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MedRxiv : the Preprint Server For... Jun 2024Circulating tumor cells (CTCs) captured from the bloodstream of patients with solid tumors have the potential to accelerate precision oncology by providing insight into...
UNLABELLED
Circulating tumor cells (CTCs) captured from the bloodstream of patients with solid tumors have the potential to accelerate precision oncology by providing insight into tumor biology, disease progression and response to treatment. However, their potential is hampered by the lack of standardized CTC enrichment platforms across tumor types. EpCAM-based CTC enrichment, the most commonly used platform, is limited by EpCAM downregulation during metastasis and the low EpCAM expression in certain tumor types, including the highly prevalent and lethal NSCLC. In this study we demonstrate that Transferrin Receptor (TfR) is a selective, efficient biomarker for CTC identification and capture in patients with prostate, pancreatic and NSCLC. TfR identifies significantly higher CTC counts than EpCAM, and TfR -CTC enumeration correlates with disease progression in metastatic prostate and pancreatic cancers, and overall survival and osimetrinib-resistance in non-small cell lung cancer (NSCLC). Profiling of TfR -CTCs provides a snapshot of the molecular landscape of each respective tumor type and identifies potential mechanisms underlying treatment response to EGFR TKi and immune checkpoint inhibitors in NSCLC.
ONE SENTENCE SUMMARY
Transferrin Receptor identifies circulating tumor cells in solid tumors.
PubMed: 38947080
DOI: 10.1101/2024.06.16.24309003 -
Research Square Jun 2024Background The family includes many obligate parasitic bacterial species which are etiologically associated with a myriad of zoonotic borrelioses including Lyme disease...
Background The family includes many obligate parasitic bacterial species which are etiologically associated with a myriad of zoonotic borrelioses including Lyme disease and vector-borne relapsing fevers. Infections by the are difficult to detect by both direct and indirect methods, often leading to delayed and missed diagnoses. Efforts to improve diagnoses center around the development of molecular diagnostics (MDx), but due to deep tissue sequestration of the causative spirochaetes and the lack of persistent bacteremias, even MDx assays suffer from a lack of sensitivity. Additionally, the highly extensive genomic heterogeneity among isolates, even within the same species, contributes to the lack of assay sensitivity as single target assays cannot provide universal coverage. This within-species heterogeneity is partly due to differences in replicon repertoires and genomic structures that have likely arisen to support the complex lifecycle in which these parasites have to survive in multiple hosts each with unique immune responses. Results We constructed a family-level pangenome and characterized the phylogenetic relationships among the constituent taxa which supports the recent taxonomy of splitting the family into at least two genera. Gene content profiles were created for the majority of the replicons, providing for the first time their unambiguous molecular typing. Conclusion Our characterization of the pan-genome supports the splitting of the former genus into two genera and provides for the phylogenetic placement of several non-species designated isolates. Mining this family-level pangenome will enable precision diagnostics corresponding to gene content-driven clinical outcomes while also providing targets for interventions.
PubMed: 38947078
DOI: 10.21203/rs.3.rs-4491589/v1 -
Research Square Jun 2024Nutrient sensing and the subsequent metabolic responses are fundamental functions of animals, closely linked to diseases such as type 2 diabetes and various...
Nutrient sensing and the subsequent metabolic responses are fundamental functions of animals, closely linked to diseases such as type 2 diabetes and various obesity-related morbidities. Among different metabolic regulatory signals, cytosolic Ca plays pivotal roles in metabolic regulation, including glycolysis, gluconeogenesis, and lipolysis. Recently, intercellular calcium waves (ICWs), the propagation of Ca signaling through tissues, have been found in different systems to coordinate multicellular responses. Nevertheless, our understanding of how ICWs are modulated and operate within living organisms remains limited. In this study, we explore the real-time dynamics, both in organ culture and free-behaving animals, of ICWs in larval and adult adipose tissues. We identified Adipokinetic hormone (AKH), the fly functional homolog of mammalian glucagon, as the key factor driving Ca activities in adipose tissue. Interestingly, we found that AKH, which is released in a pulsatile manner into the circulating hemolymph from the AKH-producing neurosecretory cells (APCs) in the brain, stimulates ICWs in the larval fat by a previously unrecognized gap-junction-independent mechanism to promote lipolysis. In the adult fat body, however, gap-junction-dependent random ICWs are triggered by a presumably uniformly diffused AKH. This highlights the stage-specific interplay of hormone secretion, extracellular diffusion, and intercellular communication in the regulation of Ca dynamics. Additionally, we discovered that specific dietary amino acids activate the APCs, leading to increased intracellular Ca and subsequent AKH secretion. Altogether, our findings identify that dietary amino acids regulate the release of AKH peptides from the APCs, which subsequently stimulates novel gap-junction-independent ICWs in adipose tissues, thereby enhancing lipid metabolism.
PubMed: 38947048
DOI: 10.21203/rs.3.rs-4493132/v1 -
MedRxiv : the Preprint Server For... Jun 2024Weekly Steroids in Muscular Dystrophy (WSiMD) was a pilot study to evaluate once weekly prednisone in patients with Limb Girdle and Becker muscular dystrophy (LGMD and...
BACKGROUND
Weekly Steroids in Muscular Dystrophy (WSiMD) was a pilot study to evaluate once weekly prednisone in patients with Limb Girdle and Becker muscular dystrophy (LGMD and BMD, respectively). At study endpoint, there were trends towards increased lean mass, reduced fat mass, reduced creatine kinase and improved motor function. The investigation was motivated by studies in mouse muscular dystrophy models in which once weekly glucocorticoid exposure enhanced muscle strength and reduced fibrosis.
METHODS
WSiMD participants provided blood samples for aptamer serum profiling at baseline and after 6 months of weekly steroids. A subset completed magnetic resonance (MR) evaluation of muscle at study onset and endpoint.
RESULTS/CONCLUSIONS
At baseline compared to age and sex-matched healthy controls, the aggregate serum protein profile in the WSiMD cohort was dominated by muscle proteins, reflecting leak of muscle proteins into serum. Disease status produced more proteins differentially present in serum compared to steroid-treatment effect. Nonetheless, a response to prednisone was discernable in the WSiMD cohort, even at this low dose. Glucocorticoids downregulated muscle proteins and upregulated certain immune process- and matrix-associated proteins. Muscle MR fat fraction showed trends with functional status. The prednisone-responsive markers could be used in larger trial of prednisone efficacy.
PubMed: 38947030
DOI: 10.1101/2024.06.14.24308858 -
MedRxiv : the Preprint Server For... Jun 2024Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 gene coding for a membrane...
INTRODUCTION
Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 gene coding for a membrane component of adherens junctions is involved in response to infection, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as .
MATERIALS AND METHODS
We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor).
RESULTS
The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p<0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p<0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect.
CONCLUSION
This study reported a new causal relationship between pTau-181 and AD. We found that the association between rs6859 in the gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the gene and AD.
PubMed: 38947013
DOI: 10.1101/2024.06.21.24309310 -
Research Square Jun 2024Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome associated with cutaneous metastatic melanoma in which patients develop vision deficits that include...
Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome associated with cutaneous metastatic melanoma in which patients develop vision deficits that include reduced night vision, poor contrast sensitivity, and photopsia. MAR is caused by autoantibodies targeting TRPM1, an ion channel found in melanocytes and retinal ON-bipolar cells (ON-BCs). The visual symptoms arise when TRPM1 autoantibodies enter ON-BCs and block the function of TRPM1, thus detection of TRPM1 autoantibodies in patient serum is a key criterion in diagnosing MAR. Electroretinograms are used to measure the impact of TRPM1 autoantibodies on ON-BC function and represent another important diagnostic tool for MAR. To date, MAR case reports have included one or both diagnostic components, but only for a single time point in the course of a patient's disease. Here, we report a case of MAR supported by longitudinal analysis of serum autoantibody detection, visual function, ocular inflammation, vascular integrity, and response to slow-release intraocular corticosteroids. Integrating these data with the patient's oncological and ophthalmological records reveals novel insights regarding MAR pathogenesis, progression, and treatment, which may inform new research and expand our collective understanding of the disease. In brief, we find TRPM1 autoantibodies can disrupt vision even when serum levels are barely detectable by western blot and immunohistochemistry; intraocular dexamethasone treatment alleviates MAR visual symptoms despite high levels of circulating TRPM1 autoantibodies, implicating antibody access to the retina as a key factor in MAR pathogenesis. Elevated inflammatory cytokine levels in the patient's eyes may be responsible for the observed damage to the blood-retinal barrier and subsequent entry of autoantibodies into the retina.
PubMed: 38946992
DOI: 10.21203/rs.3.rs-4595829/v1 -
MedRxiv : the Preprint Server For... Jun 2024Previous research in India has identified urbanisation, human mobility and population demographics as key variables associated with higher district level COVID-19...
Previous research in India has identified urbanisation, human mobility and population demographics as key variables associated with higher district level COVID-19 incidence. However, the spatiotemporal dynamics of mobility patterns in rural and urban areas in India, in conjunction with other drivers of COVID-19 transmission, have not been fully investigated. We explored travel networks within India during two pandemic waves using aggregated and anonymized weekly human movement datasets obtained from Google, and quantified changes in mobility before and during the pandemic compared with the mean baseline mobility for the 8-week time period at the beginning of 2020. We fit Bayesian spatiotemporal hierarchical models coupled with distributed lag non-linear models (DLNM) within the integrated nested Laplace approximate (INLA) package in R to examine the lag-response associations of drivers of COVID-19 transmission in urban, suburban, and rural districts in India during two pandemic waves in 2020-2021. Model results demonstrate that recovery of mobility to 99% that of pre-pandemic levels was associated with an increase in relative risk of COVID-19 transmission during the Delta wave of transmission. This increased mobility, coupled with reduced stringency in public intervention policy and the emergence of the Delta variant, were the main contributors to the high COVID-19 transmission peak in India in April 2021. During both pandemic waves in India, reduction in human mobility, higher stringency of interventions, and climate factors (temperature and precipitation) had 2-week lag-response impacts on the of COVID-19 transmission, with variations in drivers of COVID-19 transmission observed across urban, rural and suburban areas. With the increased likelihood of emergent novel infections and disease outbreaks under a changing global climate, providing a framework for understanding the lagged impact of spatiotemporal drivers of infection transmission will be crucial for informing interventions.
PubMed: 38946988
DOI: 10.1101/2024.06.12.24308871 -
Research Square Jun 2024Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological...
Virus-like particle (VLP)-based vaccine targeting tau phosphorylated at Ser396/Ser404 (PHF1) site outperforms phosphorylated S199/S202 (AT8) site in reducing tau pathology and restoring cognitive deficits in the rTg4510 mouse model of tauopathy.
Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapeutic development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Qβ bacteriophage virus-like particle (VLP) that induced robust antibody responses, cleared pathological tau, and rescued memory deficits in a transgenic mouse model of tauopathy. Here we report the characterization and comparison of two additional Qβ VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Qβ-AT8) and Ser396/Ser404 (Qβ-PHF1). Both Qβ-AT8 and Qβ-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Qβ-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and reactive microgliosis in a 4-month rTg4510 model of FTD. Both sera from Qβ-AT8 and Qβ-PHF1 vaccinated mice were specifically reactive to tau pathology in human AD post-mortem brain sections. These studies further support the use of VLP-based immunotherapies to target pTau in AD and related tauopathies and provide potential insight into the clinical efficacy of various pTau epitopes in the development of immunotherapeutics.
PubMed: 38946961
DOI: 10.21203/rs.3.rs-4390998/v1 -
Clinical Epidemiology 2024
Comment on "Development and Validation of a META-Algorithm to Identify the Indications of Use of Biological Drugs Approved for the Treatment of Immune-Mediated Inflammatory Diseases from Claims Databases: Insights from the VALORE Project". [Response to Letter].
PubMed: 38946927
DOI: 10.2147/CLEP.S482719 -
World Journal of Gastroenterology Jun 2024In this editorial, we comment on an article titled "Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases", which was...
In this editorial, we comment on an article titled "Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases", which was published in a recent issue of the . We focused on the statement that "autophagy is closely related to the digestion, secretion, and regeneration of gastrointestinal cells". With advancing research, autophagy, and particularly the pivotal role of the macroautophagy in maintaining cellular equilibrium and stress response in the gastrointestinal system, has garnered extensive study. However, the significance of mitophagy, a unique selective autophagy pathway with ubiquitin-dependent and independent variants, should not be overlooked. In recent decades, mitophagy has been shown to be closely related to the occurrence and development of gastrointestinal diseases, especially inflammatory bowel disease, gastric cancer, and colorectal cancer. The interplay between mitophagy and mitochondrial quality control is crucial for elucidating disease mechanisms, as well as for the development of novel treatment strategies. Exploring the pathogenesis behind gastrointestinal diseases and providing individualized and efficient treatment for patients are subjects we have been exploring. This article reviews the potential mechanism of mitophagy in gastrointestinal diseases with the hope of providing new ideas for diagnosis and treatment.
Topics: Humans; Mitophagy; Autophagy; Gastrointestinal Diseases; Mitochondria; Gastrointestinal Tract; Animals
PubMed: 38946875
DOI: 10.3748/wjg.v30.i23.2934