findings warrant larger controlled studies that compare the efficacy of sequential bilateral rTMS and HFL rTMS in TRD.

One significant obstacle in cancer treatment is tumor heterogeneity. Different subpopulations within a tumor can respond differently to chemotherapy, resulting in resistance and recurrence. Addressing these differences while choosing a treatment modality could significantly improve chemotherapy outcomes. This work focuses on the development of a new modular device that leverages the unique advantages of a contactless dielectrophoresis, a method that uses applied electric fields in a microfluidic device to separate cells by biophysical phenotype. By optimizing force balancing between the dielectrophoretic force and the drag force on cells in the device, and by using cell-size pillars to maximize electric field gradients per volt applied while reducing cell-cell interactions,we demonstrate that it is possible to separate mouse ovarian surface epithelial (MOSE) cells at different stages while maintaining high viability. We also show other cell types to be separable with this device and develop an algorithm to rapidly analyze cell response to a variety of frequency/voltage/flow rate combinations. We also propose a microfluidic device downstream of the DEP chip that can be used to provide an integrated system for studying the subpopulations separated using dielectrophoresis by moving them into a culture chamber with hydrogel where they can be grown in 3D and characterized for a variety of parameters such as biophysical structure, metastatic capacity, and chemotherapy resistance. / Ph. D. / Dielectrophoresis is a method by which cells are polarized in response to an electric field gradient. This work optimizes this technique so that it can be used to separate highly similar subpopulations of cancer cells in a microfluidic device. Computer code is also developed to automate data processing. A technique for analyzing these cell subpopulations is also proposed and some feasibility testing performed.

Resistance to endocrine treatments in oestrogen receptor positive (ER+) breast cancer (BC) significantly contribute to patient morbidity and mortality. ER+ BC constitute 60% of all breast cancers although there is considerable clinico-pathological diversity within this group. Breast cancer initiating cells (BCICs) are implicated in tumour relapse and metastasis and are postulated to drive resistance to standard anti-cancer therapies. However little is known about the sensitivity of BCICs to endocrine therapies. We assessed the effect of tamoxifen treatment and acquired tamoxifen resistance on BCIC frequency in vitro and in vivo using breast cancer cell lines and, importantly, patient derived samples of early and metastatic ER+ breast cancer. In ER+ breast cancer, BCICs may be prospectively enriched in vitro by selecting cells by CD44+/CD24lo/ESA+ phenotype or by mammosphere initiating capacity (MIC). However the gold standard assay to determine BCIC frequency is limiting dilution transplantation in vivo. In the past it has been historically difficult to generate xenograft models of ER+ breast cancer using patient samples. In this thesis, using a novel experimental technique, patient-derived xenografts (PDX) of early and metastatic ER+ BC were generated with almost 85% efficiency in NOD/SCID IL2gammaR-/- (NSG) mice. PDX expressed ER and were able to undergo serial in vivo passage, matching the phenotype of the tumour from which they were derived. In this work, two patterns of response to tamoxifen treatment were observed in ER+ cell lines, patient derived breast cancer samples and xenografts during BCIC assays in vitro and in vivo; Limited Sensitivity (LS) or Resistance (R). In the LS group there was no change or a significant diminution in BCIC frequency in the presence of tamoxifen. In the R group, a significant increase in BCIC frequency was observed in the presence of tamoxifen. Furthermore BCIC activity was shown be enhanced by the acquisition of tamoxifen resistance using cell line models. Cellular populations enriched for BCICs in ER+ cell lines were shown to express low levels of ER compared to non-BCICs. Finally Notch (gamma-secretase inhibitor) and EGFR (gefitinib) pathway inhibitors were tested alone or in combination with tamoxifen against a panel of established and novel cell lines and ER+ patient-derived breast cancer samples for anti-BCIC activity. Tamoxifen treatment can increase BCIC frequency in vitro assays of cell lines and patient-derived samples and in vivo using patient-derived xenografts of ER+ breast cancer. However phenotypic diversity of BCIC may be present within the ER+ BC population. A pharmaceutical strategy to effectively treat BCICs alongside standard endocrine therapy is necessary for the effective future treatment of ER+ breast cancer.

Traditional antidepressants, which act on the serotonin, dopamine, and norepinephrine systems, require many weeks to produce a therapeutic effect and are not effective for every patient. A sub-anesthetic dose of the anesthetic agent ketamine, a glutamate N-methyl-D-aspartate receptor antagonist, has been shown to produce a rapid and robust antidepressant effect in treatment-resistant major depressive disorder (MDD). As depressive symptoms typically return after one week following a single infusion, recent work has begun to focus on methods for prolonging the effects. Repeated infusions on a specific dosing schedule are being explored, however, the early identification of treatment responders and non-responders would be beneficial for optimized treatment selection within this population. The mechanisms underlying ketamine’s rapid effects conceivably involve the regulation of altered glutamatergic signaling in MDD, though this is not yet completely understood. Understanding of the central mechanisms mediating ketamine’s rapid antidepressant effects may be increased through the use of non-invasive electroencephalographic measures, including resting electroencephalography (EEG) and the mismatch negativity (MMN) event-related potential. These measures have been shown to be altered in depressed individuals and are sensitive to ketamine administration. The primary objectives of this study were to 1) examine acute changes in EEG- and MMN-derived indices, immediately post- and two hours postinfusion, with a sub-anesthetic ketamine dose in comparison to an active placebo (midazolam), and 2) to examine their relationships with early and sustained antidepressant treatment response to ketamine within an eight week clinical trial involving three study phases. Ketamine decreased measures of scalp-level alpha and theta resting activity, immediately postinfusion, and increased gamma immediately and two hours postinfusion. An increase in source-localized anterior cingulate activity two hours postinfusion was also observed. Regarding the MMN, ketamine reduced frontal amplitudes as well as theta event-related oscillations and source-localized peak frontal generator activity. Measures of resting theta and change in gamma, as well as left frontal MMN amplitude, theta event-related oscillations, baseline left phase locking factor, and baseline right inferior temporal lobe activity were predictive of decreases in depressive symptoms at both early and sustained treatment time points. Alpha power was predictive of decrease in suicidal ideation, though the relationship with baseline and early change in symptoms was stronger. These findings contribute to our understanding of the role of baseline and ketamine-induced changes in both resting and task-evoked electrophysiological measures, and may have the potential to act as non-invasive biomarkers of antidepressant response prediction to glutamatergic agents.

Previous magnetic resonance imaging (MRI) studies have demonstrated brain atrophy in major depressive disorder (MDD) that is progressive with continuing illness and may be reversible with antidepressant treatment. What remains unclear is whether brain structure can be positively affected by pharmacological intervention even if patients fail to remit on the treatment. The primary aim of this thesis was to prospectively track changes in brain structure in patients with treatment-resistant depression while they underwent pharmacotherapy with the goal of attaining remission. There is evidence that gene variants associated with poorer antidepressant response also confer greater risk of volume reduction in the hippocampus. A secondary aim of the thesis was to investigate the effects of monoaminergic-related gene variants on hippocampal volume in patients and controls at baseline imaging. Outpatients with treatment-resistant MDD underwent structural MRI scans at baseline and after either 6-months of sustained remission or 12-months of failure to remit. Matched controls were scanned once to provide comparison data for patients’ baseline scans. Participants also provided blood samples for genetic analyses. Imaging outcome measures included longitudinal changes in whole-brain volume, and gray matter volume and mean cortical thickness within specific cortico-limbic regions of interest (ROIs). Over follow-up, remitted patients had an increase in whole-brain volume, while nonremitted patients lost brain volume despite receiving more treatment strategies. Remitters and nonremitters also showed subtle changes in volume and thickness over time in several ROIs in opposing directions, with increasing hippocampal volume and cortical thickness in the rostral middle frontal gyrus and orbitofrontal cortex in remitters, and decreasing volume or thickness in these regions in nonremitters. Genetic imaging analyses revealed that polymorphisms in certain norepinephrine- and serotonin-related genes have similar effects on hippocampal volume in patients and controls, while the serotonin transporter polymorphism differentially affects hippocampal volume in the presence of depression. Given the observations of volume increase in remitted patients and continuing atrophy in nonremitters, pharmacotherapy in the absence of sustained remission is likely insufficient to elicit structural recovery in depression. This finding is important since the restoration of brain structure in patients with treatment-resistant depression may have positive implications for their future prognosis.

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Yes / Alterations in integrin expression and function promote tumour growth, invasion, metastasis and neoangiogenesis. Head and neck cancers are highly vascular tumours with a tendency to metastasise. They express a wide range of integrin receptors. Expression of the αv and β1 subunits has been explored relatively extensively and linked to tumour progression and metastasis. Individual receptors αvβ3 and αvβ5 have proved popular targets for diagnostic and therapeutic agents but lesser studied receptors, such as αvβ6, αvβ8, and β1 subfamily members, also show promise. This review presents the current knowledge of integrin expression and function in squamous cell carcinoma of the head and neck (HNSCC), with a particular focus on the RGD-binding integrins, in order to highlight the potential of integrins as targets for personalised tumour specific identification and therapy.

I chose the theme of obsessive-compulsive disorder as a topic of my thesis. The main reason was that it is a disorder I have worked as a therapist in individual or group therapy frequently. Also I have participated in several studies as evaluator in Psychiatric Centre, and I collected data from dozens of patients. In the first part the thesis deals with the symptoms, clinical picture, prevalence, aetiology and treatment of OCD. Thesis is focuses on behavioural and cognitive models of the disorder in detail, because the treatment used in the present group of patients was CBT. Various models of cognitive behavioural therapy I discuss in more detail, because they allow different views of what happens to the patient and how to change it. The practical part has two parts. The first deals with the effectiveness of group cognitive behavioral approach for OCD patients, who use antidepressants but were resistant to previous treatment and were attended a daycare center at the Prague Psychiatric Center. The second part of the thesis deals with finding a predictor of successful cognitive behavioral therapy in these patients. The aim was to determine whether certain demographic or clinical factors that we evaluated before treatment may predict success outcome. The result is the finding that severity of the...