Search

Aims/hypothesis: Diabetic kidney disease (DKD) is the leading cause of chronic and end-stage kidney disease in the USA and worldwide. Animal models have taught us much about DKD mechanisms, but translation of this knowledge into treatments for human disease has been slowed by the lag in our molecular understanding of human DKD., Methods: Using our Spatial TissuE Proteomics (STEP) pipeline (comprising curated human kidney tissues, multiplexed immunofluorescence and powerful analysis tools), we imaged and analysed the expression of 21 proteins in 23 tissue sections from individuals with diabetes and healthy kidneys (n=5), compared to those with DKDIIA, IIA-B and IIB (n=2 each) and DKDIII (n=1)., Results: These analyses revealed the existence of 11 cellular clusters (kidney compartments/cell types): podocytes, glomerular endothelial cells, proximal tubules, distal nephron, peritubular capillaries, blood vessels (endothelial cells and vascular smooth muscle cells), macrophages, myeloid cells, other CD45 + inflammatory cells, basement membrane and the interstitium. DKD progression was associated with co-localised increases in inflammatory cells and collagen IV deposition, with concomitant loss of native proteins of each nephron segment. Cell-type frequency and neighbourhood analyses highlighted a significant increase in inflammatory cells and their adjacency to tubular and αSMA + (α-smooth muscle actin-positive) cells in DKD. Finally, DKD progression showed marked regional variability within single tissue sections, as well as inter-individual variability within each DKD class., Conclusions/interpretation: Using the STEP pipeline, we found alterations in protein expression, cellular phenotypic composition and microenvironment structure with DKD progression, demonstrating the power of this pipeline to reveal the pathophysiology of human DKD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To our knowledge, calibration curves or other validations for thousands of SomaScan aptamers are not publicly available. Moreover, the abundance of urine proteins obtained from these assays is not routinely validated with orthogonal methods (OMs). We report an in-depth comparison of SomaScan readout for 23 proteins in urine samples from patients with diabetic kidney disease ( n = 118) vs OMs, including liquid chromatography-targeted mass spectrometry (LC-MS), ELISA, and nephelometry. Pearson correlation between urine abundance of the 23 proteins from SomaScan 3.2 vs OMs ranged from -0.58 to 0.86, with a median (interquartile ratio, [IQR]) of 0.49 (0.18, 0.53). In multivariable linear regression, the SomaScan readout for 6 of the 23 examined proteins (26%) was most strongly associated with the OM-derived abundance of the same (target) protein. For 3 of 23 (13%), the SomaScan and OM-derived abundance of each protein were significantly associated, but the SomaScan readout was more strongly associated with OM-derived abundance of one or more "off-target" proteins. For the remaining 14 proteins (61%), the SomaScan readouts were not significantly associated with the OM-derived abundance of the targeted proteins. In 6 of the latest group, the SomaScan readout was not associated with urine abundance of any of the 23 quantified proteins. To sum, over half of the SomaScan results could not be confirmed by independent orthogonal methods.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative brain disease with rapid progression and currently limited treatment options. A comprehensive understanding of disease progression, management, and healthcare resource utilization is limited, and further research is challenging due to the small population of patients. To address these challenges in conducting PSP research, individuals with PSP were recruited using a multichannel approach tailored specifically to the PSP community. We performed a retrospective observational study using data abstracted from participant medical records collected from multiple patient care centers., Results: Seventy-two individuals with PSP were eligible for inclusion. On average, 144 medical documents per participant were collected from an average of 2.9 healthcare centers per participant, with a mean study period of 7.9 years. Among participants with a date of symptom onset documented in the medical records, the median time for the onset of the first fall was 2.0 years (IQR 3.2) before diagnosis, the median onset of unsteady gait or gait impairment was 1.2 years (IQR 1.8) before diagnosis, and the median onset of mobility problems was 0.8 years (IQR 1.8) before diagnosis. The most widely utilized healthcare resources, with at least 85% of participants using each of these resources at some point during the disease course, were medications (100%), imaging (99%), assistive devices (90%), supportive care (86%), and surgeries and procedures (85%)., Conclusions: This retrospective study adds to the current understanding of PSP symptoms, comorbidities, and healthcare resource utilization (HRU) across the disease journey. By involving individuals with PSP and their caregivers or legally authorized representatives in the research process, this study was unique in its approach to participant recruitment and enabled individuals to participate in research without the need for travel. We collected medical documents from multiple healthcare centers, allowing for broad data collection covering the entire disease journey. This approach to the collection of real-world data may be used to generate valuable insights into many aspects of disease progression and management in PSP and many other rare diseases., (© 2024. The Author(s).)

Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development but, in the adult kidney, is restricted to occasional collecting duct epithelial cells. We now show that there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI) and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protected against experimental AKI but was unexpectedly associated with increased expression of the PTEC injury marker Kim1. However, the protective effects of inhibiting PTEC RAR signaling were associated with increased Kim1-dependent apoptotic cell clearance, or efferocytosis, and this was associated with dedifferentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate the functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.

Acute kidney injury (AKI) is common in surgical and critically ill patients. This study examined whether pretreatment with a novel Toll-like receptor 4 agonist attenuated ischemia-reperfusion injury (IRI)-induced AKI (IRI-AKI). We performed a blinded, randomized-controlled study in mice pretreated with 3-deacyl 6-acyl phosphorylated hexaacyl disaccharide (PHAD), a synthetic Toll-like receptor 4 agonist. Two cohorts of male BALB/c mice received intravenous vehicle or PHAD (2, 20, or 200 µg) at 48 and 24 h before unilateral renal pedicle clamping and simultaneous contralateral nephrectomy. A separate cohort of mice received intravenous vehicle or 200 µg PHAD followed by bilateral IRI-AKI. Mice were monitored for evidence of kidney injury for 3 days postreperfusion. Kidney function was assessed by serum blood urea nitrogen and creatinine measurements. Kidney tubular injury was assessed by semiquantitative analysis of tubular morphology on periodic acid-Schiff (PAS)-stained kidney sections and by kidney mRNA quantification of injury [neutrophil gelatinase-associated lipocalin ( Ngal ), kidney injury molecule-1 ( Kim-1 ), and heme oxygenase-1 ( Ho-1 )] and inflammation [interleukin-6 ( IL-6 ), interleukin-1β ( IL-1β ), and tumor necrosis factor-α ( Tnf-α )] using quantitative RT-PCR. Immunohistochemistry was used to quantify proximal tubular cell injury and renal macrophages by quantifying the areas stained with Kim-1 and F4/80 antibodies, respectively, and TUNEL staining to detect the apoptotic nuclei. PHAD pretreatment yielded dose-dependent kidney function preservation after unilateral IRI-AKI. Histological injury, apoptosis, Kim-1 staining, and Ngal mRNA were lower in PHAD-treated mice and IL-1β mRNA was higher in PHAD-treated mice. Similar pretreatment protection was noted with 200 mg PHAD after bilateral IRI-AKI, with significantly reduced Kim-1 immunostaining in the outer medulla of mice treated with PHAD after bilateral IRI-AKI. In conclusion, PHAD pretreatment leads to dose-dependent protection from renal injury after unilateral and bilateral IRI-AKI in mice. NEW & NOTEWORTHY Pretreatment with 3-deacyl 6-acyl phosphorylated hexaacyl disaccharide; a novel synthetic Toll-like receptor 4 agonist, preserves kidney function during ischemia-reperfusion injury-induced acute kidney injury.

Diabetic kidney disease (DKD), previously encountered predominantly in adult patients, is rapidly gaining center stage as a childhood morbidity and one that pediatric nephrologists are likely to encounter with increasing frequency. This is in large part due to the obesity epidemic and the consequent rise in type 2 diabetes in children and adolescents, as well as the more aggressive diabetes phenotype in today's youth with more rapid β-cell decline and faster development and progression of diabetes-related complications along with lower responsiveness to the treatments used in adults. DKD, an end-organ complication of diabetes, is at the very least a marker of, and more likely a predisposing factor for, the development of adverse cardiovascular outcomes and premature mortality in children with diabetes. On an optimistic note, several new therapeutic approaches are now available for the management of diabetes in adults, such as GLP1 receptor agonists, SGLT2 inhibitors, and DPP4 inhibitors, that have also been shown to have a favorable impact on cardiorenal outcomes. Also promising is the success of very low-energy diets in inducing remission of diabetes in adults. However, the addition of these pharmacological and dietary approaches to the management toolbox of diabetes and DKD in children and adolescents awaits thorough assessment of their safety and efficacy in this population. This review outlines the scope of diabetes and DKD, and new developments that may favorably impact the management of children and young adults with diabetes and DKD., (© 2021. The Author(s).)

Purpose: Although BRCA1 / 2 testing in ovarian cancer improves outcomes, it is vastly underutilized. Scalable approaches are urgently needed to improve genomically guided care., Methods: We developed a Natural Language Processing (NLP) pipeline to extract electronic medical record information to identify recipients of BRCA testing. We applied the NLP pipeline to assess testing status in 308 patients with ovarian cancer receiving care at a National Cancer Institute Comprehensive Cancer Center (main campus [MC] and five affiliated clinical network sites [CNS]) from 2017 to 2019. We compared characteristics between (1) patients who had/had not received testing and (2) testing utilization by site., Results: We found high uptake of BRCA testing (approximately 78%) from 2017 to 2019 with no significant differences between the MC and CNS. We observed an increase in testing over time (67%-85%), higher uptake of testing among younger patients (mean age tested = 61 years v untested = 65 years, P = .01), and higher testing among Hispanic (84%) compared with White, Non-Hispanic (78%), and Asian (75%) patients ( P = .006). Documentation of referral for an internal genetics consultation for BRCA pathogenic variant carriers was higher at the MC compared with the CNS (94% v 31%)., Conclusion: We were able to successfully use a novel NLP pipeline to assess use of BRCA testing among patients with ovarian cancer. Despite relatively high levels of BRCA testing at our institution, 22% of patients had no documentation of genetic testing and documentation of referral to genetics among BRCA carriers in the CNS was low. Given success of the NLP pipeline, such an informatics-based approach holds promise as a scalable solution to identify gaps in genetic testing to ensure optimal treatment interventions in a timely manner., Competing Interests: Stacy W. GrayStock and Other Ownership Interests: Magenta TherapeuticsHonoraria: Triptych Health PartnersConsulting or Advisory Role: Magenta Therapeutics Rebecca A. OttesenEmployment: The Emmes CompanyConsulting or Advisory Role: Votive Health Mihaela CristeaEmployment: RegeneronStock and Other Ownership Interests: Regeneron Sam WingEmployment: Intuitive SurgicalStock and Other Ownership Interests: Intuitive SurgicalResearch Funding: Intuitive SurgicalTravel, Accommodations, Expenses: Intuitive Surgical Bedros DilsizianStock and Other Ownership Interests: CVS, Humana, Procter & Gamble Camille AdeimyStock and Other Ownership Interests: Nautilus Biotechnology, Editas Medicine, CRISPR Therapeutics Tanyanika PhillipsTravel, Accommodations, Expenses: City of HopeNo other potential conflicts of interest were reported.

Background: Poor patients often reside in neighborhoods of lower socioeconomic status (SES) with high levels of airborne pollutants. They also have higher mortality from non-small cell lung cancer (NSCLC) than those living in wealthier communities. We investigated whether living in polluted neighborhoods is associated with somatic mutations linked with lower survival rates, i.e., TP53 mutations., Methods: In a retrospective cohort of 478 patients with NSCLC treated at a comprehensive cancer center between 2015 and 2018, we used logistic regression to assess associations between individual demographic and clinical characteristics, including somatic TP53 mutation status and environmental risk factors of annual average particulate matter (PM 2.5 ) levels, and neighborhood SES., Results: 277 patients (58%) had somatic TP53 mutations. Of those, 45% lived in neighborhoods with "moderate" Environmental Protection Agency-defined PM 2.5 exposure, compared with 39% of patients without TP53 mutations. We found significant associations between living in neighborhoods with "moderate" versus "good" PM 2.5 concentrations and minority population percentage [OR, 1.06; 95% confidence interval (CI), 1.04-1.08]. There was a significant association between presence of TP53 mutations and PM 2.5 exposure (moderate versus good: OR, 1.66; 95% CI, 1.02-2.72) after adjusting for patient characteristics, other environmental factors, and neighborhood-level SES., Conclusions: When controlling for individual- and neighborhood-level confounders, we find that the odds of having a TP53 -mutated NSCLC are increased in areas with higher PM 2.5 exposure., Impact: The link between pollution and aggressive biology may contribute to the increased burden of adverse NSCLC outcomes in individuals living in lower SES neighborhoods., (©2021 American Association for Cancer Research.)

Purpose: Evidence-based somatic and germline sequencing has transformed cancer care and improves patient outcomes. However, patients' low genetic literacy and misunderstanding of their own genomic results poses a threat to the realization of precision oncology. To optimize patient genomic comprehension, we developed a Web-based, patient-directed, genomic sequencing education and return-of-results tool, HOPE-Genomics., Methods: The HOPE-Genomics prototype included somatic and germline sequencing results, embedded multimedia genomic education, and interactive features (eg, request for genetic counseling). Between January and April 2018, we elicited feedback on tool usability and comprehensiveness through participant surveys, 4 focus groups of patients with cancer and their family members, and 3 provider focus groups (comprising 8 patients, 5 family members, and 19 providers)., Results: We identified themes in patient/family tool-related responses, including the desire to view a patient-friendly report, a desire to receive multiple types of genomic information (eg, prognostic and uncertain), high acceptability of report content, and interest in tool-enabled access to genetic counseling. Major themes from the clinician focus groups included believing the tool could help patients formulate questions and facilitate patients' communication of results to family members. However, there were diverse responses from all participants in terms of tool implementation (ie, timing and nature of report release). Some participants preferred report release before meeting with the provider, and others preferred it during the appointment. Additionally, some clinicians were concerned about providing prognostic and treatment information through the tool., Conclusion: There was high acceptability and interest from patients, family members, and providers in a patient-directed genomics report. Future work will determine whether direct-to-patient reporting of genomic results improves patient knowledge, care engagement, and compliance with genomically guided interventions., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Adem AlbayrakEmployment: Health Catalyst Stock and Other Ownership Interests: Health Catalyst Honoraria: BC Platforms Research Funding: MerckMelanie DaviesEmployment: InterSystems CorporationCatherine Del Vecchio FitzEmployment: Health CatalystRachel A. FreedmanResearch Funding: Puma Biotechnology (Inst), Eisai (Inst)Lynette M. ShollHonoraria: AstraZeneca Consulting or Advisory Role: Loxo Oncology, Foghorn Therapeutics Research Funding: GenentechEliezer Van AllenStock and Other Ownership Interests: Syapse, Tango Therapeutics, Genome Medical, Microsoft, Ervaxx Consulting or Advisory Role: Syapse, Roche, Third Rock Ventures, Takeda, Novartis, Genome Medical, InVitae, Illumina, Tango Therapeutics, Ervaxx Speakers' Bureau: Illumina Research Funding: Bristol-Myers Squibb, Novartis Patents, Royalties, Other Intellectual Property: Patent on discovery of retained intron as source of cancer neoantigens (Inst), patent on discovery of chromatin regulators as biomarkers of response to cancer immunotherapy (Inst), patent on clinical interpretation algorithms using cancer molecular data (Inst) Travel, Accommodations, Expenses: GenentechJoanne MortimerHonoraria: Novartis Consulting or Advisory Role: Novartis, Karyopharm, PumaMarwan FakihConsulting or Advisory Role: Amgen, Array BioPharma, Genentech Speakers' Bureau: Amgen, Taiho Pharmaceutical Research Funding: Novartis (Inst), Amgen (Inst), AstraZeneca (Inst)Sumanta PalConsulting or Advisory Role: Genentech, Aveo, Eisai, Roche, Pfizer, Novartis, Exelixis, Ipsen, BMS, Astellas Consulting or Advisory Role: Pfizer, Novartis, Aveo, Myriad Pharmaceuticals, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Ipsen, Eisai Research Funding: MedivationKaren L. ReckampConsulting or Advisory Role: Amgen, AstraZeneca, Boehringer Ingelheim, Calithera Biosciences, Euclises, Genentech, Guardant Health, Precision Health Economics, Seattle Genetics, Takeda, Tesaro Research Funding: AbbVie (Inst), ACEA Biosciences (Inst), Adaptimmune (Inst), Boehringer Ingelheim (Inst), Bristol Myers Squibb (Inst), Genentech (Inst), GlaxoSmithKline (Inst), Guardant Health (Inst), Janssen Oncology (Inst), Loxo Oncology (Inst), Molecular Partners (Inst), Seattle Genetics (Inst), Spectrum (Inst), Takeda (Inst), Xcovery (Inst), Zeno Pharmaceuticals (Inst)Yuan YuanConsulting or Advisory Role: Novartis, Pfizer, Eisai, Genentech, Immunomedics Speakers' Bureau: Eisai, Genentech, Eisai, Pfizer, Merck, Puma Biotechnology, Novartis, Genentech Expert Testimony: NovartisStacy W. GrayStock and Other Ownership Interests: Magenta Therapeutics (I) Consulting or Advisory Role: Grail Industries, Magenta Therapeutics (I) Expert Testimony: Riley and Associates No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

In this paper, we report for the first time the identification and assignments of complex atomic emission spectra of mixed actinide oxides using laser-induced plasma spectroscopy or laser-induced breakdown spectroscopy (LIBS). Preliminary results of LIBS measurements on samples of uranium dioxide (UO2)/plutonium dioxide (PuO2) and UO2/PuO2/americium dioxide (AmO2)/neptunium dioxide (NpO2) simulated fuel pellets (or mixed actinide oxide samples) are reported and discussed. We have identified and assigned >800 atomic emission lines for a UO2/PuO2/AmO2/NpO2 fuel pellet thus far. The identification and assignments of spectral emission lines for U, Pu, and Am are consistent with wavelength data from the literature. However, only a few emission lines have been assigned with a high degree of confidence for Np compared with atomic emission data from the literature. We also indicate where atomic emission lines for Cm would most likely appear in the spectral regions shown. Finally, we demonstrate that a LIBS system with a resolving power of approximately 20,000 is adequate for analyzing complex mixtures of actinide elements within the same sample.

Most polarized epithelia constrain solute diffusion between luminal and interstitial compartments using tight junctions and generate mechanical strength using adherens junctions. These intercellular junctions are typically portrayed as incongruent macromolecular complexes with distinct protein components. Herein, we delineate the molecular composition and subdomain architecture of an intercellular junction between sensory and non-sensory cells of the inner ear. In this junction, claudins partition into claudin-14 and claudin-9/6 subdomains that are distinguishable by strand morphology, which contrasts with in vitro data that most claudins co-assemble into heteromeric strands. Surprisingly, canonical adherens junction proteins (p120ctn, alpha- and beta-catenins) colocalize with the claudin-9/6 subdomain and recruit a dense cytoskeletal network. We also find that catenins colocalize with claudin-9 and claudin-6, but not claudin-14, in a heterologous system. Together, our data demonstrate that canonical tight junction and adherens junction proteins can be recruited to a single junction in which claudins partition into subdomains and form a novel hybrid tight junction with adherens junction organization.