Search

International audience; Aging is a progressive time-dependent biological process affecting differentially individuals, who can sometimes present exceptional longevity. Epigenetic alterations are one of the hallmarks of aging, which comprise the epigenetic drift and clock at DNA methylation level. In the present study, we estimated the DNA methylation-based age (DNAmage) using four epigenetic clocks based on a small number of CpGs in French centenarians and semi-supercentenarians (CSSC, n=214) as well as nonagenarians' and centenarians' offspring (NCO, n=143) compared to individuals from the French general population (CG, n=149). DNA methylation analysis of the nine CpGs included in the epigenetic clocks showed high correlation with chronological age (-0.66>R>0.54) and also the presence of an epigenetic drift for four CpGs that was only visible in CSSC. DNAmage analysis showed that CSSC and to a lesser extend NCO present a younger DNAmage than their chronological age (15-28.5 years for CSSC, 4.4-11.5 years for NCO and 4.2-8.2 years for CG), which were strongly significant in CSSC compared to CG (p-values

Patients receiving CD19 CAR T-cell therapy for relapsed/refractory lymphoma experience prolonged and profound B-cell aplasia and hypogammaglobulinemia, placing them at a higher risk for severe COVID-19. Independently, Oh et al and Atanackovic et al demonstrate that despite attenuated humoral response to mRNA-based vaccines, patients demonstrate normal or heightened functional T-cell responses, including antiviral T-cell activity against SARS-CoV-2 variants including Omicron. Collectively, these data reinforce the importance of COVID-19 vaccination following CD19 CAR T-cell therapy, despite long-term B-cell aplasia.

A concerted commitment across research stakeholders is necessary to increase equity, diversity, and inclusion (EDI) and address barriers to cancer clinical trial recruitment and participation. Racial and ethnic diversity among trial participants is key to understanding intrinsic and extrinsic factors that may affect patient response to cancer treatments. This ASCO and Association of Community Cancer Centers (ACCC) Research Statement presents specific recommendations and strategies for the research community to improve EDI in cancer clinical trials. There are six overarching recommendations: (1) clinical trials are an integral component of high-quality cancer care, and every person with cancer should have the opportunity to participate; (2) trial sponsors and investigators should design and implement trials with a focus on reducing barriers and enhancing EDI, and work with sites to conduct trials in ways that increase participation of under-represented populations; (3) trial sponsors, researchers, and sites should form long-standing partnerships with patients, patient advocacy groups, and community leaders and groups; (4) anyone designing or conducting trials should complete recurring education, training, and evaluation to demonstrate and maintain cross-cultural competencies, mitigation of bias, effective communication, and a commitment to achieving EDI; (5) research stakeholders should invest in programs and policies that increase EDI in trials and in the research workforce; and (6) research stakeholders should collect and publish aggregate data on racial and ethnic diversity of trial participants when reporting results of trials, programs, and interventions to increase EDI. The recommendations are intended to serve as a guide for the research community to improve participation rates among people from racial and ethnic minority populations historically under-represented in cancer clinical trials. ASCO and ACCC will work at all levels to advance the recommendations in this publication.

Effects on DTIC-treated melanoma cell lines.

Supplemental Table 2

DTIC and anti-Nodal antibody combination treatment promotes cell death in SK-MEL-28 cells.

Effects of anti-Nodal antibody treatment on SK-MEL-28 cells.

Higher prevalence of cancer-related risk factors, for example, tobacco use, obesity, poor diet, and physical inactivity, is observed in the U.S. Deep South and likely contributes to its increased cancer burden. While this region is largely rural, it is unknown whether cancer-related beliefs and lifestyle practices differ by rural–urban status or are more influenced by other factors. We contacted 5,633 Alabamians to complete a cross-sectional survey to discern cancer-related beliefs and lifestyle practices, and compared data from respondents residing in rural- versus urban-designated counties. Findings were summarized using descriptive statistics; rural–urban subgroups were compared using two-tailed, χ2 and t tests. Multivariable logistic regression models were used to explore associations by rural–urban status and other sociodemographic factors. Surveys were completed by 671 rural- and 183 urban-county respondents (15.2% response rate). Overall, the prevalence for overweight and obesity (77.8%) and sugar-sweetened beverage intake (273–364 calories/day) was higher than national levels. Most respondents (58%) endorsed raising the state tobacco tax. Respondents from rural- versus urban-designated counties were significantly more likely to be racial/ethnic minority, have lower education, employment, income, food security, and internet access, and endorse fatalistic cancer-related beliefs (Prevention Relevance: Cancer incidence and mortality are higher in the U.S. Deep South, likely due to increased tobacco-use, obesity, poor diet, and physical inactivity. This study explores whether cancer-related beliefs and lifestyle practices differ by rural-urban status or other sociodemographic factors in a random sample of 855 residents across Alabama.

Nodal in SK-MEL-28 cells surviving treatment with the B-RAF inhibitor, RG7204.

Nodal expression in DTIC-treated melanoma cell lines.

Additional methods for supplementary data

Figure legends for supplementary figures 1-5

Purpose: Metastatic breast cancer (MBC) response to allogeneic lymphocytes requires donor T-cell engraftment and is limited by graft-versus-host disease (GVHD). In mice, type-II–polarized T cells promote engraftment and modulate GVHD, whereas type-I–polarized T cells mediate more potent graft-versus-tumor (GVT) effects. This phase I translational study evaluated adoptive transfer of ex vivo costimulated type-I/type-II (T1/T2) donor T cells with T-cell–depleted (TCD) allogeneic stem cell transplantation (AlloSCT) for MBC.Experimental Design: Patients had received anthracycline, taxane, and antibody therapies, and been treated for metastatic disease and a human leukocyte antigen (HLA)-identical–sibling donor. Donor lymphocytes were costimulated ex vivo with anti-CD3/anti-CD28 antibody–coated magnetic beads in interleukin (IL)-2/IL-4–supplemented media. Patients received reduced intensity conditioning, donor stem cells and T1/T2 cells, and monitoring for toxicity, engraftment, GVHD, and tumor response; results were compared with historical controls, identically treated except for T1/T2 product infusions.Results: Mixed type-I/type-II CD4+ T cells predominated in T1/T2 products. Nine patients received T1/T2 cells at dose level 1 (5 × 106 cells/kg). T-cell donor chimerism reached 100% by a median of 28 days. Seven (78%) developed acute GVHD. At day +28, five patients had partial responses (56%) and none had MBC progression; thereafter, two patients had continued responses. Donor T-cell engraftment and tumor responses appeared faster than in historical controls, but GVHD rates were similar and responders progressed early, often following treatment of acute GVHD.Conclusion: Allogeneic T1/T2 cells were safely infused with TCD-AlloSCT, appeared to promote donor engraftment, and may have contributed to transient early tumor responses. Clin Cancer Res; 17(21); 6878–87. ©2011 AACR.

PDF file - 24K

Supplementary Figure 1 from Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype

Supplementary Figure 2 from Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype

Supplementary Tables 1-4 from Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype

Supplementary Figure 5 from Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype

Metastatic melanoma is an aggressive skin cancer associated with poor prognosis. The reactivation of the embryonic morphogen Nodal in metastatic melanoma has previously been shown to regulate the aggressive behavior of these tumor cells. During the establishment of left-right asymmetry in early vertebrate development, Nodal expression is specifically regulated by a Notch signaling pathway. We hypothesize that a similar relationship between Notch and Nodal may be reestablished in melanoma. In this study, we investigate whether cross talk between the Notch and Nodal pathways can explain the reactivation of Nodal in aggressive metastatic melanoma cells. We show a molecular link between Notch and Nodal signaling in the aggressive melanoma cell line MV3 via the activity of an RBPJ-dependent Nodal enhancer element. We show a precise correlation between Notch4 and Nodal expression in multiple aggressive cell lines but not poorly aggressive cell lines. Surprisingly, Notch4 is specifically required for expression of Nodal in aggressive cells and plays a vital role both in the balance of cell growth and in the regulation of the aggressive phenotype. In addition, Notch4 function in vasculogenic mimicry and anchorage-independent growth in vitro is due in part to Notch4 regulation of Nodal. This study identifies an important role for cross talk between Notch4 and Nodal in metastatic melanoma, placing Notch4 upstream of Nodal, and offers a potential molecular target for melanoma therapy. Cancer Res; 70(24); 10340–50. ©2010 AACR.

Supplementary Figure Legends 1-5 from Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype

Supplementary Figure 3 from Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype

Supplementary Methods from Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype

Supplementary Figure 4 from Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype

Waves of COVID-19 have been managed successfully within US, EU, Southeast Asia and Latin America, however, South Asia and Sub-saharan Africa still suffer new variants and EU fights with UK and United States of ,,new waves of old disease“, postcovide or long covide syndrome. The aim of this communication and research is to prepare our auditors for the size and extent of postcovid systems and the importance of non-doctors and non-medicine experts in management of its consequences.

Research Highlight: Valenzuela-Sánchez, A., Azat, C., Cunningham, A. A., Delgado, S., Bacigalupe, L. D., Beltrand, J., Serrano, J. M., Sentenac, H., Haddow, N., Toledo, V., Schmidt, B. R.,Cayuela, H. (2022). Interpopulation differences in male reproductive effort drive the population dynamics of a host exposed to an emerging fungal pathogen. Journal of Animal Ecology, 00, 1- 12. https://doi.org/10.1111/1365-2656.13603. Understanding the nuances of population persistence in the face of a stressor can help predict extinction risk and guide conservation actions. However, the exact mechanisms driving population stability may not always be known. In this paper, Valenzuela-Sánchez et al. (2022) integrate long-term mark-recapture data, focal measurements of reproductive effort, a population matrix model and inferences on life-history variation to reveal differences in demographic response to disease in a susceptible frog species (Rhinoderma darwinii). Valenzuela-Sánchez et al. found that demographic compensation via recruitment explained the positive population growth rate in their high disease prevalence population whereas the low disease prevalence population did not compensate and thus had decreasing population growth. Compensatory recruitment was likely due to the high probability of males brooding, and the high number of brooded larvae in the high prevalence population compared to low prevalence and disease-free populations. Valenzuela-Sánchez et al. also document faster generation times in the high prevalence population, which may indicate a faster life history that may be contributing to the population's ability to compensate for reduced survival. Lastly, the authors find a positive relationship between disease prevalence and the proportion of juveniles in a given population that suggest that there may be a threshold for disease prevalence that triggers increased reproductive effort. Altogether, their study provides novel support for increased reproductive effort as the pathway for compensatory recruitment leading to increasing population growth despite strong negative effects of disease on adult survival. Their results also caution the overgeneralization of the effects of stressors (e.g. disease) on population dynamics, where context-dependent responses may differ among host populations of a given species.

Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation disorder. Use of chimeric antigen receptor T-cell therapy (CAR-T) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and secondary HLH. However, application of HLH scoring systems (H-score, HLH-2004 criteria) are not validated in this setting. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify patients with possible HLH post-CAR-T for Relapsed/Refractory Diffuse Large B-cell Lymphoma. Only two of four patients with post CAR-T HLH met five or more of the diagnostic criteria for HLH by HLH 2004 criteria. In contrast all four post CAR-T HLH patients had a high H-score (169); however, an additional ten patients that did not have HLH also had a high H-score. Thus, in this patient population, both scoring systems were demonstrated to have low prognostic significance in differentiating between high grade CRS and HLH.

We examine the relationship between the rationing of health care resources and disparities in health care delivery and the specific implications for radiologic resource allocation frameworks such as the ACR Appropriateness Criteria. We explore what rationing is in this context and how it is manifested in radiology. We review how rationing has taken many forms and how rationing has influenced the development of disparities in access and outcomes within health care and specifically within the context of radiology. We describe how the relationship between rationing and health care delivery disparities manifested during the coronavirus disease 2019 pandemic and the corrective measures that were proposed to established rationing frameworks to facilitate more equitable pandemic-related resource distribution. We offer suggestions regarding how such solutions might be brought into radiologic resource allocation schemes to help mitigate disparities in radiologic care in the future.

Magnetic resonance microscopy images at cellular resolution (< 10 microns) are limited by diffusion. SNR and spatial resolution suffer from the dephasing of transverse magnetization caused by diffusion of spins in strong gradients. Such effects may be reduced by using phase encoding instead of frequency encoding readout gradients. Demonstration of the benefits of phase encoding are lacking, and the conditions in which it is preferred are not clearly established. We quantify when phase encoding outperforms a readout gradient with emphasis on the detrimental effects of diffusion on SNR and resolution. A 15.2T MRI scanner, with 1 T/m gradients, and micro solenoid RF coils < 1 mm in diameter, were used to quantify diffusion effects on resolution and SNR of frequency and phase encoded acquisitions. Frequency and phase encoding resolution and SNR per square root time were calculated and measured for images at the diffusion limited resolution. The point-spread-function was measured for phase and frequency encoding using additional constant time gradients with voxels 3-15 microns. The effect of diffusion during the readout gradient on SNR was experimentally demonstrated. The achieved resolutions of frequency and phase encoded acquisitions were measured via the point-spread-function. SNR per square root time and actual resolution were calculated for a wide range of gradient amplitudes, diffusion coefficients, and relaxation properties. The results provide a practical guide on how to choose between phase and frequency encoding. Images of excised rat spinal cord at 10 x 10 microns in-plane demonstrate benefits of phase encoding in the form of higher measured resolution and SNR vs the same image acquired with a conventional readout. We demonstrate the extent to which phase encoding outperforms readout gradients in SNR and resolution over a wide range of voxel sizes, sample, and hardware properties., 36 pages, 9 figures, 1 table, and 4 supplemental figures. Submitted to Journal of Magnetic Resonance; cleaned up metadata, fixed heading typo

This study examines the use of individual development plans (IDPs) in a structured mentoring program as an effective mechanism for reducing identity-related anxiety for underrepresented trainees and increasing their learner agency. Social cognitive theory served to provide the theoretical framework for our implementation of IDPs and our investigation of the effects of completing IDPs on trainees attaining academic goals and subsequent success in enrolling in competitive PhD programs. Results suggest that IDPs are also an effective tool that can allow faculty mentors to provide the social support necessary for trainees to persist in accomplishing their short- and long-term learning goals. Additionally, trainee self-agency, in the use of the IDP and mentoring, seemed to provide an alternative narrative to ability as a sole predictor of STEM achievement. We also found that IDPs helped foster social support networks, providing stability, predictability, and a sense of belonging. Specifically, IDPs helped foster the emotional and informational support necessary for trainees to persist, despite obstacles, as they strived to attain their learning goals.

Awareness of the adverse effects of exposure to pollutant mixtures, possibly much more severe than individual chemicals, has drawn attention towards the necessity of using multi-residue methods to obtain the most possible comprehensive information on exposome. Among the different biological matrices used for exposure assessment, hair enables to detect the largest number of chemicals, including many classes such as persistent pollutants, hydrophilic metabolites and metals. Most biomonitoring studies are however focused on a limited number of pollutants and only give a partial information on exposure. Combining several multi-residue methods, the present study aimed at assessing the exposure of a population to an extensive variety of chemicals by hair analysis. One hair sample was collected from each participant (55 children and 134 adults). Samples were analysed with three different multi-residue methods, targeting, respectively, 152 organic pollutants (pesticides, PCBs, bisphenols, PBDEs), 62 polycyclic aromatic hydrocarbons (PAHs) and metabolites, nicotine and cotinine and 36 metals. From 33 to 70 organic chemicals were detected in each child’s hair sample, and from 34 up to 74 in adults. From 7 to 26 PAH were detected per child, and 7 to 21 in adults. Twenty-three to 27 metals were detected per child and 21 to 28 per adult. The highest median concentration were observed for zinc (143 μg /mg in children; 164 μg /mg in adults), bisphenol A (95.9 pg/mg in children; 64.7 pg/mg in adults) and nicotine (66.4 pg/mg in children; 51.9 pg/mg in adults). The present study provides the most comprehensive exposure assessment ever and highlights the simultaneous exposure to multiple classes of pollutants in the general population. The results support the use of multi-residue methods for future studies on exposure-associated effects, to document exposome and better consider the effect of chemical mixtures.

Inertial confinement fusion experiments at both the National Ignition Facility (NIF) and the Laboratory for Laser Energetics OMEGA laser facility currently utilize Cherenkov detectors, with fused silica as the Cherenkov medium. At the NIF, the Quartz Cherenkov Detectors improve the precision of neutron time-of-flight measurements; and at OMEGA, the Diagnostic for Areal Density provides measurements of capsule shell areal densities. An inherent property of fused silica is the radiator’s relatively low energy threshold for Cherenkov photon production (Ethreshold < 1 MeV), making it advantageous over gas-based Cherenkov detectors for experiments requiring low-energy γ detection. The Vacuum Cherenkov Detector (VCD) has been specifically designed for efficient detection of low energy γ’s. Its primary use is in implosion experiments, which will study reactions relevant to stellar and big-bang nucleosynthesis, such as T(4He,γ)7Li, 4He(3He,γ)7Be, and 12C(p,γ)13N. The VCD is compatible with LLE’s standard Ten-Inch Manipulator diagnostic insertion module. This work will outline the design and characterization of the VCD as well as provide results from recent experiments conducted at the OMEGA laser facility.

Knowledge gaps regarding the potential role of pesticides in the loss of agricultural biodiversity worldwide and mixture-related issues hamper proper risk assessment of unintentional impacts of pesticides, rendering essential the monitoring of wildlife exposure to these compounds. Free-ranging mammal exposure to legacy (Banned and Restricted: BRPs) and currently used (CUPs) pesticides was investigated, testing the hypotheses of: (1) a background bioaccumulation for BRPs whereas a “hot-spot” pattern for CUPs, (2) different contamination profiles between carnivores and granivores/omnivores, and (3) the role of non-treated areas as refuges towards exposure to CUPs. Apodemus mice (omnivore) and Crocidura shrews (insectivore) were sampled over two French agricultural landscapes (n = 93). The concentrations of 140 parent chemicals and metabolites were screened in hair samples. A total of 112 compounds were detected, showing small mammal exposure to fungicides, herbicides and insecticides with 32 to 65 residues detected per individual (13–26 BRPs and 18–41 CUPs). Detection frequencies exceeded 75% of individuals for 13 BRPs and 25 CUPs. Concentrations above 10 ng/g were quantified for 7 BRPs and 29 CUPs (in 46% and 72% of individuals, respectively), and above 100 ng/g for 10 CUPs (in 22% of individuals). Contamination (number of compounds or concentrations) was overall higher in shrews than rodents and higher in animals captured in hedgerows and cereal crops than in grasslands, but did not differ significantly between conventional and organic farming. A general, ubiquitous contamination by legacy and current pesticides was shown, raising issues about exposure pathways and impacts on ecosystems. We propose a concept referred to as “biowidening”, depicting an increase of compound diversity at higher trophic levels. This work suggests that wildlife exposure to pesticide mixtures is a rule rather than an exception, highlighting the need for consideration of the exposome concept and questioning appropriateness of current risk assessment and mitigation processes.

PEAK pseudokinases regulate cell migration, invasion and proliferation by recruiting key signaling proteins to the cytoskeleton. Despite lacking catalytic activity, alteration in their expression level is associated with several aggressive cancers. Here, we elucidate new molecular details of key PEAK signaling interactions with the adapter proteins CrkII and Grb2 and the scaffold protein 14-3-3. Our findings rationalize why the dimerization of PEAK proteins has a crucial function in signal transduction and provide biophysical and structural data to unravel binding specificity within the PEAK interactome. We identify a conserved high affinity 14-3-3 motif on PEAK3 and demonstrate its role as a molecular switch to regulate CrkII binding. Together, our studies provide a detailed structural snapshot of PEAK interaction networks and further elucidate how PEAK proteins, especially PEAK3, act as dynamic scaffolds that exploit adapter proteins to control signal transduction in cell growth/motility and cancer.