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The National Cancer Institute clinical trials planning meeting to address gaps in observational and intervention trials for cancer-related cognitive impairment
No full textCancer-related cognitive impairment is a broad term encompassing subtle cognitive problems to more severe impairment. The severity of this impairment is influenced by host, disease, and treatment factors, and the impairment affects patients before, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a clinical trial planning meeting to review the state of the science on cancer-related cognitive impairment and develop phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of cancer-related cognitive impairment, members of the SxQoL SC, patient advocates, representatives from all 7 NCI Community Oncology Research Program research bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacological and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three clinical trial planning meeting working groups (longitudinal studies as well as pharmacological and behavioral intervention trials) convened for 1 year to discuss and report on top priorities and to design studies. The meeting experts concluded that sufficient data exist to advance phase II/III trials using selected pharmacological and behavioral interventions for the treatment of cancer-related cognitive impairment in the non-central nervous system setting, with recommendations included herein
Dual-ligand fluorescence microscopy enables chronological and spatial histological assignment of distinct amyloid-β deposits
No full textDifferent types of deposits comprised of amyloid-β (Aβ) peptides are one of the pathological hallmarks of Alzheimer's disease (AD) and novel methods that enable identification of a diversity of Aβ deposits during the AD continuum are essential for understanding the role of these aggregates during the pathogenesis. Herein, different combinations of five fluorescent thiophene-based ligands were used for detection of Aβ deposits in brain tissue sections from transgenic mouse models with aggregated Aβ pathology, as well as brain tissue sections from patients affected by sporadic or dominantly inherited AD. When analyzing the sections with fluorescence microscopy, distinct ligand staining patterns related to the transgenic mouse model or to the age of the mice were observed. Likewise, specific staining patterns of different Aβ deposits were revealed for sporadic versus dominantly inherited AD, as well as for distinct brain regions in sporadic AD. Thus, by using dual-staining protocols with multiple combinations of fluorescent ligands, a chronological and spatial histological designation of different Aβ deposits could be achieved. This study demonstrates the potential of our approach for resolving the role and presence of distinct Aβ aggregates during the AD continuum and pinpoints the necessity of using multiple ligands to obtain an accurate assignment of different Aβ deposits in the neuropathological evaluation of AD, as well as when evaluating therapeutic strategies targeting Aβ aggregates
Biomarker Identification for Alzheimer’s Disease Using a Multi-Filter Gene Selection Approach
No full textThere is still a lack of effective therapies for Alzheimer's disease (AD), the leading cause of dementia and cognitive decline. Identifying reliable biomarkers and therapeutic targets is crucial for advancing AD research. In this study, we developed an aggregative multi-filter gene selection approach to identify AD biomarkers. This method integrates hub gene ranking techniques, such as degree and bottleneck, with feature selection algorithms, including Random Forest and Double Input Symmetrical Relevance, and applies ranking aggregation to improve accuracy and robustness. Five publicly available AD-related microarray datasets (GSE48350, GSE36980, GSE132903, GSE118553, and GSE5281), covering diverse brain regions like the hippocampus and frontal cortex, were analyzed, yielding 803 overlapping differentially expressed genes from 464 AD and 492 normal cases. An independent dataset (GSE109887) was used for external validation. The approach identified 50 prioritized genes, achieving an AUC of 86.8 in logistic regression on the validation dataset, highlighting their predictive value. Pathway analysis revealed involvement in critical biological processes such as synaptic vesicle cycles, neurodegeneration, and cognitive function. These findings provide insights into potential therapeutic targets for AD
Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster
No full textThe rapid growth that occurs during Drosophila larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the Drosophila Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. Here we discover that Sima, the Drosophila ortholog of Hif1α, is also essential for establishing the larval glycolytic program. Using a multi-omics approach, we demonstrate that sima mutants fail to properly activate aerobic glycolysis and die during larval development with metabolic defects that phenocopy dERR mutants. Moreover, we demonstrate that dERR and Sima/Hif1α protein accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance of the other protein. Considering that the mammalian homologs of ERR and Hif1α also cooperatively regulate aerobic glycolysis in cancer cells, our findings establish the fly as a powerful genetic model for studying the interaction between these two key metabolic regulators
Transcriptional signatures of hippocampal tau pathology in primary age-related tauopathy and Alzheimer’s disease
No full textIn primary age-related tauopathy (PART) and Alzheimer's disease (AD), tau aggregates share a similar structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, transcriptional similarities between PART and AD and gene expression changes within tau-pathology-bearing neurons are largely unknown. Using GeoMx spatial transcriptomics, mRNA was quantified in hippocampal neurons with and without tau pathology in PART and AD. Synaptic genes were down-regulated in disease overall but up-regulated in tau-pathology-positive neurons. Two transcriptional signatures were associated with intraneuronal tau, both validated in a cortical AD dataset. Genes in the up-regulated signature were enriched in calcium regulation and synaptic function. Notably, transcriptional changes associated with intraneuronal tau in PART and AD were similar, suggesting a possible mechanistic relationship. These findings highlight the power of molecular analysis stratified by pathology and provide insight into common pathways associated with tau pathology in PART and AD
Role of the Veterans Health Administration's LGBTQ+ Veteran Care Coordinators in Facilitating Care for Transgender and Gender-Diverse Veterans
No full textIntroduction: Transgender and gender-diverse (TGD) individuals frequently encounter discrimination in health care settings. The Veterans Health Administration (VA) is committed to addressing the health disparities experienced by TGD veterans. The purpose of this study was to explore the experiences of TGD veterans with LGBTQ+ veteran care coordinators.
Methods: The authors conducted semi-structured interviews with TGD veterans with depression between January and March 2022. Participants were recruited with assistance from the VA's network of LGBTQ+ veteran care coordinators. Interviews were recorded, transcribed, and analyzed.
Results: Twenty-six TGD veterans participated in the study, with a range of experiences, both positive and negative, with LGBTQ+ veteran care coordinators. Veterans spoke of the role of coordinators in educating both patients and clinicians about TGD health care needs. Participants who expressed dissatisfaction with their coordinators highlighted the need for a clearer definition and communication of coordinator duties.
Conclusions: This study highlights the important roles played by the VA LGBTQ+ care coordinators in addressing the needs of TGD veterans. The study also points to an immense need for clinician education in TGD care. Further training and education are recommended to improve equitable care for TGD veterans
Longitudinal changes in neuroimaging markers of small vessel disease: Implications for clinical trials
Full text linkBackground:
Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, around the same time as amyloid and tau, but the regional rates of accumulation within individuals are unknown.
Method:
Adults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n=78; age=50±6; 40% women) have two timepoints of T2 FLAIR MRI (1.2±0.6 years apart) quantified as white matter hyperintensity volume (WMH), which represents ischemic small vessel disease. Participants underwent consensus diagnosis at both timepoints (59% Cognitively‐Stable at both timepoints, 9% Cognitively‐Stable to MCI‐DS, 8% MCI‐DS at both timepoints, 14% MCI‐DS to AD, 10% AD at both timepoints). The annual rate of change in frontal, temporal, parietal, and occipital WMH volume was assessed, adjusting for baseline WMH volume.
Result:
The annual rate of change in frontal WMH was not significantly different by diagnosis. The annual rate of change in temporal (0.7 [0.4, 1.1], p<0.001) and in occipital WMH (1.6 [0.7, 2.5], p=0.0008) was faster in the group that remained AD at both timepoints compared to the group that remained Cognitively‐Stable at both timepoints. The annual rate of change in parietal WMH was greater in the group that progressed from MCI‐DS to AD (0.6 [0.1, 1.0], p=0.02) and in the group that remained AD at both timepoints (1.1 [0.6, 1.7], p=0.0002) compared to the group that remained Cognitively‐Stable at both timepoints.
Conclusion:
In adults with DS, parietal WMH accumulates fastest in those that progress to or have a diagnosis of AD, while temporal and occipital WMH accumulate fastest in those with a diagnosis of AD. Posteriorly distributed WMH may have specificity for AD progression in adults with DS with implications for anti‐amyloid therapeutics that have cerebrovascular side effects
Multi-Generational Memory in Indiana: Oral History and the Use of Descendant Testimony in Holocaust Education
No full textIUIThe year 2025 marks the eightieth anniversary of the end of the Holocaust. In the genocide’s aftermath, the state of Indiana became home to Holocaust survivors and – with time – their descendants. Indiana offered survivors a place to rebuild their lives. Unfortunately, our collective understanding of Indiana’s survivor population, their Holocaust experience, and lives in Indiana, has yet to be studied. The most significant challenge preventing that understanding is the lack of collection and accessibility to primary sources from survivors in Indiana public history institutions, namely oral histories. We must now – as a fast-approaching post-witness era arrives – investigate new opportunities to document the history of the Holocaust and its impact on Hoosiers. In this paper, I argue descendants of survivors can bridge the memory of the Holocaust to how Indiana can memorialize the Holocaust. The project, and this paper, centers around five second and third generation descendants and their recorded testimonies. By utilizing oral histories as a mechanism for documentation and storytelling, their testimonies offer an opportunity to strengthen Indiana’s historical record and Holocaust education. This paper identifies the process of conducting an oral history project including the scholarship which informs it and logistical preparation to record and preserve five oral histories. In the analysis of the project’s testimonies, themes of multi-generational trauma, memorialization of survivor ancestors, and identities of descendants illuminate the significant contributions of this project not only to Indiana’s memory, but rightfully adding to the growing studies on descendants in Holocaust studies and education across the United States. This paper provides a concise survey of the state of Holocaust education in Indiana and public history institutions who contribute to it. By identifying the contributions, the limitations of Holocaust education in Indiana – notably inaccessible collections of survivor testimony – prevent Hoosiers to participate in meaningful education and memorialization of Indiana’s survivor population. The project offers a foundation by filling a gap in Indiana’s historical record about the Holocaust and providing accessible, ready-to-use oral histories Indiana’s historians, educators, and the public can integrate in local efforts to teach, learn, and memorialize the Holocaust and Indiana’s survivors
Effect of the COVID-19 pandemic on colorectal cancer screening in two university-affiliated health care systems
No full textObjectives: In two large university affiliated healthcare systems, we examined trends in colorectal cancer (CRC) screening both prior to and during the COVID-19 pandemic to compare the trends in non-invasive screening tests and colonoscopy.
Materials and methods: In this retrospective time-trend analysis, we obtained the numbers of colonoscopies and non-invasive tests performed monthly during the pandemic and the year prior to it. We obtained colonoscopy data from five endoscopy units with the indication determined by dual independent review. Monthly numbers of completed fecal immunochemical (FIT) and FIT-DNA tests were obtained from the electronic medical records of both health systems. Trends in testing, numbers, and stage of incident CRCs diagnosed during the 30-month interval were examined using Poisson regression and logistic regression, respectively.
Results: From January 2019 to June 2021, we identified 16,939 FIT tests, 2,942 FIT-DNA tests, and 38,332 colonoscopies from the two health systems, and 368 colorectal cancers (105 early stage, 263 advanced stage) from the private hospital system. Overall colonoscopy volume declined by 18.7% (from 16,483 to 13,393) in 2020 compared to 2019 in both health systems, returning to baseline in 2021. Non-invasive tests declined by 21.9% in 2020, but increased in 2021 due to greater use of FIT/DNA. Compared to 2019, incident CRCs declined in 2020 but rebounded in 2021, with no difference in early versus late-stage cancers.
Conclusions: These trends in CRC screening tests may be useful for modeling the effects of the pandemic on the longer-term outcomes of CRC incidence and mortality
Familial complete pachydermoperiostosis presenting with vertebral hypertrophy and myelopathy
No full textPachydermoperiostosis (PDP) is a rare, male-predominant (9:1) primary hypertrophic osteoarthropathy of the skin and bone, commonly called the acromegaly mimic. Clinical diagnosis of PDP is based on a triad of digital clubbing, pachydermia with coarse facial features, and radiographic evidence of long bone periostosis. It can manifest in a complete or incomplete form, with skin involvement distinguishing the complete subtype. The etiology of PDP remains uncertain, though it has been associated with pathogenic variants in genes involved in prostaglandin E2 metabolism genes (HPGD) in autosomal recessive primary hypertrophic osteoarthropathy-1 and SLCO2A1 in autosomal dominant primary hypertrophic osteoarthropathy. We present a 31-yr-old male with complete PDP with atypical clinical features of vertebral involvement, severe myelopathy and radiculopathy, mild digital clubbing, and frontal pachydermia. IGF-1 and HGH levels were normal despite the acromegalic features. Genetic testing did not identify variants in HPGD or SLCO2A1. The patient exhibited elevated bone-specific alkaline phosphatase levels and increased BMD, supporting the diagnosis of PDP. Iliac crest bone biopsies were technically difficult and contained only dense cortical bone. Dermatologic manifestations were managed with glycopyrrolate, dupilumab, and topical treatments. His bone disease was treated with intravenous bisphosphonates, yielding a marked decrease in bone-specific alkaline phosphatase levels. This case reveals the necessity of considering PDP in differential diagnoses for patients with atypical acromegalic features and highlights the potential for vertebral involvement in PDP, expanding the understanding of its clinical presentation