Small interfering RNA for cancer treatment: overcoming hurdles in delivery

© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences In many ways, cancer cells are different from healthy cells. A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells. Currently, nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells. This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells. It also provides the necessary information about siRNA development and its mechanism of action. Overall, this review gives us a clear picture of lipid and polymer-based drug delivery systems, which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies

An overview of vaccine development for COVID-19

The COVID-19 pandemic continues to endanger world health and the economy. The causative SARS-CoV-2 coronavirus has a unique replication system. The end point of the COVID-19 pandemic is either herd immunity or widespread availability of an effective vaccine. Multiple candidate vaccines - peptide, virus-like particle, viral vectors (replicating and nonreplicating), nucleic acids (DNA or RNA), live attenuated virus, recombinant designed proteins and inactivated virus - are presently under various stages of expansion, and a small number of vaccine candidates have progressed into clinical phases. At the time of writing, three major pharmaceutical companies, namely Pfizer and Moderna, have their vaccines under mass production and administered to the public. This review aims to investigate the most critical vaccines developed for COVID-19 to date

Cellular signalling pathways mediating the pathogenesis of chronic inflammatory respiratory diseases: an update

Respiratory disorders, especially non-communicable, chronic inflammatory diseases, are amongst the leading causes of mortality and morbidity worldwide. Respiratory diseases involve multiple pulmonary components, including airways and lungs that lead to their abnormal physiological functioning. Several signaling pathways have been reported to play an important role in the pathophysiology of respiratory diseases. These pathways, in addition, become the compounding factors contributing to the clinical outcomes in respiratory diseases. A range of signaling components such as Notch, Hedgehog, Wingless/Wnt, bone morphogenetic proteins, epidermal growth factor and fibroblast growth factor is primarily employed by these pathways in the eventual cascade of events. The different aberrations in such cell-signaling processes trigger the onset of respiratory diseases making the conventional therapeutic modalities ineffective. These challenges have prompted us to explore novel and effective approaches for the prevention and/or treatment of respiratory diseases. In this review, we have attempted to deliberate on the current literature describing the role of major cell signaling pathways in the pathogenesis of pulmonary diseases and discuss promising advances in the field of therapeutics that could lead to novel clinical therapies capable of preventing or reversing pulmonary vascular pathology in such patients

Responsible, Safe, and Effective Use of Biologics in the Management of Low Back Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines

BACKGROUND: Regenerative medicine is a medical subspecialty that seeks to recruit and enhance the body\u27s own inherent healing armamentarium in the treatment of patient pathology. This therapy\u27s intention is to assist in the repair, and to potentially replace or restore damaged tissue through the use of autologous or allogenic biologics. This field is rising like a Phoenix from the ashes of underperforming conventional therapy midst the hopes and high expectations of patients and medical personnel alike. But, because this is a relatively new area of medicine that has yet to substantiate its outcomes, care must be taken in its public presentation and promises as well as in its use. OBJECTIVE: To provide guidance for the responsible, safe, and effective use of biologic therapy in the lumbar spine. To present a template on which to build standardized therapies using biologics. To ground potential administrators of biologics in the knowledge of the current outcome statistics and to stimulate those interested in providing biologic therapy to participate in high quality research that will ultimately promote and further advance this area of medicine. METHODS: The methodology used has included the development of objectives and key questions. A panel of experts from various medical specialties and subspecialties as well as differing regions collaborated in the formation of these guidelines and submitted (if any) their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these guidelines. The literature pertaining to regenerative medicine, its effectiveness, and adverse consequences was thoroughly reviewed using a best evidence synthesis of the available literature. The grading for recommendation was provided as described by the Agency for Healthcare Research and Quality (AHRQ). SUMMARY OF EVIDENCE: Lumbar Disc Injections: Based on the available evidence regarding the use of platelet-rich plasma (PRP), including one high-quality randomized controlled trial (RCT), multiple moderate-quality observational studies, a single-arm meta-analysis and evidence from a systematic review, the qualitative evidence has been assessed as Level III (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best-evidence synthesis. Based on the available evidence regarding the use of medicinal signaling/ mesenchymal stem cell (MSCs) with a high-quality RCT, multiple moderate-quality observational studies, a single-arm meta-analysis, and 2 systematic reviews, the qualitative evidence has been assessed as Level III (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Lumbar Epidural Injections Based on one high-quality RCT, multiple relevant moderate-quality observational studies and a single-arm meta-analysis, the qualitative evidence has been assessed as Level IV (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Lumbar Facet Joint Injections Based on one high-quality RCT and 2 moderate-quality observational studies, the qualitative evidence for facet joint injections with PRP has been assessed as Level IV (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Sacroiliac Joint Injection Based on one high-quality RCT, one moderate-quality observational study, and one low-quality case report, the qualitative evidence has been assessed as Level IV (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. CONCLUSION: Based on the evidence synthesis summarized above, there is Level III evidence for intradiscal injections of PRP and MSCs, whereas the evidence is considered Level IV for lumbar facet joint, lumbar epidural, and sacroiliac joint injections of PRP, (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis.Regenerative therapy should be provided to patients following diagnostic evidence of a need for biologic therapy, following a thorough discussion of the patient\u27s needs and expectations, after properly educating the patient on the use and administration of biologics and in full light of the patient\u27s medical history. Regenerative therapy may be provided independently or in conjunction with other modalities of treatment including a structured exercise program, physical therapy, behavioral therapy, and along with the appropriate conventional medical therapy as necessary. Appropriate precautions should be taken into consideration and followed prior to performing biologic therapy. Multiple guidelines from the Food and Drug Administration (FDA), potential limitations in the use of biologic therapy and the appropriate requirements for compliance with the FDA have been detailed in these guidelines. KEY WORDS: Regenerative medicine, platelet-rich plasma, medicinal signaling cells, mesenchymal stem cells, stromal vascular fraction, bone marrow concentrate, chronic low back pain, discogenic pain, facet joint pain, Food and Drug Administration, minimal manipulation, evidence synthesis

Search for direct stau production in events with two hadronic tau-leptons in root s=13 TeV pp collisions with the ATLAS detector

A search for the direct production of the supersymmetric partners ofτ-leptons (staus) in final stateswith two hadronically decayingτ-leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of139fb−1, recorded with the ATLAS detector at the LargeHadron Collider at a center-of-mass energy of 13 TeV. No significant deviation from the expected StandardModel background is observed. Limits are derived in scenarios of direct production of stau pairs with eachstau decaying into the stable lightest neutralino and oneτ-lepton in simplified models where the two staumass eigenstates are degenerate. Stau masses from 120 GeV to 390 GeV are excluded at 95% confidencelevel for a massless lightest neutralino

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

A bibliography of parasites and diseases of marine and freshwater fishes of India

With the increasing demand for fish as human food, aquaculture both in freshwater and salt water is rapidly developing over the world. In the developing countries, fishes are being raised as food. In many countries fish farming is a very important economic activity. The most recent branch, mariculture, has shown advances in raising fishes in brackish, estuarine and bay waters, in which marine, anadromous and catadromous fishes have successfully been grown and maintained

Epidural Interventions in the Management of Chronic Spinal Pain: American Society of Interventional Pain Physicians (ASIPP) Comprehensive Evidence-Based Guidelines.

BACKGROUND: Chronic spinal pain is the most prevalent chronic disease with employment of multiple modes of interventional techniques including epidural interventions. Multiple randomized controlled trials (RCTs), observational studies, systematic reviews, and guidelines have been published. The recent review of the utilization patterns and expenditures show that there has been a decline in utilization of epidural injections with decrease in inflation adjusted costs from 2009 to 2018. The American Society of Interventional Pain Physicians (ASIPP) published guidelines for interventional techniques in 2013, and guidelines for facet joint interventions in 2020. Consequently, these guidelines have been prepared to update previously existing guidelines. OBJECTIVE: To provide evidence-based guidance in performing therapeutic epidural procedures, including caudal, interlaminar in lumbar, cervical, and thoracic spinal regions, transforaminal in lumbar spine, and percutaneous adhesiolysis in the lumbar spine. METHODS: The methodology utilized included the development of objective and key questions with utilization of trustworthy standards. The literature pertaining to all aspects of epidural interventions was viewed with best evidence synthesis of available literature and recommendations were provided. RESULTS: In preparation of the guidelines, extensive literature review was performed. In addition to review of multiple manuscripts in reference to utilization, expenditures, anatomical and pathophysiological considerations, pharmacological and harmful effects of drugs and procedures, for evidence synthesis we have included 47 systematic reviews and 43 RCTs covering all epidural interventions to meet the objectives.The evidence recommendations are as follows: Disc herniation: Based on relevant, high-quality fluoroscopically guided epidural injections, with or without steroids, and results of previous systematic reviews, the evidence is Level I for caudal epidural injections, lumbar interlaminar epidural injections, lumbar transforaminal epidural injections, and cervical interlaminar epidural injections with strong recommendation for long-term effectiveness.The evidence for percutaneous adhesiolysis in managing disc herniation based on one high-quality, placebo-controlled RCT is Level II with moderate to strong recommendation for long-term improvement in patients nonresponsive to conservative management and fluoroscopically guided epidural injections. For thoracic disc herniation, based on one relevant, high-quality RCT of thoracic epidural with fluoroscopic guidance, with or without steroids, the evidence is Level II with moderate to strong recommendation for long-term effectiveness.Spinal stenosis: The evidence based on one high-quality RCT in each category the evidence is Level III to II for fluoroscopically guided caudal epidural injections with moderate to strong recommendation and Level II for fluoroscopically guided lumbar and cervical interlaminar epidural injections with moderate to strong recommendation for long-term effectiveness.The evidence for lumbar transforaminal epidural injections is Level IV to III with moderate recommendation with fluoroscopically guided lumbar transforaminal epidural injections for long-term improvement. The evidence for percutaneous adhesiolysis in lumbar stenosis based on relevant, moderate to high quality RCTs, observational studies, and systematic reviews is Level II with moderate to strong recommendation for long-term improvement after failure of conservative management and fluoroscopically guided epidural injections. Axial discogenic pain: The evidence for axial discogenic pain without facet joint pain or sacroiliac joint pain in the lumbar and cervical spine with fluoroscopically guided caudal, lumbar and cervical interlaminar epidural injections, based on one relevant high quality RCT in each category is Level II with moderate to strong recommendation for long-term improvement, with or without steroids. Post-surgery syndrome: The evidence for lumbar and cervical post-surgery syndrome based on one relevant, high-quality RCT with fluoroscopic guidance for caudal and cervical interlaminar epidural injections, with or without steroids, is Level II with moderate to strong recommendation for long-term improvement. For percutaneous adhesiolysis, based on multiple moderate to high-quality RCTs and systematic reviews, the evidence is Level I with strong recommendation for long-term improvement after failure of conservative management and fluoroscopically guided epidural injections. LIMITATIONS: The limitations of these guidelines include a continued paucity of high-quality studies for some techniques and various conditions including spinal stenosis, post-surgery syndrome, and discogenic pain. CONCLUSIONS: These epidural intervention guidelines including percutaneous adhesiolysis were prepared with a comprehensive review of the literature with methodologic quality assessment and determination of level of evidence with strength of recommendations

Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19

Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID-19. Complement activation products are detected in plasma and tissues and complement blockade considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in an COVID-19 to date, a comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalised COVID-19 patients collected across the hospitalisation period as part of the UK ISARIC4C study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to heathy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID-19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID-19 disease severity and death. The data demonstrate that early-onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID-19, further exacerbated in severe disease. These findings provide novel insights into COVID-19 immunopathogenesis and inform strategies for therapeutic intervention