Purpose This AUA Guideline focuses on evaluation/counseling and management of adult patients with clinically localized renal masses suspicious for cancer, including solid-enhancing tumors and Bosniak ...3/4 complex-cystic lesions. Materials and Methods Systematic review utilized research from the Agency for Healthcare Research and Quality and additional supplementation by the authors and consultant methodologists. Evidence-based statements were based on body of evidence strength Grade A/B/C (Strong/Moderate/Conditional Recommendations, respectively) with additional statements presented as Clinical Principles or Expert Opinions. Results Great progress has been made since the previous guidelines on management of localized renal masses was released (2009). The current guidelines provide updated, evidence-based recommendations regarding evaluation/counseling of patients with clinically localized renal masses, including the evolving role of renal mass biopsy. Given great variability of clinical, oncologic and functional characteristics, index patients are not utilized and the panel advocates individualized counseling/management. Management options (partial nephrectomy/radical nephrectomy/thermal ablation/active surveillance) are reviewed including recent data about comparative effectiveness and potential morbidities. Oncologic issues are prioritized while recognizing that functional outcomes are of great importance for survivorship for most patients with localized kidney cancer. A more restricted role for radical nephrectomy is recommended following well-defined selection criteria. Priority for partial nephrectomy is recommended for clinical T1a lesions, along with selective use of thermal ablation, particularly for tumors ≤3.0 cm. Important considerations for shared decision-making about active surveillance are explicitly defined. Conclusions Several factors should be considered during counseling/management of patients with clinically localized renal masses, including general health/comorbidities, oncologic potential of the mass, pertinent functional issues and relative efficacy/potential morbidities of various management strategies.
Mammals have extremely limited regenerative capabilities; however, axolotls are profoundly regenerative and can replace entire limbs. The mechanisms underlying limb regeneration remain poorly ...understood, partly because the enormous and incompletely sequenced genomes of axolotls have hindered the study of genes facilitating regeneration. We assembled and annotated a de novo transcriptome using RNA-sequencing profiles for a broad spectrum of tissues that is estimated to have near-complete sequence information for 88% of axolotl genes. We devised expression analyses that identified the axolotl orthologs of cirbp and kazald1 as highly expressed and enriched in blastemas. Using morpholino anti-sense oligonucleotides, we find evidence that cirbp plays a cytoprotective role during limb regeneration whereas manipulation of kazald1 expression disrupts regeneration. Our transcriptome and annotation resources greatly complement previous transcriptomic studies and will be a valuable resource for future research in regenerative biology.
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•Creation of a transcriptome with near-complete sequence data for 88% of axolotl genes•Expression analyses identify tissue-enriched transcripts for key tissues•The RNA-binding protein cirbp plays a cytoprotective role in limb regeneration•Knockdown and overexpression of kazald1 in blastema cells impair limb regeneration
Discovery of genes driving axolotl limb regeneration has been challenging, due to limited genomic resources. Bryant et al. have created a transcriptome with near-complete sequence information for most axolotl genes, identified transcriptional profiles that distinguish blastemas from differentiated limb tissues, and uncovered functional roles for cirbp and kazald1 in limb regeneration.
The findings that amyotrophic lateral sclerosis (ALS) patients almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial ...ALS have nominated altered RNA metabolism as a disease mechanism. However, the RNAs regulated by TDP-43 in motor neurons and their connection to neuropathy remain to be identified. Here we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cord. STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration. Notably, post-translational stabilization of STMN2 rescued neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose that restoring STMN2 expression warrants examination as a therapeutic strategy for ALS.
Resveratrol induces mitochondrial biogenesis and protects against metabolic decline, but whether SIRT1 mediates these benefits is the subject of debate. To circumvent the developmental defects of ...germline SIRT1 knockouts, we have developed an inducible system that permits whole-body deletion of SIRT1 in adult mice. Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased NAD+ levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. A mouse overexpressing SIRT1 mimicked these effects. A high dose of resveratrol activated AMPK in a SIRT1-independent manner, demonstrating that resveratrol dosage is a critical factor. Importantly, at both doses of resveratrol no improvements in mitochondrial function were observed in animals lacking SIRT1. Together these data indicate that SIRT1 plays an essential role in the ability of moderate doses of resveratrol to stimulate AMPK and improve mitochondrial function both in vitro and in vivo.
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► Resveratrol's ability to improve mitochondrial function requires SIRT1 in vivo ► Moderate doses of resveratrol activate AMPK and raise NAD+ in a SIRT1-dependent manner ► Activation of AMPK in the absence of SIRT1 does not improve mitochondrial function ► Overexpression of SIRT1 mimics resveratrol's effects on AMPK and mitochondria
Accurate prediction of antigen presentation by human leukocyte antigen (HLA) class II molecules would be valuable for vaccine development and cancer immunotherapies. Current computational methods ...trained on in vitro binding data are limited by insufficient training data and algorithmic constraints. Here we describe MARIA (major histocompatibility complex analysis with recurrent integrated architecture; https://maria.stanford.edu/ ), a multimodal recurrent neural network for predicting the likelihood of antigen presentation from a gene of interest in the context of specific HLA class II alleles. In addition to in vitro binding measurements, MARIA is trained on peptide HLA ligand sequences identified by mass spectrometry, expression levels of antigen genes and protease cleavage signatures. Because it leverages these diverse training data and our improved machine learning framework, MARIA (area under the curve = 0.89-0.92) outperformed existing methods in validation datasets. Across independent cancer neoantigen studies, peptides with high MARIA scores are more likely to elicit strong CD4
T cell responses. MARIA allows identification of immunogenic epitopes in diverse cancers and autoimmune disease.
The Hybrid Mouse Diversity Panel (HMDP) is a collection of approximately 100 well-characterized inbred strains of mice that can be used to analyze the genetic and environmental factors underlying ...complex traits. While not nearly as powerful for mapping genetic loci contributing to the traits as human genome-wide association studies, it has some important advantages. First, environmental factors can be controlled. Second, relevant tissues are accessible for global molecular phenotyping. Finally, because inbred strains are renewable, results from separate studies can be integrated. Thus far, the HMDP has been studied for traits relevant to obesity, diabetes, atherosclerosis, osteoporosis, heart failure, immune regulation, fatty liver disease, and host-gut microbiota interactions. High-throughput technologies have been used to examine the genomes, epigenomes, transcriptomes, proteomes, metabolomes, and microbiomes of the mice under various environmental conditions. All of the published data are available and can be readily used to formulate hypotheses about genes, pathways and interactions.
The purpose of this guideline was to provide a clinical framework for the use of radiation therapy after radical prostatectomy as adjuvant or salvage therapy.
A systematic literature review using ...PubMed, Embase, and Cochrane database was conducted to identify peer-reviewed publications relevant to the use of radiation therapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed.
Guideline statements are provided for patient counseling, use of radiation therapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a restaging evaluation.
Physicians should offer adjuvant radiation therapy to patients with adverse pathologic findings at prostatectomy (ie, seminal vesicle invastion, positive surgical margins, extraprostatic extension) and salvage radiation therapy to patients with prostate-specific antigen (PSA) or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiation therapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiation therapy as well as the potential benefits of preventing recurrence. The decision to administer radiation therapy should be made by the patient and the multidisciplinary treatment team with full consideration of the patient's history, values, preferences, quality of life, and functional status. The American Society for Radiation Oncology and American Urological Association websites show this guideline in its entirety, including the full literature review.
Translocations or other movements of wildlife sometimes accomplish their intended objectives, but unforeseen consequences may arise and disrupt locally adapted ecological communities, restructure or ...dilute genetic integrity of populations or subspecies of the moved organism, and otherwise negatively influences a species’ long‐term fitness. Two historical populations of Mottled Ducks (Anas fulvigula) exist and are endemic to (1) Mexico and the West‐Gulf Coast (A. f. maculosa) regions of the United States and (2) Florida (A. f. fulvigula). From 1975 to 1983, 1285 Mottled Ducks from Florida, Louisiana, and Texas were released to coastal South Carolina, primarily to ultimately establish a legally harvestable population. This movement stirred mixed reactions amid the conservation community. Contemporary information suggests an increasing Mottled Duck population in South Carolina and possibly dispersing into Georgia. Herein, I objectively discuss the potential consequences of this new population per the birds’ evolution, ecology, and management. Ultimately, I suggest that this translocation is a long‐term benefit to the species.
Two historical populations of Mottled Ducks exist and are endemic to (1) Mexico and the West‐Gulf Coastregions of the United States and (2) Florida. Mottled Ducks were moved by conservationists to coastal SouthCarolina in the 1970’s. This third established population has potential evolutionary and ecological outcomes for the species.
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