question:You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.Title 1:The Baseline Ratio of Neutrophils to Lymphocytes Is Associated with Patient Prognosis in Advanced Gastric CancerAbstract 1:Objective : In cancer patients , the balance between neutrophil ( N ) and lymphocyte ( L ) cell counts fluctuates with advancing disease . The objective of our study was to determine the prognostic implication s of the N/L ratio in the peripheral blood of gastric cancer patients . Methods : Study participants were identified from a prospect i ve cohort of patients with advanced gastric cancer in Japan ( n = 1,220 ) . Results : The median baseline N/L was 2.58 ( range , 0.63–12.7 ) . Univariate analysis revealed that patients with an N/L ≧2.5 ( n = 644 ) had a significantly poorer prognosis than those with an N/L < 2.5 ( n = 576 ; log rank test , p = 0.019 × 10–12 ) . The median survival times for these two groups were 239 ( 95 % confidence interval , CI , 217–251 days ) and 363 days ( 95 % CI , 334–406 days ) , respectively , while the 1-year survival rates were 30 ( 95 % CI , 26–34 % ) and 50 % ( 95 % CI , 45–54 % ) , respectively . A multivariate Cox model established a significant relationship between the N/L ratio and survival ( adjusted hazard ratio = 1.52 ; 95 % CI , 1.32–1.75 ; p = 0.077 × 10–8 ) . Conclusions : These results suggest that the N/L ratio is an independent prognostic factor in advanced gastric cancer . Measurement of this ratio may serve as a clinical ly accessible and useful biomarker for patient survivalTitle 2:Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patientsAbstract 2:Background : The concept of the involvement of systemic inflammation in cancer progression and metastases has gained attraction within the past decade . C-reactive protein ( CRP ) , a non-specific blood-based marker of the systemic inflammatory response , has been associated with decreased survival in several cancer types . The aim of the present study was to vali date the prognostic value of pre-operative plasma CRP levels on clinical outcome in a large cohort of soft-tissue sarcoma ( STS ) patients . Methods : Three hundred and four STS patients , operated between 1998 and 2010 , were retrospectively evaluated . CRP levels and the impact on cancer-specific survival ( CSS ) , disease-free survival ( DFS ) and overall survival ( OS ) were assessed using Kaplan – Meier curves and univariate as well as multivariate Cox proportional models . Additionally , we developed a nomogram by supplementing the plasma CRP level to the well-established Kattan nomogram and evaluated the improvement of predictive accuracy of this novel nomogram by applying calibration and Harrell ’s concordance index ( c-index ) . Results : An elevated plasma CRP level was significantly associated with established prognostic factors , including age , tumour grade , size and depth ( P<0.05 ) . In multivariate analysis , increased CRP levels were significantly associated with a poor outcome for CSS ( HR=2.05 ; 95 % CI=1.13–3.74 ; P=0.019 ) and DFS ( HR=1.88 ; 95 % CI=1.07–3.34 ; P=0.029 ) . The estimated c-index was 0.74 using the original Kattan nomogram and 0.77 when the plasma CRP level was added . Conclusion : An elevated pre-operative CRP level represents an independent prognostic factor that predicts poor prognosis and improves the predictive ability of the Kattan nomogram in STS patients . Our data suggest to further prospect ively vali date its potential utility for individual risk stratification and clinical management of STS patientsTitle 3:Derived neutrophil to lymphocyte ratio predicts prognosis for patients with HBV-associated hepatocellular carcinoma following transarterial chemoembolizationAbstract 3:The derived neutrophil to lymphocyte ratio ( dNLR ) has been proposed as an easily determinable prognostic factor for cancer patients , but the prognostic significance of the dNLR in hepatocellular carcinoma ( HCC ) has not been investigated . The present study aim ed to vali date the prognostic power of the NLR and dNLR in HCC patients undergoing transarterial chemoembolization ( TACE ) . The data of 279 consecutive patients who underwent TACE for unresectable HBV-associated HCC between September 2009 and November 2011 at the Department of Hepatobiliary Surgery , Sun Yat-sen University Cancer Center ( Guangzhou , China ) were retrieved from a prospect i ve data base . The cut-off values for the NLR and dNLR were determined by receiver operating characteristic ( ROC ) analysis . The association between the NLR and dNLR and the clinicopathological characteristics and overall survival ( OS ) rates and times of patients was analyzed . The area under the curve ( AUC ) was calculated to evaluate the discriminatory ability of the NLR and dNLR . The median follow-up period was 446 days , the 1 , 2 and 3-year OS rates were 38.8 , 18.5 and 11.1 % respectively , and the median OS time was 264 days . The cut-off values were determined as 2.6 and 1.8 for the NLR and dNLR , respectively . The NLR and dNLR were each associated with patient age , presence of vascular invasion , tumor size , AST level and ALP level . Multivariate analysis showed that the NLR , dNLR , ALT level and AFP level were independent prognostic factors for OS . An elevated NLR or dNLR was associated with a poor prognosis ( P=0.001 and P=0.002 , respectively ) . The prognostic power of NLR [ AUC=0.539 ; 95 % confidence interval ( CI ) , 0.423–0.656 ] and dNLR ( AUC=0.522 ; 95 % CI , 0.406–0.638 ) was similar . Elevated dNLR predicted poor prognosis for patients with HBV-associated HCC undergoing TACE , with similar prognostic power to NLR . The dNLR may be used as an alternative to the NLR , as it is easily available and inexpensive

question:You are provided with the abstract of a scientific paper and the abstracts of the papers it references. Your task is to write a Related Work section for the main paper. This section should concisely summarize and integrate the key points from the cited abstracts, reflecting how they relate to the main paper's contributions and context. In your summary, use numerical citation markers like [1], [2], etc., to refer to the corresponding papers.Main Abstract:We present a weakly-supervised approach to segmenting proposed drivable paths in images with the goal of autonomous driving in complex urban environments. Using recorded routes from a data collection vehicle, our proposed method generates vast quantities of labelled images containing proposed paths and obstacles without requiring manual annotation, which we then use to train a deep semantic segmentation network. With the trained network we can segment proposed paths and obstacles at run-time using a vehicle equipped with only a monocular camera without relying on explicit modelling of road or lane markings. We evaluate our method on the large-scale KITTI and Oxford RobotCar datasets and demonstrate reliable path proposal and obstacle segmentation in a wide variety of environments under a range of lighting, weather and traffic conditions. We illustrate how the method can generalise to multiple path proposals at intersections and outline plans to incorporate the system into a framework for autonomous urban driving.Cited Abstract(s):[1]: [2]: We trained a convolutional neural network (CNN) to map raw pixels from a single front-facing camera directly to steering commands. This end-to-end approach proved surprisingly powerful. With minimum training data from humans the system learns to drive in traffic on local roads with or without lane markings and on highways. It also operates in areas with unclear visual guidance such as in parking lots and on unpaved roads. The system automatically learns internal representations of the necessary processing steps such as detecting useful road features with only the human steering angle as the training signal. We never explicitly trained it to detect, for example, the outline of roads. Compared to explicit decomposition of the problem, such as lane marking detection, path planning, and control, our end-to-end system optimizes all processing steps simultaneously. We argue that this will eventually lead to better performance and smaller systems. Better performance will result because the internal components self-optimize to maximize overall system performance, instead of optimizing human-selected intermediate criteria, e.g., lane detection. Such criteria understandably are selected for ease of human interpretation which doesn't automatically guarantee maximum system performance. Smaller networks are possible because the system learns to solve the problem with the minimal number of processing steps. We used an NVIDIA DevBox and Torch 7 for training and an NVIDIA DRIVE(TM) PX self-driving car computer also running Torch 7 for determining where to drive. The system operates at 30 frames per second (FPS).[3]: ALVINN (Autonomous Land Vehicle In a Neural Network) is a 3-layer back-propagation network designed for the task of road following. Currently ALVINN takes images from a camera and a laser range finder as input and produces as output the direction the vehicle should travel in order to follow the road. Training has been conducted using simulated road images. Successful tests on the Carnegie Mellon autonomous navigation test vehicle indicate that the network can effectively follow real roads under certain field conditions. The representation developed to perform the task differs dramatically when the network is trained under various conditions, suggesting the possibility of a novel adaptive autonomous navigation system capable of tailoring its processing to the conditions at hand.

question:You are presented with multiple paper abstracts, alongside the associated literature review and chapter titles. Given the provided information, you are going to do a literature review. Please generate a coherent literature review that synthesizes the content, draws connections between different works, highlights major findings, and identifies any gaps in the existing research.Literature Review Title: Reconfigurable computing: a survey of systems and software Chapter Title: Hardware-Software Partitioning 1. Abstract of Cited Paper (BIB001): The paper presents an operating system (OS) for custom computing machines (CCMs) based on the Xputer paradigm. Custom computing tries to combine traditional computing with programmable hardware, attempting to gain from the benefits of both adaptive software and optimized hardware. The OS running as an extension to the actual host OS allows a greater flexibility in deciding what parts of the application should run on the configurable hardware with structural code and what on the host-hardware with conventional software. This decision can be taken late - at run-time - and dynamically, in contrast to early partitioning and deciding at compile-time as used currently on CCMs. Thus the CCM can be used concurrently by multiple users or applications without knowledge of each other. This raises programming and using CCMs to levels close to modem OSes for sequential von Neumann processors. 2. Abstract of Cited Paper (BIB002): Hybrid architectures combining conventional processors with configurable logic resources enable efficient coordination of control with datapath computation. With integration of the two components on a single device, loop control and data-dependent branching can be handled by the conventional processor. While regular datapath computation occurs on the configurable hardware. This paper describes a novel pragma-based approach to programming such hybrid devices. The NAPA C language provides pragma directives so that the programmer (or an automatic partitioner) can specify where data is to reside and where computation is to occur with statement-level granularity. The NAPA C compiler, targeting National Semiconductor's NAPA1000 chip, performs semantic analysis of the pragma-annotated program and co-synthesizes a conventional program executable combined with a configuration bit stream for the adaptive logic. Compiler optimizations include synthesis of hardware pipelines from pipelineable loops. 3. Abstract of Cited Paper (BIB003): Various projects and products have been built using off-the-shelf field-programmable gate arrays (FPGAs) as computation accelerators for specific tasks. Such systems typically connect one or more FPGAs to the host computer via an I/O bus. Some have shown remarkable speedups, albeit limited to specific application domains. Many factors limit the general usefulness of such systems. Long reconfiguration times prevent the acceleration of applications that spread their time over many different tasks. Low-bandwidth paths for data transfer limit the usefulness of such systems to tasks that have a high computation-to-memory-bandwidth ratio. In addition, standard FPGA tools require hardware design expertise which is beyond the knowledge of most programmers. To help investigate the viability of connected FPGA systems, the authors designed their own architecture called Garp and experimented with running applications on it. They are also investigating whether Garp's design enables automatic, fast, effective compilation across a broad range of applications. They present their results in this article.Literature Review:

question:You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.Title: Dissecting the Cell Entry Pathway of Dengue Virus by Single-Particle Tracking in Living Cells}Article:Abstract:Dengue virus( DENV) is an enveloped RNA virus that causes the most common arthropod-borne infection worldwide. The mechanism by which DENV infects the host cell remains unclear. In this work, we used live-cell imaging and single-virus tracking to investigate the cell entry, endocytic trafficking, and fusion behavior of DENV. Simultaneous tracking of DENV particles and various endocytic markers revealed that DENV enters cells exclusively via clathrin-mediated endocytosis. The virus particles move along the cell surface in a diffusive manner before being captured by a pre-existing clathrin-coated pit. Upon clathrin-mediated entry, DENV particles are transported to Rab5-positive endosomes, which subsequently mature into late endosomes through acquisition of Rab7 and loss of Rab5. Fusion of the viral membrane with the endosomal membrane was primarily detected in late endosomal compartments.Introduction:Dengue virus( DENV) is a mosquito-transmitted, enveloped RNA virus that belongs to the family Flaviviridae. This family also includes West-Nile virus( WNV) and tick-borne encephalitis virus( TBEV). DENV causes the most common arthropod-borne infection worldwide with 50–100 million cases annually[1]–[3]. Despite its threat to human health, there are presently neither vaccines nor antiviral drugs to prevent or treat dengue infection. The development of novel therapies requires insight into the viral life cycle. A potential target for intervention strategies is the infectious cell entry pathway. The infectious entry of DENV is mediated by the viral envelope glycoprotein E, which is organized in 90 homodimers on the surface of the virion[4],[5]. The E glycoprotein is involved in interaction with cellular receptors as well as the subsequent membrane fusion process[6]–[8]. In vitro studies with TBEV indicate that membrane fusion is triggered upon exposure of the virus to low pH[8]. At low pH, the E proteins undergo a dramatic re-organization which leads to the formation of E trimers[9]. The crystal structure of the E protein has been solved in its dimeric pre-fusion, and trimeric post-fusion configurations[10],[11]. Although much is known about the molecular mechanisms involved in the membrane fusion process, many critical questions regarding the cell entry pathway of flaviviruses remain unanswered. The cell entry mechanism of DENV remains controversial. Early electron microscopy studies provided evidence for direct fusion with the plasma membrane[12],[13], whereas a recent study indicates that DENV enters cells via clathrin-mediated endocytosis[14]. Clathrin-mediated endocytosis involves internalization of ligands and receptors through a clathrin-coated pit, which buds into the cell cytosol and delivers its cargo to early endosomes and subsequently to late endosomes and lysosomes[15]–[17]. Other flaviviruses have also been described to infect their host cell via clathrin-mediated endocytosis[18]–[21]. Evidence for flavivirus entry via this pathway is based on the use of inhibitors of clathrin-mediated uptake, such as chlorpromazine and dominant-negative mutants of Eps15[18],[20],[22]. Furthermore, addition of acidotropic reagents to cells has been observed to dramatically reduce viral infectivity and membrane fusion activity, suggesting that flaviviruses mediate membrane fusion from within acidic endosomes[23]–[26]. A recent study on the entry of WNV particles demonstrates that WNV colocalizes with the early endosome marker EEA-1( Early Endosome Antigen-1), and at later time points with the late endosome/lysosome marker LAMP-1( Lysosome-Associated Membrane Protein-1)[27]. Taken together, these studies suggest clathrin-mediated endocytosis as a viable pathway for flavivirus entry, but the exact manner in which DENV virus particles enter cells and traffic through the endocytic network remains unclear, as does the identity of the organelle in which viral fusion occurs. In this study, we dissected the cell entry pathway of DENV by tracking fluorescently labeled DENV particles in living cells expressing various fluorescent cellular markers using real-time multi-color fluorescence microscopy. These experiments demonstrate that DENV infects its host cell via clathrin-mediated endocytosis. DENV particles move on the cell surface in a diffusive manner until they join a pre-existing clathrin-coated pit. Following clathrin-mediated uptake, the majority of DENV particles enter early endosomes that progress to late endosomes, where membrane fusion occurs.Discussion:Despite the medical importance of DENV, little information is available about the infectious cell entry pathway of the virus. In this study, we investigated the cell entry process of single DENV particles in real-time by simultaneous tracking of fluorescently labeled DENV particles and endocytic structures in cells. This approach allowed us to obtain mechanistic and kinetic insights into the route of internalization and endocytic trafficking behavior of individual DENV particles in living cells. Previous electron-microscopy studies suggested that DENV penetrates both mammalian and insect cells by direct fusion with the plasma membrane[12],[13]. In contrast, this report shows that DENV enters cells via clathrin-mediated endocytosis and fuses from within late endosomes. We observed that more than 98% of the particles that underwent membrane fusion, first associated with a clathrin-coated structure for a substantial time period. Furthermore, treatment of cells with chlorpromazine as well as expression of a dominant-negative Eps15 mutant significantly suppressed the number of DENV-infected cells. It is not clear what the explanation is for the discrepancy, but it might be related to the methodology that was used to investigate the cell entry process of the virus. The conclusion that DENV utilizes clathrin-mediated endocytosis for internalization is in agreement with recent observations of Acosta and co-workers[14]. During the course of this study, these investigators published that DENV infectivity in C6/36 mosquito cells is severely inhibited after treatment of the cells with a variety of chemical and molecular inhibitors of clathrin-mediated endocytosis. Real-time imaging studies showed that macromolecules either induce de novo formation of clathrin-coated pits or are recruited to pre-existing clathrin-coated pits[31],[44],[45]. For example, influenza virus particles land on the cell surface and induce de novo formation of clathrin-coated pits at the site of binding[30]. This study indicates that DENV particles first diffuse along the cell surface before they encounter pre-existing clathrin-coated pits. After the virus associates with the pit, the clathrin signal around the virus particle increases, which implies maturation of the clathrin-coated pit and formation of a clathrin-coated vesicle. Thereafter, the clathrin signal rapidly disappears again, typically within a time scale of a few seconds. This behavior is similar to that of reoviruses, which have been shown to stabilize and induce maturation of pre-existing clathrin-coated pits[31]. Recently, several modes of endosome maturation have been described. Rink et al. showed that Rab5-positive vesicles, which have split off from a dynamic early endosomal network, accumulate Rab7 and subsequently gradually lose Rab5[35]. Vonderheit et al. found that Rab5-positive endosomes, containing Semliki Forest Virus( SFV) particles, gradually acquire Rab7 in a separate domain. The SFV particles are sequestered into this Rab7 domain, which pinches off as a Rab7-positive late endosome, leaving a Rab5-positive endosome behind[37]. We observed both modes of endosome maturation. Most DENV particles progressed from early to late endosomes by gradual appearance of Rab7 and a gradual loss of Rab5. In addition, 45% of Rab5-positive endosomes carrying DENV merged with existing Rab7-positive endosomes. Occasionally, we observed that DENV particles sequestered into a distinct Rab7 domain, similar to the behavior observed from endosomes containing SFV[37]. DENV particles predominantly fused from within Rab7-positive endosomes. Furthermore, the membrane fusion activity was significantly impaired in cells expressing dominant-negative forms of Rab7, which indicates that progression of DENV to Rab7-positive endosomes is important for its infectious entry. In contrast, Krishnan et al. have recently demonstrated that the infectivity of DENV-2 strain NGC was not affected by dominant-negative Rab7, while ablation of Rab5 severely reduced the number of infected cells[22]. A direct comparison between both virus strains revealed that viral infectivity of S1 was severely impaired in cells expressing dominant-negative Rab7, whereas the infectivity of NGC was unaffected. These results suggest that both virus strains have distinct entry characteristics. In this respect it is interesting to note that DENV-2 strain NGC induces syncytium formation in a fusion from without assay at pH 6. 4, whereas the pH threshold for the DENV-2 S1 strain is around pH 5. 8( personal communication, Dr. P. Young, University of Queensland, Australia). The different pH-dependent properties of these virus strains may therefore reflect the distinct requirements for functional endocytic trafficking in cells. Future experiments should reveal whether the pH threshold determines in which organelle membrane fusion occurs. DENV particles reside on average for 5. 5 min in Rab7-positive endosomes prior to the onset of membrane fusion. This result is surprising considering that TBEV efficiently fuses with liposomes in a model system in a time scale of seconds after low-pH exposure[46]. Pre-exposure of TBEV to low pH for 10–20 seconds in the absence of liposomes completely abolishes the membrane fusion activity of the virus[46]. Similar results were obtained for WNV( unpublished results, J. Wilschut and J. M. Smit). Our finding that DENV fuses several minutes after entering a late endosome might therefore suggest that, in addition to exposure to the acidic lumen of the late endosome, other cellular factors are involved in the activation of the membrane fusion machinery of DENV. Another possibility is that the accumulation of Rab7 significantly precedes acidification to the fusion pH. Taken together, we propose the following model for cell entry of DENV S1 strain. First, the virus particle binds to a cellular receptor. Subsequently, DENV diffuses as a virus-receptor complex or rolls over multiple receptors along the cell surface towards a clathrin-coated pit. Upon capture by a pre-existing clathrin-coated pit, the virus particles loses its mobility. Then, the clathrin-coated pit matures and pinches off into the cell cytoplasm to deliver the particles to Rab5-positive early endosomes. In general, the early endosome carrying the virus matures into a late endosome by gradual accumulation of Rab7, followed by a gradual loss of Rab5. Finally, the DENV particles localize to Rab7-positive late endosomes and move through the cytoplasm of the cell until the onset of membrane fusion allows the genetic material of the virus to be delivered into the cytoplasm. Single-particle tracking has substantially enriched our knowledge on viral cell entry mechanisms and has revealed previously unknown aspects of virus-host interactions[30],[47],[48]. The mechanistic and kinetic insights offered by this technique provide a better understanding of disease pathogenesis and may lead to a rational design of antiviral drugs and vaccines. This is the first study that describes the cell entry pathway of DENV at a single-particle level. The parameters obtained in this study will serve as a framework for our current study on the fate of individual antibody-opsonized DENV particles into Fc receptor-bearing to elucidate the molecular basis of antibody-dependent enhancement of DENV infection.

question:You will be shown a question, followed by excerpts from biomedical research papers. Please answer the question based on the provided context. Do not include any text in your response other than the answer.Question: What is the mechanism of action of Inclisiran?Context: Inclisiran is a promising RNA-based therapy that promotes the degradation of PCSK9 mRNA transcripts and has similar efficacy to mAbs, but with a much longer duration of action.Recently marketed monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown the way towards innovation, while other ways of PCSK9 inhibition like small interfering RNA (Inclisiran) are already being tested.Inclisiran, a novel, synthetic, siRNA molecule, inhibits PCSK9 synthesis in hepatocytes. Inclisiran targets intracellular PCSK9 synthesis specifically, resulting in a dose-dependent, long-term, significant reduction in LDL-C.BACKGROUND: To our knowledge, inclisiran was the first agent composed of small interfering RNAs (siRNAs) to be preliminarily used to reduce proatherogenic lipoprotein cholesterol levels.BACKGROUND: The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol [LDL-C]) demonstrated that inclisiran, an siRNA therapeutic that targets protease proprotein convertase subtilisin/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction.The development of inclisiran, siRNA silencer targeting PCSK9 gene, is a one step forward in these endeavors.Inclisiran is a long-acting, synthetic siRNA directed against PCSK9 and it has been shown to significantly decrease hepatic production of PCSK9 and cause a marked reduction in LDL-C levels.Inclisiran is a novel drug that inhibits PCSK9 synthesis specifically in the liver, harnessing the natural mechanism of RNAi.BACKGROUND Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol.CONCLUSIONS Inclisiran produces significant and prolonged reductions in atherogenic lipoproteins, suggesting that inhibiting the synthesis of protease proprotein convertase subtilisin/kexin type 9 through siRNA may be a viable alternative to other approaches that target protease proprotein convertase subtilisin/kexin type 9.Inclisiran targets intracellular PCSK9 synthesis specifically, resulting in a dose-dependent, long-term, significant reduction in LDL-C. Inclisiran has been well tolerated and safe, without severe adverse events so far.Areas covered: PCSK9 inhibition has emerged as a promising new therapeutic strategy to reduce LDL-C. Inclisiran, a novel, synthetic, siRNA molecule, inhibits PCSK9 synthesis in hepatocytes.BACKGROUND The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol [LDL-C]) demonstrated that inclisiran, an siRNA therapeutic that targets protease proprotein convertase subtilisin/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction.Recently marketed monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown the way towards innovation, while other ways of PCSK9 inhibition like small interfering RNA (Inclisiran) are already being tested.Inclisiran inhibits translation of PCSK9 mRNA and thus switches off PCSK9 production and provides advantages over monoclonal antibodies with an infrequent dosing interval of twice a year to reduce LDL-C by over 50%.Inclisiran is a long-acting, synthetic siRNA directed against PCSK9 and it has been shown to significantly decrease hepatic production of PCSK9 and cause a marked reduction in LDL-C levels.Inclisiran for the treatment of cardiovascular disease: the ORION clinical development program.Inclisiran is a novel drug that inhibits PCSK9 synthesis specifically in the liver, harnessing the natural mechanism of RNAi.Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia.The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled.Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial.Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels.Inclisiran targets intracellular PCSK9 synthesis specifically, resulting in a dose-dependent, long-term, significant reduction in LDL-C. Inclisiran has been well tolerated and safe, without severe adverse events so far.This review discusses current PCSK9 inhibitors and the results of phase I and II clinical trials of inclisiran.Areas covered: PCSK9 inhibition has emerged as a promising new therapeutic strategy to reduce LDL-C. Inclisiran, a novel, synthetic, siRNA molecule, inhibits PCSK9 synthesis in hepatocytes.Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol.

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