Search

The Baltic Sea is still impacted by numerous pressures. More efforts are needed to reduce them for achieving healthy and resilient marine ecosystems and their sustainable uses. This can only be reached through the cooperation of Baltic Sea states and strong regional governance. The HELCOM Baltic Sea Action Plan 2021 is the promising instrument to implement these efforts for the Baltic Sea and to advance the global objectives of marine protection.

The functions of many microbial communities exhibit remarkable stability despite fluctuations in the compositions of these communities. To date, a mechanistic understanding of this function-composition decoupling is lacking. Statistical mechanisms have been commonly hypothesized to explain such decoupling. Here, we proposed that dynamic mechanisms, mediated by horizontal gene transfer (HGT), also enable the independence of functions from the compositions of microbial communities. We combined theoretical analysis with numerical simulations to illustrate that HGT rates can determine the stability of gene abundance in microbial communities. We further validated these predictions using engineered microbial consortia of different complexities transferring one or more than a dozen clinically isolated plasmids, as well as through the re-analysis of data from the literature. Our results demonstrate a generalizable strategy to program the gene stability of microbial communities.

Background: Palliative care is well suited to support patients hospitalized with COVID-19, but integration into care has been variable and generally poor. Aim: To understand barriers and facilitators of palliative care integration for hospitalized patients with COVID-19. Methods: Internists, Intensivists and palliative care physicians completed semi-structured interviews about their experiences providing care to patients with COVID-19. Results were analysed using thematic analysis. Results: Twenty-three physicians (13 specialist palliative care, five intensivists, five general internists) were interviewed; mean ± SD age was 42 ± 11 years and 61% were female. Six thematic categories were described including: patient and family factors, palliative care knowledge, primary provider factors, COVID-19 specific factors, palliative care service factors, and leadership and culture factors. Patient and family factors included patient prognosis, characteristics that implied prognosis (i.e., age, etc.), and goals of care. Palliative care knowledge included confidence in primary palliative care skills, misperception that COVID-19 is not a ‘palliative diagnosis’, and the need to choose quantity or quality of life in COVID-19 management. Primary provider factors included available time, attitude, and reimbursement. COVID-19 specific factors were COVID-19 as an impetus to act, uncertain illness trajectory, treatments and outcomes, and infection control measures. Palliative care service factors were accessibility, adaptability, and previous successful relationships. Leadership and culture factors included government-mandated support, presence at COVID planning tables, and institutional and unit culture. Conclusion: The study findings highlight the need for leadership support for formal integrated models of palliative care for patients with COVID-19, a palliative care role in pandemic planning, and educational initiatives with primary palliative care providers.

Microbial communities inhabit spatial architectures that divide a global environment into isolated or semi-isolated local environments, which leads to the partitioning of a microbial community into a collection of local communities. Despite its ubiquity and great interest in related processes, how and to what extent spatial partitioning affects the structures and dynamics of microbial communities are poorly understood. Using modeling and quantitative experiments with simple and complex microbial communities, we demonstrate that spatial partitioning modulates the community dynamics by altering the local interaction types and global interaction strength. Partitioning promotes the persistence of populations with negative interactions but suppresses those with positive interactions. For a community consisting of populations with both positive and negative interactions, an intermediate level of partitioning maximizes the overall diversity of the community. Our results reveal a general mechanism underlying the maintenance of microbial diversity and have implications for natural and engineered communities.

Combined application of multiple therapeutic agents presents the possibility of enhanced efficacy and reduced development of resistance. Definition of the most appropriate combination for any given disease phenotype is challenged by the vast number of theoretically possible combinations of drugs and doses, making extensive empirical testing a virtually impossible task. We have used the streamlined-feedback system control (s-FSC) technique, a phenotypic approach, which converges to optimized drug combinations (ODC) within a few experimental steps. Phosphoproteomics analysis coupled to kinase activity analysis using the novel INKA (integrative inferred kinase activity) pipeline was performed to evaluate ODC mechanisms in a panel of renal cell carcinoma (RCC) cell lines. We identified different ODC with up to 95% effectivity for each RCC cell line, with low doses (ED5&ndash, 25) of individual drugs. Global phosphoproteomics analysis demonstrated inhibition of relevant kinases, and targeting remaining active kinases with additional compounds improved efficacy. In addition, we identified a common RCC ODC, based on kinase activity data, to be effective in all RCC cell lines under study. Combining s-FSC with a phosphoproteomic profiling approach provides valuable insight in targetable kinase activity and allows for the identification of superior drug combinations for the treatment of RCC.

Despite significant advances in treatment, chronic obstructive pulmonary disease (COPD) remains a chronic and progressive disease that frequently leads to premature mortality. COPD is associated with a constellation of significant symptoms, including dyspnea, cough, wheezing, pain, fatigue, anxiety, depression, and insomnia, and is associated with increased morbidity. Palliative care is appropriate to support these patients. However, historically, palliative care has focused on supporting patients with malignant disease, rather than progressive chronic diseases such as COPD. Therapies for COPD often result in functional and symptomatic improvements, including health-related quality of life (HRQL), and palliative care may further improve symptoms and HRQL. Provision of usual palliative care therapies for this patient population requires understanding the pathogenesis of COPD and common disease-targeted pharmacotherapies, as well as an approach to balancing life-prolonging and HRQL care strategies. This review describes COPD and current targeted therapies and their effects on symptoms, exercise tolerance, HRQL, and survival. It is important to note that medications commonly used for symptom management in palliative care can interact with COPD medications resulting in increased risk of adverse effects, enhanced toxicity, or changes in clearance of medications. To address this, we review pharmacologic interactions with and precautions related to use of COPD therapies in conjunction with commonly used palliative care medications.

Despite several advances in treatment, idiopathic pulmonary fibrosis (IPF) remains a progressive, symptomatic, and terminal disease in patients not suitable for lung transplantation. With disease progression, IPF often leads to a constellation of symptoms, including dyspnea, cough, anxiety, and depression. Palliative care is appropriate to support these patients. However, traditional curriculum in palliative care has often focused on supporting patients with malignant disease, and clinicians are not universally trained to manage patients with progressive nonmalignant diseases such as IPF. Current antifibrotic therapies aim to slow disease progression but are not able to reduce symptoms or improve daily function and health-related quality of life (HRQL). Palliative care in this patient group requires an understanding of the clinical characteristics of IPF, comorbidities, common medications used, and nonpharmacological strategies that can be undertaken to improve daily function and HRQL. This review focuses on IPF management strategies and their effects on symptoms, exercise tolerance, HRQL, and survival. Pharmacological interactions and considerations related to commonly used palliative care medications are also reviewed. This review highlights the needs of patients with IPF and caregivers, psychosocial function, patient-reported assessment tools, and topics related to advance care planning.

Pulmonary arterial hypertension (PAH) is often a progressive and ultimately fatal disease. It is characterized by an elevated mean pulmonary arterial pressure because of disease of the small pulmonary arterioles. PAH leads to a constellation of symptoms, including dyspnea, fatigue, syncope, chest discomfort, and peripheral edema. Disease-targeted therapies for PAH produce symptomatic and functional improvement, but long-term survival remains uncommon without lung transplantation. Palliative care is appropriate to support patients with advanced PAH who typically have a high symptom burden. However, palliative care has historically focused on supporting patients with malignant disease, rather than progressive chronic disease such as PAH. Our aim is to provide palliative care clinicians with a background in the classification, pathophysiology, and modern treatment of PAH. This review describes disease-targeted therapies and their effects on symptoms, physical functioning, and health-related quality of life. We also review the unique physiology of PAH and its implication for palliative interventions. Pharmacological interactions with, and precautions related to commonly used palliative care medications, are discussed.

Effective communication between healthcare providers (HCPs) and patients is important for HCP well-being, patient engagement, and health outcomes. Yet, HCPs do not receive adequate communication skills training and report feeling unprepared for difficult conversations. A needs assessment of 64 cancer HCP trainees in Toronto, Canada, found that a majority of trainees rated themselves with low competency in communication skills to support patients through difficult conversations, while nearly all rated these skills as important to their practice. A blended multiprofessional communications program was developed including online theoretical learning and reflective practice in addition to in-person simulation with standardised patient actors. Since communication skills mastery is highly unlikely to occur at the termination of a single training program, the goal of the program was to stimulate participants’ motivational beliefs about difficult conversations communication skills in order to deepen their commitment to learning and mastery. The motivational beliefs assessed included self-efficacy (self-perceived competence), intent to use techniques learned, and confidence in task mastery. After completing the course, participants’ self-perceived competence in dealing with difficult conversations significantly increased by an average of 25 points (p

The spread of genes encoding antibiotic resistance is often mediated by horizontal gene transfer (HGT). Many of these genes are associated with transposons, a type of mobile genetic element that can translocate between the chromosome and plasmids. It is widely accepted that the translocation of antibiotic resistance genes onto plasmids potentiates their spread by HGT. However, it is unclear how this process is modulated by environmental factors, especially antibiotic treatment. To address this issue, we asked whether antibiotic exposure would select for the transposition of resistance genes from chromosomes onto plasmids and, if so, whether antibiotic concentration could tune the distribution of resistance genes between chromosomes and plasmids. We addressed these questions by analysing the transposition dynamics of synthetic and natural transposons that encode resistance to different antibiotics. We found that stronger antibiotic selection leads to a higher fraction of cells carrying the resistance on plasmids because the increased copy number of resistance genes on multicopy plasmids leads to higher expression of those genes and thus higher cell survival when facing antibiotic selection. Once they have transposed to plasmids, antibiotic resistance genes are primed for rapid spread by HGT. Our results provide quantitative evidence for a mechanism by which antibiotic selection accelerates the spread of antibiotic resistance in microbial communities.

The article compiles essential information regarding the Rules of Origin provided in the trade agreements to which Brazil is a party, including the Free Trade Agreement (FTA)’s signed by Mercosur. The focus is to point out the differences in the preferential Rules of origin provided in the different trade agreements signed by Brazil and Mercosur, especially in relation to the value-added requirement when imported inputs from non-state parties are used to manufacture a finished product. Rules of origin, preferential rules of origin, non-preferential rules of origin, Brazil, Certificates of Origin

The past 20 years have witnessed enormous progress in synthetic biology in the development of engineered cells for diverse applications, including biomanufacturing, materials fabrication, and potential therapeutics and diagnostics. However, it still remains a major challenge to maintain long-term performance of synthetic gene circuits, due to the emergence of mutants that lose circuit function. Here, we highlight major vulnerabilities of synthetic gene circuits resulting in circuit failure and mutant escape. We also discuss engineering strategies to enhance long-term circuit stability and performance. These approaches can be divided into two strategies: the suppression of the emergence of mutants and the suppression of their relative fitness if mutants do emerge. We anticipate that mechanistic understanding of the modes of circuit failure will facilitate future efforts to design evolutionarily robust synthetic biology-inspired applications.

Plasmids are a major type of mobile genetic elements (MGEs) that mediate horizontal gene transfer. The stable maintenance of plasmids plays a critical role in the functions and survival for microbial populations. However, predicting and controlling plasmid persistence and abundance in complex microbial communities remain challenging. Computationally, this challenge arises from the combinatorial explosion associated with the conventional modeling framework. Recently, a plasmid-centric framework (PCF) has been developed to overcome this computational bottleneck. This framework enables the derivation of a simple metric, the persistence potential, to predict plasmid persistence and abundance. Here, we discuss how PCF can be extended to account for plasmid interactions. We also discuss how such model-guided predictions of plasmid fates can benefit from the development of new experimental tools and data-driven computational methods.

Ammon’s book Georgia Between Statehood and Russian Occupation. The Roots of the Russian-Georgian Conflict From the 18th Century to the End of the First Georgian Republic (1921) moves against the in...

Changes not only at macro level but also at micro level are required to create more sustainable and efficient essential services in Africa. From this perspective, how can we promote change in consumer behaviour when we know that it is difficult to transform habits and beliefs that are rooted in everyday life? A set of four articles has been chosen to describe in detail consumer education strategies put in place to create awareness and changes in consumer and citizen behavior. A comparative and analytical approach helps understand how: i) the diffusion of off-grid solar energy in rural areas is facilitated by a few key principles of consumer education strategy; ii) social network have become a civic mobilization channel for cleaning up garbage in public spaces; iii) the future of drinking water is transformed by journeys of citizen mobilization.

Effective communication between healthcare providers (HCPs) and patients is important for HCP well-being, patient engagement, and health outcomes. Yet, HCPs do not receive adequate communication skills training and report feeling unprepared for difficult conversations. A needs assessment of 64 cancer HCP trainees in Toronto, Canada, found that a majority of trainees rated themselves with low competency in communication skills to support patients through difficult conversations, while nearly all rated these skills as important to their practice. A blended multiprofessional communications program was developed including online theoretical learning and reflective practice in addition to in-person simulation with standardised patient actors. Since communication skills mastery is highly unlikely to occur at the termination of a single training program, the goal of the program was to stimulate participants' motivational beliefs about difficult conversations communication skills in order to deepen their commitment to learning and mastery. The motivational beliefs assessed included self-efficacy (self-perceived competence), intent to use techniques learned, and confidence in task mastery. After completing the course, participants' self-perceived competence in dealing with difficult conversations significantly increased by an average of 25 points (p 0.001) on a rating scale of 1-100 (n = 40). Participants' intent to use techniques did not change significantly and remained high with an overall average of 89 points. After the course, participants rated their confidence in mastering techniques learned at an average score of 71 points. Multiprofessional, simulation-based training is an effective way to improve HCP trainees' motivational beliefs around having difficult conversations.

ObjectivesPatients with chronic respiratory disease have significant palliative care needs, but low utilisation of specialist palliative care (SPC) services. Decreased access to SPC results in unmet palliative care needs among this patient population. We sought to determine the referral practices to SPC among respirologists in Canada.MethodsRespirologists across Canada were invited to participate in a survey about their referral practices to SPC. Associations between referral practices and demographic, professional and attitudinal factors were analysed using regression analyses.ResultsThe response rate was 64.7% (438/677). Fifty-nine per cent of respondents believed that their patients have negative perceptions of palliative care and 39% were more likely to refer to SPC earlier if it was renamed supportive care. While only 2.7% never referred to SPC, referral was late in 52.6% of referring physicians. Lower frequency of referral was associated with equating palliative care to end-of-life care (pConclusionsPossible barriers to respirologists’ timely SPC referral include misperceptions about palliative care, lack of awareness of referral criteria and the belief that SPC services prioritise patients with cancer. Future studies should confirm these barriers and evaluate the effectiveness of strategies to overcome them.

Re-visiting the “territorial trap,” the introduction reviews approaches that have substantially addressed Agnew’s critique, such as in transnational scholarship, governance research, border studies...

The article provides a comparative exploration of the role of Ottoman legacies and contemporary Turkish influences in shaping political space in the Black Sea regions of Adjara and Abkhazia. Conceptualizing both as borderlands, the article focuses on borderland practices related to three kinds of transboundary flows between Turkey and Adjara and Abkhazia, respectively: flows of goods and capital, flows of people, and flows of ideas. The article draws on a wide range of secondary sources as well as on data from field research in Abkhazia, Adjara, and Turkey. It discloses how borderland practices have contributed to fragmented and convergent configurations of authority in both regions and underlines a threefold character of borderland practices which reflect and reproduce understandings of illegitimacy and illicitness, cosmopolitan sociability, and struggles over belonging.

Background Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance. Methods We approached this challenge mathematically by using the validated technology called the Therapeutically Guided Multidrug Optimization (TGMO) method. In a set of genetically distinct human renal cell carcinoma (RCC) cell lines, either treated chronically with sunitinib (−ST) or sunitinib-naive, we identified cell line-specific low-dose-optimised drug combinations (ODC). Results Six cell-type-specific low-dose drug combinations for three sunitinib-naive as well as three sunitinib pre-treated cells were established. These ODCs effectively inhibited the RCC cell metabolic activity while being ineffective in non-cancerous cells. Based on a single screening test and three searches, starting with ten drugs, we identified highly efficacious drug mixtures containing four drugs. All ODCs contained AZD4547 (FGFR signalling pathway inhibitor) and pictilisib (pan-phosphatidylinositol 3-kinase inhibitor), but varied in the third and fourth drug. ODC treatment significantly decreased cell metabolic activity (up to 70%) and induced apoptosis, independent of the pretreatment with sunitinib. The ODCs outperformed sunitinib, the standard care for RCC. Moreover, short-term starvation potentiated the ODC activity. The translation of the 2D-based results to 3D heterotypic co-culture models revealed significant inhibition of the spheroid growth (up to 95%). Conclusion We demonstrate a promising low-dose drug combination development to obtain drug combinations effective in naive as well as resistant tumours. Nevertheless, we emphasise the need for further mechanistic investigation and preclinical development.

Clear cell renal cell carcinoma (ccRCC) is characterized by high histone deacetylase (HDAC) activity triggering both cell motility and the development of metastasis. Therefore, there is an unmet need to establish innovative strategies to advance the use of HDAC inhibitors (HDACIs). We selected a set of tyrosine kinase inhibitors (TKIs) and HDACIs to test them in combination, using the validated therapeutically guided multidrug optimization (TGMO) technique based on experimental testing and in silico data modeling. We determined a synergistic low-dose three-drug combination decreasing the cell metabolic activity in metastatic ccRCC cells, Caki-1, by over 80%. This drug combination induced apoptosis and showed anti-angiogenic activity, both in original Caki-1 and in sunitinib-resistant Caki-1 cells. Through phosphoproteomic analysis, we revealed additional targets to improve the translation of this combination in 3-D (co-)culture systems. Cell&ndash, cell and cell&ndash, environment interactions increased, reverting the invasive and metastatic phenotype of Caki-1 cells. Our data suggest that our optimized low-dose drug combination is highly effective in complex in vitro settings and promotes the activity of HDACIs.

During sprouting angiogenesis, an individual endothelial tip cell grows out from a pre-existing vascular network and guides following and proliferating stalk cells to form a new vessel. Metabolic pathways such as glycolysis and mitochondrial respiration as the major sources of adenosine 5′-triphosphate (ATP) for energy production are differentially activated in these types of endothelial cells (ECs) during angiogenesis. Therefore, we studied energy metabolism during angiogenesis in more detail in tip cell and non-tip cell human umbilical vein ECs. Small interfering RNA was used to inhibit transcription of glycolytic enzymes PFKFB3 or LDHA and mitochondrial enzyme PDHA1 to test whether inhibition of these specific pathways affects tip cell differentiation and sprouting angiogenesis in vitro and in vivo. We show that glycolysis is essential for tip cell differentiation, whereas both glycolysis and mitochondrial respiration occur during proliferation of non-tip cells and in sprouting angiogenesis in vitro and in vivo. Finally, we demonstrate that inhibition of mitochondrial respiration causes adaptation of EC metabolism by increasing glycolysis and vice versa. In conclusion, our studies show a complex but flexible role of the different metabolic pathways to produce ATP in the regulation of tip cell and non-tip cell differentiation and functioning during sprouting angiogenesis.

A major limitation of clinically used cancer drugs is the lack of specificity resulting in toxicity. To address this, we performed a phenotypically-driven screen to identify optimal multidrug combinations acting with high efficacy and selectivity in clear cell renal cell carcinoma (ccRCC). The search was performed using the Therapeutically Guided Multidrug Optimization (TGMO) method in ccRCC cells (786-O) and nonmalignant renal cells and identified a synergistic low-dose four-drug combination (C2) with high efficacy and negligible toxicity. We discovered that C2 inhibits multipolar spindle pole clustering, a survival mechanism employed by cancer cells with spindle abnormalities. This phenotype was also observed in 786-O cells resistant to sunitinib, the first line ccRCC treatment, as well as in melanoma cells with distinct percentages of supernumerary centrosomes. We conclude that C2-treatment shows a high efficacy in cells prone to form multipolar spindles. Our data suggest a highly effective and selective C2 treatment strategy for malignant and drug-resistant cancers.

Despite significant advances in heart failure (HF) treatment, HF remains a progressive, extremely symptomatic, and terminal disease with a median survival of 2.1 years after diagnosis. HF often leads to a constellation of symptoms, including dyspnea, fatigue, depression, anxiety, insomnia, pain, and worsened cognitive function. Palliative care is an approach that improves the quality of life of patients and their caregivers facing the problems associated with life-threatening illness and therefore is well suited to support these patients. However, historically, palliative care has often focused on supporting patients with malignant disease, rather than a progressive chronic disease such as HF. Predicting mortality in patients with HF is challenging. The lack of obvious transition points in disease progression also raises challenges to primary care providers and specialists to know at what point to integrate palliative care during a patient's disease trajectory. Although therapies for HF often result in functional and symptomatic improvements including health-related quality of life (HRQL), some patients with HF do not demonstrate these benefits, including those patients with a preserved ejection fraction. Provision of palliative care for patients with HF requires an understanding of HF pathogenesis and common medications used for these patients, as well as an approach to balancing life-prolonging and HRQL care strategies. This review describes HF and current targeted therapies and their effects on symptoms, hospital admission rates, exercise performance, HRQL, and survival. Pharmacological interactions with and precautions related to commonly used palliative care medications are reviewed. The goal of this review is to equip palliative care clinicians with information to make evidence-based decisions while managing the balance between optimal disease management and patient quality of life.

Background: Crenolanib is a tyrosine kinase inhibitor targeting PDGFR-α, PDGFR-β and Fms related tyrosine kinase-3 (FLT3) that is currently evaluated in several clinical trials. Although platelet-derived growth factor receptor (PDGFR) signalling pathway is believed to play an important role in angiogenesis and maintenance of functional vasculature, we here demonstrate a direct angiostatic activity of crenolanib independently of PDGFR signalling. Methods: The activity of crenolanib on cell viability, migration, sprouting, apoptosis and mitosis was assessed in endothelial cells, tumour cells and fibroblasts. Alterations in cell morphology were determined by immunofluorescence experiments. Flow-cytometry analysis and mRNA expression profiles were used to investigate cell differentiation. In vivo efficacy was investigated in human ovarian carcinoma implanted on the chicken chorioallantoic membrane (CAM). Results: Crenolanib was found to inhibit endothelial cell viability, migration and sprout length, and induced apoptosis independently of PDGFR expression. Treated cells showed altered actin arrangement and nuclear aberrations. Mitosis was affected at several levels including mitosis entry and centrosome clustering. Crenolanib suppressed human ovarian carcinoma tumour growth and angiogenesis in the CAM model. Conclusions: The PDGFR/FLT3 inhibitor crenolanib targets angiogenesis and inhibits tumour growth in vivo unrelated to PDGFR expression. Based on our findings, we suggest a broad mechanism of action of crenolanib.

Formal training for residents-as-teachers in psychiatry is increasingly emphasized. However, little is known about the quantity and content of residents’ teaching, their attitudes toward teaching, or the training received on how to teach. An online survey was disseminated to American and Canadian psychiatry residents. Three hundred eighty-two residents from all postgraduate years (PGY) responded, representing about 7 % of all trainees. About half of PGY-1 have not received residents-as-teachers training, but by PGY-3 most have. The majority of respondents reported teaching, most commonly 1–5 h. Most found teaching enjoyable or rewarding (n = 304; 87 %); however, 40 % (n = 138) found teaching burdensome, 43 % (n = 151) lacked sufficient time to teach, and many (n = 226; 64 %) reported insufficient feedback from supervisors. Although the sampling methodology and low response rate limit the generalizability of findings, respondents typically seemed to value teaching, though the majority felt that they lacked feedback on their teaching skills.

Chlorambucil (CLB) derivatives with long fluorous (referred to as 1 and 2) or hydrocarbon (3) chains have been evaluated in a series of in vitro and in vivo assays. In cell viability inhibition assays, both derivatives 2 and 3 show selective cytotoxicity towards human immortalized endothelial cells (ECRF24), while lacking activity against human ovarian carcinoma cell lines, contrary to the activity of CLB. Compound 3 also significantly inhibits sprout formation in an in vivo model of induced angiogenesis following photodynamic vascular occlusion in the chorioallantoic membrane (CAM) model. Moreover, intravenous administration of CLB and its derivatives in the non-perturbed CAM vasculature resulted in important changes in the vascular morphology. Notably, the growth of human ovarian carcinoma tumors implanted on the CAM was significantly inhibited by 2 and 3, i.e. by 70 and 53%, respectively, compared to vehicle treated tumors. Taken together, these results show that anchoring long fluorous or hydrocarbon chains to the carboxylic group of CLB leads to compounds showing increased anti-angiogenic activity which also effectively inhibit tumor growth in vivo.

The cytotoxicity of cisplatin (cDDP) is enhanced when co-administered with ethacrynic acid (EA), a glutathione S-transferase (GST) inhibito r. A Pt-lV­ EA conjugate containing a cDDP core and two axial ethacrynate ligands (compound 1) was shown to be an excellent inhibitor of GST, but did not readily release a Pt-li species to exert a synergistic cytotoxic effect. ln this study, a redesigned Pt-IV construct composed of a cDDP core with one axial ethacrynate ligand and one axial hydroxido ligand (compound 2) was prepared and shown to overcome the limitations of compound 1. The EA ligand in 2 is readily released in vitro together with a cytotoxic Pt-li species derived from cisplatin, working together to inhibit cell proliferation in cDDP-resistant human ovarian cancer cells. The in vitro activity translates well in vivo with 2, showing effective (approximate to 80%) inhibition of tumor growth in a human ovarian carcinoma A2780 tumor model, while showing considerably lower toxicity than cisplatin, thus validating the new design strategy.

Purpose To develop entrustable professional activities (EPAs) for psychiatry and to demonstrate an innovative, validity-enhancing methodology that may be relevant to other specialties. Method A national task force employed a three-stage process from May 2014 to February 2017 to develop EPAs for psychiatry. In stage 1, the task force used an iterative consensus-driven process to construct proposed EPAs. Each included a title, full description, and relevant competencies. In stage 2, the task force interviewed four nonpsychiatric experts in EPAs and further revised the EPAs. In stage 3, the task force performed a Delphi study of national experts in psychiatric education and assessment. All survey participants completed a brief training program on EPAs. Quantitative and qualitative analysis led to further modifications. Essentialness was measured on a five-point scale. EPAs were included if the content validity index was at least 0.8 and the lower end of the asymmetric confidence interval was not lower than 4.0. Results Stages 1 and 2 yielded 24 and 14 EPAs, respectively. In stage 3, 31 of the 39 invited experts participated in both rounds of the Delphi study. Round 1 reduced the proposed EPAs to 13. Ten EPAs met the inclusion criteria in Round 2. Conclusions The final EPAs provide a strong foundation for competency-based assessment in psychiatry. Methodological features such as critique by nonpsychiatry experts, a national Delphi study with frame-of-reference training, and stringent inclusion criteria strengthen the content validity of the findings and may serve as a model for future efforts in other specialties.

We investigated perceived authoritarian and authoritative parenting styles in mothers and fathers, academic procrastination, maladaptive perfectionism, and both affective and cognitive test anxieties using self-reports of 206 undergraduates (women = 160; men = 46). Supporting study hypotheses, academic procrastination and maladaptive perfectionism concurrently mediated the positive relationship between perceived authoritarian fathering and both affective and cognitive test anxieties, but only maladaptive perfectionism mediated the positive relationship between perceived authoritarian mothering and both affective and cognitive test anxieties. Conversely, supporting study hypotheses, academic procrastination and maladaptive perfectionism concurrently mediated the inverse relationship between perceived authoritative parenting (in mothers and fathers separately) and both affective and cognitive test anxieties. Our study added to the literature by establishing academic procrastination and maladaptive perfectionism as concurrent mediators in the relationships between perceived parenting styles and test anxiety, except for perceived authoritarian mothering. These findings could improve academic success and retention efforts among vulnerable undergraduates.

Angiostatic therapies are now routinely embedded in the daily clinical management of cancer. Although these agents clearly benefit patient survival rates, the effect is only moderate with sometimes considerable side effects. A major cause of failure in this respect is the induction of resistance and tolerability against these drugs. Most angiostatic drugs are tyrosine kinase inhibitors that aim to inhibit or neutralize the activity of tumour-produced growth factors. Frustrating the tumour cells in this way results in genetic adaptations in the cells, turning them into mutants that are dependent on other growth mechanisms. It may therefore be necessary to shift to another class of drugs that directly target the tumour vasculature. It is evident that improvement of future angiogenesis inhibitors can only arise from two efforts. First, through the identification of better targets, preferably specifically expressed in the tumour vasculature. Secondly, through the development of combination therapies. The present review highlights the current efforts and challenges in trying to develop effective angiostatic combination therapies.

Ruthenium-based compounds show strong potential as anti-cancer drugs and are being investigated as alternatives to other well-established metal-based chemotherapeutics. The organometallic compound [Ru(η6-p-cymene)Cl2(pta)], where pta = 1,3,5-triaza-7-phosphaadamantane (RAPTA-C) exhibits broad acting anti-tumor efficacy with intrinsic angiostatic activity. In the search for an optimal anti-angiogenesis drug combination, we identified synergistic potential between RAPTA-C and the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. This drug combination results in strong synergistic inhibition of cell viability in human endothelial (ECRF24 and HUVEC) and human ovarian carcinoma (A2780 and A2780cisR) cells. Additionally, erlotinib significantly enhances the cellular uptake of RAPTA-C relative to treatment with RAPTA-C alone in human ovarian carcinoma cells, but not endothelial cells. Drug combinations induce the formation of chromosome bridges that persist after mitotic exit and delay abscission in A2780 and A2780cisR, therefore suggesting initiation of cellular senescence. The therapeutic potential of these compounds and their combination is further validated in vivo on A2780 tumors grown on the chicken chorioallantoic membrane (CAM) model, and in a preclinical model in nude mice. Immunohistochemical analysis confirms effective anti-angiogenic and anti-proliferative activity in vivo, based on a significant reduction of microvascular density and a decrease in proliferating cells.

Palliative care is an interprofessional approach that focuses on quality of life of patients who are facing life-threatening illness. Palliative care is consistently associated with improvements in advance care planning, patient and caregiver satisfaction, quality of life, symptom burden, and lower healthcare utilization. Most transplant patients have advanced chronic disease, significant symptom burden, and mortality awaiting transplant. Transplantation introduces new risks including perioperative death, organ rejection, infection, renal insufficiency, and malignancy. Numerous publications over the last decade identify that palliative care is well-suited to support these patients and their caregivers, yet access to palliative care and research within this population are lacking. This review describes palliative care and summarizes existing research supporting palliative intervention in advanced organ failure and transplant populations. A proposed model to provide palliative care in parallel with disease-directed therapy in a transplant program has the potential to improve symptom burden, quality of life, and healthcare utilization. Further studies are needed to elucidate specific benefits of palliative care for this population. In addition, there is a tremendous need for education, specifically for clinicians, patients, and families, to improve understanding of palliative care and its benefits for patients with advanced disease.

The identification of effective and long-lasting cancer therapies still remains elusive, partially due to patient and tumor heterogeneity, acquired drug resistance, and single-drug dose-limiting toxicities. The use of drug combinations may help to overcome some limitations of current cancer therapies by challenging the robustness and redundancy of biological processes. However, effective drug combination optimization requires the careful consideration of numerous parameters. The complexity of this optimization problem is clearly nontrivial and likely requires the assistance of advanced heuristic optimization techniques. In the current review, we discuss the application of optimization techniques for the identification of optimal drug combinations. More specifically, we focus on the application of phenotype-based screening approaches in the field of cancer therapy. These methods are divided into three categories: (1) modeling methods, (2) model-free approaches based on biological search algorithms, and (3) merged approaches, particularly phenotypically driven network biology methods and computation network models relying on phenotypic data. In addition to a brief description of each approach, we include a critical discussion of the advantages and disadvantages of each method, with a strong focus on the limitations and considerations needed to successfully apply such methods in biological research.