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Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.

Recent advancements in shRNA and Cas protein technologies have enabled functional screening methods targeting genes or non-coding regions using single or pooled shRNA and sgRNA. CRISPR-based systems have also been developed for modulating DNA accessibility, resulting in CRISPR-mediated interference (CRISPRi) or activation (CRISPRa) of targeted genes or genomic DNA elements. However, there is still a lack of software tools for integrating diverse array of functional genomics screening outputs that could offer a cohesive framework for comprehensive data integration. Here, we developed PitViper, a flexible and interactive open-source software designed to fill this gap, providing reliable results for the type of elements being screened. It is an end-to-end automated and reproducible bioinformatics pipeline integrating gold-standard methods for functional screening analysis. Our sensitivity analyses demonstrate that PitViper is a useful tool for identifying potential super-enhancer liabilities in a leukemia cell line through genome-wide CRISPRi-based screening. It offers a robust, flexible, and interactive solution for integrating data analysis and reanalysis from functional screening methods, making it a valuable resource for researchers in the field.

Evaluating health outcomes in Down syndrome-associated Alzheimer's disease (DS-AD) is challenging due to variability in baseline function and cognition. Personalized outcome assessments, like Goal Attainment Scaling (GAS), can address this gap and capture treatment responses across varying baseline states and symptom manifestations. However, implementation must be standardized through tools such as goal inventories. Here, we assessed the content validity of the DS-AD goal inventory (Knox et al., 2020, 2021) and investigated the feasibility and acceptability of inventory-facilitated GAS as a patient-centric tool to evaluate treatment response.BACKGROUNDEvaluating health outcomes in Down syndrome-associated Alzheimer's disease (DS-AD) is challenging due to variability in baseline function and cognition. Personalized outcome assessments, like Goal Attainment Scaling (GAS), can address this gap and capture treatment responses across varying baseline states and symptom manifestations. However, implementation must be standardized through tools such as goal inventories. Here, we assessed the content validity of the DS-AD goal inventory (Knox et al., 2020, 2021) and investigated the feasibility and acceptability of inventory-facilitated GAS as a patient-centric tool to evaluate treatment response.We conducted a prospective, 16-month, non-interventional study using the DS-AD goal inventory to facilitate GAS with caregivers of individuals with Down syndrome. The inventory included 58 goal areas distributed across behavior, cognition, daily function, executive function, and physical manifestation domains. The content validity of the goal inventory was assessed through a qualitative analysis of goal scales and alignment with the existing inventory. Goal count, goal scale completeness, and interview durations were used as feasibility indicators. An end-of-study survey evaluated acceptability.METHODWe conducted a prospective, 16-month, non-interventional study using the DS-AD goal inventory to facilitate GAS with caregivers of individuals with Down syndrome. The inventory included 58 goal areas distributed across behavior, cognition, daily function, executive function, and physical manifestation domains. The content validity of the goal inventory was assessed through a qualitative analysis of goal scales and alignment with the existing inventory. Goal count, goal scale completeness, and interview durations were used as feasibility indicators. An end-of-study survey evaluated acceptability.Forty-six caregivers set 3 goals with 5-levels each and assessed goal attainment at the 3 (n =45) and 16-month follow-ups (n =43). Mean interview times were 38.6 (±10.4) minutes for goal-setting and 17.9 (±9.5) and 14.5 (±4.7) minutes for 3- and 16-month follow-ups. Out of 138 goals, 117 were initially selected from the inventory. The qualitative analysis indicated that the majority of the goals were from the Daily Function (n =65) and Behavior (n =26) domains (Figures 1&2), and that the inventory covered 125 (91%) goals. A qualitative analysis of the remaining goals (n =13) revealed diet and physical activity as additional goal areas. Survey results (n =33) indicated that caregivers had positive experiences with GAS (n =31), found their goals meaningful (n =31), valued improved clinician communication (n =30), and gained new perspectives and knowledge (n =10).RESULTForty-six caregivers set 3 goals with 5-levels each and assessed goal attainment at the 3 (n =45) and 16-month follow-ups (n =43). Mean interview times were 38.6 (±10.4) minutes for goal-setting and 17.9 (±9.5) and 14.5 (±4.7) minutes for 3- and 16-month follow-ups. Out of 138 goals, 117 were initially selected from the inventory. The qualitative analysis indicated that the majority of the goals were from the Daily Function (n =65) and Behavior (n =26) domains (Figures 1&2), and that the inventory covered 125 (91%) goals. A qualitative analysis of the remaining goals (n =13) revealed diet and physical activity as additional goal areas. Survey results (n =33) indicated that caregivers had positive experiences with GAS (n =31), found their goals meaningful (n =31), valued improved clinician communication (n =30), and gained new perspectives and knowledge (n =10).Our findings indicate GAS is feasible and acceptable to caregivers, and the DS-AD goal inventory comprehensively reflects patient priorities. Additional gaps identified led to inventory enhancements, resulting in a more comprehensive resource to standardize GAS implementation in DS-AD studies.CONCLUSIONOur findings indicate GAS is feasible and acceptable to caregivers, and the DS-AD goal inventory comprehensively reflects patient priorities. Additional gaps identified led to inventory enhancements, resulting in a more comprehensive resource to standardize GAS implementation in DS-AD studies.

Background Evaluating health outcomes in Down syndrome‐associated Alzheimer’s disease (DS‐AD) is challenging due to variability in baseline function and cognition. Personalized outcome assessments, like Goal Attainment Scaling (GAS), can address this gap and capture treatment responses across varying baseline states and symptom manifestations. However, implementation must be standardized through tools such as goal inventories. Here, we assessed the content validity of the DS‐AD goal inventory (Knox et al., 2020, 2021) and investigated the feasibility and acceptability of inventory‐facilitated GAS as a patient‐centric tool to evaluate treatment response. Method We conducted a prospective, 16‐month, non‐interventional study using the DS‐AD goal inventory to facilitate GAS with caregivers of individuals with Down syndrome. The inventory included 58 goal areas distributed across behavior, cognition, daily function, executive function, and physical manifestation domains. The content validity of the goal inventory was assessed through a qualitative analysis of goal scales and alignment with the existing inventory. Goal count, goal scale completeness, and interview durations were used as feasibility indicators. An end‐of‐study survey evaluated acceptability. Result Forty‐six caregivers set 3 goals with 5‐levels each and assessed goal attainment at the 3 (n =45) and 16‐month follow‐ups (n =43). Mean interview times were 38.6 (±10.4) minutes for goal‐setting and 17.9 (±9.5) and 14.5 (±4.7) minutes for 3‐ and 16‐month follow‐ups. Out of 138 goals, 117 were initially selected from the inventory. The qualitative analysis indicated that the majority of the goals were from the Daily Function (n =65) and Behavior (n =26) domains (Figures 1&2), and that the inventory covered 125 (91%) goals. A qualitative analysis of the remaining goals (n =13) revealed diet and physical activity as additional goal areas. Survey results (n =33) indicated that caregivers had positive experiences with GAS (n =31), found their goals meaningful (n =31), valued improved clinician communication (n =30), and gained new perspectives and knowledge (n =10). Conclusion Our findings indicate GAS is feasible and acceptable to caregivers, and the DS‐AD goal inventory comprehensively reflects patient priorities. Additional gaps identified led to inventory enhancements, resulting in a more comprehensive resource to standardize GAS implementation in DS‐AD studies.

Prostate cancer is the most common cancer in men and it is estimated that over 350,000 men worldwide die of prostate cancer every year. There remains an unmet clinical need to improve how clinically significant prostate cancer is diagnosed and develop new treatments for advanced disease. Aberrant glycosylation is a hallmark of cancer implicated in tumour growth, metastasis, and immune evasion. One of the key drivers of aberrant glycosylation is the dysregulated expression of glycosylation enzymes within the cancer cell. Here, we demonstrate using multiple independent clinical cohorts that the glycosyltransferase enzyme GALNT7 is upregulated in prostate cancer tissue. We show GALNT7 can identify men with prostate cancer, using urine and blood samples, with improved diagnostic accuracy than serum PSA alone. We also show that GALNT7 levels remain high in progression to castrate-resistant disease, and using in vitro and in vivo models, reveal that GALNT7 promotes prostate tumour growth. Mechanistically, GALNT7 can modify O -glycosylation in prostate cancer cells and correlates with cell cycle and immune signalling pathways. Our study provides a new biomarker to aid the diagnosis of clinically significant disease and cements GALNT7-mediated O -glycosylation as an important driver of prostate cancer progression.

It's official: the old marketing model is dead, and word of mouth is king. But while a lot of attention has been paid to the mechanics of creating buzz, only the savviest of marketers have learned to focus on crafting the right kind of message -- because without it, even the loudest buzz will soon die down. Beyond Buzz shows readers how to listen to customers, identify what is important to them, and then craft the kind of message that will truly resonate and spark conversation.

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer, yet our ability to map these connections systematically remains limited. Individual gene-gene interaction studies have provided insights , but they miss the emergent properties of pathways working together. To address this challenge, we developed a multi-gene approach to pathway mapping and applied it to CRISPR data from the Cancer Dependency Map . Our analysis of the electron transport chain revealed certain blood cancers, including acute myeloid leukemia (AML), depend on an unexpected link between Complex II and purine metabolism. Through stable isotope metabolomic tracing, we found that Complex II directly supports purine biosynthesis and exogenous purines rescue AML from Complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that Complex II must oxidize to sustain purine synthesis. This connection translated to a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML to Complex II inhibition. In mouse models, targeting Complex II triggered rapid disease regression and extended survival in aggressive AML. The clinical relevance of this pathway emerged in human studies, where higher Complex II gene expression correlates with both resistance to mitochondria-targeted therapies and worse survival outcomes specifically in AML patients. These findings establish Complex II as a central regulator of purine biosynthesis and identify it as a promising therapeutic target in AML.

This book explores the science inherent in good early years practice and provides a rich range of ideas to inspire you to 'have a go' in your setting.It provides a balance between theory which underpins good practice and plenty of ideas of how you might put the theory into practice.

ObjectivesTo investigate the association of the CharlsonComorbidity Index (CCI) with clinical outcomes after transcatheter aortic valve implantation (TAVI).BackgroundPatients undergoing TAVI have high comorbid burden; however, there is limited evidence of its impact on clinical outcomes.MethodsData from 1887 patients from the UK, Canada, Spain, Switzerland and Italy were collected between 2007 and 2016. The association of CCI with 30-day mortality, Valve Academic Research Consortium-2 (VARC-2) composite early safety, long-term survival and length of stay (LoS) was calculated using logistic regression and Cox proportional hazard models, as a whole cohort and at a country level, through a two-stage individual participant data (IPD) random effect meta-analysis.ResultsMost (60%) of patients had a CCI ≥3. A weak correlation was found between the total CCI and four different preoperative risks scores (ρ=0.16 to 0.29), and approximately 50% of patients classed as low risk from four risk prediction models still presented with a CCI ≥3. Per-unit increases in total CCI were not associated with increased odds of 30-day mortality (OR 1.09, 95% CI 0.96 to 1.24) or VARC-2 early safety (OR 1.04, 95% CI 0.96 to 1.14) but were associated with increased hazard of long-term mortality (HR 1.10, 95% CI 1.05 to 1.16). The two-stage IPD meta-analysis indicated that CCI was not associated with LoS (HR 0.97, 95% CI 0.93 to 1.02).ConclusionIn this multicentre international study, patients undergoing TAVI had significant comorbid burden. We found a weak correlation between the CCI and well-established preoperative risks scores. The CCI had a moderate association with long-term mortality up to 5 years post-TAVI.

Science education has been a particular interest throughout my teaching career. My focus has been to develop children’s understanding of science through science enquiry. More recently, I have worked as a lecturer in primary science supporting students to become confident to teach science. Working with primary teachers in both India and Uganda to promote effective science education has given me further insights into science education.