Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: The CINDERELLA trial

<p>Abstract</p> <p>Background</p> <p>Treatment of patients with recurrent glioma includes neurosurgical resection, chemotherapy, or radiation therapy. In most cases, a full course of radiotherapy has been applied after primary diagnosis, therefore application of re-irradiation has to be applied cauteously. With modern precision photon techniques such as fractionated stereotactic radiotherapy (FSRT), a second course of radiotherapy is safe and effective and leads to survival times of 22, 16 and 8 months for recurrent WHO grade II, III and IV gliomas.</p> <p>Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.</p> <p>First Japanese Data on the evaluation of carbon ion radiation therapy for the treatment of primary high-grade gliomas showed promising results in a small and heterogeneous patient collective.</p> <p>Methods Design</p> <p>In the current Phase I/II-CINDERELLA-trial re-irradiation using carbon ions will be compared to FSRT applied to the area of contrast enhancement representing high-grade tumor areas in patients with recurrent gliomas. Within the Phase I Part of the trial, the Recommended Dose (RD) of carbon ion radiotherapy will be determined in a dose escalation scheme. In the subsequent randomized Phase II part, the RD will be evaluated in the experimental arm, compared to the standard arm, FSRT with a total dose of 36 Gy in single doses of 2 Gy.</p> <p>Primary endpoint of the Phase I part is toxicity. Primary endpoint of the randomized part II is survival after re-irradiation at 12 months, secondary endpoint is progression-free survival.</p> <p>Discussion</p> <p>The Cinderella trial is the first study to evaluate carbon ion radiotherapy for recurrent gliomas, and to compare this treatment to photon FSRT in a randomized setting using an ion beam delivered by intensity modulated rasterscanning.</p> <p>Trial Registration</p> <p>NCT01166308</p

Chemotherapy with BCNU in recurrent glioma: Analysis of clinical outcome and side effects in chemotherapy-naïve patients

Background: To date, standardized strategies for the treatment of recurrent glioma are lacking. Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitroso-urea) is a therapeutic option even though its efficacy and safety, particularly the risk of pulmonary fibrosis, remains controversial. To address these issues, we performed a retrospective analysis on clinical outcome and side effects of BCNU-based chemotherapy in recurrent glioma. Methods: Survival data of 34 mostly chemotherapy-naïve glioblastoma patients treated with BCNU at 1st relapse were compared to 29 untreated control patients, employing a multiple Cox regression model which considered known prognostic factors including MGMT promoter hypermethylation. Additionally, medical records of 163 patients treated with BCNU for recurrent glioma WHO grade II to IV were retrospectively evaluated for BCNU-related side effects classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 2.0. Results: In recurrent glioblastoma, multiple regression survival analysis revealed a significant benefit of BCNU-based chemotherapy on survival after relapse (p = 0.02; HR = 0.48; 95 % CI = 0.26–0.89) independent of known clinical and molecular prognostic factors. Exploratory analyses suggested that survival benefit was most pronounced in MGMT-hypermethylated, BCNU-treated patients. Moreover, BCNU was well tolerated by 46 % of the 163 patients analyzed for side effects; otherwise, predominantly mild side effects occurred (CTCAE I/II; 45 %). Severe side effects CTCAE III/IV were observed in 9 % of patients including severe hematotoxicity, thromboembolism, intracranial hemorrhage and injection site reaction requiring surgical intervention. One patient presented with a clinically apparent pulmonary fibrosis CTCAE IV requiring temporary mechanical ventilation. Conclusion: In this study, BCNU was rarely associated with severe side effects, particularly pulmonary toxicity, and, in case of recurrent glioblastoma, even conferred a favorable outcome. Therefore BCNU appears to be an appropriate alternative to other nitrosoureas although the efficacy against newer drugs needs further evaluation

Assessing Chronic Pain Among Adults Diagnosed with Diabetes Residing in Rural Appalachia

Introduction: Appalachian populations have some of the highest rates of overdose and comorbidity, all of which are considered risk factors for and contributors to chronic pain. Purpose: The purpose of this study was to examine the associations of comorbidity, disability (physical limitations), and depression with chronic pain among a community-based sample of Appalachian adults living with diabetes. Methods: This study used baseline data to conduct a secondary analysis of cross-sectional data (n=356). Data included sociodemographic, disability (physical limitations), chronic pain, and depression measures. These data were collected and analyzed from 2017–2019. Multiple logistic regression was used to investigate the association between comorbidity, disability, depression, and chronic pain. Results: Participants were predominantly non Hispanic white (98.0%), women (64.6%), and had a mean age of 64.2 years. Comorbidity (p=.044), physical limitations (pp Implications: Chronic pain affects physical and psychosocial health among those diagnosed with diabetes who live in rural Appalachian communities. Alleviating chronic pain could have a synergistic benefit to healthy functioning

Proton and carbon ion radiotherapy for primary brain tumors delivered with active raster scanning at the Heidelberg Ion Therapy Center (HIT): early treatment results and study concepts

<p>Abstract</p> <p>Background</p> <p>Particle irradiation was established at the University of Heidelberg 2 years ago. To date, more than 400 patients have been treated including patients with primary brain tumors. In malignant glioma (WHO IV) patients, two clinical trials have been set up-one investigating the benefit of a carbon ion (18 GyE) vs. a proton boost (10 GyE) in addition to photon radiotherapy (50 Gy), the other one investigating reirradiation with escalating total dose schedules starting at 30 GyE. In atypical meningioma patients (WHO °II), a carbon ion boost of 18 GyE is applied to macroscopic tumor residues following previous photon irradiation with 50 Gy.</p> <p>This study was set up in order to investigate toxicity and response after proton and carbon ion therapy for gliomas and meningiomas.</p> <p>Methods</p> <p>33 patients with gliomas (n = 26) and meningiomas (n = 7) were treated with carbon ion (n = 26) and proton (n = 7) radiotherapy. In 22 patients, particle irradiation was combined with photon therapy. Temozolomide-based chemotherapy was combined with particle therapy in 17 patients with gliomas. Particle therapy as reirradiation was conducted in 7 patients. Target volume definition was based upon CT, MRI and PET imaging. Response was assessed by MRI examinations, and progression was diagnosed according to the Macdonald criteria. Toxicity was classified according to CTCAE v4.0.</p> <p>Results</p> <p>Treatment was completed and tolerated well in all patients. Toxicity was moderate and included fatigue (24.2%), intermittent cranial nerve symptoms (6%) and single episodes of seizures (6%). At first and second follow-up examinations, mean maximum tumor diameters had slightly decreased from 29.7 mm to 27.1 mm and 24.9 mm respectively. Nine glioma patients suffered from tumor relapse, among these 5 with infield relapses, causing death in 8 patients. There was no progression in any meningioma patient.</p> <p>Conclusions</p> <p>Particle radiotherapy is safe and feasible in patients with primary brain tumors. It is associated with little toxicity. A positive response of both gliomas and meningiomas, which is suggested in these preliminary data, must be evaluated in further clinical trials.</p

Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) – protocol of a randomized phase II trial (NOA 10/ARO 2013-1)

Background: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone. Methods: This protocol describes a prospective, open label, randomized, multi-center phase II trial designed to test if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS) in patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based on T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary endpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious of progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression or death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRIor PET-derived target volumes, rate of long term survivors (> 1 year), localization of necrosis after re-irradiation, quality of life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET imaging and toxicity of re-irradiation. Discussion: This is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target volume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a standardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning. Trial registration: The GLIAA trial is registered with ClinicalTrials.gov (NCT01252459, registration date 02.12.2010), German Clinical Trials Registry (DRKS00000634, registration date 10.10.2014), and European Clinical Trials Database (EudraCT-No. 2012-001121-27, registration date 27.02.2012)

The Mediating/Moderating Role of Cultural Context Factors on Self-Care Practices among Those Living with Diabetes in Rural Appalachia

Background The aim of this study was to examine whether cultural factors, such as religiosity and social support, mediate/moderate the relationship between personal/psychosocial factors and T2DM self-care in a rural Appalachian community. Methods Regression models were utilized to assess for mediation and moderation. Multilevel linear mixed effects models and GEE-type logistic regression models were fit for continuous (social support, self-care) and binary (religiosity) outcomes, respectively. Results The results indicated that cultural context factors (religiosity and social support) can mediate/moderate the relationship between psychosocial factors and T2DM self-care. Specifically, after adjusting for demographic variables, the findings suggested that social support may moderate the effect of depressive symptoms and stress on self-care. Religiosity may moderate the effect of distress on self-care, and empowerment was a predictor of self-care but was not mediated/moderated by the assessed cultural context factors. When considering health status, religiosity was a moderately significant predictor of self-care and may mediate the relationship between perceived health status and T2DM self-care. Conclusions This study represents the first known research to examine cultural assets and diabetes self-care practices among a community-based sample of Appalachian adults. We echo calls to increase the evidence on social support and religiosity and other contextual factors among this highly affected population. Trial registration US National Library of Science identifier NCT03474731. Registered March 23, 2018, www.clinicaltrials.gov

Critical Communication: Improving Care Transitions for Incarcerated Patients Requiring Palliative and End-of-Life Care

Background: Incarcerated persons are often sicker than the general population, with high levels of medical comorbidities [1]. Among those incarcerated, the elderly population is increasing at much higher rates than younger inmates, and with it rates of age-related chronic illnesses [2-3]. Care transitions, or movement from patients between healthcare settings, increase risk for adverse events due to potential miscommunication during transfers [4-5]. When hospitalized with life-limiting diagnoses, interdisciplinary palliative medicine teams advocate for appropriate patient care for persons who are incarcerated. However, limited resources and communication challenges often lead to inadequate care transitions upon discharge to correctional facilities. Methods: A quality improvement project was designed to address the challenges related to communication between Corrections Department (CD) Long Term Care Unit (LTCU) staff and our academic hospital. The aims of this project include the following: Identify unique challenges related to care transitions of persons who are incarcerated, specifically those with complex medical and palliative care needs. Create an educational intervention for inpatient clinical staff to identify patients with palliative care needs and encourage use of a “Best Practice Algorithm” when discharging these patients to CD LTCU facilities. Establish relationships between the inpatient Palliative Medicine Consultation Service and CD LTCU staff to improve care coordination and communication about shared patients during and after hospital discharge. Expected Outcome: By facilitating direct communication between hospital medicine services and the Corrections Department staff, we expect to improve the frequency and quality of care transitions for incarcerated persons being discharged to the CD LTCU. Discussion: Care transitions from hospital to CD facilities are challenging for multiple reasons, but this can be an especially vulnerable period for persons with serious illnesses and palliative medicine needs. A quality improvement project to enhance communication between hospital and CD staff is ongoing, with hopes that improved care transitions will heighten quality of patient care and reduce patient suffering. References: Linder J and Meyers F. Palliative Care for Prison Inmates, “Don’t Let Me Die in Prison”. JAMA. 2007: 298(8): 894-901. Cloyes K, Berry P, Martz K, and Supiano K. Characteristics of Prison Hospice Patients: Medical History, Hospice Care, and End-of-Life Symptom Prevalence. Journal of Correctional Health Care 2015: 21(3): 298-308. Stephens S, Cassel J B, Norieka D, and Del Fabbro E. Palliative Care for Inmates in the Hospital Setting. American Journal of Hospice and Palliative Medicine 2019: 36(4) 321-325. Center for Medicare and Medicaid Services: Improving Care Transitions. https://www.medicaid.gov/medicaid/quality-of-care/quality-improvement-initiatives/improving-care-transitions/index.html (Last accessed 03/22/2021) Agency for Healthcare Quality and Research: Chartbook on Care Coordination. https://www.ahrq.gov/research/findings/nhqrdr/chartbooks/carecoordination/measure1.html (Last accessed 01/02/2021

Racism as a determinant of health: a systematic review and meta-analysis

Despite a growing body of epidemiological evidence in recent years documenting the health impacts of racism, the cumulative evidence base has yet to be synthesized in a comprehensive meta-analysis focused specifically on racism as a determinant of health. This meta-analysis reviewed the literature focusing on the relationship between reported racism and mental and physical health outcomes. Data from 293 studies reported in 333 articles published between 1983 and 2013, and conducted predominately in the U.S., were analysed using random effects models and mean weighted effect sizes. Racism was associated with poorer mental health (negative mental health: r = -.23, 95% CI [-.24,-.21], k = 227; positive mental health: r = -.13, 95% CI [-.16,-.10], k = 113), including depression, anxiety, psychological stress and various other outcomes. Racism was also associated with poorer general health (r = -.13 (95% CI [-.18,-.09], k = 30), and poorer physical health (r = -.09, 95% CI [-.12,-.06], k = 50). Moderation effects were found for some outcomes with regard to study and exposure characteristics. Effect sizes of racism on mental health were stronger in cross-sectional compared with longitudinal data and in non-representative samples compared with representative samples. Age, sex, birthplace and education level did not moderate the effects of racism on health. Ethnicity significantly moderated the effect of racism on negative mental health and physical health: the association between racism and negative mental health was significantly stronger for Asian American and Latino(a) American participants compared with African American participants, and the association between racism and physical health was significantly stronger for Latino(a) American participants compared with African American participants.<br /