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Project description:Progress in clinical translation of gene edited porcine kidney xenotransplantation is accelerating. However, kidney function entails more than removal of metabolic waste products and it is unknown if all endocrine functions will be faithfully reproduced by porcine kidneys in primate recipients. Seventeen cynomolgus macaques with survival >60days after life sustaining kidney xenotransplantation (LSKX) from gene edited Yucatan minipigs underwent measurement of xenograft growth and two kidney dependent endocrine pathways: renin-angiotensin-aldosterone-system (RAAS) and calcium-vitamin D-parathyroid-hormone. Clinical chemistries, plasma-renin-activity, Beta-C-terminal-telopeptide (CTx) assay, RNA-seq, single-cell RNA-seq, and serial ultrasonography were conducted and generalized linear models assessed statistical relationships. Xenografts transplanted from minipigs demonstrated only modest growth (estimated ~8.0% per year) and didn’t significantly contribute to recipient RAAS pathway. However, PTH-independent hypercalcemia and hypophosphatemia were observed and might be xenograft intrinsic suggesting close monitoring and timely intervention during the first month post-transplant. Further study of these phenotypes is warranted in designing prospective clinical trials.
2023-04-25 | GSE216033 | GEO
Project description:Progress in clinical translation of gene edited porcine kidney xenotransplantation is accelerating. However, kidney function entails more than removal of metabolic waste products and it is unknown if all endocrine functions will be faithfully reproduced by porcine kidneys in primate recipients. Seventeen cynomolgus macaques with survival >60days after life sustaining kidney xenotransplantation (LSKX) from gene edited Yucatan minipigs underwent measurement of xenograft growth and two kidney dependent endocrine pathways: renin-angiotensin-aldosterone-system (RAAS) and calcium-vitamin D-parathyroid-hormone. Clinical chemistries, plasma-renin-activity, Beta-C-terminal-telopeptide (CTx) assay, RNA-seq, single-cell RNA-seq, and serial ultrasonography were conducted and generalized linear models assessed statistical relationships. Xenografts transplanted from minipigs demonstrated only modest growth (estimated ~8.0% per year) and didn’t significantly contribute to recipient RAAS pathway. However, PTH-independent hypercalcemia and hypophosphatemia were observed and might be xenograft intrinsic suggesting close monitoring and timely intervention during the first month post-transplant. Further study of these phenotypes is warranted in designing prospective clinical trials.
2023-04-25 | GSE216029 | GEO
Project description:The development of the mammalian kidney is well conserved from mouse to man. Despite considerable temporal and spatial data on gene expression in mammalian kidney development, primarily in rodent species, there is a paucity of genes whose expression is absolutely specific to a given anatomical compartment and/or developmental stage, defined here as 'anchor' genes. We previously generated an atlas of gene expression in the developing mouse kidney using microarray analysis of anatomical compartments collected via laser capture microdissection. Here, this data is further analysed to identify anchor genes via stringent bioinformatic filtering followed by high resolution section in situ hybridisation performed on 200 transcripts selected as specific to one of 11 anatomical compartments within the midgestation mouse kidney. A total of 37 anchor genes were identified across 6 compartments with the early proximal tubule being the compartment richest in anchor genes. Analysis of minimal and evolutionarily conserved promoter regions of this set of 25 anchor genes identified enrichment of transcription factor binding sites for Hnf4a and Hnf1b, RbpJ (Notch signalling), PPAR?:RxRA and COUP-TF family transcription factors. This was reinforced by GO analyses which also identified these anchor genes as targets in processes including epithelial proliferation and proximal tubular function. As well as defining anchor genes, this large scale validation of gene expression identified a further 92 compartment-enriched genes able to subcompartmentalise key processes during murine renal organogenesis spatially or ontologically. This included a cohort of 13 ureteric epithelial genes revealing previously unappreciated compartmentalisation of the collecting duct system and a series of early tubule genes suggesting that segmentation into proximal tubule, loop of Henle and distal tubule does not occur until the onset of glomerular vascularisation. Overall, this study serves to illuminate previously ill-defined stages of patterning and will enable further refinement of the lineage relationships within mammalian kidney development.
| S-EPMC3046260 | biostudies-literature
Project description:BackgroundCompared to the conventional differential expression approach, differential coexpression analysis represents a different yet complementary perspective into diseased transcriptomes. In particular, global loss of transcriptome correlation was previously observed in aging mice, and a most recent study found genetic and environmental perturbations on human subjects tended to cause universal attenuation of transcriptome coherence. While methodological progresses surrounding differential coexpression have helped with research on several human diseases, there has not been an investigation of coexpression disruptions in chronic kidney disease (CKD) yet.MethodsRNA-seq was performed on total RNAs of kidney tissue samples from 140 CKD patients. A combination of differential coexpression methods were employed to analyze the transcriptome transition in CKD from the early, mild phase to the late, severe kidney damage phase.ResultsWe discovered a global expression correlation attenuation in CKD progression, with pathway Regulation of nuclear SMAD2/3 signaling demonstrating the most remarkable intra-pathway correlation rewiring. Moreover, the pathway Signaling events mediated by focal adhesion kinase displayed significantly weakened crosstalk with seven pathways, including Regulation of nuclear SMAD2/3 signaling. Well-known relevant genes, such as ACTN4, were characterized with widespread correlation disassociation with partners from a wide array of signaling pathways.ConclusionsAltogether, our analysis reported a global expression correlation attenuation within and between key signaling pathways in chronic kidney disease, and presented a list of vanishing hub genes and disrupted correlations within and between key signaling pathways, illuminating on the pathophysiological mechanisms of CKD progression.
| S-EPMC7504859 | biostudies-literature
Project description:Here we analyze existing quantitative data available for cephalopod brains based on classical contributions by J.Z. Young and colleagues, to cite some. We relate the relative brain size of selected regions (area and/or lobe), with behavior, life history, ecology and distribution of several cephalopod species here considered. After hierarchical clustering we identify and describe ten clusters grouping 52 cephalopod species. This allows us to describe cerebrotypes, i.e., differences of brain composition in different species, as a sign of their adaptation to specific niches and/or clades in cephalopod molluscs for the first time. Similarity reflecting niche type has been found in vertebrates, and it is reasonable to assume that it could also occur in Cephalopoda. We also attempted a phylogenetic PCA using data by Lindgren et al. (2012) as input tree. However, due to the limited overlap in species considered, the final analysis was carried out on <30 species, thus reducing the impact of this approach. Nevertheless, our analysis suggests that the phylogenetic signal alone cannot be a justification for the grouping of species, although biased by the limited set of data available to us. Based on these preliminary findings, we can only hypothesize that brains evolved in cephalopods on the basis of different factors including phylogeny, possible development, and the third factor, i.e., life-style adaptations. Our results support the working hypothesis that the taxon evolved different sensorial and computational strategies to cope with the various environments (niches) occupied in the oceans. This study is novel for invertebrates, to the best of our knowledge.
| S-EPMC7884766 | biostudies-literature
Project description:BACKGROUNDMolecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODSWe explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.RESULTSWe identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERG-overexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.
| S-EPMC8121518 | biostudies-literature
Project description:ImportanceCritically ill patients often receive high-intensity life sustaining treatments (LST) in the intensive care unit (ICU), although they can be ineffective and eventually undesired. Determining the risk factors associated with reversals in LST goals can improve patient and provider appreciation for the natural history and epidemiology of critical care and inform decision making around the (continued) use of LSTs.MethodsThis is a single institution retrospective cohort study of patients receiving life sustaining treatment in an academic tertiary hospital from 2009 to 2013. Deidentified patient electronic medical record data was collected via the clinical data warehouse to study the outcomes of treatment limiting Comfort Care and do-not-resuscitate (DNR) orders. Extended multivariable Cox regression models were used to estimate the association of patient and clinical factors with subsequent treatment limiting orders.Results10,157 patients received life-sustaining treatment while initially Full Code (allowing all resuscitative measures). Of these, 770 (8.0%) transitioned to Comfort Care (with discontinuation of any life-sustaining treatments) while 1,669 (16%) patients received new DNR orders that reflect preferences to limit further life-sustaining treatment options. Patients who were older (Hazard Ratio(HR) 1.37 [95% CI 1.28-1.47] per decade), with cerebrovascular disease (HR 2.18 [95% CI 1.69-2.81]), treated by the Medical ICU (HR 1.92 [95% CI 1.49-2.49]) and Hematology-Oncology (HR 1.87 [95% CI 1.27-2.74]) services, receiving vasoactive infusions (HR 1.76 [95% CI 1.28, 2.43]) or continuous renal replacement (HR 1.83 [95% CI 1.34, 2.48]) were more likely to transition to Comfort Care. Any new DNR orders were more likely for patients who were older (HR 1.43 [95% CI 1.38-1.48] per decade), female (HR 1.30 [95% CI 1.17-1.44]), with cerebrovascular disease (HR 1.45 [95% CI 1.25-1.67]) or metastatic solid cancers (HR 1.92 [95% CI 1.48-2.49]), or treated by Medical ICU (HR 1.63 [95% CI 1.42-1.86]), Hematology-Oncology (HR 1.63 [95% CI 1.33-1.98]) and Cardiac Care Unit-Heart Failure (HR 1.41 [95% CI 1.15-1.72]).ConclusionDecisions to reverse or limit treatment goals occurs after more than 1 in 13 trials of LST, and is associated with older female patients, receiving non-ventilator forms of LST, cerebrovascular disease, and treatment by certain medical specialty services.
| S-EPMC5830043 | biostudies-literature
Project description:Most successfully resuscitated cardiac arrest patients do not survive to hospital discharge. Many have withdrawal of life sustaining therapy (WLST) as a result of the perception of poor neurologic prognosis. The characteristics of these patients and differences in their post-arrest care are largely unknown.Utilizing the Penn Alliance for Therapeutic Hypothermia Registry, we identified a cohort of 1311 post-arrest patients from 26 hospitals from 2010 to 2014 who remained comatose after return of spontaneous circulation. We stratified patients by whether they had WLST post-arrest and analyzed demographic, arrest, and post-arrest variables.In our cohort, 565 (43%) patients had WLST. In multivariate regression, patients who had WLST were less likely to go to the cardiac catheterization lab (OR 0.40; 95% CI: 0.26-0.62) and had shorter hospital stays (OR 0.93; 95% CI: 0.91-0.95). When multivariate regression was limited to patient demographics and arrest characteristics, patients with WLST were older (OR 1.18; 95% CI: 1.07-1.31 by decade), had a longer arrest duration (OR 1.14; 95% CI: 1.05-1.25 per 10min), more likely to be female (OR: 1.41; 95% CI: 1.01-1.96), and less likely to have a witnessed arrest (OR 0.65; 95% CI: 0.42-0.98).Patients with WLST differ in terms of demographic, arrest, and post-arrest characteristics and treatments from those who did not have WLST. Failure to account for this variability could affect both clinical practice and the interpretation of research.
| S-EPMC5541857 | biostudies-literature
Project description:Designing and producing novel proteins that fold into stable structures and provide essential biological functions are key goals in synthetic biology. In initial steps toward achieving these goals, we constructed a combinatorial library of de novo proteins designed to fold into 4-helix bundles. As described previously, screening this library for sequences that function in vivo to rescue conditionally lethal mutants of Escherichia coli (auxotrophs) yielded several de novo sequences, termed SynRescue proteins, which rescued four different E. coli auxotrophs. In an effort to understand the structural requirements necessary for auxotroph rescue, we investigated the biophysical properties of the SynRescue proteins, using both computational and experimental approaches. Results from circular dichroism, size-exclusion chromatography, and NMR demonstrate that the SynRescue proteins are ?-helical and relatively stable. Surprisingly, however, they do not form well-ordered structures. Instead, they form dynamic structures that fluctuate between monomeric and dimeric states. These findings show that a well-ordered structure is not a prerequisite for life-sustaining functions, and suggests that dynamic structures may have been important in the early evolution of protein function.
| S-EPMC4744525 | biostudies-literature
Project description:Background/objectivesMany older persons with chronic illness use Physician Orders for Life-Sustaining Treatment (POLST) to document portable medical orders for emergency care. However, some POLSTs contain combinations of orders that do not translate into a cohesive care plan (eg, cardiopulmonary resuscitation [CPR] without intensive care, or intensive care without antibiotics). This study characterizes the prevalence and predictors of POLSTs with conflicting orders.DesignRetrospective cohort study.SettingLarge academic health system.ParticipantsA total of 3,123 POLST users with chronic life-limiting illness who died between 2010 and 2015 (mean age = 69.7 years).MeasurementsIn a retrospective review of all POLSTs in participants' electronic health records, we describe the prevalence of POLSTs with conflicting orders for cardiac arrest and medical interventions, and use clustered logistic regression to evaluate potential predictors of conflicting orders. We also examine the prevalence of conflicts between POLST orders for antibiotics and artificial nutrition with orders for cardiac arrest or medical interventions.ResultsAmong 3,924 complete POLSTs belonging to 3,123 decedents, 209 (5.3%) POLSTs contained orders to "attempt CPR" paired with orders for "limited interventions" or "comfort measures only"; 745/3169 (23.5%) POLSTs paired orders to restrict antibiotics with orders to deliver non-comfort-only care; and, 170/3098 (5.5%) POLSTs paired orders to withhold artificial nutrition with orders to deliver CPR or intensive care. Among POLSTs with orders to avoid intensive care, orders to attempt CPR were more likely to be present in POLSTs completed earlier in the patient's illness course (adjusted odds ratio = 1.27 per twofold increase in days from POLST to death; 95% confidence interval = 1.18-1.36; P < .001).ConclusionAlthough most POLSTs are actionable by clinicians, 5% had conflicting orders for cardiac arrest and medical interventions, and 24% had one or more conflicts between orders for cardiac arrest, medical interventions, antibiotics, and artificial nutrition. These conflicting orders make implementation of POLST challenging for clinicians in acute care settings.
| S-EPMC7744421 | biostudies-literature