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Antiandrogen is part of the standard-of-care treatment option for metastatic prostate cancer. However, prostate cancers frequently relapse, and the underlying resistance mechanism remains incompletely understood. This study seeks to investigate whether long non-coding RNAs (lncRNAs) contribute to the resistance against the latest antiandrogen drug, darolutamide. Our RNA sequencing analysis revealed significant overexpression of LOC730101 in darolutamide-resistant cancer cells compared to the parental cells. Elevated LOC730101 levels were also observed in clinical samples of metastatic castration-resistant prostate cancer (CRPC) compared to primary prostate cancer samples. Silencing LOC730101 with siRNA significantly impaired the growth of darolutamide-resistant cells. Additional RNA sequencing analysis identified a set of genes regulated by LOC730101, including key players in the cell cycle regulatory pathway. We further demonstrated that LOC730101 promotes darolutamide resistance by competitively inhibiting microRNA miR-1-3p. Moreover, by Hi-C sequencing, we found that LOC730101 is located in a topologically associating domain (TAD) that undergoes specific gene induction in darolutamide-resistant cells. Collectively, our study demonstrates the crucial role of the lncRNA LOC730101 in darolutamide resistance and its potential as a target for overcoming antiandrogen resistance in CRPC.
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OBJECTIVE: This study evaluated the efficacy of the Minimally Invasive Targeted Resection (MiTR) device, a novel electrosurgical instrument that allows for targeted excision of a lung abnormality while using bipolar radiofrequency (RF) energy to seal blood vessels and airways. METHODS: The MiTR system was evaluated in 7 acute and 2 chronic porcine (7-day) models to evaluate the efficacy of tissue excision with bipolar RF sealing of blood vessels and airways and application of an autologous blood patch into the excised tissue cavity. Air leak was recorded for all evaluations. The study was approved by the institutional ethical board. RESULTS: Nineteen lung tissue samples, measuring 2.5 cm long × 1.2 cm diameter, were excised. In 8 of 9 animals (89%), hemostasis and pneumostasis were observed visually at the completion of the procedure. In 2 of 2 chronic animals (100%), hemostasis and pneumostasis persisted for the 7-day observation period. Histologic examination of the excised samples showed preservation of the core parenchymal architecture without evident tissue damage of the samples that would impair pathologic analysis. CONCLUSIONS: Percutaneous resection of targeted lung tissue with the MiTR system demonstrated hemostasis and pneumostasis while obtaining a histologically intact sample. After regulatory approval, the use of this device could offer more tissue for analysis than a transthoracic needle biopsy or bronchoscopy and a far less invasive alternative to video-assisted thoracic surgery or thoracotomy. This may also expand patient and physician options for the early diagnosis and treatment of lung cancer.
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Pulmón , Animales , Porcinos , Pulmón/cirugía , Pulmón/patología , Neumonectomía/instrumentación , Neumonectomía/métodos , Electrocirugia/instrumentación , Electrocirugia/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/instrumentación , Hemostasis Quirúrgica/instrumentación , Hemostasis Quirúrgica/métodos , Cirugía Asistida por Computador/métodos , Cirugía Asistida por Computador/instrumentaciónRESUMEN
Vitamin B6 is a vital micronutrient across cell types and tissues, and dysregulated B6 levels contribute to human disease. Despite its importance, how B6 vitamer levels are regulated is not well understood. Here, we provide evidence that B6 dynamics are rapidly tuned by precise compartmentation of pyridoxal kinase (PDXK), the rate-limiting B6 enzyme. We show that canonical Wnt rapidly led to the accumulation of inactive B6 by shunting cytosolic PDXK into lysosomes. PDXK was modified with methyl-arginine Degron (MrDegron), a protein tag for lysosomes, which enabled delivery via microautophagy. Hyperactive lysosomes resulted in the continuous degradation of PDXK and B6 deficiency that promoted proliferation in Wnt-driven colorectal cancer (CRC) cells. Pharmacological or genetic disruption of the coordinated MrDegron proteolytic pathway was sufficient to reduce CRC survival in cells and organoid models. In sum, this work contributes to the repertoire of micronutrient-regulated processes that enable cancer cell growth and provides insight into the functional impact of B6 deficiencies for survival.
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Péptido Hidrolasas , Vitamina B 6 , Humanos , Proteolisis , Micronutrientes , VitaminasRESUMEN
Oxidative stress is proven to be a leading factor in a multitude of adverse conditions, from Alzheimer's disease to cancer. Thus, developing effective radical scavenging agents to eliminate reactive oxygen species (ROS) driving many oxidative processes has become critical. In addition to conventional antioxidants, nanoscale structures and metal-organic complexes have recently shown promising potential for radical scavenging. To design an optimal nanoscale ROS scavenging agent, we have synthesized ten types of biocompatible graphene quantum dots (GQDs) augmented with various metal dopants. The radical scavenging abilities of these novel metal-doped GQD structures were, for the first time, assessed via the DPPH, KMnO4, and RHB (Rhodamine B protectant) assays. While all metal-doped GQDs consistently demonstrate antioxidant properties higher than the undoped cores, aluminum-doped GQDs exhibit 60-95% radical scavenging ability of ascorbic acid positive control. Tm-doped GQDs match the radical scavenging properties of ascorbic acid in the KMnO4 assay. All doped GQD structures possess fluorescence imaging capabilities that enable their tracking in vitro, ensuring their successful cellular internalization. Given such multifunctionality, biocompatible doped GQD antioxidants can become prospective candidates for multimodal therapeutics, including the reduction of ROS with concomitant imaging and therapeutic delivery to cancer tumors.
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Castration-resistant prostate cancer (CRPC) poses a major clinical challenge with the androgen receptor (AR) remaining to be a critical oncogenic player. Several lines of evidence indicate that AR induces a distinct transcriptional program after androgen deprivation in CRPCs. However, the mechanism triggering AR binding to a distinct set of genomic loci in CRPC and how it promotes CRPC development remain unclear. We demonstrate here that atypical ubiquitination of AR mediated by an E3 ubiquitin ligase TRAF4 plays an important role in this process. TRAF4 is highly expressed in CRPCs and promotes CRPC development. It mediates K27-linked ubiquitination at the C-terminal tail of AR and increases its association with the pioneer factor FOXA1. Consequently, AR binds to a distinct set of genomic loci enriched with FOXA1- and HOXB13-binding motifs to drive different transcriptional programs including an olfactory transduction pathway. Through the surprising upregulation of olfactory receptor gene transcription, TRAF4 increases intracellular cAMP levels and boosts E2F transcription factor activity to promote cell proliferation under androgen deprivation conditions. Altogether, these findings reveal a posttranslational mechanism driving AR-regulated transcriptional reprogramming to provide survival advantages for prostate cancer cells under castration conditions.
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Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Masculino , Humanos , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Andrógenos , Antagonistas de Andrógenos , Factor 4 Asociado a Receptor de TNF/metabolismo , Línea Celular Tumoral , Ubiquitinación , Regulación Neoplásica de la Expresión GénicaRESUMEN
Graphene-based materials have been the subject of interest for photothermal therapy due to their high light-to-heat conversion efficiency. Based on recent studies, graphene quantum dots (GQDs) are expected to possess advantageous photothermal properties and facilitate fluorescence image-tracking in the visible and near-infrared (NIR), while surpassing other graphene-based materials in their biocompatibility. Several GQD structures including reduced graphene quantum dots (RGQDs) derived from reduced graphene oxide via top-down oxidation and hyaluronic acid graphene quantum dots (HGQDs) hydrothermally bottom-up synthesized from molecular hyaluronic acid were employed to test these capabilities in the present work. These GQDs possess substantial NIR absorption and fluorescence throughout the visible and NIR beneficial for in vivo imaging while being biocompatible at up to 1.7 mg/mL concentrations. In aqueous suspensions, RGQDs and HGQDs irradiated with a low power (0.9 W/cm2) 808 nm NIR laser facilitate a temperature increase up to 47.0 °C, which is sufficient for cancer tumor ablation. In vitro photothermal experiments sampling multiple conditions directly in the 96-well plate were performed using an automated simultaneous irradiation/measurement system developed on the basis of a 3D printer. In this study, HGQDs and RGQDs facilitated the heating of HeLa cancer cells up to 54.5 °C, leading to the drastic inhibition of cell viability from over 80% down to 22.9%. GQD's fluorescence in the visible and NIR traces their successful internalization into HeLa cells maximized at 20 h suggesting both extracellular and intracellular photothermal treatment capabilities. The combination of the photothermal and imaging modalities tested in vitro makes the GQDs developed in this work prospective agents for cancer theragnostics.
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Human papilloma virus (HPV)-associated oropharyngeal cancer (OPC) is a unique entity with increased responsiveness to treatment and excellent oncologic outcomes. The purpose of this narrative review is to highlight how an improved prognosis for HPV (+) tumors and an ever-increasing understanding of the risk factors, risk stratification, and areas of potential spread are shaping management options. Additionally, we aim to detail how advances in treatment technology on both the surgical and radiation fronts are facilitating the delivery of increasingly personalized and precise treatments. This review will describe key aspects of recent and currently-ongoing trials investigating the de-escalation and individualization of treatment in this patient cohort, and how they are building a foundation for distinct treatment paradigms for HPV (+) tumors. Further studies into the integration of biomarker-guided treatments combined with clinical trial enrollment will help ensure a future of personalized treatments and improved outcomes, both in terms of oncologic outcomes and toxicity, for patients with HPV (+) OPC.
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Vitamin B micronutrients are essential regulators of one carbon metabolism that ensures human health. Vitamin B9, or folate, lies at the heart of the folate cycle and converges with the methionine cycle to complete the one carbon pathway. Additionally, vitamin B6 contributes by orchestrating the flux of one carbon cycling. Dysregulation of vitamin B contributes to altered biochemical signaling that manifests in a spectrum of human diseases. This review presents an analysis of the past, present, and future work, highlighting the interplay between folate and vitamin B6 in one carbon metabolism. Emerging insights include advances in metabolomic-based mass spectrometry and the use of live-cell metabolic labeling. Cancer is used as a focal point to dissect vitamin crosstalk and highlight new insights into the roles of folate and vitamin B6 in metabolic control. This collection of vitamin-based research detailing the trends of one carbon metabolism in human disease exemplifies how the future of personalized medicine could unfold using this new base of knowledge and ultimately provide next-generation therapeutics.
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Sonography offers many advantages over standard methods of diagnostic imaging due to its non-invasiveness, substantial tissue penetration depth, and low cost. The benefits of ultrasound imaging call for the development of ultrasound-trackable drug delivery vehicles that can address a variety of therapeutic targets. One disadvantage of the technique is the lack of high-precision imaging, which can be circumvented by complementing ultrasound contrast agents with visible and, especially, near-infrared (NIR) fluorophores. In this work, we, for the first time, develop a variety of lightly metal-doped (iron oxide, silver, thulium, neodymium, cerium oxide, cerium chloride, and molybdenum disulfide) nitrogen-containing graphene quantum dots (NGQDs) that demonstrate high-contrast properties in the ultrasound brightness mode and exhibit visible and/or near-infrared fluorescence imaging capabilities. NGQDs synthesized from glucosamine precursors with only a few percent metal doping do not introduce additional toxicity in vitro, yielding over 80% cell viability up to 2 mg/mL doses. Their small (<50 nm) sizes warrant effective cell internalization, while oxygen-containing surface functional groups decorating their surfaces render NGQDs water soluble and allow for the attachment of therapeutics and targeting agents. Utilizing visible and/or NIR fluorescence, we demonstrate that metal-doped NGQDs experience maximum accumulation within the HEK-293 cells 6-12 h after treatment. The successful 10-fold ultrasound signal enhancement is observed at 0.5-1.6 mg/mL for most metal-doped NGQDs in the vascular phantom, agarose gel, and animal tissue. A combination of non-invasive ultrasound imaging with capabilities of high-precision fluorescence tracking makes these metal-doped NGQDs a viable agent for a variety of theragnostic applications.
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Grafito , Puntos Cuánticos , Animales , Humanos , Células HEK293 , Nitrógeno , Imagen Óptica , UltrasonografíaRESUMEN
Early-stage pancreatic cancer remains challenging to detect, leading to a poor five-year patient survival rate. This obstacle necessitates the development of early detection approaches based on novel technologies and materials. In this work, the presence of a specific pancreatic cancer-derived miRNA (pre-miR-132) is detected using the fluorescence properties of biocompatible nitrogen-doped graphene quantum dots (NGQDs) synthesized using a bottom-up approach from a single glucosamine precursor. The sensor platform is comprised of slightly positively charged (1.14 ± 0.36 mV) NGQDs bound via π-π stacking and/or electrostatic interactions to the negatively charged (-22.4 ± 6.00 mV) bait ssDNA; together, they form a complex with a 20 nm average size. The NGQDs' fluorescence distinguishes specific single-stranded DNA sequences due to bait-target complementarity, discriminating them from random control sequences with sensitivity in the micromolar range. Furthermore, this targetability can also detect the stem and loop portions of pre-miR-132, adding to the practicality of the biosensor. This non-invasive approach allows cancer-specific miRNA detection to facilitate early diagnosis of various forms of cancer.
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We present a unique case of a 60-year-old male with congestive heart failure who was admitted for a pre-syncopal episode and found to be in atrial fibrillation with rapid ventricular response (RVR). In order to effectively rate control the patient, he was administered an amiodarone bolus and intravenous (IV) infusion over 24 hours, along with a single oral 200 mg dose the following day. The patient subsequently developed acute hepatotoxicity along with features of acute kidney injury (AKI), pulmonary distress, and leukocytosis. After ruling out other etiologies for acute liver, pulmonary, and kidney injury, amiodarone-induced multi-organ toxicity was suspected and amiodarone was discontinued. Within hours of amiodarone discontinuation, the patient's clinical status and organ function improved remarkably. In the setting of a patient being treated with IV amiodarone and presenting with sudden signs of dyspnea, acute elevation of transaminases and AKI within one to two days of initial dosing, acute amiodarone-induced organ toxicity should be considered.
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CONTEXT: Age-dependent dementia is a devastating disorder afflicting a growing older population. Although pharmacological agents improve symptoms of dementia, age-related comorbidities combined with adverse effects often outweigh their clinical benefits. Therefore, nonpharmacological therapies are being investigated as an alternative. In a previous pilot study, aged rats demonstrated improved spatial memory after osteopathic cranial manipulative medicine (OCMM) treatment. OBJECTIVES: In this continuation of the pilot study, we examine the effect of OCMM on gene expression to elicit possible explanations for the improvement in spatial memory. METHODS: OCMM was performed on six of 12 elderly rats every day for 7 days. Rats were then euthanized to obtain the brain tissue, from which RNA samples were extracted. RNA from three treated and three controls were of sufficient quality for sequencing. These samples were sequenced utilizing next-generation sequencing from Illumina NextSeq. The Cufflinks software suite was utilized to assemble transcriptomes and quantify the RNA expression level for each sample. RESULTS: Transcriptome analysis revealed that OCMM significantly affected the expression of 36 genes in the neuronal pathway (false discovery rate [FDR] <0.004). The top five neuronal genes with the largest-fold change were part of the cholinergic neurotransmission mechanism, which is known to affect cognitive function. In addition, 39.9% of 426 significant differentially expressed (SDE) genes (FDR<0.004) have been previously implicated in neurological disorders. Overall, changes in SDE genes combined with their role in central nervous system signaling pathways suggest a connection to previously reported OCMM-induced behavioral and biochemical changes in aged rats. CONCLUSIONS: Results from this pilot study provide sufficient evidence to support a more extensive study with a larger sample size. Further investigation in this direction will provide a better understanding of the molecular mechanisms of OCMM and its potential in clinical applications. With clinical validation, OCMM could represent a much-needed low-risk adjunct treatment for age-related dementia including Alzheimer's disease.
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Osteopatía , Animales , Colinérgicos , Expresión Génica , Humanos , Osteopatía/métodos , Proyectos Piloto , RatasRESUMEN
Rapamycin is an exogenous compound that has been shown to improve cognition in Alzheimer's disease mouse models and can regulate pathways downstream of the insulin receptor signaling pathway. Insulin is also known to improve cognition in rodent models of Alzheimer's disease. Central nervous system (CNS) insulin must first cross the blood-brain barrier (BBB), a specialized network of brain endothelial cells. This transport process is regulated by physiological factors, such as insulin itself, triglycerides, cytokines, and starvation. Since rapamycin treatment can alter the metabolic state of rodents, increase the circulating triglycerides, and acts as a starvation mimetic, we hypothesized rapamycin could alter the rate of insulin transport across the BBB, providing a potential mechanism for the beneficial effects of rapamycin on cognition. Using young male and female CD-1 mice, we measured the effects of rapamycin on the basal levels of serum factors, insulin receptor signaling, vascular binding, and BBB pharmacokinetics. We found chronic rapamycin treatment was able to affect basal levels of circulating serum factors and endothelial cell insulin receptor signaling. In addition, while acute rapamycin treatment did affect insulin binding at the BBB, overall transport was unaltered. Chronic rapamycin slowed insulin BBB transport non-significantly (p = 0.055). These results suggest that rapamycin may not directly impact the transport of insulin at the BBB but could be acting to alter insulin signaling within brain endothelial cells, which can affect downstream signaling.
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Barrera Hematoencefálica , Inanición , Enfermedad de Alzheimer , Animales , Encéfalo , Células Endoteliales , Femenino , Insulina , Masculino , Ratones , Receptor de Insulina , Transducción de Señal , Sirolimus/farmacología , TriglicéridosRESUMEN
Long noncoding RNAs (lncRNAs) are a heterogenous group of RNAs, which can encode small proteins. The extent to which developmentally regulated lncRNAs are translated and whether the produced microproteins are relevant for human development is unknown. Using a human embryonic stem cell (hESC)-based pancreatic differentiation system, we show that many lncRNAs in direct vicinity of lineage-determining transcription factors (TFs) are dynamically regulated, predominantly cytosolic, and highly translated. We genetically ablated ten such lncRNAs, most of them translated, and found that nine are dispensable for pancreatic endocrine cell development. However, deletion of LINC00261 diminishes insulin+ cells, in a manner independent of the nearby TF FOXA2. One-by-one disruption of each of LINC00261's open reading frames suggests that the RNA, rather than the produced microproteins, is required for endocrine development. Our work highlights extensive translation of lncRNAs during hESC pancreatic differentiation and provides a blueprint for dissection of their coding and noncoding roles.
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Diferenciación Celular/fisiología , Islotes Pancreáticos/citología , ARN Largo no Codificante/fisiología , Sistemas CRISPR-Cas , Células Cultivadas , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica , Técnicas de Inactivación de Genes , Células HEK293 , Células Madre Embrionarias Humanas , Humanos , Islotes Pancreáticos/embriología , Masculino , Biosíntesis de Proteínas , ARN Largo no Codificante/genética , Factores de Transcripción/metabolismoRESUMEN
Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.
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Analgésicos/uso terapéutico , Catepsinas/antagonistas & inhibidores , Hiperalgesia/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Neuralgia/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Inhibidores de Proteasas/uso terapéutico , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Encéfalo/metabolismo , Catepsinas/genética , Catepsinas/metabolismo , Línea Celular , Citocinas/inmunología , Calor , Humanos , Hiperalgesia/inmunología , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Inmunosupresores/farmacocinética , Inmunosupresores/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neuralgia/inmunología , Traumatismos de los Nervios Periféricos/inmunología , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Nervio Ciático/lesiones , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Toxoide Tetánico/administración & dosificación , TactoRESUMEN
BACKGROUND: Cross-reactive carbohydrate determinant (CCD) structures found in plant and insect glycoproteins are commonly recognized by IgE antibodies as epitopes that can lead to extensive cross-reactivity and obscure in vitro diagnostic (IVD) serology results. With the introduction of component resolved diagnosis (CRD), recombinant non-glycosylated components have been utilized to mitigate the risk of CCD-specific IgE (sIgE) detection. However, a recent study has shown that CCD-sIgE may bind directly to the cellulose solid phase matrix used in certain in vitro diagnostic assays, eliminating the advantage of CRD over traditional extract-based testing. The aim of this study is to further investigate the prevalence of CCD-sIgE interference on a commonly-used in vitro sIgE automated platform which employs a cellulose-based matrix to immobilize CCD-free recombinant components. METHODS: Sera from patients sensitized to peanut, silver birch, and/or timothy grass were analyzed for CCD-sIgE reactivity on ImmunoCAP/Phadia and NOVEOS autoanalyzers against the MUXF3 carbohydrate component. Positive CCD-sIgE sera were further analyzed against non-glycosylated recombinant components bound to the ImmunoCAP solid phase in the absence and presence of a soluble CCD inhibitor. For comparison, sera were then analyzed on NOVEOS, a non-cellulose based automated sIgE assay. RESULTS: Sera from 35% of the sensitized population tested in this study were positive (≥0.35 kU/L) for CCD-sIgE. Of those positives, 17% resulted in CCD-sIgE-positive (false positive) results on ImmunoCAP using non-glycosylated allergosorbents that were negative on NOVEOS. Sera producing false-positive results on ImmunoCAP had varying levels of CCD-sIgE from 0.67 kU/L to 36.52 kU/L. The incidence of CCD interference was predominantly delimited to low-positive IgE results (0.35 kUA/L- 3.00 kUA/L). CONCLUSION: Falsely elevated diagnostic allergen-sIgE results can commonly occur due to the presence of CCD-sIgE using assays that employ a carbohydrate matrix-based allergosorbent. Even the use of non-glycosylated recombinant allergenic components coupled to cellulose matrices do not reduce their risk of detection. The risk of CCD interference that compromises quantitative IgE results can be mitigated by the addition of a soluble CCD inhibitor to positive CCD-sIgE containing sera or by alternatively using a non-cellulose based sIgE assay, such as the NOVEOS assay.
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Alérgenos/inmunología , Celulosa/inmunología , Inmunoglobulina E/inmunología , Alérgenos/genética , Alérgenos/metabolismo , Arachis/inmunología , Betula/inmunología , Reacciones Cruzadas , Humanos , Hipersensibilidad/sangre , Hipersensibilidad/patología , Inmunoglobulina E/sangre , Phleum/inmunología , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/inmunologíaRESUMEN
Abnormalities of mineral bone disorder (MBD) parameters have been suggested to be associated with poor renal outcome in predialysis patients. However, the impact of those parameters on decline in residual kidney function (RKF) is uncertain among incident hemodialysis (HD) patients. We performed a retrospective cohort study in 13,772 patients who initiated conventional HD during 2007 to 2011 and survived 6 months of dialysis. We examined the association of baseline serum phosphorus, calcium, intact parathyroid hormone (PTH), and alkaline phosphatase (ALP) with a decline in RKF. Decline in RKF was assessed by estimated slope of renal urea clearance (KRU) over 6 months from HD initiation. Our cohort had a mean ± SD age of 62 ± 15 years; 64% were men, 57% were white, 65% had diabetes, and 51% had hypertension. The median (interquartile range [IQR]) baseline KRU level was 3.4 (2.0, 5.2) mL/min/1.73 m2 . The median (IQR) estimated 6-month KRU slope was -1.47 (-2.24, -0.63) mL/min/1.73 m2 per 6 months. In linear regression models, higher phosphorus categories were associated with a steeper 6-month KRU slope compared with the reference category (phosphorus 4.0 to <4.5 mg/dL). Lower calcium and higher intact PTH and ALP categories were also associated with a steeper 6-month KRU slope compared with their respective reference groups (calcium 9.2 to <9.5 mg/dL; intact PTH 150 to <250 pg/mL; ALP <60 U/L). The increased number of parameter abnormalities had an additive effect on decline in RKF. Abnormalities of MBD parameters including higher phosphorus, intact PTH, ALP and lower calcium levels were independently associated with decline in RKF in incident HD patients. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.
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Fallo Renal Crónico , Diálisis Renal , Anciano , Densidad Ósea , Enfermedades Óseas , Calcio , Femenino , Humanos , Riñón , Masculino , Persona de Mediana Edad , Hormona Paratiroidea , Estudios RetrospectivosRESUMEN
Research on intranasal delivery of drugs, peptides, and proteins has grown over the past decade as an alternate way to deliver substrates to the brain. Recent work has shown intranasal (INL) delivery of insulin improves memory and cognition in healthy subjects as well as patients with Alzheimer's disease (AD) and in AD mouse models. However, the molecular mechanism(s) for the beneficial effect of insulin on memory are still unclear. Using the SAMP8 mouse model of AD, we investigated the impact of INL insulin on protein and gene expression in brain regions including the olfactory bulb, hypothalamus, and hippocampus. We found genes and proteins in the insulin receptor signaling pathway were not activated by the doses tested. However, we did find the expression of genes present in the hippocampus involved in other pathways, especially those related to inflammation, were altered due to age and with a dose of INL insulin previously shown to improve cognition. These alternate pathways could be targets of insulin when delivered via the INL route to aid in memory improvement.