We have previously shown that autophagy is required for chronological longevity in the budding yeast Saccharomyces cerevisiae. Here we examine the requirements for autophagy during extension of ...chronological life span (CLS) by calorie restriction (CR). We find that autophagy is upregulated by two CR interventions that extend CLS: water wash CR and low glucose CR. Autophagy is required for full extension of CLS during water wash CR under all growth conditions tested. In contrast, autophagy was not uniformly required for full extension of CLS during low glucose CR, depending on the atg allele and strain genetic background. Leucine status influenced CLS during CR. Eliminating the leucine requirement in yeast strains or adding supplemental leucine to growth media extended CLS during CR. In addition, we observed that both water wash and low glucose CR promote mitochondrial respiration proficiency during aging of autophagy-deficient yeast. In general, the extension of CLS by water wash or low glucose CR was inversely related to respiration deficiency in autophagy-deficient cells. Also, autophagy is required for full extension of CLS under non-CR conditions in buffered media, suggesting that extension of CLS during CR is not solely due to reduced medium acidity. Thus, our findings show that autophagy is: (1) induced by CR, (2) required for full extension of CLS by CR in most cases (depending on atg allele, strain, and leucine availability) and, (3) promotes mitochondrial respiration proficiency during aging under CR conditions.
► Autophagy is induced during calorie restriction (CR) in yeast (S. cerevisiae). ► Autophagy is required for full extension of chronological life span (CLS) during CR. ► Leucine during CR extends CLS and diminishes the requirement for autophagy. ► CR, autophagy, and leucine are associated with respiration proficiency during aging. ► We propose a model for how autophagy functions to extend CLS during CR.
Finally, after a lengthy hiatus, the empirical facts of economic inequality need no introduction. In a blaze of publicity during a decade or more, the re-polarization of income and wealth across ...nearly half a century has been widely documented and is substantially uncontested. There is debate on whether incomes have peaked, no doubt that capital is back, and a great deal of speculation on what might happen next. What is surprising is the limited attention afforded to the pivotal role of housing. To address that gap, conceptually and empirically, this paper draws from panel surveys in three countries across two decades to locate residential property generally, and owner-occupation in particular, within a wider literature on the shape of economic inequality in the long run.
Purpose
Patients undergoing a hematopoietic stem cell transplantation (HCT) have varied symptoms during their hospitalization. This study examined whether daily symptom reporting (with electronic ...patient-reported outcomes PROs) in an inpatient bone marrow transplant clinic reduced symptom burden on post-transplant days +7, +10, and +14.
Methods
A prospective, single-institution 1:1 pilot randomized, two-arm study recruited HCT patients. HCT inpatients (
N
= 76) reported daily on 16 common symptoms using the PRO version of the Common Terminology for Adverse Events (PRO-CTCAE). Fisher’s exact test was used to examine differences in the proportion of patients reporting individual symptoms. Multivariable linear regression modeling was used to examine group differences in peak symptom burden, while controlling for symptom burden at baseline, age, comorbidity, and transplantation type (autologous or allogeneic).
Results
HCT patients receiving the PRO intervention also experienced lower peak symptom burden (average of 16 symptoms) at days +7, +10, and +14 (10.4 vs 14.5,
p
= 0.03).
Conclusions
Daily use of electronic symptom reporting to nurses in an inpatient bone marrow transplant clinic reduced peak symptom burden and improved individual symptoms during the 2 weeks post-transplant. A multi-site trial is warranted to demonstrate the generalizability, efficacy, and value of this intervention.
Trial registration
ClinicalTrials.gov
identifier: NCT 02574897
Mucosal-associated invariant T (MAIT) cells have properties of both the innate and adaptive immune systems but are an understudied population within exercise immunology. These lymphocytes aggregate ...at the mucous membranes, but it is unknown if submaximal exercise alters their circulating numbers or function.
To determine the MAIT cell response to submaximal exercise on activation and homing marker expression and stimulated cytokine production.
Twenty healthy, young, recreationally active males cycled for 40 min at 86% of VT after an overnight fast. Peripheral blood mononuclear cells were isolated and labeled to identify specific MAIT cell populations using flow cytometry. Cytokine production after stimulation was also determined.
Mucosal-associated invariant T cells were 2.9% of T cells and increased to 3.9% after exercise and with recovery whereas cell numbers significantly increased by 91.5% after exercise before returning to resting levels. Chemokine and activation marker absolute cell number significantly increased while expression levels remained constant but the high levels of CCR5 may help direct MAIT cells to sites of inflammation. After stimulation, TNFα expression significantly increased after exercise before returning to baseline with a similar trend for IFNγ.
The MAIT cell numbers undergo a partial biphasic response after submaximal exercise and appear to be preferentially mobilized within T cells; however, the magnitude of the submaximal response was attenuated relative to maximal exercise. Stimulated MAIT cells increase TNFα expression, indicating greater responsiveness to pathogens after acute exercise.
Follicular lymphoma (FL) is a low-grade B-cell malignancy that transforms into a highly aggressive and lethal disease at a rate of 2% per year. Perfect isolation of the malignant B-cell population ...from a surgical biopsy is a significant challenge, masking important FL biology, such as immune checkpoint coexpression patterns. To resolve the underlying transcriptional networks of follicular B-cell lymphomas, we analyzed the transcriptomes of 34 188 cells derived from 6 primary FL tumors. For each tumor, we identified normal immune subpopulations and malignant B cells, based on gene expression. We used multicolor flow cytometry analysis of the same tumors to confirm our assignments of cellular lineages and validate our predictions of expressed proteins. Comparison of gene expression between matched malignant and normal B cells from the same patient revealed tumor-specific features. Malignant B cells exhibited restricted immunoglobulin (Ig) light chain expression (either Igκ or Igλ), as well the expected upregulation of the BCL2 gene, but also downregulation of the FCER2, CD52, and major histocompatibility complex class II genes. By analyzing thousands of individual cells per patient tumor, we identified the mosaic of malignant B-cell subclones that coexist within a FL and examined the characteristics of tumor-infiltrating T cells. We identified genes coexpressed with immune checkpoint molecules, such as CEBPA and B2M in regulatory T (Treg) cells, providing a better understanding of the gene networks involved in immune regulation. In summary, parallel measurement of single-cell expression in thousands of tumor cells and tumor-infiltrating lymphocytes can be used to obtain a systems-level view of the tumor microenvironment and identify new avenues for therapeutic development.
•Malignant follicular lymphoma B cells segregate into multiple coexisting subclones, characterized by differential pathway activities.•In CD4+ Tregs, known immune checkpoint genes are coexpressed with transcription factors and immune regulators, including CEBPA and B2M.
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Athletic trainers (ATs) are employed in various settings, which may use 1 of 3 organizational infrastructure models: (1) the sport/athletic model, (2) the medical model, and (3) the academic model. ...These different settings and organizational infrastructure models may result in varying levels of organizational-professional conflict (OPC). However, how OPC may differ across infrastructure models and practice settings is not known.
To examine the prevalence of OPC among ATs in various organizational infrastructures and explore ATs' perceptions of OPC, including its precipitating and mitigating factors.
Sequential explanatory mixed-methods study with equal emphasis on quantitative and qualitative components.
Collegiate and secondary school institutions.
Five hundred ninety-four ATs from collegiate and secondary schools.
We conducted a national cross-sectional survey using a validated scale to assess OPC. We then followed the quantitative survey with individual interviews. Trustworthiness was established with multiple-analyst triangulation and peer debriefing.
Athletic trainers experienced low to moderate degrees of OPC with no differences across practice settings or infrastructure models. Poor communication, others' unfamiliarity with the AT's scope of practice, and lack of medical knowledge were precipitating factors for OPC. Organizational relationships founded on trust and respect for one another; administrative support in that ATs were listened to, decisions were endorsed, and appropriate resources provided; and autonomy given to the AT were key components to preventing OPC.
Most ATs experienced primarily low to moderate OPC. However, OPC continues to permeate professional practice to some extent in collegiate and secondary school settings, regardless of the infrastructure model used. The findings of this study highlight the role of administrative support that allows for autonomous AT practice as well as effective communication that is direct, open, and professional to decrease OPC.
Background
In the current study, the authors investigated the incidence of moderate to severe chemotherapy‐induced peripheral neuropathy (CIPN) for chemotherapy regimens commonly used in current ...clinical practice for the treatment of patients with early breast cancer. Patient‐reported and clinician‐assessed CIPN severity scores were compared, and risk factors for CIPN severity were identified.
Methods
Patients completed a Patient‐Reported Symptom Monitoring form and oncologists completed a Common Terminology Criteria for Adverse Events form. CIPN reports were collected prospectively during regularly scheduled infusion visits throughout the duration of chemotherapy.
Results
The sample included 184 women with a mean age of 55 years; approximately 73% were white. The 4 chemotherapy regimens used were doxorubicin and cyclophosphamide plus paclitaxel (60 patients); docetaxel and cyclophosphamide (50 patients); docetaxel, carboplatin, and anti–human epidermal growth factor receptor 2 (HER2) (24 patients); and doxorubicin and cyclophosphamide plus paclitaxel and carboplatin (18 patients). All patients treated with doxorubicin and cyclophosphamide plus paclitaxel and doxorubicin and cyclophosphamide plus paclitaxel and carboplatin received paclitaxel; all patients treated with docetaxel and cyclophosphamide and docetaxel, carboplatin, and anti‐HER2 received docetaxel. The chemotherapy dose was reduced in 52 patients (28%); in 15 patients (29%), this reduction was due to CIPN. Chemotherapy was discontinued in 26 patients (14%), 8 because of CIPN. Agreement between patient‐reported and clinician‐assessed CIPN severity scores was minimal (weighted Cohen kappa, P = .34). Patient‐reported moderate to severe CIPN was higher for paclitaxel (50%) compared with docetaxel (17.7%) (P < .001). Pretreatment arthritis and/or rheumatism (relative risk RR, 1.58; 95% CI, 1.06‐2.35 P = .023) and regimens containing paclitaxel (RR, 2.88; 95% CI, 1.72‐4.83 P < .0001) were associated with higher CIPN severity. Being married (RR, 0.57; 95% CI, 0.37‐0.887 P = .01) was found to be associated with lower CIPN severity.
Conclusions
The discrepancy between patient‐reported and clinician‐assessed CIPN underscores the need for both patient and clinician perspectives regarding this common, dose‐limiting, and potentially disabling side effect of chemotherapy.
The severity of patient‐reported chemotherapy‐induced peripheral neuropathy (CIPN) varies by the regimen used in current clinical practice for the treatment of early breast cancer. The discrepancy between patient‐reported and clinician‐assessed CIPN underscores the need for both patient and clinician perspectives on this common, dose‐limiting, and potentially disabling side effect of chemotherapy.
Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.
We conducted a prospective, multicenter, randomized, ...two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy.
SCR was observed in 9 of 35 26%; 95% confidence interval (CI); 13%-43% participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients.
These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.
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