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Abstract The kidney proximal tubule is the primary site for solute reabsorption, secretion and where kidney diseases can originate, including drug-induced toxicity. Two-dimensional cell culture systems of the human proximal tubule cells (hPTCs) are often used to study these processes. However, these systems fail to model the interplay between filtrate flow, fluid shear stress (FSS), and functionality essential for understanding renal diseases and drug toxicity. The impact of FSS exposure on gene expression and effects of FSS at differing rates on gene expression in hPTCs has not been thoroughly investigated. Here, we performed RNA-sequencing of human RPTEC/TERT1 cells in a microfluidic chip-based 3D model to determine transcriptomic changes. We measured transcriptional changes following treatment of cells in this device at three different fluidic shear stress. We observed that FSS changes the expression of PTC-specific genes and impacted genes previously associated with renal diseases in genome-wide association studies (GWAS). At a physiological FSS level, we observed cell morphology, enhanced polarization, presence of cilia, and transport functions using albumin reabsorption via endocytosis and efflux transport. Here, we present a dynamic view of hPTCs response to FSS with increasing fluidic shear stress conditions and provide insight into hPTCs cellular function under biologically relevant conditions.

Simple Summary: Esophageal cancer is a severe disease with a high mortality rate. Recent advancements in treatments have improved outcomes, but survival rates remain low. This study investigates the use of immunotherapy, a treatment that helps the immune system fight cancer, in combination with standard chemoradiation and surgery for patients with locally advanced esophageal cancer. By analyzing data from the National Cancer Database, we found that patients who received adjuvant immunotherapy had better survival rates than those who did not receive immunotherapy or who received neoadjuvant immunotherapy. These findings suggest that adjuvant immunotherapy could be a beneficial addition to existing treatment protocols, and further research is needed to confirm these results and optimize patient outcomes. Background: The current National Comprehensive Cancer Network advises neoadjuvant chemoradiotherapy followed by surgery for locally advanced cases of esophageal cancer. The role of immunotherapy in this context is under heavy investigation. Methods: Patients with esophageal adenocarcinoma were identified in the National Cancer Database (NCDB) from 2004 to 2019. Three groups were generated as follows: (a) no immunotherapy, (b) neoadjuvant immunotherapy, and (c) adjuvant immunotherapy. Overall survival was evaluated using the Kaplan–Meier method and Cox proportional hazard analysis, adjusting for previously described risk factors for mortality. Results: Of the total 14,244 patients diagnosed with esophageal adenocarcinoma who received neoadjuvant chemoradiation, 14,065 patients did not receive immunotherapy, 110 received neoadjuvant immunotherapy, and 69 received adjuvant immunotherapy. When adjusting for established risk factors, adjuvant immunotherapy was associated with significantly improved survival compared to no immunotherapy and neoadjuvant immunotherapy during a median follow-up period of 35.2 months. No difference was noted among patients who received no immunotherapy vs. neoadjuvant immunotherapy in the same model. Conclusions: In this retrospective analysis of the NCDB, receiving adjuvant immunotherapy offered a significant survival advantage compared to no immunotherapy and neoadjuvant immunotherapy in the treatment of esophageal adenocarcinoma. The addition of neoadjuvant immunotherapy to patients treated with neoadjuvant chemoradiation did not improve survival in this cohort. Further studies are warranted to investigate the long-term outcomes of immunotherapy in esophageal cancer. [ABSTRACT FROM AUTHOR]

Separation of blood components is required in many diagnostic applications and blood processes. In laboratories, blood is usually fractionated by manual operation involving a bulk centrifugation equipment, which significantly increases logistic burden. Blood sample processing in the field and resource-limited settings cannot be readily implemented without the use of microfluidic technology. In this study, we developed a small footprint, rapid, and passive microfluidic channel device that relied on margination and inertial focusing effects for blood component separation. No blood dilution, lysis, or labeling step was needed as to preserve sample integrity. One main innovation of this work was the insertion of fluidic restrictors at outlet ports to divert the separation interface into designated outlet channels. Thus, separation efficiency was significantly improved in comparison to previous works. We demonstrated different operation modes ranging from platelet or plasma extraction from human whole blood to platelet concentration from platelet-rich plasma through the manipulation of outlet port fluidic resistance. Using straight microfluidic channels with a high aspect ratio rectangular cross section, we demonstrated 95.4% platelet purity extracted from human whole blood. In plasma extraction, 99.9% RBC removal rate was achieved. We also demonstrated 2.6× concentration of platelet-rich plasma solution to produce platelet concentrate. The extraction efficiency and throughput rate are scalable with continuous and clog-free recirculation operation, in contrast to other blood fractionation approaches using filtration membranes or affinity-based purification methods. Our microfluidic blood separation method is highly tunable and versatile, and easy to be integrated into multi-step blood processing and advanced sample preparation workflows. [ABSTRACT FROM AUTHOR]

Pulmonary vein isolation (PVI) is the cornerstone tor ablative management of atrial fibrillation. Traditional mapping using a circular catheter collects electrograms (EGMs) along the circumference of the vein. Cardiac fibers, however, enter the veins at oblique angles. Due to variable fiber orientation and wavefront activation which may produce signal cancelation, fractionation and collision events, signals near fibrotic tissue and along ablation lines may not be detected. Hi-definition (HD) mapping with the Advisor™ HD Grid Mapping Catheter, Sensor Enabled™ addresses this problem by mapping in multiple directions. The unique 16 electrode (4X4 pattern) Advisor™ HD Grid Mapping Catheter, Sensor Enabled™ coupled with HD Wave Solution™ software helped reduce the issue of "bipolar blindness." Coupled with Ensite™ Omnipolar Technology (OT) algorithm that derives a wavesfront's direction and speed, this hardware-software solution allows for the rapid mapping of both overt and occult gaps in pulmonary vein isolation lines. In so doing, this technology offers the potential for faster procedures with precisely targeted lesions, fewer complications, and improved durability. The following article explores the role of Advisor™ HD Grid Mapping Catheter, Sensor Enabled™, HD Wave Solution™ software and EnSite™ Omnipolar Technology in identification of gaps in lesion sets following PVI. [ABSTRACT FROM AUTHOR]

Clinical guidelines recommend implantable cardioverter-defibrillators (ICDs) to prevent sudden cardiac death in patients with systolic heart failure. Black patients are less likely to receive an ICD. This randomized trial examined the use of a video decision support tool with Black patients and subsequent decisions to agree to ICD implantation. Visual Abstract. Shared Decision Making Among Black Patients at Risk for Cardiac Arrest.: Clinical guidelines recommend implantable cardioverter-defibrillators (ICDs) to prevent sudden cardiac death in patients with systolic heart failure. Black patients are less likely to receive an ICD. This randomized trial examined the use of a video decision support tool with Black patients and subsequent decisions to agree to ICD implantation. Background: Racial disparities in implantable cardioverter-defibrillator (ICD) implantation are multifactorial and are partly explained by higher refusal rates. Objective: To assess the effectiveness of a video decision support tool for Black patients eligible for an ICD. Design: Multicenter, randomized clinical trial conducted between September 2016 and April 2020. (ClinicalTrials.gov: NCT02819973) Setting: Fourteen academic and community-based electrophysiology clinics in the United States. Participants: Black adults with heart failure who were eligible for a primary prevention ICD. Intervention: An encounter-based video decision support tool or usual care. Measurements: The primary outcome was the decision regarding ICD implantation. Additional outcomes included patient knowledge, decisional conflict, ICD implantation within 90 days, the effect of racial concordance on outcomes, and the time patients spent with clinicians. Results: Of the 330 randomly assigned patients, 311 contributed data for the primary outcome. Among those randomly assigned to the video group, assent to ICD implantation was 58.6% compared with 59.4% in the usual care group (difference, −0.8 percentage point [95% CI, −13.2 to 11.1 percentage points]). Compared with usual care, participants in the video group had a higher mean knowledge score (difference, 0.7 [CI, 0.2 to 1.1]) and a similar decisional conflict score (difference, −2.6 [CI, −5.7 to 0.4]). The ICD implantation rate within 90 days was 65.7%, with no differences by intervention. Participants randomly assigned to the video group spent less time with their clinician than those in the usual care group (mean, 22.1 vs. 27.0 minutes; difference, −4.9 minutes [CI, −9.4 to −0.3 minutes]). Racial concordance between video and study participants did not affect study outcomes. Limitation: The Centers for Medicare & Medicaid Services implemented a requirement for shared decision making for ICD implantation during the study. Conclusion: A video-based decision support tool increased patient knowledge but did not increase assent to ICD implantation. Primary Funding Source: Patient-Centered Outcomes Research Institute. [ABSTRACT FROM AUTHOR]

Human adipose tissue is a rich source of mesenchymal stem cells (MSCs). Human adipose-derived stem cells (ADSCs) are first prepared by tissue digestion of lipoaspirate. The remaining constituent contains a mixture of ADSCs, other cell types and lysed fragments. We have developed a scalable microfluidic sorter cascade which enabled high-throughput and label-free enrichment of ADSCs prepared from tissue-digested human adipose samples to improve the quality of purified stem cell product. The continuous microfluidic sorter cascade was composed of spiral-shaped inertial and deterministic lateral displacement (DLD) sorters which separated cells based on size difference. The cell count characterization results showed >90% separation efficiency. We also demonstrated that the enriched ADSC sub-population by the microfluidic sorter cascade yielded 6× enhancement of expansion capacity in tissue culture. The incorporation of this microfluidic sorter cascade into ADSC preparation workflow facilitates the generation of transplantation-scale stem cell product. We anticipate our stem cell microfluidic sorter cascade will find a variety of research and clinical applications in tissue engineering and regeneration medicine. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.

Mutations in lamins cause premature aging syndromes in humans, including the Hutchinson-Gilford Progeria Syndrome (HGPS) and Atypical Werner Syndrome. It has been shown that HGPS cells in culture undergo age-dependent progressive changes in nuclear architecture. However, it is unknown whether similar changes in nuclear architecture occur during the normal aging process. We have observed that major changes of nuclear architecture accompany Caenorhabditis elegans aging. We found that the nuclear architecture in most nonneuronal cell types undergoes progressive and stochastic age-dependent alterations, such as changes of nuclear shape and loss of peripheral heterochromatin. Furthermore, we show that the rate of these alterations is influenced by the insulin/IGF-1 like signaling pathway and that reducing the level of lamin and lamin-associated LEM domain proteins leads to shortening of lifespan. Our work not only provides evidence for changes of nuclear architecture during the normal aging process of a multicellular organism, but also suggests that HGPS is likely a result of acceleration of the normal aging process. Because the nucleus is vital for many cellular functions, our studies raise the possibility that the nucleus is a prominent focal point for regulating aging. lamin | LEM domain | nuclear envelope | nuclear lamina

Objective: Intrapleural fibrinolytic enzymes have been used for over 60 years in the treatment of complicated pleural effusions to lyse loculations and promote resolution. Despite this extensive history of use, however, little is known about complications that may arise with the use of this therapy. Here we discuss a patient with chronic renal failure on hemodialysis who developed an intrapleural hemorrhage after the administration of intrapleural tPA to treat a complicated parapneumonic effusion. A review of the literature examines the efficacy and safety of this therapy, focusing on bleeding complications. Specific attention is paid to patients who have underlying coagulopathies or who are receiving anticoagulation. Data sources: A review of the literature, as indexed in PubMed, was undertaken using the following search terms in combination: tPA, pleural effusion, complications of thrombolytics, and intrapleural hemorrhage. The search was inclusive of patients under the age of 18, but was limited by English language and human subjects. Study selection/data extraction: All relevant articles identified during the search were reviewed. Those studies that reported on bleeding complications, or lack thereof, were included in this review. Limitations of each article are noted in the text. Conclusions: Multiple studies, including a 2000 ACP consensus statement and a 2008 Cochrane review, indicate the need for further investigations to evaluate the safety and efficacy of intrapleural thrombolytics for the treatment of complicated pleural effusions and empyemas. Limited studies specifically address bleeding complications, especially in subpopulations of patients receiving concurrent anticoagulant therapy.