OBJECTIVE: Various treatments of brain tumors may affect ovarian and endocrine function, resulting in a plethora of disorders. The purpose of this study was to analyze the impact of brain tumors on ...ovarian health and endocrine function in female childhood survivors. STUDY DESIGN: Ovarian and endocrine function in 222 childhood cancer survivors diagnosed with brain tumors at a tertiary comprehensive cancer center between 1997-2008 was retrospectively analyzed and compared. RESULTS: An equal proportion of childhood survivors of brain tumors (N = 39) and survivors of non-brain tumors (N = 183) developed ovarian dysfunction. Of those children older than 13 years, menstrual cycle irregularity (36% of brain tumor survivors vs. 21% of non-brain survivors, p = 0.3), amenorrhea (22% vs. 22% respectively, p = 0.9), and elevated FSH levels (40% vs. 50%, p = 0.9) were not statistically significant between the two groups. Brain tumor survivors experienced increased risk of endocrine disorders, such as precocious puberty (13% vs. 2%, P = 0.005), delayed puberty (8% vs. 1%, P = 0.0178), and hypopituitarism (10% vs. 1%, P = 0.01). Furthermore, children with brain tumors were significantly more likely to develop multiple endocrine disorders at the same time (31% vs. 7%, P = 0.001 for two endocrine disorders and 23% vs. 2%, P= 0.0001 for three or more endocrine disorders) and were more likely to visit with an endocrinologist (46% vs. 14%, p = 0.0001), when compared to non-brain tumor cancer survivors. While all brain tumor patients were seen at the multi-specialty neuroncology clinic, they were less likely to attend survivor clinic (4% vs. 28%, p = <0.003), and more likely to receive assistance from survivor clinic staff (97% vs. 57%, p = 0.001), when compared to non-brain tumor cancer survivors. CONCLUSIONS: Female pediatric brain tumor survivors are equally likely to experience ovarian insufficiency when compared to non-brain tumor survivors, but were significantly more likely to suffer coexistence of multiple endocrine problems.
Older individuals typically display stronger regional brain activity than younger subjects during motor performance. However, knowledge regarding age-related changes of motor network interactions ...between brain regions remains scarce. We here investigated the impact of ageing on the interaction of cortical areas during movement selection and initiation using dynamic causal modelling (DCM). We found that age-related psychomotor slowing was accompanied by increases in both regional activity and effective connectivity, especially for ‘core’ motor coupling targeting primary motor cortex (M1). Interestingly, younger participants within the older group showed strongest connectivity targeting M1, which steadily decreased with advancing age. Conversely, prefrontal influences on the motor system increased with advancing age, and were inversely correlated with reduced parietal influences and core motor coupling. Interestingly, higher net coupling within the prefrontal-premotor-M1 axis predicted faster psychomotor speed in ageing. Hence, as opposed to a uniform age-related decline, our findings are compatible with the idea of different age-related compensatory mechanisms, with an important role of the prefrontal cortex compensating for reduced coupling within the core motor network.
•Enhanced motor network activity and connectivity in ageing•Parietal-premotor and premotor-M1 coupling decreases with advancing age.•Prefrontal influences on the motor system increase with advancing age.•Prefrontal cortex compensates for age-related decline in other motor connections.•Prefrontal-premotor-M1 coupling predicts psychomotor speed in ageing.
Background and Purpose
The cyclin‐dependent kinase CDK9 is an important therapeutic target but currently available inhibitors exhibit low specificity and/or narrow therapeutic windows. Here we have ...used a new highly specific CDK9 inhibitor, LDC000067 to interrogate gene control mechanisms mediated by CDK9.
Experimental Approach
The selectivity of LDC000067 was established in functional kinase assays. Functions of CDK9 in gene expression were assessed with in vitro transcription experiments, single gene analyses and genome‐wide expression profiling. Cultures of mouse embryonic stem cells, HeLa cells, several cancer cell lines, along with cells from patients with acute myelogenous leukaemia were also used to investigate cellular responses to LDC000067.
Key Results
The selectivity of LDC000067 for CDK9 over other CDKs exceeded that of the known inhibitors flavopiridol and DRB. LDC000067 inhibited in vitro transcription in an ATP‐competitive and dose‐dependent manner. Gene expression profiling of cells treated with LDC000067 demonstrated a selective reduction of short‐lived mRNAs, including important regulators of proliferation and apoptosis. Analysis of de novo RNA synthesis suggested a wide ranging positive role of CDK9. At the molecular and cellular level, LDC000067 reproduced effects characteristic of CDK9 inhibition such as enhanced pausing of RNA polymerase II on genes and, most importantly, induction of apoptosis in cancer cells.
Conclusions and Implications
Our study provides a framework for the mechanistic understanding of cellular responses to CDK9 inhibition. LDC000067 represents a promising lead for the development of clinically useful, highly specific CDK9 inhibitors.
Patients suffering from Parkinson's disease (PD) often show impairments in executive function (EF) like decision-making and action control. The right dorsolateral prefrontal cortex (dlPFC) has been ...strongly implicated in EF in healthy subjects and has repeatedly been reported to show alterations related to EF impairment in PD. Recently, two key regions for cognitive action control have been identified within the right dlPFC by co-activation based parcellation. While the posterior region is engaged in rather basal EF like stimulus integration and working memory, the anterior region has a more abstract, supervisory function. To investigate whether these functionally distinct subdivisions of right dlPFC are differentially affected in PD, we analyzed resting-state functional connectivity (FC) in 39 PD patients and 44 age- and gender-matched healthy controls. Patients were examined both after at least 12 h withdrawal of dopaminergic drugs (OFF) and under their regular dopaminergic medication (ON). We found that only the posterior right dlPFC subdivision shows FC alterations in PD, while the anterior part remains unaffected. PD-related decreased FC with posterior right dlPFC was found in the bilateral medial posterior parietal cortex (mPPC) and left dorsal premotor region (PMd) in the OFF state. In the medical ON, FC with left PMd normalized, while decoupling with bilateral mPPC remained. Furthermore, we observed increased FC between posterior right dlPFC and the bilateral dorsomedial prefrontal cortex (dmPFC) in PD in the ON state. Our findings point to differential disturbances of right dlPFC connectivity in PD, which relate to its hierarchical organization of EF processing by stronger affecting the functionally basal posterior aspect than the hierarchically higher anterior part.
The number of molecular imaging studies in the field of brain connectivity is steadily increasing.Molecular imaging is not yet widely used by the MRI-predominant neuroimaging community as tool of ...choice for studying brain connectomics.Because chemical synapses are essential to signal transduction, targeting the molecular level of brain communication is indispensable for our understanding of the brain connectome.PET as major molecular imaging tool provides various established markers of neural activity, neurotransmitter systems, and proteinopathies.Integration of connectomes produced with different neurophysiological methods, including molecular imaging, might be key for advancing the field of neuroscience.
In the past two decades brain connectomics has evolved into a major concept in neuroscience. However, the current perspective on brain connectivity and how it underpins brain function relies mainly on the hemodynamic signal of functional magnetic resonance imaging (MRI). Molecular imaging provides unique information inaccessible to MRI-based and electrophysiological techniques. Thus, positron emission tomography (PET) has been successfully applied to measure neural activity, neurotransmission, and proteinopathies in normal and pathological cognition. Here, we position molecular imaging within the brain connectivity framework from the perspective of timeliness, validity, reproducibility, and resolution. We encourage the neuroscientific community to take an integrative approach whereby MRI-based, electrophysiological techniques, and molecular imaging contribute to our understanding of the brain connectome.
Evidence for the potent influence of stromal organization and function on invasion and metastasis of breast tumors is ever growing. We have performed a rigorous examination of the relationship of a ...tumor-associated collagen signature-3 (TACS-3) to the long-term survival rate of human patients. TACS-3 is characterized by bundles of straightened and aligned collagen fibers that are oriented perpendicular to the tumor boundary. An evaluation of TACS-3 was performed in biopsied tissue sections from 196 patients by second harmonic generation imaging of the backscattered signal generated by collagen. Univariate analysis of a Cox proportional hazard model demonstrated that the presence of TACS-3 was associated with poor disease-specific and disease-free survival, resulting in hazard ratios between 3.0 and 3.9. Furthermore, TACS-3 was confirmed to be an independent prognostic indicator regardless of tumor grade and size, estrogen or progesterone receptor status, human epidermal growth factor receptor-2 status, node status, and tumor subtype. Interestingly, TACS-3 was positively correlated to expression of stromal syndecan-1, a receptor for several extracellular matrix proteins including collagens. Because of the strong statistical evidence for poor survival in patients with TACS, and because the assessment can be performed in routine histopathological samples imaged via second harmonic generation or using picrosirius, we propose that quantifying collagen alignment is a viable, novel paradigm for the prediction of human breast cancer survival.
Malignant dysphagia due to esophagogastric cancer is associated with poor overall prognosis. Placements of self-expandable metal stents or plastic tubes are established methods as palliative ...treatment options. As an alternative and/or complementary therapy, radiologic techniques (external beam radiation/brachytherapy) and locally endoscopic techniques (laser, APC-beamer, PDT) are often used. STUDY AND GOALS: Retrospective trial of 153 patients treated in our department between 1993 and 2001. Forty-five patients received a plastic tube (Group A) and 108 patients were treated with metal stents (Group B). Both groups were compared for improvement of dysphagia score, survival, recurrent dysphagia and complications.
Stent placement was successful in 41 of 45 (93%) patients of Group A and 107 of 108 (99%) of Group B. The median dysphagia score improved significantly in Group A (from 3.03 to 1.55, P = 0.010) and Group B (from 2.77 to 1.44, P = 0.009). Recurrent dysphagia was noted in 12 of 45 (27%) patients of Group A and 27 of 108 (25%) patients of Group B. Median survival time after stent insertion was 78 days (Group A) and 113 days (Group B). Overall complications occurred in 15 of 45 (33%) patients of Group A and 28 of 108 (26%) patients of Group B. However, significantly (P = 0.05) more major complications were seen in Group A than in Group B (22% vs. 9%).
Our results indicate a marginal clinical benefit for metal stents versus plastic tubes in malignant dysphagia in the long run. However, metal stents seem to be safer and associated with a prolonged improvement of dysphagia score.
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