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Over the past 5 years, improvements in the design of antibody–drug conjugates (ADCs) have enabled major advances that have reshaped the treatment of several advanced-stage solid tumours. Considering the intended rationale behind the design of ADCs, which is to achieve targeted delivery of cytotoxic molecules by linking them to antibodies targeting tumour-specific antigens, ADCs would be expected to be less toxic than conventional chemotherapy. However, most ADCs are still burdened by off-target toxicities that resemble those of the cytotoxic payload as well as on-target toxicities and other poorly understood and potentially life-threatening adverse effects. Given the rapid expansion in the clinical indications of ADCs, including use in curative settings and various combinations, extensive efforts are ongoing to improve their safety. Approaches currently being pursued include clinical trials optimizing the dose and treatment schedule, modifications of each ADC component, identification of predictive biomarkers for toxicities, and the development of innovative diagnostic tools. In this Review, we describe the determinants of the toxicities of ADCs in patients with solid tumours, highlighting key strategies that are expected to improve tolerability and enable improvements in the treatment outcomes of patients with advanced-stage and those with early stage cancers in the years to come.Advances in technology have enabled the development of several novel antibody–drug conjugates (ADCs) with encouraging clinical activity in patients with advanced-stage solid tumours. Indications for these therapies are expanding rapidly to earlier lines of therapy. Nonetheless, the toxicities of these various agents are not trivial and can be fatal, even in patients with early stage disease. In this Review, the authors summarize the toxicities of ADCs in patients with solid tumours both as monotherapies and in combination with other agents and discuss various ongoing research efforts attempting to optimize the therapeutic index of these agents.

In a study involving men with castration-resistant prostate cancer and bone metastases, the alpha emitter radium-223 significantly prolonged survival, as compared with placebo, and was associated with fewer adverse events. More than 90% of patients with metastatic castration-resistant prostate cancer have radiologic evidence of bone metastases, which are a major cause of death, disability, decreased quality of life, and increased treatment cost among these patients. 1 , 2 Unlike deaths from many other types of cancer, deaths from prostate cancer are often due to bone disease and its complications. 3 Current bone-targeted therapies have not been shown to improve survival, and the benefits derived from bisphosphonates, denosumab, and existing radioisotope treatments are primarily limited to pain relief and delay of skeletal events. 4 – 13 Radium-223 dichloride (radium-223) is a targeted alpha emitter that selectively . . .

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-ß signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1β as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight diabetic PDAC patients.

The purpose of this research is to synthesize the fragmented extant knowledge on flexible and green supply chain management (FGSCM) in the context of emerging economies and to unearth research gaps to motivate future research. We adopted a novel structured systematic literature review by triangulating a systematic literature review, text mining, and network analysis. Institutional theory and contingency theory were employed to analyze the results of the review. The results show that, firstly, research on FGSCM in emerging economies, despite its importance, is immature compared to general FGSCM literature. Second, the specificities of strategies and practices that distinguish this topic in emerging economies are discussed and the drivers and barriers are identified with respect to sources of institutional pressure. Third, a research framework for FGSCM in emerging economies is developed and 12 gaps for future research are identified. This study has exclusively developed a research framework for FGSCM in an emerging economy which has received the least consideration in the literature and practice. The framework was developed to synthesize the existing literature and to identify the research gaps to inspire future research.

The EUROFORGEN NAME panel is a regional ancestry panel designed to differentiate individuals from the Middle East, North Africa, and Europe. The first version of the panel was developed for the MassARRAY system and included 111 SNPs. Here, a custom AmpliSeq EUROFORGEN NAME panel with 102 of the original 111 loci was used to sequence 1098 individuals from 14 populations from Europe, the Middle East, North Africa, North-East Africa, and South-Central Asia. These samples were also sequenced with a global ancestry panel, the Precision ID Ancestry Panel. The GenoGeographer software was used to assign the AIM profiles to reference populations and calculate the weight of the evidence as likelihood ratios. The combination of the EUROFORGEN NAME and Precision ID Ancestry panels led to fewer ambiguous assignments, especially for individuals from the Middle East and South-Central Asia. The likelihood ratios showed that North African individuals could be separated from European and Middle Eastern individuals using the Precision ID Ancestry Panel. The separation improved with the addition of the EUROFORGEN NAME panel. The analyses also showed that the separation of Middle Eastern populations from European and South-Central Asian populations was challenging even when both panels were applied.

Background To understand how suicide management occurs within the primary care setting in terms of follow-up assessments and referral practices. Methods At an initial primary care visit, adolescents (aged 12–20 years old) completed electronic screening. Data were focused on youth who endorsed a suicidal risk item while completing screening at two Midwestern primary care clinics. Data were collected through retrospective chart reviews to analyze actions taken by the primary care physician at the youth’s initial visit and follow-up visit within the next 12 months. Results At initial visits 200 adolescents endorsed a suicidal risk item and 39 (19.5%) were considered to be concerning by their primary care physician. The average age was 14.7 years old (SD ± 2.0). Seventy-two percent ( n  = 144) were female, and 65% ( n  = 129) identified as Black. At initial visits, significant differences between suicidal concern groups were found in reporting active suicidal ideation, past suicide attempts, those who were referred to behavioral health counseling, and those who had a diagnosis of depression. Interestingly, only 13% ( n  = 25) of all patients who endorsed the suicide item were asked whether or not there were weapons in their home and primary care providers asked only 7% ( n  = 13) of all patients whether they had a safety plan. Conclusions There was inconsistent follow-up for adolescents with a history of suicide concerns. At this time, national guidelines do not exist regarding primary care follow-up of youth with suicide concerns. Guidelines are a necessary precursor for practice improvement. Trial Registration Clinical Trials Registry: NCT02244138 . Registration date, September 1, 2014.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders without available pharmacological therapies. Dynasore is a cell-permeable molecule that inhibits GTPase activity and exerts protective effects in several disease models. However, whether dynasore can alleviate lipopolysaccharide (LPS)-induced ALI is unknown. This study investigated the effect of dynasore on macrophage activation and explored its potential mechanisms in LPS-induced ALI in vitro and in vivo. Bone marrow-derived macrophages (BMDMs) were activated classically with LPS or subjected to NLRP3 inflammasome activation with LPS+ATP. A mouse ALI model was established by the intratracheal instillation (i.t.) of LPS. The expression of PYD domains-containing protein 3 (NLRP3), caspase-1, and gasdermin D (GSDMD) protein was detected by Western blots. Inflammatory mediators were analyzed in the cell supernatant, in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assays. Morphological changes in lung tissues were evaluated by hematoxylin and eosin staining. F4/80, Caspase-1 and GSDMD distribution in lung tissue was detected by immunofluorescence. Dynasore downregulated nuclear factor (NF)-κB signaling and reduced proinflammatory cytokine production in vitro and inhibited the production and release of interleukin (IL)-1β, NLRP3 inflammasome activation, and macrophage pyroptosis through the Drp1/ROS/NLRP3 axis. Dynasore significantly reduced lung injury scores and proinflammatory cytokine levels in both BALF and serum in vivo, including IL-1β and IL-6. Dynasore also downregulated the co-expression of F4/80, caspase-1 and GSDMD in lung tissue. Collectively, these findings demonstrated that dynasore could alleviate LPS-induced ALI by regulating macrophage pyroptosis, which might provide a new therapeutic strategy for ALI/ARDS.

Dupilumab‐associated head and neck dermatitis (HND) is a rare and often underrecognized condition, especially in patients with skin of color. It can vary from subtle to severe presentations, with violaceous hues and seborrheic distribution after dupilumab initiation. Early recognition and management are crucial to prevent treatment discontinuation.

Experiments are performed in a supersonic non-reacting flow facility to investigate the performance of an axisymmetric aft wall angled cavity with upstream fuel injection in a Mach 1.8 flow field. The supersonic combustor has a circular cross sectional duct in which cavities are introduced at a distance of 20 mm from the inlet. The aft wall of the cavity is tapered towards flow downstream and inclined with two step consecutive angles. Flush wall mounted injector is mounted at the upstream of the cavity. The tests are conducted at three fuel injection pressures to simulate the flow field in the present study. The mixing performance of the aft wall angled cavities are analysed based on the momentum flux distribution at the exit of the combustor and the stagnation pressure loss across the combustor and compared with the rectangular cavity. Transverse upstream injection of aft wall angled cavities enhances mixing than rectangular cavities, deliberated with less stagnation pressure loss from the former. Increase in injection pressures resulted in more uniform mixing across the flow direction of the combustor irrespective of the cavity configuration, concurrently induces more stagnation pressure loss due to increase in jet penetration depth into the main stream.

Improved cookstoves and fuels, such as advanced gasifier stoves, carry the promise of improving health outcomes, preserving local environments, and reducing climate-forcing air pollutants. However, low adoption and use of these stoves in many settings has limited their benefits. We aimed to improve the understanding of improved stove use by describing the patterns and predictors of adoption of a semi-gasifier stove and processed biomass fuel intervention in southwestern China. Of 113 intervention homes interviewed, 79% of homes tried the stove, and the majority of these (92%) continued using it 5-10 months later. One to five months after intervention, the average proportion of days that the semi-gasifier stove was in use was modest (40.4% [95% CI 34.3-46.6]), and further declined over 13 months. Homes that received the stove in the first batch used it more frequently (67.2% [95% CI 42.1−92.3] days in use) than homes that received it in the second batch (29.3% [95% CI 13.8−44.5] days in use), likely because of stove quality and user training. Household stove use was positively associated with reported cooking needs and negatively associated with age of the main cook, household socioeconomic status, and the availability of substitute cleaner-burning stoves. Our results show that even a carefully engineered, multi-purpose semi-gasifier stove and fuel intervention contributed modestly to overall household energy use in rural China.