Combination of dual JAK/HDAC inhibitor with regorafenib synergistically reduces tumor growth, metastasis, and regorafenib-induced toxicity in colorectal cancer.

BACKGROUND: Treatment with regorafenib, a multiple-kinase inhibitor, to manage metastatic colorectal cancers (mCRCs) shows a modest improvement in overall survival but is associated with severe toxicities. Thus, to reduce regorafenib-induced toxicity, we used regorafenib at low concentration along with a dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition to enhance antitumor activity. The therapeutic efficacy and safety of the combination treatment was evaluated with CRC models. METHODS: The cytotoxicity of JAK/HDACi, regorafenib, and their combination were tested with normal colonic and CRC cells exhibiting various genetic backgrounds. Kinomic, ATAC-seq, RNA-seq, cell cycle, and apoptosis analyses were performed to evaluate the cellular functions/molecular alterations affected by the combination. Efficacy of the combination was assessed using patient-derived xenograft (PDX) and experimental metastasis models of CRC. To evaluate the interplay between tumor, its microenvironment, and modulation of immune response, MC38 syngeneic mice were utilized. RESULTS: The combination therapy decreased cell viability; phosphorylation of JAKs, STAT3, EGFR, and other key kinases; and inhibited deacetylation of histone H3K9, H4K8, and alpha tubulin proteins. It induced cell cycle arrest at G0-G1 phase and apoptosis of CRC cells. Whole transcriptomic analysis showed that combination treatment modulated molecules involved in apoptosis, extracellular matrix-receptor interaction, and focal adhesion pathways. It synergistically reduces PDX tumor growth and experimental metastasis, and, in a syngeneic mouse model, the treatment enhances the antitumor immune response as evidenced by higher infiltration of CD45 and cytotoxic cells. Pharmacokinetic studies showed that combination increased the bioavailability of regorafenib. CONCLUSIONS: The combination treatment was more effective than with regorafenib or JAK/HDACi alone, and had minimal toxicity. A clinical trial to evaluate this combination for treatment of mCRCs is warranted.

Far-UVC: The impact of optical filters on real-world deployment.

In 2015, a study showed that Krypton-Chloride (KrCl) excimer lamps could induce erythema and basal layer DNA damage in human skin. Later studies found that filtering out longer wavelength emissions from these lamps resulted in no acute skin effects. However, there is a limited understanding of how much to reduce unwanted emissions and which wavelengths are important. Accurate spectral irradiance data is therefore crucial for safety, as variance in optical filtering significantly affects the weighted irradiance of a lamp. To simplify the risk assessment process for Far-UVC lamps, we highlight the usefulness of the lamp exposure limit (HLEL) and present this in the context of spectral emission data for 14 commercially available Far-UVC lamps. Our results demonstrate that relying solely on a radiometric measurement and a single-wavelength exposure limit at 222 nm could lead to over-exposure. The HLEL is a practical metric which can be utilized to determine the exposure time before reaching the exposure limit. It can also be used in the determination of the minimum ceiling height for compliance with standards like UL 8802. Manufacturers are urged to provide HLEL for their products; installers should adhere to HLEL; and standards and regulatory bodies should insist on this information in new guidance.

Long-term comparison and performance study of consumer grade electronic radon integrating monitors.

This study reports the performance of 7 types of consumer grade passive Electronic Radon Integrating Monitors, ERIM (AlphaE, AER Plus, Canary, Corentium Pro, Radon Scout Home, Ramon and Wave) and passive etched track radon detectors. All monitors and passive radon detectors were exposed side by side for 2 periods of 3 months under controlled conditions in the UKHSA radon chamber and in a stainless steel container to an average radon concentration of 4781 Bq m-3 and 166 Bq m-3, respectively. The performance of each individual monitor was compared with Atmos 12DPX and AlphaGUARD P30 reference instruments. The performance of the monitors was evaluated by estimating the biased, precision and measurement errors of each type. It was found that UKHSA passive radon detectors showed excellent performance (measurement error < 10%) at both higher and lower exposures. The AlphaE, Canary and Ramon showed excellent performance, with measurement error < 10%, when they were exposed to radon concentrations between 4000 Bq m-3 and 6000 Bq m-3 in the UKHSA radon chamber. However, when the monitors were exposed to radon levels below the UK radon Action Level of 200 Bq m-3, the only ERIM which had a measurement error <10% was the Radon Scout Home. All other monitors showed a significant decrease in their performance with measurement errors ranging between 20% and 50%. The calibration factor, which is the ratio between the measured value (background is subtracted) and the reference value, was also studied. It was found that the calibration factors of individual monitors changed significantly. Calibration measurements in 2019 and in 2023 found that the percentage change varied between -46% and +63%. This shows the importance of initial and regular calibration, and maintenance of the monitors. .

Results of an interlaboratory study on the working curve in vat photopolymerization.

The working curve informs resin properties and print parameters for stereolithography, digital light processing, and other photopolymer additive manufacturing (PAM) technologies. First demonstrated in 1992, the working curve measurement of cure depth vs radiant exposure of light is now a foundational measurement in the field of PAM. Despite its widespread use in industry and academia, there is no formal method or procedure for performing the working curve measurement, raising questions about the utility of reported working curve parameters. Here, an interlaboratory study (ILS) is described in which 24 individual laboratories performed a working curve measurement on an aliquot from a single batch of PAM resin. The ILS reveals that there is enormous scatter in the working curve data and the key fit parameters derived from it. The measured depth of light penetration Dp varied by as much as 7x between participants, while the critical radiant exposure for gelation Ec varied by as much as 70x. This significant scatter is attributed to a lack of common procedure, variation in light engines, epistemic uncertainties from the Jacobs equation, and the use of measurement tools with insufficient precision. The ILS findings highlight an urgent need for procedural standardization and better hardware characterization in this rapidly growing field.

Warning labels for sugar-sweetened beverages and fruit juice: evaluation of 27 different labels on health effects, sugar content, energy and exercise equivalency.

OBJECTIVES: Front-of-pack warning labels may reduce consumption of sugar-sweetened beverages, potentially mitigating negative health outcomes. Comparisons between different warning label types to inform future research and policy directions are lacking. This study compared 27 warning labels across six message types for their potential to reduce sugar-sweetened beverage consumption. DESIGN AND METHODS: A national sample of regular soda (n = 2578) and juice (n = 1048) consumers aged 14-60 years participated in an online survey. Participants evaluated randomly allocated labels; one from each of six warning label sets (health-graphic, sugar-pictogram, sugar-text, exercise equivalents, health-text, energy information) on four measures of perceived effectiveness (PE: overall effectiveness, discourage from drinking, emotional response, persuasive potential). Participants could also provide open comments. A general linear model compared differences in mean scores across label sets for each measure of PE. RESULTS: PE ratings differed significantly between label sets. Labels clearly quantifying sugar content (sugar-teaspoons) received consistently high PE ratings, whereas 'high in sugar' labels did not. Health-graphic labels were rated highly across all PE measures except persuasive potential. Exercise labels only rated highly on persuasive potential. Health-text results were mixed, and energy labels were consistently low. CONCLUSIONS: Simple, factual labels were easily interpreted and perceived as most effective. Labels quantifying sugar content were consistently high performers and should be advanced into policy to help decrease overconsumption of sugar-sweetened beverages.

Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma.

Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.

A scoping review on tools and methods for trait prioritization in crop breeding programmes.

Trait prioritization studies have guided research, development and investment decisions for public-sector crop breeding programmes since the 1970s, but the research design, methods and tools underpinning these studies are not well understood. We used PRISMA-ScR (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) to evaluate research on trait ranking for major crops over the past 40 years (1980-2023). Data extraction and descriptive analysis on 657 papers show uneven attention to crops, lack of systematic sex disaggregation and regional bias. The lack of standardized trait data taxonomy across studies, and inconsistent research design and data collection practices make cross-comparison of findings impossible. In addition, network mapping of authors and donors shows patterns of concentration and the presence of silos within research areas. This study contributes to the next generation of innovation in trait preference studies to produce more inclusive, demand-driven varietal design that moves beyond trait prioritization focused on productivity and yield.

Cross infection of Haemonchus contortus between calves and lambs.

Haemonchus contortus can frequently be found infecting pre-weaned beef calves on sheep and beef farms around the North Island of New Zealand. The purpose of this study was to determine whether parasites cycling in young cattle constitute a potentially important source of infection for sheep. A field isolate of H. contortus was cycled through either calves or lambs for 3 generations. The larvae resulting from the third cycle of infection were then used to infect both lambs and calves and the resulting faecal nematode egg count (FEC), worm burden, adult worm length and in utero egg count were measured. Larvae derived from lambs inoculated into calves exhibited lower establishment rates, the adult worms were shorter, had lower in utero egg counts, and the resulting faecal egg counts were also lower than when inoculated into lambs (p < 0.01). H. contortus' lack of ability to passage freely between lambs and calves indicates that large populations are unlikely to occur under mixed grazing, resulting in limited potential as a source of infection in sheep. However, indications of an ability to adapt to the alternative host suggest that some investigation of infection in cattle dominant farming operations in the north of the country might be warranted.

Wildfire-related smoke inhalation worsens cardiovascular risk in sleep disrupted rats.

Introduction: As a lifestyle factor, poor sleep status is associated with increased cardiovascular morbidity and mortality and may be influenced by environmental stressors, including air pollution. Methods: To determine whether exposure to air pollution modified cardiovascular effects of sleep disruption, we evaluated the effects of single or repeated (twice/wk for 4 wks) inhalation exposure to eucalyptus wood smoke (ES; 964 µg/m3 for 1 h), a key wildland fire air pollution source, on mild sleep loss in the form of gentle handling in rats. Blood pressure (BP) radiotelemetry and echocardiography were evaluated along with assessments of lung and systemic inflammation, cardiac and hypothalamic gene expression, and heart rate variability (HRV), a measure of cardiac autonomic tone. Results and Discussion: GH alone disrupted sleep, as evidenced by active period-like locomotor activity, and increases in BP, heart rate (HR), and hypothalamic expression of the circadian gene Per2. A single bout of sleep disruption and ES, but neither alone, increased HR and BP as rats transitioned into their active period, a period aligned with a critical early morning window for stroke risk in humans. These responses were immediately preceded by reduced HRV, indicating increased cardiac sympathetic tone. In addition, only sleep disrupted rats exposed to ES had increased HR and BP during the final sleep disruption period. These rats also had increased cardiac output and cardiac expression of genes related to adrenergic function, and regulation of vasoconstriction and systemic blood pressure one day after final ES exposure. There was little evidence of lung or systemic inflammation, except for increases in serum LDL cholesterol and alanine aminotransferase. These results suggest that inhaled air pollution increases sleep perturbation-related cardiovascular risk, potentially in part by increased sympathetic activity.

Breaking the feed forward inflammatory cytokine loop in the tumor microenvironment of PDGFB-driven glioblastomas.

Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of proinflammatory factors, including IL-1. In this issue of the JCI, Chen, Giotti, and colleagues investigated loss of ll1b in the immune tumor microenvironment (TME) in GBM models driven by PDGFB expression and Nf1 knockdown. Survival was only improved in PDGFB-driven GBM models, suggesting that tumor cell genotype influenced the immune TME. IL-1ß in the TME increased PDGFB-driven GBM growth by increasing tumor-derived NF-κB, expression of monocyte chemoattractants, and increased infiltration of bone marrow-derived myeloid cells (BMDMs). In contrast, no requirement for IL-1ß was evident in Nf1-silenced tumors due to high basal levels of NF-κB and monocyte chemoattractants and increased infiltration of BMDM and TAMs. Notably, treatment of mice bearing PDGFB-driven GBM with anti-IL-1ß or an IL1R1 antagonist extended survival. These findings suggest that effective clinical immunotherapy may require differential targeting strategies.

Effects of physical fitness training on the mental and physical health of stroke survivors.

After a stroke, physical activity can be key in enhancing the rehabilitation of patients and preventing a secondary stroke. In this commentary, we critically appraise a systematic review which investigated how different types of physical fitness training impact on the mental and physical conditions of stroke survivors. Cardiorespiratory, resistance and mixed training (especially when including walking) can improve key outcomes such as the balance and mobility of stroke survivors, but the most suitable type of training depends on the individual needs and aims of the rehabilitation process. More research is needed to understand how the effects of the different types of training vary by considering the time between stroke and intervention onset, stroke severity, and the dose of intervention.

Monitoring environmental microbiomes: Alignment of microbiology and computational biology competencies within a culturally integrated curriculum and research framework.

We have developed a flexible undergraduate curriculum that leverages the place-based research of environmental microbiomes to increase the number of Indigenous researchers in microbiology, data science and scientific computing. Monitoring Environmental Microbiomes (MEM) provides a curriculum and research framework designed to integrate an Indigenous approach when conducting authentic scientific research and to build interest and confidence at the undergraduate level. MEM has been successfully implemented as a short summer workshop to introduce computing practices in microbiome analysis. Based on self-assessed student knowledge of topics and skills, increased scientific confidence and interest in genomics careers were observed. We propose MEM be incorporated in a scalable course-based research experience for undergraduate institutions, including tribal colleges and universities, community colleges and other minority serving institutions. This coupled curricular and research framework explicitly considers cultural perspectives, access and equity to train a diverse future workforce that is more informed to engage in microbiome research and to translate microbiome science to benefit community and environmental health.

A proof of concept that experience-based management of endometriosis can complement evidence-based guidelines.

Background: Management of endometriosis should be based on the best available evidence. The pyramid of evidence reflects unbiased observations analysed with traditional statistics. Evidence-based medicine (EBM) is the clinical interpretation of these data by experts. Unfortunately, traditional statistical inference can refute but cannot confirm a hypothesis and clinical experience is considered a personal opinion. Objectives: A proof of concept to document clinical experience by considering each diagnosis and treatment as an experiment with an outcome, which is used to update subsequent management. Materials and Methods: Experience and knowledge-based questions were answered on a 0 to 10 visual analogue scale (VAS) by surgery-oriented clinicians with experience of > 50 surgeries for endometriosis. Results: The answers reflect the collective clinical experience of managing >10.000 women with endometriosis. Experience-based management was overall comparable as approved by >75% of answers rated ≥ 8/10 VAS. Knowledge-based management was more variable, reflecting debated issues and differences between experts and non-experts. Conclusions: The collective experience-based management of those with endometriosis is similar for surgery-oriented clinicians. Results do not conflict with EBM and are a Bayesian prior, to be confirmed, refuted or updated by further observations. What is new?: Collective experience-based management can be measured and is more than a personal opinion. This might extend EBM trial results to the entire population and add data difficult to obtain in RCTs, such as many aspects of surgery.

Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases.

Glioblastoma (GBM) remains an incurable disease with an extremely high five-year recurrence rate. We studied apoptosis in glioma stem cells (GSCs) in response to HDAC inhibition (HDACi) combined with MEK1/2 inhibition (MEKi) or BCL-2 family inhibitors. MEKi effectively combined with HDACi to suppress growth, induce cell cycle defects, and apoptosis, as well as to rescue the expression of the pro-apoptotic BH3-only proteins BIM and BMF. A RNAseq analysis of GSCs revealed that HDACi repressed the pro-survival BCL-2 family genes MCL1 and BCL-XL. We therefore replaced MEKi with BCL-2 family inhibitors and observed enhanced apoptosis. Conversely, a ligand for the cancer stem cell receptor CD44 led to reductions in BMF, BIM, and apoptosis. Our data strongly support further testing of HDACi in combination with MEKi or BCL-2 family inhibitors in glioma.

The Ornaments of the Arma Veirana Early Mesolithic Infant Burial.

Personal ornaments are widely viewed as indicators of social identity and personhood. Ornaments are ubiquitous from the Late Pleistocene to the Holocene, but they are most often found as isolated objects within archaeological assemblages without direct evidence on how they were displayed. This article presents a detailed record of the ornaments found in direct association with an Early Mesolithic buried female infant discovered in 2017 at the site of Arma Veirana (Liguria, Italy). It uses microscopic, 3D, and positional analyses of the ornaments as well as a preliminary perforation experiment to document how they were perforated, used, and what led to their deposit as part of the infant's grave goods. This study provides important information on the use of beads in the Early Mesolithic, in general, as well as the relationship between beads and young subadults, in particular. The results of the study suggest that the beads were worn by members of the infant's community for a considerable period before they were sewn onto a sling, possibly used to keep the infant close to the parents while allowing their mobility, as seen in some modern forager groups. The baby was then likely buried in this sling to avoid reusing the beads that had failed to protect her or simply to create a lasting connection between the deceased infant and her community. Supplementary Information: The online version contains supplementary material available at 10.1007/s10816-022-09573-7.

Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

Stretch goals have enduring appeal, but are the right organisations using them?

BACKGROUND: The healthcare industry faces significant challenges and opportunities that demand lofty aspirations and novel approaches. Pursuing seemingly impossible goals, popularly known as 'stretch goals', can be a way to instigate dramatic change and innovation, but such extreme goals also come with substantial risks. After briefly reporting the results of a national survey we conducted to provide examples of how stretch goals are used in healthcare, we review and translate prior research on the effects of stretch goals on organisations and their members. FINDINGS: The survey results indicate that stretch goals are used regularly in healthcare and a wide range of other industries. Roughly half of respondents indicated that their current employer had used a stretch goal in the past 12 months. Healthcare stretch goals were focused on reductions in errors, wait times, and no-show rates, and increases in workload, patient satisfaction, clinical research participation, and vaccination uptake. Our review of prior research suggests that stretch goals can instigate both positive and negative psychological, emotional, and behavioural reactions. Although existing scholarly evidence suggests that stretch goals will have problematic effects on learning and performance for the majority of organisations that use them, stretch goals actually can have beneficial effects under some specific circumstances that we outline. CONCLUSION: Stretch goals are risky yet regularly used in healthcare and many other industries. They can be valuable, but only when an organisation has both strong recent performance and available slack resources to devote to goal pursuit. Under other conditions, stretch goals tend to be demotivating and destructive. We explain the paradoxical nature of stretch goals, whereby the organisations least likely to benefit from them are most likely to adopt them, and offer guidance on how healthcare leaders can tailor their goal setting practices to conditions most likely to lead to successful outcomes.

Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease.

The abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). In addition, assembled tau associates with extracellular vesicles (EVs) in the central nervous system of patients with AD, which is linked to its clearance and prion-like propagation between neurons. However, the identities of the assembled tau species and the EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from AD patients. We found filaments of truncated tau enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.

Tunneled island pedicle flap reconstruction for upper lateral cutaneous lip defects.

BACKGROUND: Esthetic upper lateral cutaneous lip reconstruction preserves the apical triangle, nasolabial fold symmetry, and free margin position. The tunneled island pedicle flap (IPF) is a novel single-stage reconstruction to achieve these goals. OBJECTIVES: Describe the technique and patient and surgeon-reported outcomes for the tunneled IPF reconstruction of upper lateral cutaneous lip defects. METHODS: Retrospective chart review of consecutive tunneled IPF reconstruction following Mohs micrographic surgery (MMS) at a tertiary care center between 2014 and 2020. Patients rated their scars using the validated Patient Scar Assessment Scale (PSAS), and independent surgeons rated scars using the validated Observer Scar Assessment Scale (OSAS). Descriptive statistics were generated for patient demographics and tumor defect characteristics. RESULTS: Twenty upper lateral cutaneous lip defects were repaired with the tunneled IPF. Surgeons rated scars with a composite OSAS score of 11.83 ± 4.29 (mean, SD) [scale of 5 (normal skin) to 50 (worst scar imaginable)] and an overall scar score of 2.81 ± 1.11 [scale of 1 (normal skin) to 10 (worst scar imaginable)]. Patients rated their scars with a composite PSAS score of 10 ± 5.39 [scale of 6 (best possible score) to 60 (worst)] and with an overall score of 2.2 ± 1.78 [scale of 1 (normal skin) and 10 (very different from normal skin)]. One flap was surgically revised for pincushioning, but none experienced necrosis, hematoma, or infection. CONCLUSIONS: The tunneled IPF is a single-stage reconstruction for upper lateral cutaneous lip defects with favorable scar ratings by patients and observers.