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Nanotechnology provides platforms to deliver medical agents to specific cells. However, the nanoparticle’s surface becomes covered with serum proteins in the blood after administration despite engineering efforts to protect it with targeting or blocking molecules. Here, we developed a strategy to identify the main interactions between nanoparticle-adsorbed proteins and a cell by integrating mass spectrometry with pooled genome screens and Search Tool for the Retrieval of Interacting Genes analysis. We found that the low-density lipoprotein (LDL) receptor was responsible for approximately 75% of serum-coated gold nanoparticle uptake in U-87 MG cells. Apolipoprotein B and complement C8 proteins on the nanoparticle mediated uptake through the LDL receptor. In vivo, nanoparticle accumulation correlated with LDL receptor expression in the organs of mice. A detailed understanding of how adsorbed serum proteins bind to cell receptors will lay the groundwork for controlling the delivery of nanoparticles at the molecular level to diseased tissues for therapeutic and diagnostic applications.A combination of mass spectrometry, pooled genome screens and STRING analysis identifies key uptake mediating interactions between nanoparticle-adsorbed proteins and cells via the low-density lipoprotein receptor.

The genetic circuits that allow cancer cells to evade destruction by the host immune system remain poorly understood 1 – 3 . Here, to identify a phenotypically robust core set of genes and pathways that enable cancer cells to evade killing mediated by cytotoxic T lymphocytes (CTLs), we performed genome-wide CRISPR screens across a panel of genetically diverse mouse cancer cell lines that were cultured in the presence of CTLs. We identify a core set of 182 genes across these mouse cancer models, the individual perturbation of which increases either the sensitivity or the resistance of cancer cells to CTL-mediated toxicity. Systematic exploration of our dataset using genetic co-similarity reveals the hierarchical and coordinated manner in which genes and pathways act in cancer cells to orchestrate their evasion of CTLs, and shows that discrete functional modules that control the interferon response and tumour necrosis factor (TNF)-induced cytotoxicity are dominant sub-phenotypes. Our data establish a central role for genes that were previously identified as negative regulators of the type-II interferon response (for example, Ptpn2 , Socs1 and Adar1 ) in mediating CTL evasion, and show that the lipid-droplet-related gene Fitm2 is required for maintaining cell fitness after exposure to interferon-γ (IFNγ). In addition, we identify the autophagy pathway as a conserved mediator of the evasion of CTLs by cancer cells, and show that this pathway is required to resist cytotoxicity induced by the cytokines IFNγ and TNF. Through the mapping of cytokine- and CTL-based genetic interactions, together with in vivo CRISPR screens, we show how the pleiotropic effects of autophagy control cancer-cell-intrinsic evasion of killing by CTLs and we highlight the importance of these effects within the tumour microenvironment. Collectively, these data expand our knowledge of the genetic circuits that are involved in the evasion of the immune system by cancer cells, and highlight genetic interactions that contribute to phenotypes associated with escape from killing by CTLs. Genome-wide CRISPR screens in mouse cancer cell lines are used to identify a core, conserved set of genes and pathways that govern how cancer cells evade killing by cytotoxic T lymphocytes.

BackgroundThe adoption of docetaxel for systemic treatment of metastatic prostate cancer (PCa), in both castration-sensitive (mCSPC) and castration-resistant (mCRPC) settings, is poorly understood. This study examined the real-world utilization of docetaxel in these patients and their outcomes.MethodsA retrospective population-based study used administrative data from Ontario, Canada, to identify men aged ≥66 years who were diagnosed with de novo mCSPC or mCRPC between 2014 and 2019 and received docetaxel. The study assessed treatment tolerability and toxicity, and survival in both cohorts. Descriptive and comparative statistical analysis were conducted.ResultsThe study identified 11.2% (399/3556) and 13.2% (203/1534) patients diagnosed with de novo mCSPC and with mCRPC who received docetaxel respectively. The median age in both cohorts was 72 years (IQR: 68–76). Overall, 43.9% (n = 175) patients with de novo mCSPC and 52.1% (n = 85) with mCRPC completed ≥6 cycles of docetaxel. Over two-fifth also needed dose adjustments in both cohorts. Hospitalization or emergency department visit for febrile neutropenia were noted in 15.8% (n = 63) of de novo mCSPC patients and similarly in 19% (n = 31) of mCRPC cohort. The median survival of PCa patients who completed ≥6 cycles of docetaxel was significantly longer relative to those who completed <4 cycles: 32.7 vs. 23.5 months (p < 0.001) for mCSPC and 20.5 vs. 10.7 (p = 0.012) for mCRPC respectively.ConclusionsIn this population-based study of elderly patients with metastatic PCa, treatment with docetaxel was associated with poor tolerability and higher toxicity compared with clinical trials. Receipt of limited cycles and reduced overall dose of docetaxel were associated with inferior overall survival.

Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin ligase complex UBR4-KCMF1 and the acetyltransferase NatC recognize proteins bearing an unacetylated N-terminal methionine followed by a hydrophobic residue. NatC KO-induced protein degradation and phenotypes are reversed by UBR knockdown, demonstrating the central cellular role of this interplay. We reveal that loss of Drosophila NatC is associated with male sterility, reduced longevity, and age-dependent loss of motility due to developmental muscle defects. Remarkably, muscle-specific overexpression of UbcE2M, one of the proteins targeted for NatC KO-mediated degradation, suppresses defects of NatC deletion. In conclusion, NatC-mediated N-terminal acetylation acts as a protective mechanism against protein degradation, which is relevant for increased longevity and motility. The most common protein modification in eukaryotes is N-terminal acetylation, but its functional impact has remained enigmatic. Here, the authors find that a key role for N-terminal acetylation is shielding proteins from ubiquitin ligase-mediated degradation, mediating motility and longevity.

Cohesin-mediated loop extrusion has been shown to be blocked at specific cis -elements, including CTCF sites, producing patterns of loops and domain boundaries along chromosomes. Here we explore such cis -elements, and their role in gene regulation. We find that transcription termination sites of active genes form cohesin- and RNA polymerase II-dependent domain boundaries that do not accumulate cohesin. At these sites, cohesin is first stalled and then rapidly unloaded. Start sites of transcriptionally active genes form cohesin-bound boundaries, as shown before, but are cohesin-independent. Together with cohesin loading, possibly at enhancers, these sites create a pattern of cohesin traffic that guides enhancer-promoter interactions. Disrupting this traffic pattern, by removing CTCF, renders cells sensitive to knockout of genes involved in transcription initiation, such as the SAGA complexes, and RNA processing such DEAD/H-Box RNA helicases. Without CTCF, these factors are less efficiently recruited to active promoters. The authors describe how three types of cis -element (CTCF sites, active TSSs and TTSs) regulate cohesin trafficking along chromosomes. They uncover that this cohesin traffic pattern is genetically linked to gene regulation and RNA processing.

Background Despite the wealth of evidence demonstrating the efficacy of treatment intensification beyond androgen-deprivation therapy (ADT) among patients with de novo metastatic castration-sensitive prostate cancer (mCSPC), little is known of its real-world use. This study examined the real-world uptake of ADT treatment intensification among older men in a large Canadian province. Methods We performed a retrospective population-based cohort study using province-wide linked administrative data in Ontario, Canada. Patients 66 years of age and older with de novo mCSPC were included and their treatment with conventional ADT-based regimens, ADT plus next-generation androgen receptor axis–targeted therapy, and ADT plus docetaxel were identified and stratified by time. Results From 2014 to 2019, 3556 patients were identified with de novo mCSPC. Most patients (n = 2794 [78.6%]) were treated with a conventional ADT regimen, whereas 399 (11.2%) patients received ADT intensification with docetaxel and 52 (1.5%) patients received abiraterone acetate plus prednisone. In a time-stratified analysis of ADT intensification before and after the pivotal AA+P trial (LATITUDE), AA+P uptake increased from 0.5% to 3.0%, whereas docetaxel use dropped from 12.0% to 10.0%. The median survival of the study population was 18 months (interquartile range = 10-31). Conclusions The majority of patients with de novo mCSPC are treated with ADT alone in the Canadian real-world setting, despite randomized clinical trial evidence of benefit with the use of ADT-intensified regimens. As ADT treatment intensification is substantially underused, better understanding of the barriers to treatment and targeted education to address them are needed.

Activity-based therapy (ABT) has shown promise as a viable therapeutic intervention to promote neurorecovery in people with spinal cord injury/disease (SCI/D). Tools that track the details of ABT sessions may facilitate the collection of data needed to inform best practice guidelines for ABT. The purpose of this study was to evaluate the content validity of a prototype ABT tracking tool. Nine clinicians and five individuals with SCI/D from three community-based ABT clinics in Canada used the prototype tracking tool over three ABT sessions and then participated in individual cognitive debriefing interviews. The interview guide was developed based on recommendations by Brod and colleagues for establishing content validity (i.e., appropriate, comprehensive, comprehensibility). Interviews were transcribed verbatim and analysed using deductive followed by inductive content analysis. Overall, the ABT tracking tool was found to have good content validity. Identified categories included: (1) Content validity of the ABT tracking tool. Participants found the tool to be comprehensive and appropriate for all levels and severities of injury. Recommendations to improve the tool included adding a comment section and additional parameters to each activity. (2) Facilitators of tool use, dissemination and implementation. Using the tool during rest breaks or after the session were suggested to maximize therapy time. Providing the tool as an app and offering education and training on use of the tool were highly recommended. Advertising through community clinics and social media may facilitate dissemination of the tool. (3) Barriers of tool use, dissemination and implementation. The paper format of the tool, added workload, learning curve and challenge to adopt a new documentation system were considered barriers to tool use. The prototype ABT tracking tool was validated for content using cognitive debriefing interviews. Recommendations will be used to improve the tool and assist in dissemination and implementation efforts.

Previous findings indicate that co-contractions of plantarflexors and dorsiflexors during quiet standing increase the ankle mechanical joint stiffness, resulting in increased postural sway. Balance impairments in individuals with incomplete spinal cord injury (iSCI) may be due to co-contractions like in other individuals with reduced balance ability. Here we investigated the effect of co-contraction between plantar- and dorsiflexors on postural balance in individuals with iSCI (iSCI-group) and able-bodied individuals (AB-group). Thirteen able-bodied individuals and 13 individuals with iSCI were asked to perform quiet standing with their eyes open (EO) and eyes closed (EC). Kinetics and electromyograms from the tibialis anterior (TA), soleus and medial gastrocnemius were collected bilaterally. The iSCI-group exhibited more co-contractions than the AB-group (EO: 0.208% vs. 75.163%, p = 0.004; EC: 1.767% vs. 92.373%, p = 0.016). Furthermore, postural sway was larger during co-contractions than during no co-contraction in the iSCI-group (EO: 1.405 cm/s 2 vs. 0.867 cm/s 2 , p = 0.023; EC: 1.831 cm/s 2 vs. 1.179 cm/s 2 , p = 0.030), but no differences were found for the AB-group (EO: 0.393 cm/s 2 vs. 0.499 cm/s 2 , p = 1.00; EC: 0.686 cm/s 2 vs. 0.654 cm/s 2 , p = 1.00). To investigate the mechanism, we performed a computational simulation study using an inverted pendulum model and linear controllers. An increase of mechanical stiffness in the simulated iSCI-group resulted in increased postural sway (EO: 2.520 cm/s 2 vs. 1.174 cm/s 2 , p < 0.001; EC: 4.226 cm/s 2 vs. 1.836 cm/s 2 , p < 0.001), but not for the simulated AB-group (EO: 0.658 cm/s 2 vs. 0.658 cm/s 2 , p = 1.00; EC: 0.943 cm/s 2 vs. 0.926 cm/s 2 , p = 0.190). Thus, we demonstrated that co-contractions may be a compensatory strategy for individuals with iSCI to accommodate for decreased motor function, but co-contractions may result in increased ankle mechanical joint stiffness and consequently postural sway.

This article briefly documents the history and significance of PubMed Central (PMC) Journal Backfiles Digitization, 2004-2024 to raise awareness of this open access project among researchers who will find much to discover to advance understanding about the human condition across time and place. The success of PMC Journal Backfiles Digitization—including the interdisciplinary teamwork and partnerships underpinning it— provides a blueprint for future efforts to make the globally appreciated collections of the National Library of Medicine (NLM) accessible to all. By continuing to prioritize open access, teamwork, and partnerships, NLM and likeminded institutions can ensure that knowledge and data inform the advancement of medicine and public health.

Individuals living with chronic spinal cord injury or disease (SCI/D) are at an increased risk of falling. However, little is known about the impact of falls and fall risk in the subacute phase of SCI/D, despite this being a time when fall prevention initiatives are delivered. Hence, we explored the impact of falls and fall risk in individuals with subacute SCI/D as they transitioned from inpatient rehabilitation to community living. This qualitative photo-elicitation study used an inductive thematic analysis. Eight individuals (7 male) undergoing inpatient rehabilitation at a Canadian tertiary rehabilitation hospital due to a new SCI/D participated. Six months following discharge, photo-elicitation interviewing was used to understand the impact of falls and fall risk. Over 7-14 days, participants completed a photo-assignment that involved taking photographs in response to questions, such as what increases/decreases your likelihood of falling? A semi-structured interview followed, in which participants described their photographs and discussed their experiences with falls, fall risk and fall prevention training. Four themes were identified. 1) Risk factors and strategies identified through lived experience. Participants discovered their fall risk factors and fall prevention strategies through \"trial and error\". 2) Influences on the individual's perception of their fall risk. Prior experience with falls, including falls experienced by themselves as well as friends and family, influenced their perception of fall risk. 3) Experiencing life differently due to increased fall risk. A high fall risk reduced participation, increased negative emotions and decreased independence and quality of life. 4) Falls training in rehabilitation can be improved. Prior experiences with falls training varied; however, participants expressed a desire for comprehensive and individualized training. Although participants' experiences with falls and fall prevention varied, falls and the risk of falling can have a significant impact on the first year of living with a SCI/D.