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Video to go with: Prolonging the life of people with metastatic breast cancer in routine clinical practice by adding palbociclib to an aromatase inhibitor from a real-world database analysis: a plain language summary

Additional file 1: Table S1. Spearman correlations between immune cell subsets and CMV-microbe score.

BackgroundDepression and anxiety are leading causes of disability worldwide. Though effective treatments exist, depression and anxiety remain undertreated. Blended care psychotherapy, combining the scalability of online interventions with the personalization and engagement of a live therapist, is a promising approach for increasing access to evidence-based care.ObjectivesTo evaluate the effectiveness and individual contribution of two components - i) digital tools and ii) video-based therapist-led sessions - in a blended care CBT-based intervention under real world conditions.MethodsA retrospective cohort design was used to analyze N=1372 US-based individuals who enrolled in blended care psychotherapy. Of these, at baseline, 761 participants had depression symptoms in the clinical range (based on PHQ-9), and 1254 had anxiety symptoms in the clinical range (based on GAD-7). Participants had access to the program as a mental health benefit offered by their employer. The CBT-based blended care psychotherapy program consisted of regular video sessions with therapists, complemented by digital lessons and digital exercises assigned by the clinician and completed in between sessions. Depression and anxiety levels and clients' treatment engagement were tracked throughout treatment. A 3-level individual growth curve model incorporating time-varying covariates was utilized to examine symptom trajectories of PHQ-9 scores (for those with clinical range of depression at baseline) and GAD-7 scores (for those with clinical range of anxiety at baseline).ResultsOn average, individuals exhibited a significant decline in depression and anxiety symptoms during the initial weeks of treatment (P&nbsp

Background Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo-fetal development testing, are we ready to consider a different approach to human developmental toxicity testing? Methods A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We first consider what changes to the current protocols might be recommended to make them more predictive for human risk (evolution). Results The evolutionary approach includes modifications of existing protocols and can include humanized models, disease models, more accurate assessment and testing of metabolites, and informed approaches to dose selection. The revolution could start with hypothesis-driven testing where we take what we know about a compound or close analog and answer specific questions using targeted experimental techniques rather than a one-protocol-fits-all approach. Central to the idea of hypothesis-driven testing is the concept that testing can be done at the level of mode of action. It might be feasible to identify a small number of key events at a molecular or cellular level that predict an adverse outcome and for which testing could be performed in vitro or in silico or, rarely, using limited in vivo models. Techniques for evaluating these key events exist today or are in development. Discussion Opportunities exist for refining and then replacing current developmental toxicity testing protocols using techniques that have already been developed or are within reach.

The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.

In the United States, recent killings of civilians by law enforcement have propelled body cameras to the forefront of solutions to the “epidemic” of police misconduct. Preliminary studies suggest that body cameras create a win-win situation for both the police and the public by producing a civilizing effect on all parties involved. The problem, however, is that not every law enforcement agency has a body camera program. And among those that do, the surprising lack of legal action raises the question: How effective are body cameras in ensuring that justice is served? This Note discusses the use of body cameras in American policing on the streets and at the borders. It provides a background into the problem of police misconduct and highlights arguments in favor of and cautioning against body camera technology. Finally, in light of the Trump administration’s pro-law enforcement stance, this Note investigates high-profile police killings and assesses existing border policies to consider whether body cameras can truly deliver on their promise.

Tissue hypoxia has been implicated in the pathogenesis of various kidney diseases. Yet, because of technical limitations, temporal and spatial aspects of tissue hypoxia in the pathogenesis of kidney disease have received little attention. The recent development of the oxygen telemeter allowed for the possibility for the investigation into the contribution of tissue hypoxia in the progression of kidney diseases over long periods of time. We validated and established that the inherent offset in the telemeter was stable throughout the implantation period after a 5 day ‘bedding in’ period. The primary aim of this PhD project was to utilize the recently developed oxygen telemeter; the Clark electrode and pimonidazole adduct immunohistochemistry to determine both the temporal and spatial distribution of tissue hypoxia in the subacute phase of acute kidney injury induced by renal ischemia reperfusion injury. The tissue damage in response to an hour of anoxia was vast, such that tubular elements were often observed to be riddled with intraluminal casts, cellular sloughing and thinning of the epithelium. Interestingly, despite the extensive cellular damage, we could not detect tissue hypoxia at 24 h and 5 days after reperfusion of the kidney in both the cortex and the medulla using the oxygen telemeter and the Clark electrode. In contrast, the widespread staining pattern of pimonidazole adduct suggest otherwise i.e. cellular hypoxia was prominent in the subacute phase of ischemia reperfusion injury. A large proportion of these stained adducts was associated with tissue damage. Thus, the presence of these adducts was likely artifactual and is not reflective of ‘true hypoxia’. The absence of tissue hypoxia was likely contributed by the marked reduction of renal oxygen consumption and well maintained renal oxygen delivery. In conclusion, the absence of tissue hypoxia in the acute and subacute phase of ischemia reperfusion injury indicates that tissue hypoxia may not be an important driver of the pathogenesis of ischemia reperfusion injury. However, tissue damage in the subacute phase may lead to tissue hypoxia in the chronic phase of ischemia reperfusion injury. This line of inquiry could be investigated by instrumenting rats with the oxygen telemeter for weeks following recovery from ischemia surgery. Using Clark electrodes, we directly quantified tissue PO2 in rats with advanced polycystic kidney disease. There was extensive tissue hypoxia in both the renal parenchyma and within the cysts. Renal tissue hypoxia in these rats was driven by a greater reduction in renal oxygen delivery than renal oxygen consumption. The data presented in this thesis reinforce the need to consider both spatial and temporal aspects of tissue hypoxia in various forms of kidney disease in order to verify the importance of tissue hypoxia in driving the pathogenesis of kidney diseases.

In a previous phase 2 trial, axitinib was active and well tolerated in patients with advanced thyroid cancer. In this second phase 2 trial, the efficacy and safety of axitinib were evaluated further in this population, and pharmacokinetic/pharmacodynamic relationships and patient-reported outcomes were assessed.Patients (N = 52) with metastatic or unresectable, locally advanced medullary or differentiated thyroid cancer that was refractory or not amenable to iodine-131 received a starting dose of axitinib 5 mg twice daily. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetic parameters, and patient-reported outcomes assessed with the MD Anderson Symptom Inventory questionnaire.The overall ORR was 35% (18 partial responses), and 18 patients had stable disease for ≥16 weeks. The median PFS was 16.1 months, and the median OS was 27.2 months. All-causality, grade ≥3 adverse events (5%) were fatigue, dyspnea, diarrhea, decreased weight, pain in extremity, hypertension, decreased appetite, palmar-plantar erythrodysesthesia, hypocalcemia, and myalgia. Patients who had greater axitinib exposure had a longer median PFS. Quality of life was maintained during treatment with axitinib, and no significant deterioration in symptoms or interference in daily life caused by symptoms, assessed on MD Anderson Symptom Inventory subscales, were observed.Axitinib has activity and a manageable safety profile while maintaining quality of life, and it represents an additional treatment option for patients with advanced thyroid cancer.

Metastatic renal cell cancer is associated with poor long-term survival and has no cure. Traditional clinical endpoints are best supplemented by patient-reported outcomes designed to assess symptoms and function. Normative data was obtained on the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Kidney Symptom Index (NFKSI) to aid in score interpretation and planning of future trials.General population data were obtained from 2000 respondents, who completed the 19-item NFKSI-19, as well the SF-36 (Short Form 36-item instrument) and the PROMIS-29 (29-item Patient Reported Outcomes Measurement Information System), both general health status measures. Basic demographic and self-reported comorbidity data were also collected.The sample was 50% female, 85.7% caucasian, with an equal distribution across age bands from 18 years to 75 years and older. Most respondents (62.8%) had more than a high school education and reported an Eastern Cooperative Oncology Group performance status of normal activity without symptoms (63.4%). Score distributions on the NFKSI-19, its subscales, and individual items are summarized.The NFKSI-19 and its subscales now have scores for the general US population, allowing comparability to generic questionnaires such as the SF-36 and PROMIS-29. These data can be used to guide treatment expectations and plan future comparative effectiveness research using the scales.

SOX2 is a pan-neural transcription factor expressed in neural precursor cells (NPCs) independently of their regional identity. It plays a crucial role in both neural development and in adult neurogenesis; however the molecular mechanisms underlying its function are poorly understood. Our previous data suggested that SOX2 controls LIN28, an inhibitor of let-7 miRNA biogenesis. We hypothesized that some of the pan-neural functions of SOX2 could be mediated by repression of let-7 miRNA activity. To identify miRNAs with pan-neural SOX2 dependency, I used NPCs with two different regional identities, dorsal and ventral. I modified a previously established human embryonic stem cell (hESC)-derivation protocol (which generated dorsal NPCs) by patterning NPCs with the Sonic hedgehog agonist purmorphamine, yieding ventral NPCs. Analysis of SOX2 targets in dorsal and ventral NPCs in addition to bioinformatics suggested that SOX2 represses the levels of let-7b and let-7i miRNA. Overexpression studies of let-7b and let-7i revealed that let-7b selectively suppresses NPC proliferation with no effect on neuronal differentiation, while let-7i abolishes neuronal differentiation without inhibiting NPC proliferation. These data suggest that the combined effect of let-7b and let-7i overexpression in NPCs photocopies the loss of SOX2 in these cells. Taken together, our results suggest that in our in vitro cultures, SOX2 suppresses the activity of let-7 miRNAs in NPCs. We propose that the function of let- 7 miRNA family downstream of SOX2 may be a general mechanism for controlling both NPC proliferation and neurogenesis in developmental and adult contexts

Mesenchymal stem cells (MSCs) are capable of differentiating into bone, cartilage and adipose tissues. We identified BMP9 as the most potent osteoinductive BMP although detailed mechanism underlying BMP9-regulated osteogenesis of MSCs is indeterminate. Emerging evidence indicates that autophagy plays a critical role in regulating bone homeostasis. We investigated the possible role of autophagy in osteogenic differentiation induced by BMP9. We showed that BMP9 upregulated the expression of multiple autophagy-related genes in MSCs. Autophagy inhibitor chloroquine (CQ) inhibited the osteogenic activity induced by BMP9 in MSCs. While overexpression of ATG5 or ATG7 did not enhance osteogenic activity induced by BMP9, silencing Atg5 expression in MSCs effectively diminished BMP9 osteogenic signaling activity and blocked the expression of the osteogenic regulator Runx2 and the late marker osteopontin induced by BMP9. Stem cell implantation study revealed that silencing Atg5 in MSCs profoundly inhibited ectopic bone regeneration and bone matrix mineralization induced by BMP9. Collectively, our results strongly suggest a functional autophagy pathway may play an essential role in regulating osteogenic differentiation induced by BMP9 in MSCs. Thus, restoration of dysregulated autophagic activity in MSCs may be exploited to treat fracture healing, bone defects or osteoporosis.