BUB1 inhibition sensitizes lung cancer cell lines to radiotherapy and chemoradiotherapy.

Background: Lung cancer is a major public health concern, with high incidence and mortality. Despite advances in targeted therapy and immunotherapy, microtubule stabilizers (paclitaxel, docetaxel), DNA intercalating platinum drugs (cisplatin) and radiation therapy continue to play a critical role in the management of locally advanced and metastatic lung cancer. Novel molecular targets would provide opportunities for improving the efficacies of radiotherapy and chemotherapy. Hypothesis: We hypothesize that BUB1 (Ser/Thr kinase) is over-expressed in lung cancers and that its inhibition will sensitize lung cancers to chemoradiation. Methods: BUB1 inhibitor (BAY1816032) was combined with platinum (cisplatin), microtubule poison (paclitaxel), a PARP inhibitor (olaparib) and radiation in cell proliferation and radiation sensitization assays. Biochemical and molecular assays were used to evaluate their impact on DNA damage signaling and cell death mechanisms. Results: BUB1 expression assessed by immunostaining of lung tumor microarrays (TMAs) confirmed higher BUB1 expression in NSCLC and SCLC compared to that of normal tissues. BUB1 overexpression in lung cancer tissues correlated directly with expression of TP53 mutations in non-small cell lung cancer (NSCLC). Elevated BUB1 levels correlated with poorer overall survival in NSCLC and small cell lung cancer (SCLC) patients. A BUB1 inhibitor (BAY1816032) synergistically sensitized lung cancer cell lines to paclitaxel and olaparib. Additionally, BAY1816032 enhanced cell killing by radiation in both NSCLC and SCLC. Molecular changes following BUB1 inhibition suggest a shift towards pro-apoptotic and anti-proliferative states, indicated by altered expression of BAX, BCL2, PCNA, and Caspases 9 and 3. Conclusion: A direct correlation between BUB1 protein expression and overall survival was shown. BUB1 inhibition sensitized both NSCLC and SCLC to various chemotherapies (cisplatin, paclitaxel) and targeted therapy (PARPi). Furthermore, we present the novel finding that BUB1 inhibition sensitized both NSCLC and SCLC to radiotherapy and chemoradiation. Our results demonstrate BUB1 inhibition as a promising strategy to sensitize lung cancers to radiation and chemoradiation therapies.

BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment. Methods: Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC 50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays. Results: BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t 1/2 , ∼8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade. Conclusions: BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.

Novel Small Molecule, UTS-1401, as a Radioprotector for Total-Body Irradiation.

We report on a new radioprotector, UTS-1401, a small molecule that was synthesized (by one of us, JS) and evaluated here for its radioprotective effect against total-body irradiation (TBI). Female and male NIH Swiss mice were subjected to TBI at doses of 6.5, 7.5 and 8.5 Gy either with or without a 24 h pretreatment of UTS-1401 given ip and observed for 30 days. Survival rates were significantly increased when mice were treated with UTS-1401 compared to those not treated. The radioprotective effect of UTS-1401 was drug-dose dependent for male mice exposed to 8.5 Gy TBI with 150 mg/kg of UTS-1401 as the optimal dose. The radioprotective effect of UTS-1401 on female mice exposed to 8.5 Gy TBI was observed at 50, 100, and 150 mg/kg, with no dose response relationship noted. Female mice were more radioresistant than male mice with LD50/30 values of 7.8 Gy vs. 6.8 Gy, respectively. Weight changes after UTS-1401 alone showed a significant body weight increase at 150 mg/kg. Both the ip and iv route for UTS-1401 were similarly effective for male mice exposed to 8 Gy TBI. Further analysis using an endogenous spleen colony assay demonstrated that pretreatment of UTS-1401 for up to 72h prior to TBI protected both spleen weight and hematopoietic stem cells with a treated/untreated ratio between 2.0 and 3.2 for the latter for times between 0.5 h and 72 h. A separate in vivo study showed that pretreatment of UTS-1401 protected bone marrow CFU-GM for mice exposed to TBI. In summary, UTS-1401 is a promising small-molecule radioprotective agent as demonstrated by whole animal, hematopoietic stem cell and bone marrow myeloid progenitor cell survival.

Associations between empirically proportionate and disproportionate fears of cancer recurrence and anxiety and depression in uveal melanoma survivors: Five-year prospective study.

OBJECTIVE: Fear of cancer recurrence (FCR) may develop into elevated anxiety or depression symptoms, but few risk factors for this development are known. Objective recurrence risk estimation is possible in some cancers. Using theories of risk communication and phobias, we examined whether the proportionality of FCR to known objective recurrence risk influences the development of anxiety and depression symptoms. METHOD: Uveal melanoma (UM) patients can opt for reliable prognostic testing. Patients experience either a 'good' or 'poor' prognostic outcome, whereby 10-year mortality due to metastatic disease is, respectively, low or high. In a five-year prospective study of a consecutive sample of 589 UM survivors, we used random intercept cross lagged panel analyses to examine whether proportionality differentially influences whether FCR progresses to anxiety and depression. RESULTS: Positive cross paths predicting anxiety from FCR were stronger in the poor prognosis group than the good prognosis and not tested groups. Prognostic group differences were not evident for depression. CONCLUSIONS: FCR was more likely to progress to elevated anxiety symptoms when proportionate to the known objective recurrence risk. Objective evidence may play a prominent role in the development and structure of fear because it assumes a high epistemic weight that activates a wide range of emotional and cognitive responses. Interventions that assist survivors to tolerate FCR in the presence of higher recurrence risks may be important in reducing anxiety symptoms.

Prevalence, temporal course and risk factors for phantom eye symptoms in uveal melanoma.

BACKGROUND: Phantom eye symptoms (PES), particularly phantom visual sensations (PVS) and phantom eye pain (PEP), are common in enucleated patients and can lead to psychological distress. Current cross-sectional studies cannot examine the temporal course of symptoms, nor can they identify dynamic risk factors or consequences of PES. METHODS: Cohort study of 105 enucleated uveal melanoma patients returning self-report questionnaires, within 4 weeks of diagnosis and 6-, 12- and 24-months post-treatment. Questionnaires measuring PVS and PEP symptoms in the week prior to completion, pain severity, Hospital Anxiety and Depression Scale scores and the Functional Assessment of Cancer Therapy scale (FACT-G) measuring quality of life. RESULTS: PVS and PEP emerged after 6 months, were relatively stable over the study and did not remit. PVS showed 6-, 12- and 24-month prevalence rates of 44.6%, 48.2% and 30.2%, and PEP 16.1%, 18.4% and 17.5% respectively. PVS were generally elementary, with only 10-15% of the total cohort experiencing complex sensations. PEP was generally neither prolonged nor intense, except in a small proportion. PVS and PEP were showed moderate associations but did not predict each other prospectively. Anxiety within 4 weeks of diagnosis was a risk factor for the initiation of PEP. Neither PVS nor PEP prospectively predicted anxiety, depression or quality of life. CONCLUSIONS: PES were prevalent and non-remitting, beginning within 6 months of enucleation. PVS and PEP may not represent symptoms of a coherent syndrome. We discuss findings with reference to theories of phantom sensations, and directions for clinical practise and research.

Multicenter Phase 1b/2a Clinical Trial of Radioprotectant BIO 300 Oral Suspension for Patients With Non-Small Cell Lung Cancer Receiving Concurrent Chemoradiotherapy.

PURPOSE: Radiation therapy is part of the standard treatment regimen for non-small cell lung cancer (NSCLC). Although radiation therapy is an effective tool to manage NSCLC, it can be associated with significant dose-limiting toxicities. These toxicities can lead to treatment interruption or early termination and worsening clinical outcomes in addition to reductions in patient quality of life. Based on preclinical efficacy for radioprotection of normal tissues, we evaluated the clinical utility of BIO 300 Oral Suspension (BIO 300; synthetic genistein nanosuspension) in patients with NSCLC. METHODS AND MATERIALS: In this multicenter, open-label, single-arm, ascending dose phase 1b/2a study, patients were enrolled with newly diagnosed stage II-IV NSCLC planned for 60 to 70/1.8-2.0 Gy radiation therapy and concurrent weekly paclitaxel/carboplatin. Oral BIO 300 (cohort 1, 500 mg/d; cohort 2, 1000 mg/d; cohort 3, 1500 mg/d) was self-administered once daily starting 2 to 7 days before initiating concurrent chemoradiotherapy and continued until the end of radiation therapy. The primary endpoint was acute dose-limiting toxicities attributable to BIO 300. Secondary outcomes included pharmacokinetics, pharmacodynamics, overall toxicity profile, quality of life, local response rate, and survival. RESULTS: Twenty-one participants were enrolled. No dose-limiting toxicities were reported. BIO 300 dosing did not alter chemotherapy pharmacokinetics. Adverse events were not dose-dependent, and those attributable to BIO 300 (n = 11) were all mild to moderate in severity (grade 1, n = 9; grade 2, n = 2) and predominantly gastrointestinal (n = 7). A dose-dependent decrease in serum transforming growth factor ß1 levels was observed across cohorts. Based on safety analysis, the maximum tolerated dose of BIO 300 was not met. Patient-reported quality of life and weight were largely stable throughout the study period. No patient had progression as their best overall response, and a 65% tumor response rate was achieved (20% complete response rate). CONCLUSIONS: The low toxicity rates, along with the pharmacodynamic results and tumor response rates, support further investigation of BIO 300 as an effective radioprotector.

PIM-COVID study: protocol for a multicentre, longitudinal study measuring the psychological impact of surviving an intensive care admission due to COVID-19 on patients in the UK.

INTRODUCTION: Psychological distress is common in intensive care unit (ICU) survivors and is anticipated in those who were treated for severe COVID-19 infection. This trainee-led, multicentre, observational, longitudinal study aims to assess the psychological outcomes of ICU survivors treated for COVID-19 infection in the UK at 3, 6 and/or 12 months after ICU discharge and explore whether there are demographic, psychosocial and clinical risk factors for psychological distress. METHODS AND ANALYSIS: Questionnaires will be provided to study participants 3, 6 and/or 12 months after discharge from intensive care, assessing for anxiety, depression, post-traumatic stress symptoms, health-related quality of life and physical symptoms. Demographic, psychosocial and clinical data will also be collected to explore risk factors for psychological distress using latent growth curve modelling. Study participants will be eligible to complete questionnaires at any of the three time points online, by telephone or by post. ETHICS AND DISSEMINATION: The PIM-COVID study was approved by the Health Research Authority (East Midlands - Derby Research and Ethics Committee, reference: 20/EM/0247). TRIAL REGISTRATION NUMBER: NCT05092529.

A phase I clinical trial of oncolytic adenovirus mediated suicide and interleukin-12 gene therapy in patients with recurrent localized prostate adenocarcinoma.

In a phase I dose escalation and safety study (NCT02555397), a replication-competent oncolytic adenovirus expressing yCD, TK and hIL-12 (Ad5-yCD/mutTKSR39rep-hIL-12) was administered in 15 subjects with localized recurrent prostate cancer (T1c-T2) at increasing doses (1 × 1010, to 1 × 1012 viral particles) followed by 7-day treatment of 5-fluorocytosine (5-FC) and valganciclovir (vGCV). The primary endpoint was toxicity through day 30 while the secondary and exploratory endpoints were quantitation of IL-12, IFNγ, CXCL10 and peripheral blood mononuclear cells (PBMC). The study maximum tolerated dose (MTD) was not reached indicating 1012 viral particles was safe. Total 115 adverse events were observed, most of which (92%) were grade 1/2 that did not require any treatment. Adenoviral DNA was detected only in two patients. Increase in IL-12, IFNγ, and CXCL10 was observed in 57%, 93%, and 79% patients, respectively. Serum cytokines demonstrated viral dose dependency, especially apparent in the highest-dose cohorts. PBMC analysis revealed immune system activation after gene therapy in cohort 5. The PSA doubling time (PSADT) pre and post treatment has a median of 1.55 years vs 1.18 years. This trial confirmed that replication-competent Ad5-IL-12 adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) was well tolerated when administered locally to prostate tumors.

Radiomics characterization of tissues in an animal brain tumor model imaged using dynamic contrast enhanced (DCE) MRI.

Here, we investigate radiomics-based characterization of tumor vascular and microenvironmental properties in an orthotopic rat brain tumor model measured using dynamic-contrast-enhanced (DCE) MRI. Thirty-two immune compromised-RNU rats implanted with human U-251N cancer cells were imaged using DCE-MRI (7Tesla, Dual-Gradient-Echo). The aim was to perform pharmacokinetic analysis using a nested model (NM) selection technique to classify brain regions according to vasculature properties considered as the source of truth. A two-dimensional convolutional-based radiomics analysis was performed on the raw-DCE-MRI of the rat brains to generate dynamic radiomics maps. The raw-DCE-MRI and respective radiomics maps were used to build 28 unsupervised Kohonen self-organizing-maps (K-SOMs). A Silhouette-Coefficient (SC), k-fold Nested-Cross-Validation (k-fold-NCV), and feature engineering analyses were performed on the K-SOMs' feature spaces to quantify the distinction power of radiomics features compared to raw-DCE-MRI for classification of different Nested Models. Results showed that eight radiomics features outperformed respective raw-DCE-MRI in prediction of the three nested models. The average percent difference in SCs between radiomics features and raw-DCE-MRI was: 29.875% ± 12.922%, p < 0.001. This work establishes an important first step toward spatiotemporal characterization of brain regions using radiomics signatures, which is fundamental toward staging of tumors and evaluation of tumor response to different treatments.

Dynamic contrast enhanced (DCE) MRI estimation of vascular parameters using knowledge-based adaptive models.

We introduce and validate four adaptive models (AMs) to perform a physiologically based Nested-Model-Selection (NMS) estimation of such microvascular parameters as forward volumetric transfer constant, Ktrans, plasma volume fraction, vp, and extravascular, extracellular space, ve, directly from Dynamic Contrast-Enhanced (DCE) MRI raw information without the need for an Arterial-Input Function (AIF). In sixty-six immune-compromised-RNU rats implanted with human U-251 cancer cells, DCE-MRI studies estimated pharmacokinetic (PK) parameters using a group-averaged radiological AIF and an extended Patlak-based NMS paradigm. One-hundred-ninety features extracted from raw DCE-MRI information were used to construct and validate (nested-cross-validation, NCV) four AMs for estimation of model-based regions and their three PK parameters. An NMS-based a priori knowledge was used to fine-tune the AMs to improve their performance. Compared to the conventional analysis, AMs produced stable maps of vascular parameters and nested-model regions less impacted by AIF-dispersion. The performance (Correlation coefficient and Adjusted R-squared for NCV test cohorts) of the AMs were: 0.914/0.834, 0.825/0.720, 0.938/0.880, and 0.890/0.792 for predictions of nested model regions, vp, Ktrans, and ve, respectively. This study demonstrates an application of AMs that quickens and improves DCE-MRI based quantification of microvasculature properties of tumors and normal tissues relative to conventional approaches.

Do student differences in reading enjoyment relate to achievement when using the random-intercept cross-lagged panel model across primary and secondary school?

Recent longitudinal research using the random-intercept cross-lagged panel model (RI-CLPM), which disentangles the within and between variances, has afforded greater insights than previously possible. Moreover, the impact of reading enjoyment and reading for fun on subsequent school achievement, and vice versa, has only recently been scrutinized through this lens. This study's longitudinal data (grades 3, 5, 7, and 9) comprised 2,716 Australian students aged 8 to 16 years, with school reading achievement measured by the National Assessment Program: Literacy and Numeracy (NAPLAN). The RI-CLPMs' within-person effects were not trivial, accounting for approximately two-thirds and one-third of the variance in enjoyment/fun and achievement, respectively, with between-person effects accounting for the balance. Here, we highlight a reversing direction of reading achievement's cross-lagged effect on subsequent reading enjoyment but note that the evidence for this over a reciprocal directionality was marginal. In mid-primary school, achievement at grade 3 predicted enjoyment at grade 5 more than the converse (i.e. enjoyment at grade 3 to achievement at grade 5). By secondary school, however, the directionality had flipped: enjoyment at grade 7 predicted achievement at grade 9 more so than the reverse. We termed this pattern the skill-leisure-skill directionality (S-L-S), as it concurred with the only two former studies that modelled equivalent instruments with the RI-CLPM. This model's cross-lagged estimates represent deviations relative to a student's average (i.e., within-person effect). In other words, students who enjoyed reading more (or less) in grade 7 achieved reading scores that were higher (or lower) than their average in grade 9. The implications for reading pedagogy are further discussed.

The radioprotectant nano-genistein enhances radiotherapy efficacy of lung tumors in mice.

Background: Radiotherapy for non-small cell lung cancer (NSCLC) can be dose-limiting due to treatment-related toxicities. Genistein has been shown to be a robust radioprotective agent in preclinical models. A novel genistein oral nanosuspension formulation (nano-genistein) has demonstrated efficacy in mitigating radiation-induced lung damage in preclinical animal models. However, while those studies have confirmed that nano-genistein can protect normal lung tissue from radiation-induced toxicities, no studies have assessed the effect of nano-genistein on lung tumors. Here, we evaluated the impact of nano-genistein on the efficacy of radiation treatment of lung tumors in a mouse xenograft model. Methods: Two separate studies were conducted utilizing human A549 cells implanted either dorsally within the upper torso or in the flank. Daily oral administration of nano-genistein (200 or 400 mg/kg/day) occurred prior to and after exposure to a single dose of thoracic or abdominal 12.5 Gy radiation. Tumor growth was monitored twice weekly, nano-genistein treatment continued for up to 20 weeks and histopathology of tissues was completed post euthanasia. Results: Continuous nano-genistein dosing was safe across all study groups in both studies. Animals receiving nano-genistein better maintained body weight following irradiation compared to corresponding vehicle treated animals. Animals that received nano-genistein also had reduced tumor growth and improved normal lung histopathology compared to those receiving vehicle suggesting that nano-genistein does not protect tumors from radiotherapy but is radioprotective of the lungs. There were no treatment-related histopathological findings noted in the skin adjacent to the tumor, esophagus, or uterus. Conclusions: These results, including the safety following extended dosing, support the continued evaluation of nano-genistein as an adjunctive treatment for patients with NSCLC undergoing radiotherapy and serve as the basis of a phase 1b/2a multicenter clinical trial.

Administrators' preparedness to address physician burnout before and during COVID-19.

Occupational burnout has become widespread. The syndrome can be especially harmful in health care settings, affecting clinicians, organizational effectiveness, and patient safety. Certain approaches have proven helpful in some cases in combatting the syndrome. The coronavirus pandemic presented physicians with unique challenges, which appeared to have magnified work stress This national survey specifically explored interventions used by health care leaders to reduce burnout and whether these interventions proved effective during a pandemic. We also discuss effective and appropriate organizational measures to reduce physician burnout and its associated risks during crises.

Persistent Peri-Ablation Blood-Brain Barrier Opening After Laser Interstitial Thermal Therapy for Brain Tumors.

Purpose Laser interstitial thermal therapy (LITT) is a minimally invasive, image-guided, cytoreductive procedure to treat recurrent glioblastoma. This study implemented dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) methods and employed a model selection paradigm to localize and quantify post-LITT blood-brain barrier (BBB) permeability in the ablation vicinity. Serum levels of neuron-specific enolase (NSE), a peripheral marker of increased BBB permeability, were measured. Methods Seventeen patients were enrolled in the study. Using an enzyme-linked immunosorbent assay, serum NSE was measured preoperatively, 24 hours postoperatively, and at two, eight, 12, and 16 weeks postoperatively, depending on postoperative adjuvant treatment. Of the 17 patients, four had longitudinal DCE-MRI data available, from which blood-to-brain forward volumetric transfer constant (Ktrans) data were assessed. Imaging was performed preoperatively, 24 hours postoperatively, and between two and eight weeks postoperatively. Results Serum NSE increased at 24 hours following ablation (p=0.04), peaked at two weeks, and returned to baseline by eight weeks postoperatively. Ktrans was found to be elevated in the peri-ablation periphery 24 hours after the procedure. This increase persisted for two weeks. Conclusion Following the LITT procedure, serum NSE levels and peri-ablation Ktrans estimated from DCE-MRI demonstrated increases during the first two weeks after ablation, suggesting transiently increased BBB permeability.

Oncolytic virus-based suicide gene therapy for cancer treatment: a perspective of the clinical trials conducted at Henry Ford Health.

Gene therapy manipulates or modifies a gene that provides a new cellular function to treat or correct a pathological condition, such as cancer. The approach of using gene manipulation to modify patient's cells to improve cancer therapy and potentially find a cure is gaining popularity. Currently, there are 12 gene therapy products approved by US-FDA, EMA and CFDA for cancer management, these include Rexin-G, Gendicine, Oncorine, Provange among other. The Radiation Biology Research group at Henry Ford Health has been actively developing gene therapy approaches for improving clinical outcome in cancer patients. The team was the first to test a replication-competent oncolytic virus armed with a therapeutic gene in humans, to combine this approach with radiation in humans, and to image replication-competent adenoviral gene expression/activity in humans. The adenoviral gene therapy products developed at Henry Ford Health have been evaluated in more than 6 preclinical studies and evaluated in 9 investigator initiated clinical trials treating more than100 patients. Two phase I clinical trials are currently following patients long term and a phase I trial for recurrent glioma was initiated in November 2022. This systematic review provides an overview of gene therapy approaches and products employed for treating cancer patients including the products developed at Henry Ford Health.

Self-care barriers and facilitators in older adults with T1D during a time of sudden isolation.

Older adults with type 1 diabetes (T1D) have unique challenges and needs. In this mixed-methods study, we explored the impact of isolation during a pandemic on diabetes management and overall quality of life in this population. Older adults (age ≥ 65 years) with T1D receiving care at a tertiary care diabetes center participated in semi-structured interviews during COVID-19 pandemic isolation between June and August 2020. A multi-disciplinary team coded transcripts and conducted thematic analysis. Thirty-four older adults (age 71 ± 5 years, 97% non-Hispanic white, diabetes duration of 38 ± 7 years, A1C of 7.4 ± 0.9% (57.3 ± 10.1 mmol/mol) were recruited. Three themes related to diabetes self-care emerged regarding impact of isolation on: (1) diabetes management and self-care behaviors (how isolation prompted changes in physical activity and dietary habits); (2) emotional stress and anxiety (related to isolation and lack of support system, economic concerns); and (3) concerns regarding the COVID-19 pandemic (impact on timely medical care and access to information). Our findings identify modifiable barriers and challenges faced by older adults with T1D during isolation. As this population has a higher risk of decline in physical and psychosocial support even during non-pandemic times, clinicians will benefit from understanding these issues to improve care of this population.

Do metacognitive beliefs predict rumination and psychological distress independently of illness representations in adults with diabetes mellitus? A prospective mediation study.

OBJECTIVE: Adults with Diabetes Mellitus (DM) experience high levels of depression and anxiety that are not always effectively ameliorated by current therapeutic approaches. The Self-Regulatory Executive Function (S-REF) model, which underpins metacognitive therapy (MCT), posits that depression and anxiety become persistent when stored metacognitive beliefs guide an individual to respond to common thoughts and feelings in a certain way. We hypothesized that (i) metacognitive beliefs would predict depression and anxiety independently of participants' representations of their illness; and (ii) rumination would mediate independent prediction of depression and anxiety by metacognitive beliefs. DESIGN: A prospective mediation study. METHODS: Four hundred and forty-one adults with DM (Types 1 and 2) completed a two time-point survey. Metacognitive beliefs, illness representations and rumination were measured at baseline, and depression and anxiety measured at baseline and 6-months later. Data were analysed using structural equation modelling. Baseline illness representations, depression and anxiety were used as control variables. RESULTS: A structural equation analysis showed potential mediation, by baseline rumination, of any effects of baseline metacognitive variables on 6-month distress in Type 1 and 2 diabetes samples. Significant standardized coefficients for relationships between the metacognitive latent variable and rumination were .67 (Type 1) and .75 (Type 2) and between rumination and distress of .36 and .43, respectively. These effects were independent of direct and independent effects of illness representation variables. CONCLUSIONS: Findings are consistent with metacognitive beliefs playing a key role in depression and anxiety by increasing the likelihood of rumination in adults with DM. MCT may be an effective intervention for this population, subsequent to further longitudinal testing of the S-REF model.

Seven-year distress trajectories in uveal melanoma survivors.

OBJECTIVE: Severe or persistent distress is associated with poorer quality of life in cancer survivors. Distress follows distinct trajectories within different population subgroups. Identifying characteristics and causes of trajectories can assist intervention development and targeting. In a 7-year study of uveal melanoma survivors, we aimed to characterize anxiety, depression, and fear of cancer recurrence (FCR) trajectories, and identify whether concerns about symptoms and functional problems over the first 3 years of survivorship predict memberships of high distress trajectories. METHOD: In a closed cohort study, we used growth mixture modeling (GMM) to identify statistically optimal trajectories over 6-, 12-, 24-, 36-, 48-, 60-, 72-, and 84-month time point posttreatment in 475 patients. We then regressed trajectory memberships onto a 3-year series of measures of concerns about symptoms and functional problems, controlling demographic, clinical, and 6-month anxiety, depression, or FCR indicators. RESULTS: Anxiety, depression, and FCR were represented by two-class linear GMMs. The majority scored consistently low, but 17.5% showed consistently elevated anxiety, 10.9% consistently elevated depression, and 19.4% consistently elevated FCR. Higher anxiety trajectory membership was predicted by greater concerns about symptoms at 6 and 24 months, higher depression trajectory membership by symptoms at 24 months, and higher FCR trajectory membership by symptoms at 6 and 24 months and functional problems at 12 months. CONCLUSIONS: Much of the burden of persistent distress in cancer patients falls on a small proportion of survivors. Concerns about symptoms and functional problems are potential risk factors for distress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Radiation-induced senescence: therapeutic opportunities.

The limitation of cancer radiotherapy does not derive from an inability to ablate tumor, but rather to do so without excessively damaging critical tissues and organs and adversely affecting patient's quality of life. Although cellular senescence is a normal consequence of aging, there is increasing evidence showing that the radiation-induced senescence in both tumor and adjacent normal tissues contributes to tumor recurrence, metastasis, and resistance to therapy, while chronic senescent cells in the normal tissue and organ are a source of many late damaging effects. In this review, we discuss how to identify cellular senescence using various bio-markers and the role of the so-called senescence-associated secretory phenotype characteristics on the pathogenesis of the radiation-induced late effects. We also discuss therapeutic options to eliminate cellular senescence using either senolytics and/or senostatics. Finally, a discussion of cellular reprogramming is presented, another promising avenue to improve the therapeutic gain of radiotherapy.

Characterization of the Response of 9L and U-251N Orthotopic Brain Tumors to 3D Conformal Radiation Therapy.

In a study employing MRI-guided stereotactic radiotherapy (SRS) in two orthotopic rodent brain tumor models, the radiation dose yielding 50% survival (the TCD50) was sought. Syngeneic 9L cells, or human U-251N cells, were implanted stereotactically in 136 Fischer 344 rats or 98 RNU athymic rats, respectively. At approximately 7 days after implantation for 9L, and 18 days for U-251N, rats were imaged with contrast-enhanced MRI (CE-MRI) and then irradiated using a Small Animal Radiation Research Platform (SARRP) operating at 220 kV and 13 mA with an effective energy of ∼70 keV and dose rate of ∼2.5 Gy per min. Radiation doses were delivered as single fractions. Cone-beam CT images were acquired before irradiation, and tumor volumes were defined using co-registered CE-MRI images. Treatment planning using MuriPlan software defined four non-coplanar arcs with an identical isocenter, subsequently accomplished by the SARRP. Thus, the treatment workflow emulated that of current clinical practice. The study endpoint was animal survival to 200 days. The TCD50 inferred from Kaplan-Meier survival estimation was approximately 25 Gy for 9L tumors and below 20 Gy, but within the 95% confidence interval in U-251N tumors. Cox proportional-hazards modeling did not suggest an effect of sex, with the caveat of wide confidence intervals. Having identified the radiation dose at which approximately half of a group of animals was cured, the biological parameters that accompany radiation response can be examined.