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51.
The advent of precision medicine has changed the landscape of oncologic biomarkers, drug discovery, drug development, and, more importantly, outcomes for patients with cancer. Precision oncology entails the genomic profiling of tumors to detect actionable aberrations. The advances in clinical next-generation sequencing from both tumor tissue and liquid biopsy and availability of targeted therapies has rapidly entered mainstream clinical practice. In this review, recent major developments in precision oncology that have affected outcomes for patients with cancer are discussed. Rapid clinical development was seen of targeted agents across various mutational profiles such as KRASG12C (which was considered “undruggable” for almost 4 decades), Exon 20 insertions, and RET mutations. Approaches to precision chemotherapy delivery by the introduction of antibody drug conjugates in the armamentarium against lung cancer has been appreciated. 相似文献
52.
Emily H. Steen Walker D. Short Hui Li Umang M. Parikh Alexander Blum Natalie Templeman Nadine Nagy Paul L. Bollyky Sundeep G. Keswani Swathi Balaji 《Drug delivery》2021,28(1):422
Hyaluronan (HA) is abundant in the skin; while HA can be synthesized by the synthases (HAS1-3), HAS2 is the leading contributor. Dysregulation and accumulation of HA is implicated in the pathogenesis of diseases such as keloid scarring, lymphedema and metastatic melanoma. To understand how HA synthesis contributes to skin physiology, and pathologic and fibrotic disorders, we propose the development of skin-specific HA inhibition model, which tests an optimal delivery system of topical 4-methylumbelliferone (4-MU).A design-of-experiments (DOE) approach was employed to develop an optimal 4-MU skin-delivery formulation comprising propylene glycol, ethanol, and water, topically applied to dorsal skin in male and female C57BL/6J wildtype mice to determine the effect on HAS gene expression and HA inhibition. Serum and skin samples were analyzed for HA content along with analysis of expression of HAS1-3, hyaluronidases (HYAL 1-2), and KIAA1199.Using results from DOE and response surface methodology with genetic algorithm optimization, we developed an optimal topical 4-MU formulation to result in ∼70% reduction of HA in dorsal skin, with validation demonstrating ∼50% reduction in HA in dorsal skin. 4-MU topical application resulted in significant decrease in skin HAS2 expression in female mice only. Histology showed thicker dermis in male mice, whereas female mice had thinner dermal layer with more adiposity; and staining for HA-binding protein showed that topical 4-MU resulted in breakdown in HA.Our data suggest a topical 4-MU formulation-based dermal HA inhibition model that would enable elucidating the skin-specific effects of HA in normal and pathologic states. 相似文献
53.
Chirag K. Shah Aakash Keswani Ben D. Boodaie Dong-Han Yao Karl M. Koenig Calin S. Moucha 《The Journal of arthroplasty》2017,32(1):246-251
Background
This study aimed at assessing short-term risk of serious cardiac events after elective total joint arthroplasty (TJA) as compared to a less-invasive procedure, knee arthroscopy (KA).Methods
Patients who underwent elective primary total hip arthroplasty (THA), total knee arthroplasty (TKA), or KA from 2011 to 2014 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. A 1:1 propensity matching was used to generate 2 control cohorts of KA patients with similar characteristics. Bivariate and multivariate analyses were assessed using perioperative variables.Results
A total of 24,203 THA, 21,740 TKA, and 45,943 KA patients were included. Bivariate analysis revealed significantly higher rates of serious 30-day cardiac events (myocardial infarction or cardiac arrest) among THA (0.15% vs 0.05%, P < .001) and TKA patients (0.14% vs 0.05%, P < .03) vs KA controls. In multivariate analysis controlling for patient characteristics and comorbidities, THA and TKA were associated with a 2.61 and 1.98 times odds of serious 30-day cardiac events as compared to controls (P ≤ .03 for both). Additional independent predictors of serious 30-day cardiac events included age, smoking, cardiac disease, and American Society of Anesthesiologists class 3/4. In the THA and TKA cohorts, serious cardiac events occurred within the first 3 days postoperation compared to 4 days in controls.Conclusion
After controlling for patient characteristics and comorbidities, TJA increased the short-term risk of serious cardiac event compared to a less-invasive procedure. This information better quantifies the risk differential for patients considering surgery as they engage in shared decision making with their providers. In addition, our data may have an impact on perioperative management of antithrombotic medications used in patients with cardiac disease. The median time in days to serious cardiac event was 2 in THA and 3 in TKA vs 4 in KA, which may have implications in postoperative monitoring of patients after surgery. 相似文献54.
Anne-Laurence Blanc Tarun Keswani Olivier Gorgette Antonio Bandeira Bernard Malissen Pierre-André Cazenave Sylviane Pied 《Infection and immunity》2016,84(1):329-338
The role of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4+ T cells in an attenuated model of Plasmodium berghei ANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6) P. berghei ANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4+ T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4+ T cell response to P. berghei ANKA infection in vivo in both CM-susceptible (B6) and CM-resistant (B6-CD4−/−) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional during P. berghei ANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria. 相似文献
55.
Aakash Shetty Ziv Gan-Or Setareh Ashtiani Jennifer A. Ruskey Bart van de Warrenburg Tessa Wassenberg Erik-Jan Kamsteeg Guy A. Rouleau Oksana Suchowersky 《European journal of medical genetics》2019,62(12):103605
Aims and objectiveTo characterize the phenotype of CAPN1 (SPG76) mutations in patients diagnosed with hereditary spastic paraplegia (HSP).BackgroundThe CAPN1 gene, located on chromosome 11q13.1, is a protein-coding gene involved in neuronal plasticity, migration, microtubular regulation and cerebellar development. Several families with CAPN1 mutations have recently been reported to present with autosomal recessive (AR) HSP and/or ataxia.MethodPatients with HSP were identified through neurological and genetic clinics with detailed phenotyping. Whole exome sequencing revealed novel pathogenic CAPN1 mutations in four patients from 3 families.ResultsAffected families were of Turkish, Japanese, and Punjabi descent and all were consanguineous. Onset of spastic paraplegia in the four patients was between 20 and 37 years. Two also had mild ataxia. Three different novel, homozygous mutations in CAPN1 were found: c.2118+1G > T, c.397C > T, c.843+1G > C. The patient with the earliest onset also manifested profound muscle weakness, likely related to a second homozygous mutation in DYSF (dysferlinopathy).ConclusionsThe phenotype of AR CAPN1 mutations appears to be spastic paraplegia with or without ataxia; onset is most commonly in adulthood. Eye movement abnormalities, skeletal defects, peripheral neuropathy and amyotrophy can sometimes be seen. Occasionally, patients can present with ataxia, illustrating the genotypic and phenotypic overlap between HSP and spastic ataxia. With the advent of exome sequencing, mutations in more than one gene can be identified, which may contribute to the phenotypic variation, even within a family. 相似文献
56.
Analysis of 5 patients with gallbladder tuberculosis
who had open cholecystectomy and review of
literature have shown that, although still rare it presents
as a part of systemic miliary tuberculosis,
abdominal tuberculosis, isolated gallbladder tuberculosis
and as acalculus cholecystitis in anergic
patients. There are no pathognomonic signs, the
diagnosis depends on suspicion of tuberculosis, peroperative
findings and histological examination. 相似文献
57.
58.
Aakash Deep Sandeep Jain Prabodh Chander Sharma Priyanka Phogat Manav Malhotra 《Medicinal chemistry research》2012,21(8):1652-1659
A series of novel N-[5-(arylidene)-2-(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide derivatives was synthesized and evaluated for analgesic and anti-inflammatory activity. In this study, biphenyl-4-carboxylic acid hydrazide was converted to the corresponding aryl hydrazones using aryl aldehydes in the presence of catalytic amount of glacial acetic acid. The aryl hydrazones on reaction with thioglycolic acid in the presence of anhydrous zinc chloride yielded N-[2-(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide which further on reaction with aromatic aldehydes in the presence of anhydrous sodium acetate and glacial acetic acid furnished the title compounds. All compound exhibited anti-inflammatory activity at the dose 10?mg/kg. The structures of all these newly synthesized compounds were confirmed by their elemental analyses (C, H, N) and spectral data (IR and 1H NMR). 相似文献
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