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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.

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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