Understanding common key indicators of successful and unsuccessful cancer drug trials using a contrast mining framework on ClinicalTrials.gov.

Clinical trials are essential to the process of new drug development. As clinical trials involve significant investments of time and money, it is crucial for trial designers to carefully investigate trial settings prior to designing a trial. Utilizing trial documents from ClinicalTrials.gov, we aim to understand the common characteristics of successful and unsuccessful cancer drug trials to provide insights about what to learn and what to avoid. In this research, we first computationally classified cancer drug trials into successful and unsuccessful cases and then utilized natural language processing to extract eligibility criteria information from the trial documents. To provide explainable and potentially modifiable recommendations for new trial design, contrast mining was applied to discoverhighly contrasted patterns with a significant difference in prevalence between successful (completion with advancement to the next phase) and unsuccessful (suspended, withdrawn, or terminated) groups. Our method identified contrast patterns consisting of combinations of drug categories, eligibility criteria, study organization, and study design for nine major cancers. In addition to a literature review for the qualitative validation of mined contrast patterns, we found that contrast-pattern-based classifiers using the top 200 contrast patterns as feature representations can achieve approximately 80% F1 score for eight out of ten cancer types in our experiments. In summary, aligning with the modernization efforts of ClinicalTrials.gov, our study demonstrates that understanding the contrast characteristics of successful and unsuccessful cancer trials may provide insights into the decision-making process for trial investigators and therefore facilitate improved cancer drug trial design.

One-year duplex ultrasound-assessed closure outcomes of percutaneous endovenous microwave ablation for the treatment of varicose veins of the lower limbs.

PURPOSE: This study aims to investigate the safety and efficacy of a new device using microwave technology for the endovenous ablation of the great saphenous vein (GSV) causing symptomatic lower limb varicose veins (LLVV). MATERIALS AND METHODS: This prospective, single-arm, single-center, cohort study investigated the safety and effectiveness of endovenous microwave ablation for the treatment of symptomatic LLVV. Enrollment period was set between January and December 2020. Primary safety endpoint was the occurrence of procedure-related complications and primary efficacy endpoint was anatomical success defined as the duplex ultrasound (DUS)-proven GSV occlusion at 1 year follow-up. Secondary endpoints included 1-year clinical success (CEAP classification improvement), repeat procedures rate due to GSV recanalization, and pain assessment at 24 h post treatment. RESULTS: In total, 50 patients (42 female; mean age: 62 ± 12 years) with 64 limbs were treated. No procedure-related complications were noted. Technical success was 95.3% (61/64 GSVs), as three cases of GSV recanalization were detected. Clinical success was 100%, as in all cases symptoms improvement by at least one grade according to CEAP classification, was achieved. Mean CEAP grade significantly improved from 3.3 ± 0.72 (median: 3) at baseline to 1.8 ± 0.85 (median: 2) at 1-year (p < 0.0001). There were no repeat procedures due to GSC recanalization. The median 24-h VAS value was 2 (mean: 1.9 ± 1.4). CONCLUSIONS: Endovenous microwave ablation was safe and effective for the treatment of varicose veins, achieving high 1-year GSV occlusion rates.

Health Related Quality of Life and Cardiovascular Risk Factors.

Cardiovascular diseases (CVD) is associated with deteriorating of quality of life (QOL) and exercise capacity (EC) but less is known on how EC interplays with QOL. The present study explores the relationship between quality of life and cardiovascular risk factors in people who present in cardiology clinics. A total of 153 adult presentations completed the SF-36 Health Survey and provided data for hypertension, diabetes mellitus, smoking, obesity, hyperlipidemia and history of coronary heart disease. Physical capacity was assessed by treadmill test. were correlated with the scores of the psychometric questionnaires. Participants with longer duration on treadmill exercise score higher on the scale of physical functioning. The study found that treadmill exercise intensity and duration were associated with improved scores in dimensions of the physical component summary and the physical functioning of SF-36, respectively. The presence of cardiovascular risk factors is related to a decreased quality of life. Patients with cardiovascular diseases should undergo particularly detailed analysis of the quality of life along with specific mental factors such as depersonalization and posttraumatic stress disorder.

Burnout Related to Diabetes Mellitus: A Critical Analysis.

Background: Diabetes burnout is a condition when a patient with diabetes feels tired from his/her disease and neglects it for a certain period or continuously. Objective: Diabetes burnout is frequent, and there is extended literature about psychosocial stress and its negative effects on health. Methods: A search for relevant studies was conducted using PubMed, Google Scholar and ResearchGate. A systematic review was conducted on the relevant articles after critical appraisal. Only publications in English were selected. The objective of this study was to evaluate the association between burnout syndrome and diabetes mellitus. Results: This article mainly focused on studies that evaluated the presence of burnout and diabetes mellitus effects. Diabetes can influence psychological health equally with somatic strength. Relatives can also express depression, guilt, fright, worry, rage, and burnout. Psychosocial job stress and extended working hours are linked with a higher possibility of myocardial infarction, diabetes mellitus, and hypertension. Conclusion: Diabetes burnout is a combination of emotions and practices, ranging from tiredness to indifference, linked with a distressing sense of hopelessness. Revealing this health condition is necessary so that preventive measures can be taken.

A High-Cholesterol Diet Increases Toll-like Receptors and Other Harmful Factors in the Rabbit Myocardium: The Beneficial Effect of Statins.

BACKGROUND: A high-cholesterol diet (HCD) induces vascular atherosclerosis through vascular inflammatory and immunological processes via TLRs. The aim of this study is to investigate the mRNA expression of TLRs and other noxious biomarkers expressing inflammation, fibrosis, apoptosis, and cardiac dysfunction in the rabbit myocardium during (a) high-cholesterol diet (HCD), (b) normal diet resumption and (c) fluvastatin or rosuvastatin treatment. METHODS: Forty-eight male rabbits were randomly divided into eight groups (n = 6/group). In the first experiment, three groups were fed with HCD for 1, 2 and 3 months. In the second experiment, three groups were fed with HCD for 3 months, followed by normal chow for 1 month and administration of fluvastatin or rosuvastatin for 1 month. Control groups were fed with normal chow for 90 and 120 days. The whole myocardium was removed; total RNA was isolated from acquired samples, and polymerase chain reaction, reverse transcription PCR and quantitative real-time PCR were performed. RESULTS: mRNA of TLRs 2, 3, 4 and 8; interleukin-6; TNF-a; metalloproteinase-2; tissue inhibitor of metalloproteinase-1; tumor protein 53; cysteinyl aspartate specific proteinase-3; and brain natriuretic peptide (BNP) increased in HCD. Statins but not resumption of a normal diet decreased levels of these biomarkers and increased levels of antifibrotic factors. CONCLUSIONS: HCD increases the levels of TLRs; inflammatory, fibrotic and apoptotic factors; and BNP in the rabbit myocardium. Atherogenic diets adversely affect the myocardium at a molecular level and are reversed by statins.

Cardiac amyloidosis presenting with coronary artery embolization.

Amyloid light-chain (AL) amyloidosis is a multisystemic disease. Among its clinical manifestations, vein and arterial thromboembolic events are included. We report the unusual case of a 57-year-old female patient with AL amyloidosis presenting with an ST segment elevation myocardial infarction due to coronary artery embolization (CE). The patient reported a history of exertional dyspnoea along with episodes of haemoptysis for the last few months. Her coronary angiography demonstrated embolization of the distal segment of the left anterior descending artery. The main findings of her cardiac ultrasound included concentric left ventricular hypertrophy, mildly impaired left ventricular systolic function, left atrium enlargement and a restrictive-like filling pattern, while her chest computed tomography (CT) demonstrated bilateral pleural effusions. Cardiac magnetic resonance imaging that was performed afterwards, indicated areas of microvascular infarction, a small apex infarct and findings compatible with possible amyloidosis, a diagnosis that was confirmed later by fat tissue biopsy. Patient was referred for an oncology consultation, started therapy with direct oral anticoagulants, angiotensin converting enzyme inhibitor, statins and anti-plasma cell therapy. She has been improving since then and has been free of cardiovascular events for a follow-up period of 12 months. Cardiologists ought to be aware of amyloidosis as a rare but possible cause of coronary embolization, while close collaboration with oncologists is required for the establishment of the correct diagnosis.

Explainable artificial intelligence in high-throughput drug repositioning for subgroup stratifications with interventionable potential.

Enabling precision medicine requires developing robust patient stratification methods as well as drugs tailored to homogeneous subgroups of patients from a heterogeneous population. Developing de novo drugs is expensive and time consuming with an ultimately low FDA approval rate. These limitations make developing new drugs for a small portion of a disease population unfeasible. Therefore, drug repositioning is an essential alternative for developing new drugs for a disease subpopulation. This shows the importance of developing data-driven approaches that find druggable homogeneous subgroups within the disease population and reposition the drugs for these subgroups. In this study, we developed an explainable AI approach for patient stratification and drug repositioning. Contrast pattern mining and network analysis were used to discover homogeneous subgroups within a disease population. For each subgroup, a biomedical network analysis was done to find the drugs that are most relevant to a given subgroup of patients. The set of candidate drugs for each subgroup was ranked using an aggregated drug score assigned to each drug. The proposed method represents a human-in-the-loop framework, where medical experts use the data-driven results to generate hypotheses and obtain insights into potential therapeutic candidates for patients who belong to a subgroup. Colorectal cancer (CRC) was used as a case study. Patients' phenotypic and genotypic data was utilized with a heterogeneous knowledge base because it gives a multi-view perspective for finding new indications for drugs outside of their original use. Our analysis of the top candidate drugs for the subgroups identified by medical experts showed that most of these drugs are cancer-related, and most of them have the potential to be a CRC regimen based on studies in the literature.

Idiopathic hip chondrolysis: a case report of a Caucasian HLA-B27 positive adolescent with a history of long walking.

Idiopathic hip chondrolysis is a rare disorder, the pathophysiology of which has not been fully elucidated. Several theories have been proposed regarding the cause of the disease with some of them involving autoimmune-mediated cartilage destruction. There are several similar features between idiopathic hip chondrolysis and rheumatologic diseases such as juvenile idiopathic arthritis, so whether these two disorders are different or not is still debatable. This case report aims to help comprehending this complex disorder by presenting a case of idiopathic hip chondrolysis with apparent risk factors, such as repetitive microtrauma and presence of HLA-B27 antigens. A 15-year-old HLA-B27 positive male presented with idiopathic hip chondrolysis after excessive walking. Initial treatment consisted of medications including corticosteroids, protected weight bearing and surgical soft tissue release. After failure of all these modalities in restoring the decreased range of motion of the hip, a course of a TNF-inhibitor, etanercept was tried. Alleviation of pain achieved early in the treatment period, but range of motion remained mainly unchanged. Although there was a brief improvement of stiffness for a short period after surgery which lasted for about 3 months, stiffness came back afterwards. Administration of a TNF inhibitor in the following period significantly improved his range of motion. The presence of laboratory findings indicating an autoimmune tendency in this patient supports the hypothesis of susceptibility of these patients to autoimmune reactions, while excessive walking was an apparent trigger factor. In future, traditional treatments may be abandoned in favor of novel medications targeting immunologic pathways.

Electrical Storm: Current Evidence, Clinical Implications, and Future Perspectives.

PURPOSE OF REVIEW: Electrical storm (ES) is a life-threatening medical emergency of repetitive episodes of sustained ventricular arrhythmias within a short period. Its occurrence is associated with poor short- and long-term survival, even in patients with implantable cardioverter defibrillators (ICD). Management of ES is challenging and mainly based on retrospective studies. This article reviews the existing literature on ES, presents the available data regarding its management, and proposes a new algorithm based on current evidence. RECENT FINDINGS: Recent research could modify the management of ES supporting the role of non-selective ß1 and ß2 blockade and the early intervention with catheter ablation as well as strengthening the role of cardiac sympathetic denervation. A multipronged approach should be considered for the management of ES including identification and correction of reversible causes, ICD reprogramming, drug therapy (beta-blockers-especially non-selective ones-and other anti-arrhythmic drugs) and non-pharmacologic therapies such as catheter ablation and techniques of neuroaxial modulation. Although current data suggest early aggressive management, further research is required to clarify the optimal order and combination of therapies for the prevention of future events.

Effect of clarithromycin in patients with suspected Gram-negative sepsis: results of a randomized controlled trial.

BACKGROUND: A previous randomized study showed that clarithromycin decreases the risk of death due to ventilator-associated pneumonia and shortens the time until infection resolution. The efficacy of clarithromycin was tested in a larger population with sepsis. METHODS: Six hundred patients with systemic inflammatory response syndrome due to acute pyelonephritis, acute intra-abdominal infections or primary Gram-negative bacteraemia were enrolled in a double-blind, randomized, multicentre trial. Clarithromycin (1 g) was administered intravenously once daily for 4 days consecutively in 302 patients; another 298 patients were treated with placebo. Mortality was the primary outcome; resolution of infection and hospitalization costs were the secondary outcomes. RESULTS: The groups were well matched for demographics, disease severity, microbiology and appropriateness of the administered antimicrobials. Overall 28 day mortality was 17.1% (51 deaths) in the placebo arm and 18.5% (56 deaths) in the clarithromycin arm (P = 0.671). Nineteen out of 26 placebo-treated patients with septic shock and multiple organ dysfunctions died (73.1%) compared with 15 out of 28 clarithromycin-treated patients (53.6%, P = 0.020). The median time until resolution of infection was 5 days in both arms. In the subgroup with severe sepsis/shock, this was 10 days in the placebo arm and 6 days in the clarithromycin arm (P = 0.037). The cost of hospitalization was lower after treatment with clarithromycin (P = 0.044). Serious adverse events were observed in 1.3% and 0.7% of placebo- and clarithromycin-treated patients, respectively (P = 0.502). CONCLUSIONS: Intravenous clarithromycin did not affect overall mortality; however, administration shortened the time to resolution of infection and decreased the hospitalization costs.

Left Anterior Descending Artery Dissection in a Female Patient With History of Chest Radiation Treatment and Separate Ostia of the Left Coronary Arteries.

Obstructive and flow limiting coronary artery dissections can be a catastrophic clinical scenario, requiring urgent treatment and tailored approach for each case. A 55-year-old female patient, with a history of breast cancer, chest radiation treatments and hypertension presented with episodes of angina and significant area of reversible ischemia on single-photon emission computerized tomography (SPECT). Coronary angiogram revealed separate ostia of the left coronary arteries and three-vessel disease (SYNTAX (Synergy between percutaneous coronary intervention (PCI) with Taxus and Cardiac Surgery) = 15); subsequent full revascularization was achieved successfully with two drug-eluting stents (DES) (mid left anterior descending artery (LAD), left circumflex coronary artery (LCx)) and one drug-coated balloon (posterior descending artery (PDA)). However, after a few hours the patient underwent an urgent second angiography due to ongoing chest pain and electrocardiogram (ECG) changes. Proximal complete occlusion of the anomalous LAD was displayed and a long dissection attributable to an intimal tear following first stent implantation was recorded (well expanded and apposed stent (proximal stent edges were implanted in an unhealthy vessel area infiltrated with fibrotic and calcified plaque) not detectable by conventional angiography). A second 3.5 × 38 mm DES was implanted optimally in the proximal LAD segment and overlapped with the first one, with immediate restoration of the flow and relief of the patient's symptoms. The patient was discharged symptom free and with recommendation for optimal medical treatment for secondary coronary artery disease (CAD) prevention. Conventional coronary angiography in patients with history of chest radiation treatment might not detect accurately the extent and characteristics of the underlying CAD. Appropriate use of intravascular imaging in these cases secures a safe approach for ambiguous lesions and facilitates treatment of iatrogenic coronary dissections following PCI.

Left Axillary Access for Transcatheter Aortic Valve Implantation in a Patient With Two Dependent Internal Mammary Artery Grafts and a Permanent Left-Sided Implanted Pacemaker.

Transfemoral access has been established as the gold standard approach for the majority of patients undergoing transcatheter aortic valve implantation (TAVI). However, in cases with anatomical difficulties or severely diffused peripheral arterial disease, alternative vascular access may be considered such as the transaxillary approach. We present the case of a 92-year-old gentleman with exertional dyspnea due to severe symptomatic aortic stenosis and a history of peripheral femoro-femoral bypass surgery, coronary arterial bypass surgery and a permanent dual-chamber left-side implanted pacemaker. Due to the high surgical risk and the severe anatomical difficulties, the method of TAVI using the left axillary approach was opted. A 14-F vascular sheath was inserted with surgical cutdown and with fluoroscopic guidance while small injections of contrast confirmed the non-occlusive position and the patency of the left internal mammary artery (LIMA) graft. A stiff guidewire was used to cross the heavily calcified aortic valve and subsequently was placed into the left ventricle. Balloon aortic valvuloplasty was performed followed by a successful TAVI with no significant aortic regurgitation or paravalvular leak. The patient recuperated uneventfully and was discharged after 72 h. Axillary access for TAVI is a feasible option for high-risk patients with extended peripheral arteriopathy. To our knowledge this is the first case report describing the implantation of a newer type of intra-annular self-expanding valve platform in a nonagenarian patient with severe comorbidities and such a remarkable history of multiple previous interventions in the selected access site. Meticulous upfront strategy planning and efficient collaboration between specialties is of outmost importance in hybrid procedures for favorable clinical outcomes, especially in cases with challenging anatomies.

Asclepion of Epidaurus: the application of a historical perspective in medical education.

BACKGROUND: The Asclepion of Epidaurus is one of the first healing environments in the world. Descendants of Asclepius, specifically medical students, have been singularly deprived of any information concerning this legacy. This article illuminates the role of Asclepion of Epidaurus and examines the view of medical students upon the subject and the possible benefits of this knowledge in their medical education. METHODS: The participants were 105 senior-year students from the Athens Medical School, who attended a multi-media assisted lecture related to the structure and the role of the Asclepion of Epidaurus. Afterwards, they answered anonymously a questionnaire of 12 pairs of opposite adjectives in order to describe their view regarding the meaning of Asclepion. The method used in the evaluation of their answers was that of semantic differential. RESULTS: The attitude of the students towards the meaning of Asclepion was positive, showing interest and excitement about a powerful, though unfamiliar piece of knowledge. CONCLUSION: Today's novice doctors have welcomed the concept of Asclepion as essential knowledge for the service they will be called to fulfill. The potential benefits of the Asclepian ideals in medical education and ethos are thoroughly discussed.

Psychopathology and Alexithymia in Patients with Moderate-to-Severe Psoriasis: Development of a Novel Index with Prognostic Value.

BACKGROUND: Psoriasis is a chronic, relapsing, inflammatory disease with a high risk of developing mental health difficulties. OBJECTIVE: The purposes of the study were to evaluate in moderate-to-severe psoriasis (a) the prevalence of depression and psychopathology, (b) the relationship between depression, psychopathology symptoms, and alexithymia, including its three dimensions, difficulty in identifying feelings (DIF), difficulty in describing feelings (DDF), and externally oriented thinking (EOT), and (c) to establish a novel index for the development of depression according to patients' psychopathological profile. METHODS: In 104 patients, alexithymia was evaluated with the Toronto Alexithymia Scale (TAS-20), depression with the Beck Depression Inventory (BDI), and psychopathology with the Brief Symptom Inventory SCL-90 (SCL90). A psychopathology index that combines information from the BDI and SCL90 scales was constructed and the performance of the index with alexithymia was examined. RESULTS: Female patients and active smokers score higher on BDI and SCL90 scales. Overweight patients tend to score arithmetically higher. The psychopathology index developed correlates significantly with age, DIF, DDF, and TAS-20. DIF, DDF, and TAS-20 are significant predictors of the psychopathology index. Patients with alexithymia/possible alexithymia are six times as likely to score higher in one of the psychopathology scales. CONCLUSIONS: Alexithymia is a significant factor in the development of psychopathology in psoriasis patients. The use of the proposed novel psychopathology index could be essential in order to identify patients with moderate-to-severe psoriasis who are more likely to experience depression and psychopathology. This could have an impact on the decision-making of psoriasis treatment and monitoring of the patient.

Immune-Related Gene Signatures to Predict the Effectiveness of Chemoimmunotherapy in Triple-Negative Breast Cancer Using Exploratory Subgroup Discovery.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. Although immunotherapy has shown potential in TNBC patients, clinical studies have only demonstrated a modest response. Therefore, the exploration of immunotherapy in combination with chemotherapy is warranted. In this project we identified immune-related gene signatures for TNBC patients that may explain differences in patients' outcomes after anti-PD-L1+chemotherapy treatment. First, we ran the exploratory subgroup discovery algorithm on the TNBC dataset comprised of 422 patients across 24 studies. Secondly, we narrowed down the search to twelve homogenous subgroups based on tumor mutational burden (TMB, low or high), relapse status (disease-free or recurred), tumor cellularity (high, low and moderate), menopausal status (pre- or post) and tumor stage (I, II and III). For each subgroup we identified a union of the top 10% of genotypic patterns. Furthermore, we employed a multinomial regression model to predict significant genotypic patterns that would be linked to partial remission after anti-PD-L1+chemotherapy treatment. Finally, we uncovered distinct immune cell populations (T-cells, B-cells, Myeloid, NK-cells) for TNBC patients with various treatment outcomes. CD4-Tn-LEF1 and CD4-CXCL13 T-cells were linked to partial remission on anti-PD-L1+chemotherapy treatment. Our informatics pipeline may help to select better responders to chemoimmunotherapy, as well as pinpoint the underlying mechanisms of drug resistance in TNBC patients at single-cell resolution.

TBX21 Methylation as a Potential Regulator of Immune Suppression in CMS1 Subtype Colorectal Cancer.

Cytotoxic T lymphocyte (CTL) infiltration is associated with survival, recurrence, and therapeutic response in colorectal cancer (CRC). Immune checkpoint inhibitor (ICI) therapy, which requires CTLs for response, does not work for most CRC patients. Therefore, it is critical to improve our understanding of immune resistance in this disease. We utilized 2391 CRC patients and 7 omics datasets, integrating clinical and genomic data to determine how DNA methylation may impact survival and CTL function in CRC. Using comprehensive molecular subtype (CMS) 1 patients as reference, we found TBX21 to be the only gene with altered expression and methylation that was associated with CTL infiltration. We found that CMS1 patients with high TBX21 expression and low methylation had a significant survival advantage. To confirm the role of Tbx21 in CTL function, we utilized scRNAseq data, demonstrating the association of TBX21 with markers of enhanced CTL function. Further analysis using pathway enrichment found that the genes TBX21, MX1, and SP140 had altered expression and methylation, suggesting that the TP53/P53 pathway may modify TBX21 methylation to upregulate TBX21 expression. Together, this suggests that targeting epigenetic modification more specifically for therapy and patient stratification may provide improved outcomes in CRC.

Cardiovascular toxicity of breast cancer treatment: an update.

Novel chemotherapeutic agents have marked a new era in oncology during the past decade, prolonging significantly the overall survival of breast cancer patients. Nevertheless, contemporary antineoplastic treatments can frequently cause adverse cardiovascular side effects. Common manifestations of chemotherapy-induced cardiotoxicity include cardiomyopathy, ischemia, conduction disturbances, hypertension and thromboembolic events, while the type of the treatment regimen administered crucially determines clinical outcome. The aim of this literature review is to analyze the incidence and the underlying mechanisms of cardiovascular toxicity caused by agents approved for breast cancer, as well as to describe ways of monitoring and treating the cardiotoxic effects in breast cancer patients. Moreover, our work intends to provide an easy-to-grasp synopsis of recent and clinically meaningful advances in the field.

Drug Repositioning and Subgroup Discovery for Precision Medicine Implementation in Triple Negative Breast Cancer.

Breast cancer (BC) is the leading cause of death among female patients with cancer. Patients with triple-negative breast cancer (TNBC) have the lowest survival rate. TNBC has substantial heterogeneity within the BC population. This study utilized our novel patient stratification and drug repositioning method to find subgroups of BC patients that share common genetic profiles and that may respond similarly to the recommended drugs. After further examination of the discovered patient subgroups, we identified five homogeneous druggable TNBC subgroups. A drug repositioning algorithm was then applied to find the drugs with a high potential for each subgroup. Most of the top drugs for these subgroups were chemotherapy used for various types of cancer, including BC. After analyzing the biological mechanisms targeted by these drugs, ferroptosis was the common cell death mechanism induced by the top drugs in the subgroups with neoplasm subdivision and race as clinical variables. In contrast, the antioxidative effect on cancer cells was the common targeted mechanism in the subgroup of patients with an age less than 50. Literature reviews were used to validate our findings, which could provide invaluable insights to streamline the drug repositioning process and could be further studied in a wet lab setting and in clinical trials.

Copper metabolism as a unique vulnerability in cancer.

The last 25 years have witnessed tremendous progress in identifying and characterizing proteins that regulate the uptake, intracellular trafficking and export of copper. Although dietary copper is required in trace amounts, sufficient quantities of this metal are needed to sustain growth and development in humans and other mammals. However, copper is also a rate-limiting nutrient for the growth and proliferation of cancer cells. Oral copper chelators taken with food have been shown to confer anti-neoplastic and anti-metastatic benefits in animals and humans. Recent studies have begun to identify specific roles for copper in pathways of oncogenic signaling and resistance to anti-neoplastic drugs. Here, we review the general mechanisms of cellular copper homeostasis and discuss roles of copper in cancer progression, highlighting metabolic vulnerabilities that may be targetable in the development of anticancer therapies.

Differences in Performance of ASD and ADHD Subjects Facing Cognitive Loads in an Innovative Reasoning Experiment.

We aim to investigate whether EEG dynamics differ in adults with ASD (Autism Spectrum Disorders) and ADHD (attention-deficit/hyperactivity disorder) compared with healthy subjects during the performance of an innovative cognitive task, Aristotle's valid and invalid syllogisms, and how these differences correlate with brain regions and behavioral data for each subject. We recorded EEGs from 14 scalp electrodes (channels) in 21 adults with ADHD, 21 with ASD, and 21 healthy, normal subjects. The subjects were exposed in a set of innovative cognitive tasks (inducing varying cognitive loads), Aristotle's two types of syllogism mentioned above. A set of 39 questions were given to participants related to valid-invalid syllogisms as well as a separate set of questionnaires, in order to collect a number of demographic and behavioral data, with the aim of detecting shared information with values of a feature extracted from EEG, the multiscale entropy (MSE), in the 14 channels ('brain regions'). MSE, a nonlinear information-theoretic measure of complexity, was computed to extract a feature that quantifies the complexity of the EEG. Behavior-Partial Least Squares Correlation, PLSC, is the method to detect the correlation between two sets of data, brain, and behavioral measures. -PLSC, a variant of PLSC, was applied to build a functional connectivity of the brain regions involved in the reasoning tasks. Graph-theoretic measures were used to quantify the complexity of the functional networks. Based on the results of the analysis described in this work, a mixed 14 × 2 × 3 ANOVA showed significant main effects of group factor and brain region* syllogism factor, as well as a significant brain region* group interaction. There are significant differences between the means of MSE (complexity) values at the 14 channels of the members of the 'pathological' groups of participants, i.e., between ASD and ADHD, while the difference in means of MSE between both ASD and ADHD and that of the control group is not significant. In conclusion, the valid-invalid type of syllogism generates significantly different complexity values, MSE, between ASD and ADHD. The complexity of activated brain regions of ASD participants increased significantly when switching from a valid to an invalid syllogism, indicating the need for more resources to 'face' the task escalating difficulty in ASD subjects. This increase is not so evident in both ADHD and control. Statistically significant differences were found also in the behavioral response of ASD and ADHD, compared with those of control subjects, based on the principal brain and behavior saliences extracted by PLSC. Specifically, two behavioral measures, the emotional state and the degree of confidence of participants in answering questions in Aristotle's valid-invalid syllogisms, and one demographic variable, age, statistically and significantly discriminate the three groups' ASD. The seed-PLC generated functional connectivity networks for ASD, ADHD, and control, were 'projected' on the regions of the Default Mode Network (DMN), the 'reference' connectivity, of which the structural changes were found significant in distinguishing the three groups. The contribution of this work lies in the examination of the relationship between brain activity and behavioral responses of healthy and 'pathological' participants in the case of cognitive reasoning of the type of Aristotle's valid and invalid syllogisms, using PLSC, a machine learning approach combined with MSE, a nonlinear method of extracting a feature based on EEGs that captures a broad spectrum of EEGs linear and nonlinear characteristics. The results seem promising in adopting this type of reasoning, in the future, after further enhancements and experimental tests, as a supplementary instrument towards examining the differences in brain activity and behavioral responses of ASD and ADHD patients. The application of the combination of these two methods, after further elaboration and testing as new and complementary to the existing ones, may be considered as a tool of analysis in helping detecting more effectively such types of disorders.