Because trypsin-like serine proteases have a major role in the truncation of CCL23 in NPs and inhibitors of neutrophil elastase (SSR69071) and matrix metalloproteinases (MMPs; marimastat), which are ...known to cleave CCL23,8,9 did not block the truncation (Fig 1, C), we focused on the mast cell trypsin-like serine protease tryptase. Importantly, the CCR1 antagonist CCX8960 completely blocked NP-treated CCL23-dependent but not CCL2 (a CCR2 ligand)-dependent migration of THP-1 cells, indicating that truncation of CCL23 by NP extracts results in increased CCR1-dependent migration of THP-1 cells (see Fig E3, B). Because previously known active truncated forms of CCL23 are formed by N-terminal truncations, we initially assessed N-terminal protein sequences.
Hyaluronidases in Human Diseases Kaul, Aditya; Short, Walker D; Wang, Xinyi ...
International journal of molecular sciences,
03/2021, Letnik:
22, Številka:
6
Journal Article
Recenzirano
Odprti dostop
With the burgeoning interest in hyaluronic acid (HA) in recent years, hyaluronidases (HYALs) have come to light for their role in regulating catabolism of HA and its molecular weight (MW) ...distribution in various tissues. Of the six hyaluronidase-like gene sequences in the human genome,
and
are of particular significance because they are the primary hyaluronidases active in human somatic tissue. Perhaps more importantly, for the sake of this review, they cleave anti-inflammatory and anti-fibrotic high-molecular-weight HA into pro-inflammatory and pro-fibrotic oligosaccharides. With this, HYALs regulate HA degradation and thus the development and progression of various diseases. Given the dearth of literature focusing specifically on HYALs in the past decade, this review seeks to expound their role in human diseases of the skin, heart, kidneys, and more. The review will delve into the molecular mechanisms and pathways of HYALs and discuss current and potential future therapeutic benefits of HYALs as a clinical treatment.
Preparing a grant proposal is no small feat, especially for research (R-series) grants from the National Institutes of Health. The National Institutes of Health is the largest public funder of ...biomedical research in the world, and as such, procuring a research grant from the National Institutes of Health is one of the ultimate benchmarks of success for a surgeon–scientist. Most investigators are familiar with the page limits for most R-series grants (12 pages for an R01 and 6 pages for an R21), with the addition of a single page allotted for the specific aims. Interestingly, despite the usual focus on the aforementioned research section, the rest of the application can routinely consist of an additional 100 to 150 pages, which means that pages allotted for the specific aims and research strategy represent only 10% of the complete application package. For busy surgeons, it is this abundance of ancillary documentation that can make preparing a research grant particularly onerous. Fortunately, for some, support exists within the department to help prepare much of this documentation by drawing from previous sources, templates, and boilerplate language that has been developed. Although these resources can significantly reduce the burden on individual investigators, there is a danger of leaning on generalized templates that can dilute the message of the overall grant proposal and introduce extraneous or incorrect information that can ultimately impact the cohesiveness and ultimately the competitiveness of the grant. The focus of this article is to educate surgeon–scientists regarding the purpose and importance of the ancillary information required for National Institutes of Health research grants and how to make the most of institutional resources while tailoring these materials to create a cohesive, competitive grant application.
Fibrosis is the endpoint of chronic disease in multiple organs, including the skin, heart, lungs, intestine, liver, and kidneys. Pathologic accumulation of fibrotic tissue results in a loss of ...structural integrity and function, with resultant increases in morbidity and mortality. Understanding the pathways governing fibrosis and identifying therapeutic targets within those pathways is necessary to develop novel antifibrotic therapies for fibrotic disease.
Given the connection between inflammation and fibrogenesis, Interleukin-10 (IL-10) has been a focus of potential antifibrotic therapies because of its well-known role as an anti-inflammatory mediator. Despite the apparent dissimilarity of diseases associated with fibrotic progression, pathways involving IL-10 appear to be a conserved molecular theme. More recently, many groups have worked to develop novel delivery tools for recombinant IL-10, such as hydrogels, and cell-based therapies, such as
activated macrophages, to directly or indirectly modulate IL-10 signaling.
Some efforts in this area, however, have been stymied by IL-10's pleiotropic and sometimes conflicting effects. A deeper, contextual understanding of IL-10 signaling and its interaction with effector cells, particularly immune cells, will be critical to future studies in the field.
IL-10 is clearly a gatekeeper of fibrotic/antifibrotic signaling. The development of novel therapeutics and cell-based therapies that capitalize on targets within the IL-10 signaling pathway could have far-reaching implications for patients suffering from the consequences of organ fibrosis.
The widespread use of high-spatial-resolution cross-sectional imaging has led to an increase in detection of incidental pancreatic cystic lesions. These lesions are a diverse group, ranging from ...indolent and premalignant lesions to invasive cancers. The diagnosis of several of these lesions can be suggested on the basis of their imaging appearance, while many other lesions require follow-up imaging and/or aspiration. The smaller cystic lesions, often branch-duct intraductal papillary mucinous neoplasms, have overlapping imaging characteristics that make diagnostic assessment of the natural history and malignancy risk confusing. Expert panels have developed societal guidelines, based on a consensus, for surveillance of these lesions. However, these guidelines are often inconsistent and are constantly evolving as additional scientific data are accumulated. Identification of features associated with increased risk of malignancy is important for proper management. The concept of field defect, whereby pancreatic adenocarcinoma develops at a site different from the site of the pancreatic cyst, adds to the complexity of screening guidelines. As a result of the differences in guidelines, key stakeholders (eg, radiologists, gastroenterologists, and surgeons) must review and come to a consensus regarding which guideline, or combination of guidelines, to follow at their individual institutions. Standardized reporting and macros are helpful for ensuring the uniformity of interpretations. Radiologists play a critical role in the detection and characterization of pancreatic cystic lesions, in the follow-up recommendations for these lesions, and in the detection of associated cancer.
RSNA, 2021.
Over the years, hyaluronic acid (HA) has emerged as an important molecule in nephrological and urological studies involving extracellular matrix (ECM) organization, inflammation, tissue regeneration, ...and viral sensing. During this time, many have noted the perplexing double-edged nature of the molecule, at times promoting pro-fibrotic events and at other times promoting anti-fibrotic events. Different molecular weights of HA can be attributed to these disparities, though most studies have yet to focus on this subtlety. With regard to the kidney, HA is induced in the initial response phase of injury and is subsequently decreased during disease progression of AKI, CKD, and diabetic nephropathy. These and other kidney diseases force patients, particularly pediatric patients, to face dialysis, surgical procedures, and ultimately, transplant. To summarize the current literature for researchers and pediatric nephrologists, this review aims to expound HA and elucidate its paradoxical effects in multiple kidney diseases using studies that emphasize HA molecular weight when available.
The natural history of extremity amniotic band syndrome (ABS) is a progression to deformity or amputation. Fetoscopic laser release of amniotic bands in extremity ABS offers the potential to prevent ...limb amputation. The authors report on 2 patients with isolated extremity ABS who underwent fetoscopic release. Both patients had isolated extremity ABS with compromised extremity perfusion and no other significant structural abnormality diagnosed sonographically. The first patient underwent fetoscopic release of bands of the left wrist, and the second patient underwent lysis of bands around the right wrist and an unsuspected band around the right lower extremity. Both patients had restoration of blood flow by color Doppler to the affected extremity. There were no perioperative complications. In select patients with isolated extremity ABS, early fetoscopic release may prevent amputation and allow improved limb development.
Surgeon-scientists are an essential component of the field of academic surgery, contributing to the fundamental understanding of disease and the discovery of innovative therapies. Despite this ...recognized value, the current landscape of academic medicine presents significant barriers to establishing and maintaining a successful career as a surgeon performing basic/translational research. Our objective is to define these barriers to academic success for surgeons, and to provide a consensus strategy for optimizing the chances of success.
There is a significant decline in the proportion of academic surgeons who are pursuing basic science/translational research, which represents a potential threat to the very identify of the translational surgeon-scientist.
Based on published literature and expert opinion, the Basic Science Committee of the Society of University of Surgeons prepared this roadmap to encourage and guide the next generation of surgeon-scientists as they embark on their academic careers.
This roadmap highlights key elements to consider in choosing an initial job and the importance of identifying a team of committed mentors. Expectations and guidelines for the first several years in practice are offered.
With guidance and mentorship, aspiring surgeonscientists can overcome the challenges inherent in choosing this career path and sustain the important legacy of those before them.
To describe development of a two-port fetoscopic technique for spina bifida repair in the exteriorized, carbon dioxide-filled uterus and report early results of two cohorts of patients: the first 15 ...treated with an iterative technique and the latter 13 with a standardized technique.
This was a retrospective cohort study (2014-2016). All patients met Management of Myelomeningocele Study selection criteria. The intraoperative approach was iterative in the first 15 patients and was then standardized. Obstetric, maternal, fetal, and early neonatal outcomes were compared. Standard parametric and nonparametric tests were used as appropriate.
Data for 28 patients (22 endoscopic only, four hybrid, two abandoned) are reported, but only those with a complete fetoscopic repair were analyzed (iterative technique n=10 compared with standardized technique n=12). Maternal demographics and gestational age (median range) at fetal surgery (25.4 22.9-25.9 compared with 24.8 24-25.6 weeks) were similar, but delivery occurred at 35.9 (26-39) weeks of gestation with the iterative technique compared with 39 (35.9-40) weeks of gestation with the standardized technique (P<.01). Duration of surgery (267 107-434 compared with 246 206-333 minutes), complication rates, preterm prelabor rupture of membranes rates (4/12 33% compared with 1/10 10%), and vaginal delivery rates (5/12 42% compared with 6/10 60%) were not statistically different in the iterative and standardized techniques, respectively. In 6 of 12 (50%) compared with 1 of 10 (10%), respectively (P=.07), there was leakage of cerebrospinal fluid from the repair site at birth. Management of Myelomeningocele Study criteria for hydrocephalus-death at discharge were met in 9 of 12 (75%) and 3 of 10 (30%), respectively, and 7 of 12 (58%) compared with 2 of 10 (20%) have been treated for hydrocephalus to date. These latter differences were not statistically significant.
Fetoscopic open neural tube defect repair does not appear to increase maternal-fetal complications as compared with repair by hysterotomy, allows for vaginal delivery, and may reduce long-term maternal risks.
ClinicalTrials.gov, https://clinicaltrials.gov, NCT02230072.
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