3-Hydroxyanthranilic Acid Delays Paralysis in Models of Amyloid-Beta and Polyglutamine Proteotoxicity.

Age is the primary risk factor for neurodegenerative diseases such as Alzheimer's and Huntington's disease. Alzheimer's disease is the most common form of dementia and a leading cause of death in the elderly population of the United States. No effective treatments for these diseases currently exist.

A machine learning approach for quantifying age-related histological changes in the mouse kidney.

The ability to quantify aging-related changes in histological samples is important, as it allows for evaluation of interventions intended to effect health span. We used a machine learning architecture that can be trained to detect and quantify these changes in the mouse kidney. Using additional held out data, we show validation of our model, correlation with scores given by pathologists using the Geropathology Research Network aging grading scheme, and its application in providing reproducible and quantifiable age scores for histological samples.

On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging.

Tryptophan metabolism through the kynurenine pathway influences molecular processes critical to healthy aging including immune signaling, redox homeostasis, and energy production. Aberrant kynurenine metabolism occurs during normal aging and is implicated in many age-associated pathologies including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. We and others previously identified three kynurenine pathway genes-tdo-2, kynu-1, and acsd-1-for which decreasing expression extends lifespan in invertebrates.

A machine learning approach for quantifying age-related histological changes in the mouse kidney.

The ability to quantify aging-related changes in histological samples is important, as it allows for evaluation of interventions intended to effect health span. We used a machine learning architecture that can be trained to detect and quantify these changes in the mouse kidney. Using additional held out data, we show validation of our model, correlation with scores given by pathologists using the Geropathology Research Network aging grading scheme, and its application in providing reproducible and quantifiable age scores for histological samples.

Inpatient Capacity Management during COVID-19 Pandemic: The Yale New Haven Hospital Capacity Expansion Experience.

The 2019 SARS-CoV2 virus presented a capacity demand scenario for Yale New Haven Hospital. The response was created with a focus on clinical needs, but was also driven by the unique characteristics of the buildings within our institution. These physical characteristics were considered in the response as a safety measure as little was known about the transmissibility risk in the acute hospital setting of SARS-CoV2 at the time of response.

Uncovering Modifier Genes of X-Linked Alport Syndrome Using a Novel Multiparent Mouse Model.

Background: Mutations in are responsible for 80% of cases of X-linked Alport Syndrome (XLAS). Although genes that cause AS are well characterized, people with AS who have similar genetic mutations present with a wide variation in the extent of kidney impairment and age of onset, suggesting the activities of modifier genes.

Methods: We created a cohort of genetically diverse XLAS male and female mice using the Diversity Outbred mouse resource and measured albuminuria, GFR, and gene expression.

Deep Learning-Based Segmentation and Quantification in Experimental Kidney Histopathology.

Background: Nephropathologic analyses provide important outcomes-related data in experiments with the animal models that are essential for understanding kidney disease pathophysiology. Precision medicine increases the demand for quantitative, unbiased, reproducible, and efficient histopathologic analyses, which will require novel high-throughput tools. A deep learning technique, the convolutional neural network, is increasingly applied in pathology because of its high performance in tasks like histology segmentation.

Hepsin-mediated Processing of Uromodulin is Crucial for Salt-sensitivity and Thick Ascending Limb Homeostasis.

Uromodulin is a zona pellucida-type protein essentially produced in the thick ascending limb (TAL) of the mammalian kidney. It is the most abundant protein in normal urine. Defective uromodulin processing is associated with various kidney disorders.

Detection and Classification of Novel Renal Histologic Phenotypes Using Deep Neural Networks.

With the advent and increased accessibility of deep neural networks (DNNs), complex properties of histologic images can be rigorously and reproducibly quantified. We used DNN-based transfer learning to analyze histologic images of periodic acid-Schiff-stained renal sections from a cohort of mice with different genotypes. We demonstrate that DNN-based machine learning has strong generalization performance on multiple histologic image processing tasks.

Genome assembly and gene expression in the American black bear provides new insights into the renal response to hibernation.

The prevalence of chronic kidney disease (CKD) is rising worldwide and 10-15% of the global population currently suffers from CKD and its complications. Given the increasing prevalence of CKD there is an urgent need to find novel treatment options. The American black bear (Ursus americanus) copes with months of lowered kidney function and metabolism during hibernation without the devastating effects on metabolism and other consequences observed in humans.

Automatic glomerular identification and quantification of histological phenotypes using image analysis and machine learning.

Current methods of scoring histological kidney samples, specifically glomeruli, do not allow for collection of quantitative data in a high-throughput and consistent manner. Neither untrained individuals nor computers are presently capable of identifying glomerular features, so expert pathologists must do the identification and score using a categorical matrix, complicating statistical analysis. Critical information regarding overall health and physiology is encoded in these samples.

FAR2 is associated with kidney disease in mice and humans.

Mesangial matrix expansion is an important process in the initiation of chronic kidney disease, yet the genetic factors driving its development are unknown. Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred strains. Consistent with the hypothesis that increased expression of Far2 leads to mesangial matrix expansion through increased production of platelet-activating factor precursors, we show that FAR2 is capable of mediating de novo platelet-activating factor synthesis in vitro and driven by the transcription factor NKX3.

Lithium reduces blood glucose levels, but aggravates albuminuria in BTBR-ob/ob mice.

Glycogen synthase kinase 3 (GSK3) plays an important role in the development of diabetes mellitus and renal injury. GSK3 inhibition increases glucose uptake in insulin-insensitive muscle and adipose tissue, while it reduces albuminuria and glomerulosclerosis in acute kidney injury. The effect of chronic GSK3 inhibition in diabetic nephropathy is not known.

Hearing loss without overt metabolic acidosis in ATP6V1B1 deficient MRL mice, a new genetic model for non-syndromic deafness with enlarged vestibular aqueducts.

Mutations of the human ATP6V1B1 gene cause distal renal tubular acidosis (dRTA; OMIM #267300) often associated with sensorineural hearing impairment; however, mice with a knockout mutation of Atp6v1b1 were reported to exhibit a compensated acidosis and normal hearing. We discovered a new spontaneous mutation (vortex, symbol vtx) of Atp6v1b1 in an MRL/MpJ (MRL) colony of mice. In contrast to the reported phenotype of the knockout mouse, which was developed on a primarily C57BL/6 (B6) strain background, MRL-Atp6v1b1vtx/vtx mutant mice exhibit profound hearing impairment, which is associated with enlarged endolymphatic compartments of the inner ear.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity.

We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C.

Loss of Kynurenine 3-Mono-oxygenase Causes Proteinuria.

Changes in metabolite levels of the kynurenine pathway have been observed in patients with CKD, suggesting involvement of this pathway in disease pathogenesis. Our recent genetic analysis in the mouse identified the kynurenine 3-mono-oxygenase (KMO) gene (Kmo) as a candidate gene associated with albuminuria. This study investigated this association in more detail.

Aging Research Using Mouse Models.

Despite the dramatic increase in human lifespan over the past century, there remains pronounced variability in "health-span," or the period of time in which one is generally healthy and free of disease. Much of the variability in health-span and lifespan is thought to be genetic in origin. Understanding the genetic mechanisms of aging and identifying ways to boost longevity is a primary goal in aging research.

A phase I and pharmacokinetic study of ganetespib (STA-9090) in advanced hepatocellular carcinoma.

Background: Ganetespib (STA-9090) is an Hsp90 inhibitor that downregulates VEGFR, c-MET, HER2, IGF-IR, EGFR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary clinical activity of ganetespib in previously treated patients with advanced HCC.

Methods: Patients with advanced HCC, Child-Pugh A cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at doses of 100 mg/m(2), 150 mg/m(2), and 200 mg/m(2) IV given on days 1, 8, and 15 of each 28-day cycle.

Genetic analysis of mesangial matrix expansion in aging mice and identification of Far2 as a candidate gene.

Aging of the kidney is associated with renal damage, in particular mesangial matrix expansion (MME). Identifying the genes involved in this process will help to unravel the mechanisms of aging and aid in the design of novel therapeutic modalities aimed at prevention and regression. In this study, structural changes in glomeruli of 24 inbred mouse strains were characterized in male mice at 6, 12, and 20 months of age.

Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study.

Purpose: We conducted a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Experimental Design: Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months.

Discovery and characterization of AZD9272 and AZD6538-Two novel mGluR5 negative allosteric modulators selected for clinical development.

AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step.

Genetic analysis of albuminuria in collaborative cross and multiple mouse intercross populations.

Albuminuria is an important marker of nephropathy that increases the risk of progressive renal and chronic cardiovascular diseases. The genetic basis of kidney disease is well-established in humans and rodent models, but the causal genes remain to be identified. We applied several genetic strategies to map and refine genetic loci affecting albuminuria in mice and translated the findings to human kidney disease.

The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol.

Genome-wide association (GWA) studies represent a powerful strategy for identifying susceptibility genes for complex diseases in human populations but results must be confirmed and replicated. Because of the close homology between mouse and human genomes, the mouse can be used to add evidence to genes suggested by human studies. We used the mouse quantitative trait loci (QTL) map to interpret results from a GWA study for genes associated with plasma HDL cholesterol levels.

Succinic acid amides as P2-P3 replacements for inhibitors of interleukin-1beta converting enzyme (ICE or caspase 1).

Succinic acid amides have been found to be effective P2-P3 scaffold replacements for peptidic ICE inhibitors. Heteroarylalkyl fragments occupying the P4 position provided access to compounds with nM affinities. Utilization of an acylal prodrug moiety was required to overcome biopharmaceutical issues which led to the identification of 17f, a potential clinical candidate.

Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study.

Background: Previous phase 2 studies have shown antitumour activity with gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary-tract cancers (BTCs). In this phase 2 study, we assessed the efficacy and safety of combined bevacizumab with GEMOX (GEMOX-B) in patients with advanced BTCs, and investigated how changes in 18-fluorodeoxyglucose ([(18)F]FDG)-PET correlate with clinical outcome.

Methods: Patients with advanced measurable BTCs were given the following treatment on days 1 and 15 of a 28-day cycle: bevacizumab 10 mg/kg, followed by gemcitabine 1000 mg/m(2) (10 mg/m(2) per min) and oxaliplatin 85 mg/m(2) (2-h infusion).