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The materialistic properties of a cell largely depend on the biological activities of the cell. These properties are the indicators of the maintenance of homeostasis in the human body. Any abnormal alterations in these properties can affect the day-to-day physiological functions of a healthy human body. In the present paper, we inquest the materialistic properties of a tumor cell in comparison with normal healthy somatic cells. Later continued research targets to mathematically model the tumor-immune system compartmentally by coupling with the materialistic property equation for the tumor cells. At the end of the paper, we present a continuum model for the spread of tumors as a function of the elastic modulus of the tumor cells. The model fabricated is a novel model that takes into account both the role of elastic modulus decrease as well as the role of immune cells in anti-tumor activities. The models available in the literature do not consider the role of the elastic property of the tumor cells into account.

In this paper, an Average Information based approach for lung cancer analysis and diagnosis has been proposed. Suggested methodology is established on average information parameters by utilizing image processing tools for lung cancer investigation. The real issue for the lung cancer diagnosis is the time constrictions for physical diagnosis that expands the death possibilities. Henceforth essentially proposed technique is an approach that would help the medical practitioners for precise and superior decision against the lung cancer discovery. Microscopic lung images are taken for analysis and investigation by using digital image processing with MATLAB. The statistical and mathematical parameters under statistical analysis are selected on the basis of the principle working of Average information technique. The input parameters like Entropy, Standard Deviation, Mean, Variance and MSE for average information method are implemented over a large microscopic lung image database. The individual statistical and mathematical parameter analysis with its impact on lung cancer images is successfully carried out and finally the accuracy, selectivity, and sensitivity of the proposed method is calculated by implementing the standard diagnostic test on the proposed method. This method also successfully rejects null hypothesis test by implementing one of the standard statistical methods.

Advancement of RNAi-based therapeutics depends on effective delivery to the site of protein synthesis. Although intravenously administered, multi-component delivery vehicles have enabled small interfering RNA (siRNA) delivery and progression into clinical development, advances of single-component, systemic siRNA delivery have been challenging. In pre-clinical models, attachment of a triantennary N -acetylgalactosamine (GalNAc) ligand to an siRNA mediates hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated gene silencing. In this phase 1 study, we assessed translation of this delivery approach by evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a GalNAc-siRNA conjugate, revusiran, targeting transthyretin (TTR). Subjects received a placebo or ascending doses of revusiran subcutaneously ranging from 1.25–10 mg/kg in the single and 2.5–10 mg/kg in the multiple ascending dose phases. Revusiran was generally well tolerated, with transient, mild to moderate injection site reactions the most common treatment-emergent adverse events. Doses of 2.5–10 mg/kg revusiran elicited a significant reduction of serum TTR versus the placebo (p 0.01), with mean TTR reductions of approximately 90% observed with multiple dosing. These results demonstrate translation of this novel delivery platform, enabling clinical development of subcutaneously administered GalNAc-siRNAs for liver-based diseases.

Introduction Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, life-threatening disease due to deposition of transthyretin (TTR) amyloid in various organs and tissues. Historically the disease has been described by predominant clinical manifestation of cardiomyopathy (CM) or polyneuropathy (PN), however a majority of patients are known to develop a mixed phenotype. Because of this, PN symptoms may not always be assessed in patients with predominant CM and neuropathy progression may continue. The potential of neurofilament light chain (NfL) as a non-invasive biomarker of nerve damage in patients with hATTR amyloidosis with PN has previously been described; however to date no studies have investigated NfL in patients with predominant CM. Hypothesis NfL may serve as a biomarker of co-existing neuropathy in patients with hATTR amyloidosis with predominant CM and could lead to early detection and treatment of nerve damage, thus improving patient care. Methods Plasma NfL levels were measured in baseline samples from patients with hATTR amyloidosis with CM from the Phase 3 ENDEAVOUR study (n = 194; V122I variant = 111) and compared with NfL levels from healthy controls (n = 53) and baseline samples from patients with hATTR amyloidosis with PN from the Phase 3 APOLLO study (n = 193). Polyneuropathy Disability (PND) score was also taken into account for NfL analyses. Results Elevated plasma NfL levels were observed in patients with hATTR amyloidosis with CM relative to healthy controls (54.1 pg/mL vs 16.3 pg/mL, p 0 (n = 101; evidence of neurological impairment) were not significantly different to those in patients with hATTR amyloidosis with PN (p = 0.15), where all patients had a PND>0. Patients with hATTR amyloidosis with CM and the V122I variant, generally considered to cause a predominant CM phenotype, also had elevated plasma NfL levels relative to healthy controls (44.9 pg/mL vs 16.3 pg/mL, p Conclusions NfL may serve as a biomarker of nerve damage in patients with hATTR amyloidosis, regardless of the predominant manifestation. This analysis also suggests PN may be underdiagnosed in patients with predominant CM, such as those with a V122I variant, and NfL may be a useful biomarker to support earlier diagnosis of PN in these patients.

Introduction L’amylose hereditaire a transthyretine (hATTR) est une maladie rare engageant le pronostic vital. Des biomarqueurs plasmatiques peuvent faciliter le diagnostic, evaluer le pronostic et permettre de surveiller la maladie. Objectifs Analyser l’evolution des biomarqueurs proteiques circulants en reponse au patisiran chez les patients atteints d’amylose hATTR avec polyneuropathie. Patients et methodes L’analyse proteomique a ete utilisee pour mesurer 1164 proteines dans des echantillons de plasma preleves sur des patients de l’etude de phase 3 APOLLO ayant recu soit du placebo soit du patisiran 0,3 mg/kg IV toutes les 3 semaines. Un modele mixte lineaire a permis de determiner l’impact du patisiran sur le profil de chaque taux de proteines a 0, 9 et 18 mois. Resultats 66 proteines ont montre un changement significatif de leur taux apres traitement par patisiran (p Discussion Les NfL peuvent servir de biomarqueur d’evolution des lesions nerveuses et de la polyneuropathie dues aux depots amyloides comme le montre la correlation avec le patisiran et l’evolution du mNIS + 7. Cela peut permettre un diagnostic precoce de la polyneuropathie chez les patients atteints d’amylose hATTR et le suivi de la progression/regression de la maladie dans le temps. Conclusion Le taux de neurofilaments a chaine legere peut servir de biomarqueur d’evolution des lesions nerveuses et de la polyneuropathie dans l’amylose hereditaire a transthyretine avec ou sans traitement.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment.We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059.Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p0·0001).Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings.Alnylam Pharmaceuticals.

Oligonucleotide-based therapeutics are an emerging class of drugs that hold the promise for silencing "un-druggable" targets,thus creating unique opportunities for innovative medicines. As opposed to gene therapy, oligonucleotides are considered to be more akin to small molecule therapeutics because they are small,completely synthetic in origin, do not integrate into the host genome,and have a defined duration of therapeutic activity after which effects recover to baseline. They offer a high degree of specificity at the genetic level, thereby reducing off-target effects.At the same time, they provide a strategy for targeting any gene in the genome, including transcripts that produce mutated proteins.Oligonucleotide-based therapeutics include short interfering RNA (siRNA), that degrade target mRNA through RISC mediated RNAi; anti-miRs, that target miRNAs; miRNA mimics, that regulate target mRNA; antisense oligonucleotides, that may be working through RNAseH mediated mRNA decay; mRNA upregulation,by targeting long non-coding RNAs; and oligonucleotides induced alternative splicing [1]. All these approaches require some minimal degree of homology at the nucleic acid sequence level for them to be functional. The different mechanisms of action and their relevant activity are outlined in Fig. 1. Besides homology,RNA secondary structure has also been exploited in the case of ribozymes and aptamers, which act by binding to nucleic acids or proteins, respectively. While there have been many reports of gene knockdown and gene modulation in cell lines and mice with all these methods, very few have advanced to clinical stages.The main obstacle to date has been the safe and effective intracellular delivery of these compounds in higher species, including humans. Indeed, their action requires direct interaction with DNA/RNA within the target cell so even when one solves the issues of tissue and cellular access, intracellular/intranuclear location represents yet another barrier to overcome. To date,hepatic delivery of oligonucleotides has been the area with greatest progress, and thus we have focused on liver-targeted therapeutics that have shown promise at the preclinical and/or clinical level.The liver is the largest internal organ in the body, playing a central role in metabolism, detoxification, synthesis, and secretion of major plasma proteins (carrier proteins, coagulation factors,complement components, hormones, and apolipoproteins),and iron homeostasis. It is therefore not surprising that a large number of disease targets reside in the liver where they are susceptible to modulation by oligonucleotide therapies.

Background Alefacept, human LFA-3/IgG 1 fusion protein, selectively reduces memory-effector (CD45RO + ) T cells, a source of the pathogenic mediators of psoriasis. Objective To evaluate the effect of alefacept on immune function, T-cell-dependent humoral responses to a neoantigen (φX174) and recall antigen (tetanus toxoid) were assessed. Methods Patients with psoriasis were randomized to the control group or to receive alefacept (7.5 mg intravenously weekly for 12 weeks). The alefacept group received φX174 immunizations at weeks 6, 12, 20, and 26 and tetanus toxoid at week 21; control subjects received φX174 at weeks 6 and 12 and tetanus at week 10. Results Mean anti-φX174 titers were comparable in both groups. There was no difference in the percentage of responders (anti-φX174 IgG ≥30% of the total anti-φX174) between the alefacept group and the control group (86% and 82%, respectively; P = .73). The percentage of patients with anti-tetanus toxoid titer increases ≥2 times baseline also was similar (alefacept, 89%; control 91%). Conclusion A single 12-week course of alefacept did not impair primary or secondary antibody responses to a neoantigen or memory responses to a recall antigen. The selective immunomodulatory effect of alefacept against a potentially pathogenic T-cell subset is associated with maintenance of a significant aspect of immune function (antibody response) to fight infection and respond to vaccinations.

The Fas receptor is a member of a family of cell death receptors, including tumor necrosis factor receptor I (TNFR I), death receptor 3 and 4 (DR3 and DR4), and cytopathic avian receptor 1 (CAR1). The Fas receptor is composed of several discrete domains, including three cysteine-rich domains (CRDs), a transmembrane domain, and an intracellular domain responsible for transmitting an apoptotic signal. While the mechanism of Fas-mediated cell death has become elucidated, the requirements for Fas ligand binding to the receptor have not been fully defined. Using a series of chimeric Fc-receptor fusion proteins between the human Fas receptor and TNFR I, each cysteine-rich domain of Fas was found to be required for interaction with the Fas ligand. Interestingly, TNFR I CRD1 could partially substitute for the Fas CRD1. The importance of this domain was underscored by the analysis of a Fas extracellular mutation (C66R), which resulted in a complete loss of ligand binding. This mutation was cloned from a human patient suffering from Canale-Smith syndrome, which is characterized by autoimmunity resembling that observed in the lpr and lprcg mice. The localization of essential ligand binding domains in the Fas receptor correlated exactly with the ability of the Fas receptor fusion proteins to prevent cell death mediated by the Fas ligand.

treatment group began to show evidence of statistically significant lower left ventricular ejection fraction (LVEF) levels at 6 to 12 month followup, the trial was halted. Conclusions: Despite comparable patient population characteristcs, the addition of pentoxifylline treatment to standard heart failure treatment of PPCM patients showed no benefits and failed to match the LVEF gains that were experienced by the non-pentoxifylline treatment group.