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Klotho is an aging-suppressor gene. Klotho gene deficiency causes heart failure in Klotho-hypomorphic mutant (KL (-/-)) mice. RNA-seq and western blot analysis showed that adenylyl cyclase type IV (AC4) mRNA and protein expression was largely decreased in cardiomyocytes of KL (-/-) mice. The objective of this study was to investigate whether in vivo cardiac-specific expression of AC4 gene protects against Klotho deficiency-induced heart failure. Interestingly, in vivo AAV-based cardiac-specific AC4 gene expression increased left ventricular fractional shortening, ejection fraction, stroke volume, and left ventricular end-diastolic volume in KL (-/-) mice, suggesting that cardiac-specific AC4 gene expression improves Klotho deficiency-induced heart dysfunction. Cardiac-specific AC4 gene expression also decreased Klotho deficiency-induced cardiac hypertrophy. Cardiac-specific AC4 gene expression alleviated Klotho deficiency-induced cardiac fibrosis and calcification. Furthermore, cardiac-specific AC4 gene expression attenuated mitochondrial dysfunction, superoxide accumulation and cardiomyocyte apoptotic cell death. Thus, downregulation of AC4 may contribute to Klotho deficiency-induced heart failure. Mechanistically, AAV2/9-αMHC-AC4 increased cardiomyocytic cAMP levels and thus regulated the PKA-PLN-SERCA2 signal pathway, which is critical in modulating calcium flux and mitochondrial function. In conclusion, cardiac-specific AC4 gene expression protects against Klotho deficiency-induced heart failure through increasing cardiomyocytic cAMP levels, which alleviates cAMP-dependent mitochondrial dysfunction, superoxide accumulation and apoptotic cell death. AC4 regulates superoxide levels via the cAMP-PKA pathway. AC4 could be a potential therapeutic target for heart failure associated with Klotho deficiency. Heart failure is the major cause of mortality in patients with chronic kidney disease (CKD). A decrease in Klotho levels is linked to CKD.

Shirley V Wang, Sebastian Schneeweiss Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USACorrespondence: Shirley V Wang, Brigham and Women’s Hospital, Harvard Medical School, 1620 Tremont St, Suite 303, Boston, MA, 02120, USA, Tel +1 617-525-8376, Email Swang1@bwh.harvard.eduBackground: There is growing interest in using evidence generated from clinical practice data to support regulatory, coverage and other healthcare decision-making. A graphical framework for depicting longitudinal study designs to mitigate this barrier was introduced and has found wide acceptance. We sought to enhance the framework to contain information that helps readers assess the appropriateness of the source data in which the study design was applied.Methods: For the enhanced graphical framework, we added a simple visualization of data type and observability to capture differences between electronic health record (EHR) and other registry data that may have limited data continuity and insurance claims data that have enrollment files.Results: We illustrate the revised graphical framework with 2 example studies conducted using different data sources, including administrative claims only, EHR only, linked claims and EHR, as well as specialty community based EHRs with and without external linkages.Conclusion: The enhanced visualization framework is important because evaluation of study validity needs to consider the triad of study question, design, and data together. Any given data source or study design may be appropriate for some questions but not others.Keywords: study design, real world evidence, real world data, visualization, methods, bias

Purpose Muscle invasive bladder cancer surgical management has been historically a radical cystoprostatectomy in males and an anterior exenteration in females. Uterine, ovarian, and vaginal preservation are utilized, but raise concerns regarding risk to oncologic control, especially in variant histopathology or advanced stage. Materials and Methods A retrospective single institutional analysis identified radical cystectomies performed in women, including those with variant histology, which were defined as reproductive organ sparing (uterine, vaginal, and ovary sparing) or non-organ sparing. The Kaplan-Meier method was used for recurrence-free (RFS) cancer specific survival (CSS) and overall (OS) survival in patients with advanced disease. Results From 2000 to 2020, 289 women were identified, 188 underwent reproductive organ-sparing cystectomy. No statistical differences were noted for clinical parameters or presence of variant histology for organ-sparing (ROS) and non-organ sparing (non-ROS). Positive margin rates did not differ for ROS and non-ROS; 4.3% vs 7.9%, p=0.19, respectively. Median RFS was not statistically significantly different for ROS vs non-ROS (26.1 vs 15.3 months) p=0.937 HR 1.024. CSS was not statistically different for ROS vs non-ROS (36.3 vs 28.6 months), p=0.755 HR 0.9. OS was not statistically different for ROS vs non-ROS (25.8 v 23.8 months), p=0.5 HR=1.178. Variant histology did not change survival (HR 1.1, p=0.643). Conclusions In this analysis, ROS in women with advanced disease did not increase positive margin rates or decrease RFS, CSS, or OS compared to non-ROS. Variant histology did not decrease survival odds. Based on preoperative assessment and intraoperative findings, ROS in patients with variant histology and advanced disease should be considered.

CDH17 and TRAILR2 protein expression and their correlation with BI 905711 minPOC in CRC cell lines.

Supplementary Material and Methods

S1: Evaluation of CDH17 and TRAILR2 IHC staining in hepatic metastases of colorectal cancer -S2:BI 905711 kinetic and steady-state measurements -S3: CDH17 and TRAILR2 mean fluorescence intensity, antibody binding capacity and BI 905711 / TAS266' minPOC in 24 CRC cell lines -S4: Intergroup comparison of gross pathology observations in Cynomolgus Monkey small intestine, large intestine and pancreas

Activation of TRAILR2 has emerged as an important therapeutic concept in cancer treatment. TRAILR2 agonistic molecules have only had limited clinical success, to date, due either to lack of efficacy or hepatotoxicity. BI 905711 is a novel tetravalent bispecific antibody targeting both TRAILR2 and CDH17 and represents a novel liver-sparing TRAILR2 agonist specifically designed to overcome the disadvantages of previous strategies. Here, we show that BI 905711 effectively triggered apoptosis in a broad panel of CDH17-positive colorectal cancer tumor cells in vitro. Efficient induction of apoptosis was dependent on the presence of CDH17, as exemplified by the greater than 1,000-fold drop in potency in CDH17-negative cells. BI 905711 demonstrated single-agent tumor regressions in CDH17-positive colorectal cancer xenografts, an effect that was further enhanced upon combination with irinotecan. Antitumor efficacy correlated with induction of caspase activation, as measured in both the tumor and plasma. Effective tumor growth inhibition was further demonstrated across a series of different colorectal cancer PDX models. BI 905711 induced apoptosis in both a cis (same cell) as well as trans (adjacent cell) fashion, translating into significant antitumor activity even in xenograft models with heterogeneous CDH17 expression. In summary, we demonstrate that BI 905711 has potent and selective antitumor activity in CDH17-positive colorectal cancer models both in vitro and in vivo. The high prevalence of over 95% CDH17-positive tumors in patients with colorectal cancer, the molecule preclinical efficacy together with its potential for a favorable safety profile, support the ongoing BI 905711 phase I trial in colorectal cancer and additional CDH17-positive cancer types (NCT04137289).

PurposePast research on team conflict has often conceptualized it as a collective phenomenon whereby members of the same team perceive similar levels of conflict. However, similarity in perspectives can more often be the exception than the norm. As such, the purpose of this paper is to examine the effects of relationship conflict (RC) asymmetry on information elaboration and team performance. Additionally, I introduce a new construct: perception of team RC asymmetry and propose that it strengthens the positive effects of RC asymmetry.Design/methodology/approachA total of 181 MBA students comprising 52 teams participated in the research. Students worked together for the duration of the semester to complete a team project that comprised 45% of their final grade. Surveys were administered at three points in time with performance measured at the end and other focal variables measured at the midpoint. Regression analyses and the PROCESS macro were used to examine a first stage moderated mediation model.FindingsResults showed that RC asymmetry increased elaboration, which, in turn, improved team performance. The link between RC asymmetry and elaboration was moderated by the perception of team RC asymmetry.Originality/valueThe present research shows that to have a fuller understanding of RC one must consider the level of dispersion experienced by team members. Taking this approach has uncovered a way in which RC can actually benefit teams instead of lead to destructive outcomes.

Klotho is an aging-suppressor gene. The purpose of this study was to determine whether deletion of the klotho gene in kidneys causes aortic aneurysm (AA) and investigate the underlying mechanisms. Klotho-floxed alleles and tamoxifen-inducible kidney-specific CreER T2 mice were crossed to generate KL flox/flox (floxed Klotho); KspCadCreER T2 mice. Tamoxifen injection induced kidney-specific deletion of klotho gene, which led to severe hyperphosphatemia and thoracic and abdominal AA formation in mice on a normal diet. The architectural destruction of the aortic wall in the first 7 days post-Klotho ablation was manifested by overwhelming aortic cell death and calcification, massive MMP (metalloproteinase) 2/9 secretion, elastin degradation, and limited collagen deposition, resulting in aortic wall thinning and AA formation. The adverse reparative remodeling of aortas in the following 7 days exhibited robust fibroblast proliferation and osteogenic differentiation and redundant collagen deposition, further promoting aortic wall thickening and AA progression. These changes were accompanied by aortic macrophage infiltration and osteoclast transition. Interestingly, low-phosphorus diet normalized serum phosphate levels, prevented vascular cell apoptosis and osteogenic differentiation, and consequently retained aortic structure in Klotho-deficient mice. Mechanistically, excessive inorganic phosphate and calcium promoted vascular cell death, osteogenic differentiation, and MMP2/9 secretion ex vivo and in vitro. We found that NF-κB (nuclear factor-kappa B) mediated phosphate-induced MMP2 generation in human aortic smooth muscle cells in vitro. These findings provide the first evidence for a causative role of Klotho deficiency–induced hyperphosphatemia in AA development. Interventional control of dietary phosphorus may be a new preventive and therapeutic strategy for AA.

This paper covers the impact and trend of COVID-19 on Chinese tourism industry, specifically about tourist attraction, tour company, and accommodation. The whole tourism industry is facing a huge loss, and expectedly it can fully recover at the end of the third quarter. Chinese governments set up the tourism support policies to help with those companies, and many of them have already taken actions to provide things online to save their loss of income.

To investigate the intrinsic mechanism that causes the darkening of liquid foundations.A total of 36 commercial liquid foundations were firstly studied for preliminary screening of influencing factors. A basic liquid foundation was developed for controlling variables to study the influence of each single factor. These samples were evenly spread on the standard opacity charts with the thickness of 100 μm and applied onto human inner forearm skin with the dosage of 2 mg/cmOne hundred twenty-minute ΔE of all commercial foundations was highly negatively correlated with their 120-min ΔITA° (RThe process of the discoloration of liquid foundation is accompanied by the decrease of ITA° and manifested as darkening. The volatilization rate of the product and the coating method of the pigments used in the formula can noticeably affect the darkening of the liquid foundation.

Organic isothiocyanates (ITCs) are a class of anticancer agents which naturally result from the enzymatic degradation of glucosinolates produced by Brassica vegetables. Previous studies have demonstrated that the structure of an ITC impacts its potency and mode(s) of anticancer properties, opening the way to preparation and evaluation of synthetic, non-natural ITC analogues. This study describes the preparation of a library of 79 non-natural ITC analogues intended to probe further structure-activity relationships for aryl ITCs and second-generation, functionalized biaryl ITC variants. ITC candidates were subjected to bifurcated evaluation of antiproliferative and antioxidant response element (ARE)-induction capacity against human MCF-7 cells. The results of this study led to the identification of (1) several key structure-activity relationships and (2) lead ITCs demonstrating potent antiproliferative properties.

The alignment of semiconducting single-walled carbon nanotubes (SWCNTs) can contribute to faster, lighter, and more efficient transistors, but the process needs optimization for mass production. We have previously described an alignment relay technique (ART) to facilitate the simultaneous orientation, diameter, and length of SWCNTs when placed on a substrate surface. To expand ART's utility, compatibility with a broad range of surfaces needs to be achieved. Here, we report on the ineffectiveness of ART to work on Al2O3 and we suggest that the molecular tweezer requires a carboxylic acid in order to bind to alumina. We tested the new carboxylic acid moiety with two liquid crystal solvents to improve alignment on silica, as well as on atomic layer deposited alumina and alpha-Al2O3 substrates. We show that the carboxylic acid modification increased the SWCNTs' alignment on the Al2O3 surface by 20% in relation to the first-generation ART molecule. We used quantum chemical calculations to explore nanotube interactions with the iptycene molecular tweezers. Our calculations indicate a significant preference for nanotube orientations in the binding pocket of the iptycene derivative. Our work optimizes the applicability of ART towards the deposition on a variety of substrates for electrical devices.

Background: CD166 is broadly expressed in normal epithelium and overexpressed in many types of malignancies, including breast cancer. Probody® therapeutic candidates are masked antibodies, conditionally activated by tumor-associated proteases, which restricts their activity to the tumor microenvironment and minimizes ‘off-tumor’ toxicity. CX-2009 is a conditionally activated humanized anti-CD166 monoclonal antibody conjugated to DM4 that showed clinical activity in ABC patients in a phase 1 study (Boni et al. Clin Cancer Res. 2022). This phase 2 study (NCT04596150) evaluates CX-2009 as monotherapy in patients with advanced HR+/HER2− BC (Arm A) and TNBC (Arm B), and in combination with pacmilimab (a conditionally activated PD-L1) in TNBC (Arm C). Methods: Key eligibility criteria for all cohorts include: ECOG 0-1, acceptable end-organ function, measurable disease, willingness to receive ocular prophylaxis for DM-4 related toxicity, and available tumor tissue for CD166 evaluation. Eligibility criteria for HR+ BC include: 2-4 prior regimens (excluding single-agent hormonal therapy with up to 2 prior cytotoxic regimens) and a prior CDK 4/6 inhibitor in the metastatic setting; eligibility criteria for TNBC include CD166 by IHC >1% by central assessment, 1-3 prior regimens in the metastatic setting and prior taxane. All patients initially received 7 mg/kg Q3W; the protocol was subsequently amended to enroll patients at 6 mg/kg Q3W. The primary endpoint was overall response rate (ORR) using RECIST v1.1 assessed by central review. Other key endpoints include ORR by investigator assessment, clinical benefit rate at 24 weeks (CBR24; defined as any response, confirmed or unconfirmed, or SD for 24 weeks), duration of response, and progression-free survival by investigator. Archival tumor specimens and blood samples were collected for correlative research including genomic analyses. Results: As of 13 May 2022, 60 patients were enrolled in Arm A (all patients started at 7 mg/kg); 52 were evaluable for efficacy by investigator. Median duration of follow-up was 29.1 weeks (range: 3.6-60.7). Median age was 60.5 years (36, 83); pts received a median of 3.5 (1, 6) prior treatments for ABC. CD166 H-Score > 200 was reported in 53.3% of patients. Arm A met the primary efficacy endpoint with a confirmed ORR by central radiology of 14.9% (n=47); by investigator, ORR was similar at 15.4% (n=52); an additional 9 patients (17.3%) had an unconfirmed response. CBR24 was 40.4%; using only confirmed responses, CBR24 was 23.1%. Median PFS was 11.4 weeks (95% CI 9.0, 13.9). Common treatment-related all-grade adverse events (TRAEs) included blurred vision (42%), nausea (35%), fatigue (35%), diarrhea (25%), peripheral neuropathy (27%), infusion-related reaction (23%) and decreased appetite (20%). Grade ≥3 ocular and neuropathic TRAEs were 15% and 10%, respectively. AEs resulting in treatment discontinuation (AEDC) were 25%. For Arm B and C, 55 and 10 patients were enrolled (the majority received a starting dose of 6 mg/kg). For Arm B, the futility boundary was crossed (ORR < 10%). Grade ≥3 ocular and neuropathic TRAEs and AEDC at 7 mg/kg in Arm B were similar to Arm A (11%, 11% and 21% respectively); whereas at 6 mg/kg, they were reduced at 3%, 0% and 0%, respectively. Biomarker data and correlation with outcomes will be presented. Conclusions: Praluzatamab ravtansine demonstrated single-agent activity in unselected heavily pretreated patients with HR+/HER2- ABC. Time to event analyses, such as PFS, were confounded by higher-than-expected toxicity at a starting dose of 7 mg/kg. The toxicity profile was generally consistent with a DM4 payload. The lower dose of 6 mg/kg appears to be better tolerated. Additional clinical studies in HR+ABC, incorporating a starting dose of 6 mg/kg and potentially including a biomarker strategy, are warranted. Citation Format: Kathy Miller, Sara Tolaney, Leisha A. Emens, Sung-Bae Kim, Erika Hamilton, Cristina Saura, Lucia Sanz, Valentina Boni, Filipa Lynce, Juan Miguel Cejalvo, Jennifer Crozier, Shirley Wang, Hirdesh Uppal, Alison L. Hannah, Sara Hurvitz. Preliminary results from a phase 2 study of praluzatamab ravtansine (CX-2009) in patients with advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-15.

To examine opioid use following Urological trauma. Increased opioid use is associated with inferior outcomes and risk of dependence, particularly in vulnerable populations. In contrast, multimodal analgesia following trauma allows decreased pain and readmission. Currently there is a paucity of data describing opioid usage following urological trauma. The purpose of this study was to assess utilization of opioids and multimodal pain regimens following urologic trauma.We retrospectively examined 116 patients hospitalized following urologic trauma from 2016-2021. Inpatient and discharge utilization of opioids, multimodal analgesia and length of stay were stratified by affected organ. Analyses were performed in STATA with p0.05 reaching significance.116 patients were assessed; 84 (72.4%) required surgery. In the first 10 days, bladder injuries incurred higher mean and median OMEQ than other urological injuries. In nearly all groups, OMEQ prescribed at discharge is less than average inpatient OMEQ. Eighty-six (74.1%) patients received at least 2 different opioid medications while inpatient. Those with a history of opioid use received a significantly higher OMEQ dose per day (p0.001). There were no significant differences between opioid prescribing patterns or average OMEQ dosages prescribed at discharge between those patients managed either surgically or non-operatively. Only 24 (20.7%) patients met the criteria for utilization of multimodal analgesia.Multimodal analgesia is severely underutilized following urological trauma. Combined with the development of opioid tolerance over long hospital stays, this creates an avenue for opioid misuse following discharge and provides an opportunity for improvement.

Aging is associated with compromised immune function and arterial remodeling and stiffness. The purpose of this study is to investigate whether in vivo AAV-based delivery of secreted Klotho (SKL) gene (AAV-SKL) improves aging- and senescence-associated immune dysfunction and arterial stiffness.Senescence-accelerated mice prone strain 1 (SAMP1, 10 months) and old mice (20 months) were used. Serum SKL levels, B-cell population and serum IgG levels were markedly decreased in SAMP1 and old mice. Rescue of downregulation of serum SKL levels by in vivo AAV2-based delivery of SKL gene (AAV-SKL) increased B-cell population and serum IgG levels and attenuated arterial stiffness in SAMP1 and old mice. Thus, Klotho deficiency may play a role in senescence- and aging-associated humoral immune dysfunction and arterial stiffness. Vascular infiltration of inflammatory cells and expression of TGFβ1, collagen 1, scleraxis, MMP-2 and MMP-9 were increased while the elastin level was decreased in aortas of SAMP1 and old mice which can be rescued by AAV-SKL. Interestingly, treatment with IgG effectively rescued arterial inflammation and remodeling and attenuated arterial stiffness and hypertension in aging mice. In cultured B-lymphoblast cells, we further showed that SKL regulates B-cell proliferation and maturation partly via the NFkB pathway.Aging-associated arterial stiffening may be largely attributed to downregulation of B-cell population and serum IgG levels. AAV-SKL attenuates arterial stiffness in aging mice partly via restoring B-cell population and serum IgG levels which attenuates aging-associated vascular inflammation and arterial remodeling.

A Disintegrin and Metalloproteinase 10 (ADAM10) is a member of the ADAM family of cell membrane-anchored proteins which processes and influences the functions of its substrates by in-/activating them or by liberating biologically active fragments. ADAM10 is primarily expressed in kidney epithelial cells. Thus, the objective of this study is to investigate whether ADAM10 is involved in the regulation and maintenance of normal kidney function. Tamoxifen-inducible kidney-specific cre (Ksp) and ADAM170-floxed mice were cross-bred for generating Ksp/ADAM10-floxed mice. Injection of tamoxifen initiated deletion of the ADAM10 gene and led to a significant reduction in ADAM10 protein expression in renal distal and proximal tubule cells. Notably, knockout of the ADAM10 gene largely decreased soluble Klotho levels in urine, indicating that ADAM10 is a critical enzyme in shedding Klotho. We found that renal sodium excretion was decreased in kidney-specific ADAM1 0 knockout mice (ADAM10 -/-), suggesting that ADMA10 deficiency results in an increase in Na reabsorption or Na retention. Urinary potassium output tended to increase in ADAM10 -/- mice although it did not reach a significant level. It is interesting that ADAM10 gene deficiency compromises renal tubular function leading to Na retention. Glomerular filtration rate (GFR) was dramatically decreased in ADAM10 -/- mice, indicating that ADAM10 deficiency impairs glomerular function. Interestingly, treatment with recombinant Klotho improved renal glomerular function. Therefore, ADAM10 gene knockout impairs kidney function likely via suppressing Klotho shedding.

Studies that generate real-world evidence on the effects of medical products through analysis of digital data collected in clinical practice provide key insights for regulators, payers, and other healthcare decision-makers. Ensuring reproducibility of such findings is fundamental to effective evidence-based decision-making. We reproduce results for 150 studies published in peer-reviewed journals using the same healthcare databases as original investigators and evaluate the completeness of reporting for 250. Original and reproduction effect sizes were positively correlated (Pearson’s correlation = 0.85), a strong relationship with some room for improvement. The median and interquartile range for the relative magnitude of effect (e.g., hazard ratiooriginal/hazard ratioreproduction) is 1.0 [0.9, 1.1], range [0.3, 2.1]. While the majority of results are closely reproduced, a subset are not. The latter can be explained by incomplete reporting and updated data. Greater methodological transparency aligned with new guidance may further improve reproducibility and validity assessment, thus facilitating evidence-based decision-making. Study registration number: EUPAS19636.

A 74-year-old man with a penile mass was diagnosed with sarcomatoid urothelial carcinoma. Further workup did not show any other lesions or metastases. He was treated with a total penectomy, bilateral inguinal lymph node dissection, and pelvic lymphadenectomy. Following surgery, he received six cycles of cisplatin and gemcitabine. Sarcomatoid carcinoma and carcinosarcoma of the urethra are rare; six prior cases have been reported in the literature, with this being the first urothelial with sarcomatoid component. Survival in patients with sarcomatoid carcinoma or carcinosarcoma of the urinary tract is poor, with the limited data supporting a multimodal approach to improve survival.

INTRODUCTION AND OBJECTIVE:Muscle invasive bladder cancer (MIBC) surgical management has been historically a radical cystoprostatectomy in males and an anterior exenteration in females. Uterine and...

The present article explores the effects of individual task conflict asymmetry—a member’s task conflict perception relative to others on the team—on peer ratings of that member’s effectiveness. In two studies of student teams, we find that individuals who perceive more conflict than their teammates are rated as more effective team members. This effect is explained by uncertainty experienced by the high task conflict perceiver, which acts as a catalyst for additional effort expansion toward team goals. By turning our attention to peer ratings of member effectiveness, we offer an optimistic side to individual task conflict asymmetry.

To perform well over time, teams must balance competing needs—the need to make quality decisions and the need to coordinate action. However, these elements are paradoxically related because the processes that improve one can inhibit the other. The present article examines the role of task accomplishment phases as moderating the value of cognitive structure on teams’ performance trajectory and end-state performance. Using student teams engaged in a business simulation, we find that heterogeneous task cognition is beneficial in the strategizing phase, but that this effect reverses during the implementation–adjustment phase when homogeneous task cognition becomes more useful. In addition, we examine action processes as a substitute for homogeneous task cognition during implementation–adjustment and propose that teams can overcome suboptimal cognitive configurations. We discuss the implications of our research in terms of what is important for team performance.

The senescence-accelerated mouse P1 (SAMP1) suffers from humoral immune deficiency, arterial stiffness and accelerated aging. In contrast, the microRNA-150 knockout (miR-150-KO) mice show enhanced humoral immune function including increased B cell population and elevated serum immunoglobulin levels and enjoy extended lifespan. The purpose of this study was to investigate whether transplantation of bone marrow cells (BMCs) from miR-150-KO mice affects immune deficiency and arterial stiffening in SAMP1 mice.Pulse wave velocity and blood pressure were increased significantly in SAMP1 mice (10 months), indicating arterial stiffening and hypertension. Interestingly, transplantation of BMCs from miR-150-KO mice significantly attenuated arterial stiffening and hypertension in SAMP1 mice within eight weeks. BMC transplantation from miR-150-KO mice partially rescued the downregulation of B lymphocytes, largely restored serum IgG and IgM levels, decreased inflammatory cytokine and chemokine expression, and attenuated macrophage and T cell infiltration in aortas in SAMP1 mice. BMC transplantation nearly abolished the upregulation of collagen 1, TGFβ1, Scleraxis, MMP-2 and MMP-9 expression and the downregulation of elastin levels in aortas in SAMP1 mice. FISH staining confirmed existence of the transplanted BMCs at end of the experiment. In cultured endothelial cells, IgG-deficient medium invoked upregulation of inflammatory cytokine/chemokine expression which can be rescued by treatment with IgG.Accelerated senescence caused arterial stiffening via impairing the humoral immune function in SAMP1 mice. BMC transplantation from miR-150-KO mice attenuated arterial matrix remodeling and stiffening and hypertension in SAMP1 mice partly via improving the humoral immune function which attenuates vascular inflammation.

Klotho is an aging-suppressor gene. The purpose of this study was to determine whether deletion of the klotho gene in kidneys causes aortic aneurysm (AA) and investigate the underlying mechanisms. Klotho-floxed alleles and tamoxifen-inducible kidney specific CreER(T2) mice were crossed to generate KL(flox/flox); KspCadCreER(T2) mice. Tamoxifen injection induced kidney-specific deletion of klotho gene which led to severe hyperphosphatemia and thoracic (T) and abdominal (A) AA formation in mice on a normal diet. The architectural destruction of the aortic wall in the first 7 days post Klotho ablation was manifested by overwhelming aortic cell death and calcification, massive metalloproteinase (MMP) 2/9 secretion, elastin degradation and limited collagen deposition, resulting in aortic wall thinning and AA formation. The adverse reparative remodeling of aortas in the following 7 days exhibited robust fibroblast proliferation and osteogenic differentiation and redundant collagen deposition, further promoting aortic wall thickening and AA progression. These changes were accompanied by aortic macrophage infiltration and osteoclast transition. Interestingly, low phosphorus diet normalized serum phosphate levels, prevented vascular cell apoptosis and osteogenic differentiation, and consequently retained aortic structure in Klotho-deficient mice. Mechanistically, excessive inorganic phosphate and calcium promoted vascular cell death, osteogenic differentiation and MMP2/9 secretion ex vivo and in vitro. We found that NF-kB mediated phosphate-induced MMP2 generation in human aortic smooth muscle cells in vitro. These findings provide the first evidence for a causative role of Klotho deficiency-induced hyperphosphatemia in AA development. Interventional control of dietary phosphorus may be a new preventive and therapeutic strategy for AA.

Rationale: Cardiac aging is an important contributing factor for heart failure, which affects a large population but remains poorly understood. Objective: The purpose of this study is to investigate whether Klotho plays a role in cardiac aging. Methods and Results: Heart function declined in old mice (24 months), as evidenced by decreases in fractional shortening, ejection fraction, and cardiac output. Heart size and weight, cardiomyocyte size, and cardiac fibrosis were increased in old mice, indicating that aging causes cardiac hypertrophy and remodeling. Circulating Klotho levels were dramatically decreased in old mice, which prompted us to investigate whether the Klotho decline may cause heart aging. We found that Klotho gene mutation (KL−/−) largely decreased serum klotho levels and impaired heart function. Interestingly, supplement of exogenous secreted Klotho prevented heart failure, hypertrophy, and remodeling in both old mice and KL (−/−) mice. Secreted Klotho treatment inhibited excessive cardiac oxidative stress, senescence and apoptosis in old mice and KL (−/−) mice. Serum phosphate levels in KL (−/−) mice were kept in the normal range, suggesting that Klotho deficiency-induced heart aging is independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed GR (glutathione reductase) expression and activity in the heart via inhibition of transcription factor Nrf2 (nuclear factor-erythroid 2 p45-related factor 2). Furthermore, cardiac-specific overexpression of GR prevented excessive oxidative stress, apoptosis, and heart failure in both old and KL (−/−) mice. Conclusions: Klotho deficiency causes cardiac aging via impairing the Nrf2-GR pathway. Supplement of exogenous secreted Klotho represents a promising therapeutic strategy for aging-associated cardiomyopathy and heart failure.

Objective Klotho is an aging-suppressor gene which leads to accelerated aging when disrupted. This study was designed to investigate whether glutathione reductase (GR), a critical intracellular antioxidant enzyme, is involved in the pathogenesis of kidney damages associated with accelerated aging in Klotho-haplodeficient (KL+/–) mice. Methods and Results Klotho-haplodeficient (KL+/–) mice and WT mice were used. We found that Klotho haplodeficiency impaired kidney function as evidenced by significant increases in plasma urea and creatinine and a decrease in urinary creatinine in KL+/– mice. The expression and activity of GR was decreased significantly in renal tubular epithelial cells of KL+/– mice, suggesting that Klotho deficiency downregulated GR. We constructed adeno-associated virus 2 (AAV2) carrying GR full-length cDNA (AAV-GR). Interestingly, in vivo AAV-GR delivery significantly improved Klotho deficiency-induced renal functional impairment and structural remodeling. Furthermore, in vivo expression of GR rescued the downregulation of the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, which subsequently diminished oxidative damages in kidneys, as evidenced by significant decreases in renal 4-HNE expression and urinary 8-isoprostane levels in KL+/- mice. Conclusion This study provides the first evidence that Klotho deficiency-induced kidney damage may be partly attributed to downregulation of GR expression. In vivo delivery of AAV-GR may be a promising therapeutic approach for aging-related kidney damage.

Unmanned Aerial Vehicles (UAVs) are becoming increasingly popular thanks to the multiplicity of operations in which they can be deployed such as surveillance, search and rescue, mapping, transportation, hobby and recreational activities. Although sensors like LIDARs and cameras are often present on such systems for motion planning to avoid obstacles, collisions can still occur in very dense and unstructured environments, especially if disturbances are present. In this work, we research techniques to recover UAVs after a collision has occurred. We note that the on-board sensors, especially the inertial sensor used to stabilize the UAV, run at a high frequencies obtaining hundreds of data points every second. At run-time, this can be leveraged at the moment of a collision to quickly detect and recover the system. Our approach considers knowledge of UAV system dynamics to predict the expected behavior of the vehicle under safe flight conditions and leverage such expectations together with inertial data to detect collisions rapidly (on the order of milliseconds). We also propose a potential field-based approach to map the collision and create the correct reactive maneuver to avoid the collided object and bring the system back to a stable and safe configuration. Experiments are executed using ROS on two micro-quadrotor UAV platforms having different dynamics and performances, while colliding with poles and walls positioned in different configurations. In our results, we are able to show that the UAVs are successfully able to detect and avoid a collision, while also providing a rigorous analysis of the conditions in which the system can recover from imminent collisions.