Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with iron-binding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules. In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 microg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngal-dependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment

Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and ‘tumor spread through air spaces’ were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk

Patents and heart valve surgery - I : mechanical valves

Valvular heart disease, inherited or acquired, affects more than 5 million Americans yearly. Whereas medical treatment is beneficial in the initial stages of valvular heart disease, surgical correction provides symptomatic relief and long-term survival benefits. Surgical options include either repair or replacement using mechanical or bio-prosthetic valves. Patient age and the post-operative need for anticoagulation therapy are major determinants of the choice between use of mechanical or bio-prosthetic valves. Since the first mechanical valves were made available several decades ago, the incorporation of increasingly sophisticated materials and methodologies has led to substantial improvements in the valve design, and has catalyzed a parallel increase in the amount of patents issued for these emerging technologies. In this paper, we have chronologically reviewed such patents, briefly discussed various challenges that mechanical heart valve implementation is faced with and finally reviewed some of the strategies employed to overcome such obstacles. An ideal prosthetic heart valve would comprehensively mimic the natural hemodynamics and physiology of the native heart valve. Additionally, such a valve would be easily implantable, associated with a minimal risk of thrombosis and thus need for anti-coagulation, and with a proven long-term durability. With cutting edge technological advancements in the recent times, the ongoing innovative and collaborative efforts of physicians, scientists, and engineers will not seize until an ideal mechanical heart valve becomes a reality

Combining stem cells and tissue engineering in cardiovascular repair - a step forward to derivation of novel implants with enhanced function and self-renewal characteristics

The use of stem and progenitor cells in cardiovascular therapy has been proposed as a feasible option to promote repair of tissue damage by ischemia, or to devise definitive artificial tissue replacements (valves, vessels, myocardium) to be surgically implanted in patients. Whereas in other medical branches such as dermatology and ophthalmology the use of ex vivo grown tissues is already accessible to a large degree, the use of bio-artificial implants in cardiovascular surgery is still marginal. This represents a major limitation in cardiovascular medicine at present. In fact, the limited durability and the lack of full compatibility of current implantable devices or tissues prevent a long-term resolution of symptoms and often require re-intervention thereby further increasing the economic burden of the cardiovascular disease. Stem cell technology can be of help to derive tissues with improved physiologic function and permanent durability. Specifically, the intrinsic ability of stem cells to produce tissue-specific "niches", where immature cells are perpetuated while differentiated progenitors are continuously produced, makes them an ideal resource for bioengineering approaches. Furthermore, recent advancements in biocompatible material science, designing of complex artificial scaffolds and generation of animal or human-derived natural substrates have made it feasible to have ex vivo reproduction of complex cell environment interactions - a process necessary to improve stem cells biological activity. This review focuses on current understanding of cardiovascular stem cell biology as well as tissue engineering and explores their interdisciplinary approach. By reviewing the relevant recent patents which have enabled this field to advance, it concentrates on various design substrates and scaffolds that grow stem cells in order to materialize the production of cardiovascular implants with enhanced functional and self-renewal characteristics

Conservative management of the pseudoaneurysms of ascending aortic graft: a case of spontaneous regression at follow-up

Pseudoaneurysms of thoracic aorta represent life-threatening complications of cardiac surgery. We present a case report of a patient who underwent urgent aortic valvular replacement with a biological prosthesis and ascending aortic replacement with graft interposition and developed postoperative ascending aortic pseudoaneurysms. The pseudoaneurysms did not increase in the postoperative stay and a conservative management was chosen. At follow-up, the two pseudoaneurysms had completely regressed. The therapeutic steps for aortic pseudoaneurysms should be tailored to the patient and even conservative management could be effective if selected after an evaluation of the clinical status of the patient

Patents and Heart Valve Surgery - III : Percutaneous Heart Valves

Advancements in technology for the treatment of valvularcardiac diseases seek to provide solutions for high risk patients in the form of percutaneous valve insertion for patients with complicated valvular disease not amenable to more traditional options. Within the last decade, cardiac valves designed for percutaneous insertion have emerged rapidly as a treatment option for valvular disease. This procedure serves as an alternative to open heart surgery, which is more invasive and requires longer ICU stay. Thus, the percutaneous valve insertion procedure has been used on older, frailer patients who are poor candidates for open heart surgery. Designs for percutaneous valve insertion systems have been in development for decades, but have only recently been approved by the FDA for use. Important considerations include stent design, valve design, balloon catheter design, and deployment method

Reduction ascending aortoplasty: midterm follow-up and predictors of redilatation

Background: Reduction ascending aortoplasty is an alternative procedure to the replacement of the ascending aorta in case of ascending aorta aneurysm without aortic root involvement. This study was designed to evaluate the midterm follow-up of aortoplasty and to determine predictors of redilatation. Methods: From January 1, 1998, to April 30, 2005, 68 patients with dilatation of the ascending aorta underwent unsupported reduction aortoplasty in combination with other cardiac procedures. All patients underwent associated surgical procedures. Sixty patients (88.2%) underwent associated aortic valve replacement. Cumulative follow-up time was 191.4 patient-years and was 100% complete. Median follow-up time was 2.5 years, and mean follow-up time was 2.9 (plus or minus) 1.7 years (range, 0.4 to 6.3 years). Results: The overall perioperative mortality rate was 1.5%. Overall survival estimates at 3 and 6 years were 93.3% (plus or minus) 4.5% and 89.3% (plus or minus) 5.9%, respectively. The actuarial freedom from cardiac-related death at 3 and 6 years was 100% and 95.7% (plus or minus) 4.3%, respectively. Ascending aorta redilatation occurred in 5 patients (7.5%). The actuarial freedom from redilatation at 3 and 6 years was 97.7% (plus or minus) 2.3% and 79.8% (plus or minus) 8.4%, respectively. The actuarial freedom from reoperation at 3 and 6 years was 100% and 86.3% (plus or minus) 7.5%, respectively. Only preoperative diameter was a significant predictor of redilatation using multivariate stepwise logistic regression analysis. Conclusions: Unsupported reduction aortoplasty is a safe and effective technique with low mortality, low morbidity, and rare late complications for selected chronic aneurysm of the ascending aorta with diameter less than 55 mm

Rates of cycling cells in cryopreserved valvular homograft : a preliminary study

Some investigators claim that the viability of cryopreserved human valvular homograft is necessary for the duration of implanted homograft. In this preliminary study, the percentage of cycling cells in cryopreserved valvular homografts was evaluated with the use of monoclonal Ki-67 antibody. Three human aortic valves were harvested from multiorgan donors and cryopreserved. Sections of 5 mm in thickness were stained with monoclonal Ki-67 antibody. The proportion of endothelial cells with Ki-67 positive nuclei was 1.80 0.20%. No differences in distribution were observed from basal to marginal sites. Few fibroblasts showed Ki-67-immunopositivity (0.10 0.06%) while the Ki-67 immunostaining was 0.80 +/- 0.20% in myocytes.Our preliminary study shows that cryopreserved valvular homograft cells are not only viable but they also have the potential to replicate. These data can lead to the hypothesis that valvular cells could actively replicate even after implantation, permitting cellular renewal and regeneration of extracellular matrix\u2019s components