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1.
Microalgal Target of Rapamycin (TOR): A Central Regulatory Hub for Growth, Stress Response and Biomass Production.
Pancha, I, Chokshi, K, Tanaka, K, Imamura, S
Plant & cell physiology. 2020;(4):675-684
Abstract
Target of rapamycin (TOR) is an evolutionarily conserved protein kinase that plays an important role in the regulation of cell growth and the sensing of nutrient and energy status in eukaryotes. In yeasts and mammals, the roles of TOR have been very well described and various functions of TOR signaling in plant lineages have also been revealed over the past 20 years. In the case of microalgae, the functions of TOR have been primarily studied in the model green alga Chlamydomonas reinhardtii and were summarized in an earlier single review article. However, the recent development of tools for the functional analysis of TOR has helped to reveal the involvement of TOR in various functions, including autophagy, transcription, translation, accumulation of energy storage molecules, etc., in microalgae. In the present review, we discuss recent novel findings relating to TOR signaling and its roles in microalgae along with relevant information on land plants and also provide details of topics that must be addressed in future studies to reveal how TOR regulates various physiological functions in microalgae.
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2.
Pachyonychia congenita responding favorably to a combination of surgical and medical therapies.
Daroach, M, Dogra, S, Bhattacharjee, R, Tp, A, Smith, F, Mahajan, R
Dermatologic therapy. 2019;(5):e13045
Abstract
Pachyonychia congenital (PC) is a rare genetic disorder of cornification and is classified into five types on the basis of keratin gene involved. There are no established treatment options available for PC. Sirolimus in both topical and oral form has been studied in management of PC. We report a young female with a novel genetic mutation in KRT6A gene who presented with painful palmoplantar hyperkeratosis and onychogryphosis, which was cosmetically disfiguring. She was prescribed oral sirolimus after all investigations. There was significant improvement in pain within a week. Pain relief was sustained at 1 year follow-up with topical treatment only. Serial nail avulsion surgeries were also done with showed significant cosmetic improvement in the nails. Medical therapies can be combined with surgery for a better cosmetic outcome and improvement in patient quality of life.
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3.
Medical and sclerosing agents in the treatment of orbital lymphatic malformations: what's new?
Lam, SC, Yuen, HKL
Current opinion in ophthalmology. 2019;(5):380-385
Abstract
PURPOSE OF REVIEW Currently, there is no ideal management for orbital lymphatic malformations. Significant advances have been made since the discovery of new agents in the treatment. The purpose of this manuscript is to review the recent evidence on new sclerotherapy agents and systemic medications. RECENT FINDINGS Traditional sclerosants are OK-432, sodium tetradecyl sulphate and ethanol. More recent developments are the use of doxycycline, bleomycin, and pingyangmycin. Sirolimus as a systemic medication has revolutionized the medical management of lymphatic malformations. Other oral drugs such as propranolol and sildenafil are controversial. Future treatment involves targeting lymphangiogenic pathways including inhibition of vascular endothelial growth factors and the phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit. SUMMARY The development of new agents allows multimodal management either as monotherapy or combined therapy to achieve better outcomes in this difficult to manage disease.
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4.
Current concepts regarding drug dosing for peripheral stents.
Ferrone, M, Cheng, Y, Granada, JF
The Journal of cardiovascular surgery. 2019;(4):439-449
Abstract
Drug-eluting stent (DES) are the mainstay therapy for the treatment of coronary artery disease. Stent design and drug-elution strategies have evolved over the years leading to the last generation DES which shows optimal safety and efficacy outcome. Peripheral arteries have different mechanical and biological features and the lessons learned from the coronary field have been difficult to introduce into the development of peripheral vascular technologies. First, due to its complex biomechanical behavior the use of metallic stents is limited in some vascular segments (i.e., distal superficial fermoral artery [SFA]). Also, peripheral vascular atherosclerosis is different containing higher levels of plaque burden and calcium. Finally, peripheral arterial disease tends to be more aggressive including longer lesions and higher incidence of total chronic occlusion. In general terms, restenosis in the peripheral vascular territory is more aggressive and occurs at a later time (~12 months) requiring a different pharmacokinetic profile compared to coronary technologies. Several strategies have been evaluated in the peripheral arteries raging from the bare metal stent to the drug coated balloon and drug eluting stent with outcome varying depending on the different field of application (i.e. SFA and below-the-knee). Results coming from the clinical trial are encouraging but further studies and direct comparison among the different technologies are demanded to determine the best therapy for peripheral vascular disease.
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5.
Orsiro cobalt-chromium sirolimus-eluting stent: present and future perspectives.
Iglesias, JF, Roffi, M, Degrauwe, S, Secco, GG, Aminian, A, Windecker, S, Pilgrim, T
Expert review of medical devices. 2017;(10):773-788
Abstract
New-generation drug-eluting stents (DES) represent the current standard of care in patients undergoing percutaneous coronary intervention (PCI). Biodegradable polymer DES (BP-DES) were recently developed to overcome current limitations of newer-generation durable polymer DES (DP-DES) attributed to sustained inflammatory responses induced by permanent polymers. The Orsiro DES (Biotronik AG, Bülach, Switzerland) is a novel thin-strut cobalt-chromium sirolimus-eluting stent with biodegradable polymer that features some of the latest developments in DES technology. Areas covered: This article aims to review the currently available evidence on the clinical performance of the Orsiro BP-DES and its future perspectives. Expert commentary: The Orsiro DES is a recent newer-generation BP-DES that combines a highly deliverable thin-strut cobalt-chromium stent platform and a unique hybrid concept with passive and active coatings designed to enhance tissue biocompatibility. In preclinical and intravascular imaging studies, the Orsiro BP-DES was shown to induce low inflammation and promote very early arterial healing. Recently, large randomized non-inferiority clinical trials have shown similar short- and mid-term efficacy and safety outcomes with Orsiro BP-DES compared with currently established newer-generation DES among all-comers and high-risk subgroups. The potential clinical superiority of Orsiro BP-DES over Xience DP-DES in patients with STEMI is currently investigated in the BIOSTEMI trial (NCT02579031).
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6.
Sirolimus for Retinal and Uveitic Diseases.
Agarwal, A, Rajagopalan, N, Hassan, M, Sadiq, MA, Soliman, MK, Afridi, R, Sepah, YJ, Nguyen, QD
Developments in ophthalmology. 2016;:276-81
Abstract
Chronic inflammation plays an important role in the pathogenesis of ocular diseases such as diabetic retinopathy, uveitis and age-related macular degeneration. Activation and proliferation of naïve T cells may result in pathological changes responsible for significant visual morbidity. Sirolimus (earlier termed rapamycin) is a novel drug that inhibits cellular kinases and, thereby, inhibits T-cell proliferation. Preclinical studies in experimental models have shown promising results with the use of this pharmacological agent in various ocular conditions. Subsequently, early phase I/II studies have provided encouraging safety and efficacy data. This chapter focuses on the mechanisms of action, preclinical study results and data from human clinical trials of sirolimus in human eye diseases. Key highlights from ongoing phase III clinical trials are also provided. Sirolimus, thus, appears to be an important addition to the armamentarium of steroid-sparing therapeutic agents that act on various steps in the inflammatory pathway.
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7.
Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals.
Weisman, R
Microbiology spectrum. 2016;(5)
Abstract
All organisms can respond to the availability of nutrients by regulating their metabolism, growth, and cell division. Central to the regulation of growth in response to nutrient availability is the target of rapamycin (TOR) signaling that is composed of two structurally distinct complexes: TOR complex 1 (TORC1) and TOR complex 2 (TORC2). The TOR genes were first identified in yeast as target of rapamycin, a natural product of a soil bacterium, which proved beneficial as an immunosuppressive and anticancer drug and is currently being tested for a handful of other pathological conditions including diabetes, neurodegeneration, and age-related diseases. Studies of the TOR pathway unraveled a complex growth-regulating network. TOR regulates nutrient uptake, transcription, protein synthesis and degradation, as well as metabolic pathways, in a coordinated manner that ensures that cells grow or cease growth in response to nutrient availability. The identification of specific signals and mechanisms that stimulate TOR signaling is an active and exciting field of research that has already identified nitrogen and amino acids as key regulators of TORC1 activity. The signals, as well as the cellular functions of TORC2, are far less well understood. Additional open questions in the field concern the relationships between TORC1 and TORC2, as well as the links with other nutrient-responsive pathways. Here I review the main features of TORC1 and TORC2, with a particular focus on yeasts as model organisms.
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8.
mTOR inhibitors for management of encapsulating peritoneal sclerosis: a review of literatures.
Ghadimi, M, Dashti-Khavidaki, S, Khalili, H
Renal failure. 2016;(10):1574-1580
Abstract
BACKGROUND Encapsulating peritoneal sclerosis (EPS) is an infrequent, serious complication of peritoneal dialysis (PD). EPS may develop after kidney transplantation of PD-treated patients possibly due to the fibrotic effect of calcineurin inhibitors (CNIs). Some experimental and clinical studies proposed inhibitors of mammalian target of rapamycin (mTOR) for EPS management due to their anti-fibrotic and anti-angiogenesis effects. This review evaluated the therapeutic role of mTOR inhibitors in the management of EPS. METHOD Thirteen case reports/series consisted of 20 patients (16 post-transplant and four post-hemodialysis EPS cases) were evaluated. We tried to extract the effect of mTOR inhibitors according to authors' conclusion and the time of improvement of patients' symptoms and each treatment modality such as surgery, parenteral nutrition, tamoxifen and mTOR inhibitors. RESULTS Of 20 patients, clinical improvement of five patients (25%) is more attributable to mTOR inhibitor therapy. All these five patients were post-kidney transplant EPS cases. Therefore, EPS improvement rate in post-transplant EPS patients was 31.25% (5 of 16 patients). Death after EPS diagnosis occurred in two of seven patients with continued CNIs therapy (28.57%) and 1 of 11 cases (9.09%) who didn't receive CNIs after EPS diagnosis. CONCLUSION Although the therapeutic effect of mTOR inhibitors against EPS remains unproven, it seems that for patients with post kidney transplant EPS who do not have any contraindication for mTOR inhibitor administration, converting from CNIs to mTOR inhibitors in addition to other EPS treatments may result in improving EPS in approximately one-third of patients and decreasing patients' mortality.
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9.
Composite outcomes in 2.25-mm drug eluting stents: a systematic review.
Lee, JZ, Singh, N, Ortega, G, Low, SW, Kanakadandi, U, Fortuin, FD, Lassar, T, Lee, KS
Cardiovascular revascularization medicine : including molecular interventions. 2015;(4):237-42
Abstract
BACKGROUND Coronary atherosclerosis often involves small-caliber coronaries, yet the safety and efficacy of 2.25-mm DES have been poorly defined, with a general lack of separation of 2.25 with 2.5-mm performance. No randomized head-to-head 2.25 mm DES studies have been reported. There are several single-arm prospective studies, and we aim to systematically review all published specific 2.25-mm data to estimate composite DES-specific performance and highlight current knowledge gaps. METHODS We performed a systematic literature search of PubMed, EMBASE, Web of Science and Cochrane database for clinical trials of 2.25-mm DES. Angiographic and composite clinical outcomes were compared with descriptive statistics. RESULTS 2.25 mm-Paclitaxel (PES), sirolimus (SES), everolimus (EES) and platinum chromium EES DES-specific outcomes have been reported. Death at 12 months for SES, PES, EES and platinum chromium EES was 1.3%, 3.0%, 1.5%, and 4.4%. Rates of target vessel revascularization at 12 months for SES, PES, EES and platinum chromium EES were 5.7%, 13.3%, 8.8%, and 3.3%. Angiographic outcomes at 9 months to one year were as follows: mean late lumen loss (LLL) for SES, PES, and EES was 0.15 ± 0.11-mm, 0.28 ± 0.11-mm, and 0.16 ± 0.41-mm and mean diameter restenosis for SES, PES, and EES were 29.5 ± 6.2%, 34.7 ± 4.2%, and 20.9 ± 22.5%. Reported stent thrombosis rates for 2.25-mm DES were low ranging from 0% to 2.2% in up to 24-months of follow-up. CONCLUSIONS This systematic review summarizes and tabulates all available specific data on 2.25-mm DES. Based on our descriptive analysis, 2.25-mm DESs have a favorable safety and efficacy profile for the treatment of very small coronary lesions.
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10.
Cobalt chromium-based biodegradable polymer sirolimus-eluting stent: rationale, evidence and clinical experience.
Pan, DR, Zhu, H, Hu, ZY, Pang, S, Wu, W, Tian, NL, Xu, B, Iqbal, J, Zhang, YJ
Minerva cardioangiologica. 2015;(5):411-26
Abstract
Metallic drug-eluting stents (DES) are the first choice for percutaneous coronary interventional treatment of coronary artery disease at present. Although they have overcome some disadvantages and limitations of plain balloon angioplasty and bare-metal stents, chronic local inflammatory reactions related to permanent polymer existence and poor vascular healing after first generation DES implantation may translate into the increased risk of late and very late stent thrombosis. There have been technological developments in stent design, materials and coatings, including more conformable platform designs, biocompatible or biodegradable polymers and improved kinetics of drug release. The newer generation DES have proven superior to previous DES technology in terms of both safety and efficacy. Accumulating evidence has suggested that DES with cobalt chromium stent platform, modified biodegradable polymer coatings, and rapamycin derivative drugs are associated with improved clinical outcomes. Currently, several new cobalt chromium biodegradable polymer sirolimus-eluting stents have been introduced to clinical practice. This review will describe basic concept and rationale behind the newer cobalt chromium biodegradable polymer sirolimus-eluting stents, systematically present the new clinical experiences with several representative devices.