Application of the amplification-free SERS-based CRISPR/Cas12a platform in the identification of SARS-CoV-2 from clinical samples

The control of contagious or refractory diseases requires early, rapid diagnostic assays that are simple, fast, and easy-to-use. Here, easy-to-implement CRISPR/Cas12a-based diagnostic platform through Raman transducer generated by Raman enhancement effect, term as SERS-CRISPR (S-CRISPR), are described. The S-CRISPR uses high-activity noble metallic nanoscopic materials to increase the sensitivity in the detection of nucleic acids, without amplification. This amplification-free platform, which can be performed within 30–40 min of incubation time, is then used for detection of SARS-CoV-2 derived nucleic acids in RNA extracts obtained from nasopharyngeal swab specimens (n = 112). Compared with the quantitative reverse transcription polymerase chain reaction (RT-qPCR), the sensitivity and specificity of S-CRISPR reaches 87.50% and 100%, respectively. In general, the S-CRISPR can rapidly identify the RNA of SARS-CoV-2 RNA without amplification and is a potential strategy for nucleic acid point of care test (POCT).

Nanomaterials were formed into various shapes, with functionalization aimed at various internalization processes. Their nanoscale size allows drugs to reach cells or extracellular environments

Iron issues have been linked to a rising variety of refractory diseases, raising doubts about whether iron is the primary connection in etiology and pathology. Nanomaterials were transformed into diverse forms with functionalization aiming at diverse internalization processes. Their nanoscale size permits medications to penetrate cells or the extracellular environment. The original iron enrichment could be employed to fight diseases, including cancer. The effects of IONPs and intracellular iron load on macrophages is also unknown, giving the possibility for future alteration of macrophage phenotypes based on diverse situations.The data may be utilized to establish important patterns for disease risk prediction and prevention. Nano-sensing technology that reveals iron-regulating situations may deliver fresh insights into safety assessment of iron-based nanomaterials. Long-term stress caused by iron in cells and tissues does not create acute toxicity, but rather long-term damage. A better knowledge of iron homeostasis will result in further diagnostic and therapeutic applications employing nanotechnology.

Stem Cells: Novel Technologies, Therapies and Industrial Models

Stem cells are a kind of cells with the ability of self-renewal and multi-directional differentiation potential. A variety of stem cells or progenitor cells have been shown to be efficacy in the treatment of some refractory diseases. The mesenchymal stem cells (MSCs) are derived from mesoderm and have the characteristics of differentiation into three germ layers and immune regulation, which means that these cells are suitable for either autologous or allogeneic treatment and are ideal cells for regenerative medicine. MSCs can be isolated from various tissue types, including the bone marrow, fat, and perinatal tissues. From the perspective of ethics, medicine and cell engineering, adult bone marrow and adipose MSCs cannot be used as a mass production source of conventional treatment. Perinatal tissue, including umbilical cord, amniotic fluid and placenta, is a rich source of MSCs with strong immunosuppressive and proangiogeneic activities. These stem cells bring new hope for disease treatment. This paper reviews the research progress of stem cells as novel technology, novel therapies and industrial model in the field of regenerative medicine.

Integrin-α9β1 as a Novel Therapeutic Target for Refractory Diseases: Recent Progress and Insights

Integrins refer to heterodimers consisting of subunits α and β. They serve as receptors on cell membranes and interact with extracellular ligands to mediate intracellular molecular signals. One of the least-studied members of the integrin family is integrin-α9β1, which is widely distributed in various human tissues and organs. Integrin-α9β1 regulates the physiological state of cells through a variety of complex signaling pathways to participate in the specific pathological processes of some intractable diseases. In recent years, an increasing amount of research has focused on the role of α9β1 in the molecular mechanisms of different refractory diseases and its promising potential as a therapeutic target. Accordingly, this review introduces and summarizes recent research related to integrin-α9β1, describes the synergistic functions of α9β1 and its corresponding ligands in cancer, autoimmune diseases, nerve injury and thrombosis and, more importantly, highlights the potential of α9β1 as a distinctive target for the treatment of these intractable diseases.

Drug Repurposing in Neurological Diseases: Opportunities and Challenges

Drug repurposing or repositioning refers to “studying of clinically approved drugs in one disease to see if they have therapeutic value and do not trigger side effects in other diseases.” Nowadays, it is a vital drug discovery approach to explore new therapeutic benefits of existing drugs or drug candidates in various human diseases including neurological disorders. This approach overcomes the shortage faced during traditional drug development in grounds of financial support and timeline. It is especially hopeful in some refractory diseases including neurological diseases. The feature that structure complexity of the nervous system and influence of blood–brain barrier permeability often becomes more difficult to develop new drugs in neuropathological conditions than diseases in other organs; therefore, drug repurposing is particularly of utmost importance. In this chapter, we discuss the role of drug repurposing in neurological diseases and make a summarization of repurposing candidates currently in clinical trials for neurological diseases and potential mechanisms as well as preliminary results. Subsequently we also outline drug repurposing approaches and limitations and challenges in the future investigations.

The Meridian-like High Thermal Line as the Evidence on Existence of Meridians in Human Body

Background; The acupuncture meridian is the channel through which Qi & Blood flow, and acupuncture is having many thousands year history for treating various illnesses. However, there was no powerful evidence to prove the existence of meridians until now. Objectives; The purpose of this study is to explain that the meridian-like high thermal line (MLHTL) is the powerful evidence to prove the existence of meridians in human body. Methods; The meridian-like high thermal line inducing and the disease cure effect in the target organs connected along the meridians by the mineral pulse light stimuli, was researched and analyzed. Results; The meridian-like high thermal lines were induced along the classic meridians course at the human body surface, and simultaneously the internal refractory diseases such as nephrotic syndrome and angina pectoris were treated in the target organs connected along the meridians without drug use by the mineral pulse light stimuli. Conclusions; The meridian-like high thermal line is the powerful evidence to prove the existence of meridians in human body. From now on, MPL stimulator (Version 1) can induce MLHTL, and can show the non-drug cure effect in target organ connected along MLHTL.

Explaining the Process of Spiritual healing of Critically-ill Patients: A Grounded Theory Study

BACKGROUND: Spiritual healing is one of the most intriguing category of alternative and complementary medicine. The aim of this study was to explain the process of spiritual healing in patients with refractory diseases in Iran.METHODS: This grounded theory study was conducted in Iran from 2018 to 2019. The participants were 14 patients with refractory diseases and 4 healers whom were first selected through purposeful and then theoretical sampling. Semi-structured interviews were used to collect data on patients and healers. All the interviews were transcribed verbatim. Data were coded and grouped under specific categories and analyzed using the Strauss and Corbin’s approach (2008).RESULTS: Four main categories emerged from data analysis including: I) frustration to initial acceptance II) disbelief to trust III) evaluation to action and IV) doubt to certainty.CONCLUSION: The results of our study provide context-specific factors affecting the complex and multifactorial nature of spiritual healing process in patients with refractory diseases. Health care professional can use these findings in designing and implementing appropriate interventions to integrate spiritual healing into their holistic practices of care. .

Therapeutic Considerations for Docetaxel and Paclitaxel in Metastatic Breast Cancer

Breast cancer is the main source of death among women. Currently, 77% of women diagnosed with breast cancer are age 50 and older; however, it is projected that approximately 66% of the new cases diagnosed will occur in women younger than 65. Several clinical trials have assessed the wellbeing and adequacy of taxanes along with their tolerability in patients with metastatic cancer (MBC) The overview of these Paclitaxel and Docetaxel, the mechanism of action, pharmacokinetics and pharmacodynamics, dose and administration, adverse effects, clinical potency, and sufferable profiles combination therapies, the pathological complete response of these taxanes are included. The different novel formulations of taxanes are formulated from nanoparticles, polyglutamate, liposomes to improve the wellbeing and adequacy taxanes to reduce their toxicities. Single-agent research located with docetaxel and paclitaxel in metastatic breast most cancers show clinically huge antitumor motion even in the advanced stage, heavily pretreated, safe, as properly as in refractory diseases. This action is likewise clear with taxane-based combination regimens. Serious hematologic and nonhematologic toxicities are incompatible, with different toxicities noted dependent on the portion and weekly regimen selected. Weekly docetaxel and paclitaxel regimens speak to important helpful treatment options for women suffering from metastatic breast cancer and have entered assessment as a major aspect of adjuvant treatment for this disease Toxicity associated with taxanes chemotherapy are based totally on the dose schedules and weekly regimen selected and the most frequent toxicities related with these marketers include myalgia, peripheral neuropathy, neutropenia, etc Docetaxel retains in tumor cells for longer duration when compared to paclitaxel because of its slow efflux and large amounts of uptake into the cell which explains its more benefits when compared to paclitaxel. Clinical studies conducted so far suggested a more benefit to risk ratio for docetaxel when compared to paclitaxel. This article reviews mainly different actions exhibited by taxanes in the therapy of metastatic breast cancer and others on stages of cancer along with the toxicities associated with these agents.

PALLIATIVE CARE FOR CHILDREN WITH SEVERE, REFRACTORY DISEASES. ANALYTICAL REVIEW

Significance. Improving quality and availability of palliative care for children with severe refractory diseases is one of the main objectives of the federal and reginal authorities. The efforts are focused on improving quality of patients’ life, increasing satisfaction of patients (their legal representatives) and families with availability of palliative care, that relieves suffering of patients and reduces symptoms of depression. Purpose of the study. To analyze modern forms and methods of palliative care delivery to children with severe refractory diseases. Material and methods. The authors have conducted a content analysis of scientific publications on organization of palliative care delivery to children with severe refractory diseases. A total of 153 publications were analyzed, including 141 foreign publications for the period from 1998 to the second quarter of 2020. A total of 44 publications have been selected for the analytical review including 28 publications from the international Scopus database, 12 – from the Russian scientific citation index database, including 7 publications from the list of VAK journals (Higher Attestation Commission Journals), and 4 - materials of international medical organizations (WHO, WHA, AHA, European Council). Results. Children with severe refractory diseases need specialized medical, psychological and social assistance. Palliative care includes active and comprehensive support for physical, psychological, social and spiritual well-being of these children, relieving their suffering, from diagnosis to outcome, reducing symptoms of depression in their families, ensuring the best quality of life. More than 21 million children worldwide require palliative care every year, ranging from 20 to 120 per 10,000 children around the world. However, palliative care is often discussed in the late stages of the disease, not always resulting in its early initiation, only little more than half the patients in need receive palliative care, there are differences in tools for assessing care results. It is necessary to early initiate palliative care, increase volumes of its provision, increase the number of specialists and institutions involved in palliative care delivery, as well as implement a comprehensive balanced assessment of care results.

The Efficacy and Safety Profile of Ixazomib-Based Regimens in Patients with Relapsed/Refractory Multiple Myeloma in Routine Clinical Practice: Real World Data from a Multi-Center Study in China

J Li, L Bao, ZJ Xia and KY Ding contributed equally to this study. Background: Based on the promising results shown in the phase 3 trial (TOURMALINE-MM1, NCT01564537) and the China Continuation Study of MM1, the oral proteasome inhibitor (PI) ixazomib (ixa) was approved in China in April of 2018, in combination with lenalidomide (len) and dexamethasone (dex) (IRd), for patients (pts) with relapsed/refractory multiple myeloma (RRMM). Data on the efficacy and safety of ixa-based therapy in Chinese pts with MM in real-life practice is rather limited. A large national, multi-center, real-world study involving 14 centers from different areas of China was performed to investigate the current status of ixa usage in China and to evaluate the efficacy and safety in routine clinical practice. A total of 246 ixa-treated MM pts was enrolled, with 163 (66.3%) RRMM, 60 (24.4%) newly diagnosed MM and 23 (9.4%) pts received ixa as maintenance. Herein, we reported the data of RRMM in this study. Methods: Medical records, including demographics, disease characteristics, treatment regimen and duration, response rate, adverse events (AEs) and survival, of ixa-treated (at least one cycle completed with response evaluation result) RRMM pts were analyzed. Results: A total of 149 evaluable pts (out of 163 RRMM pts) treated from April 2018, to July 2019 were included in analysis. Baseline features and prior treatment are summarized in Table 1. Patients were categorized into MM1 trial-eligible/-ineligible groups according to the inclusion and exclusion criteria of MM1 study. Median age was 62 years (range 33 - 87) with 52 (34.9%) ≥65 years. Most pts (75.2%) had ISS stage II-III disease. High-risk cytogenetic abnormalities (including del 17p, t (4;14), and/or t (14;16)) were detected in 19 patients (21.1%, among 90 patients with FISH results). Fifty-two (34.9%) pts had a ECOG PS ≥2. Overall, ixa-based regimens were used as the 2nd/3rd/4th/≥5th-line therapy in 29.7%, 33.1%, 16.2% and 17.4% of the pts, respectively. Prior treatment included bortezomib (91.9%), len (52.0%) and thalidomide (58.8%). More than half pts (54.7%) were refractory to previous bortezomib treatment, and 32.2% pts were len-refractory. MM-1 trial-ineligible pts had more advanced ISS stage, higher ECOG PS, more severe anemia, more lines of prior therapy and more refractory diseases. Treatment, outcome and survival were listed in Table 2. Ixa-based regimens included IRd in 70 (47.0%) patients, ixa-dex (Id) in 31 (20.8%) patients and Id plus chemotherapeutics/other agents (44, 29.5%; including cyclophosphamide in 14 pts, thalidomide in 12 pts, adriamycin in 6 pts, melphalan in 5 pts and daratumumab in 3 pts) in 20 (33.3%). (Table 2). One patient received stem cell transplantation (SCT) during follow-up. The best confirmed ORR (≥PR) for all 149 patients was 53.7% (80/149), including 28.2% of patients with ≥VGPR and 7.4% with a CR, with a median time to response of 41.5 days. Surprisingly, ixa-based regimens demonstrated efficacy in pts with PI/len refractory diseases, with an ORR and ≥VGPR rate of 44.4% and 19.9% for PI-refractory pts, and an ORR and ≥VGPR rate of 30.6% and 12.2% for len-refractory pts. Pts eligible for MM1 study shown comparable ORR (76.7%) with that reported in MM1 (ORR 78%). No significant difference in response between different ixa-based regimens was observed. The median PFS of the whole cohort, pts with standard/high cytogenetic risks, pts refractory to bortezomib/len and pts eligible/ineligible for MM1 trial was 8.2, 8.2, 6.8, 6.7, 5.9months, not reached and 6.6months respectively. The median overall survival (OS) of the whole cohort and every subgroup was not reached. Adverse events (AEs) of grade 3/4, reported in 40 (27.2%) patients, included 10.1% thrombocytopenia, 5.4% anemia, 3.4% diarrhea and 6.0% pneumonia. Only 3 (2.01%) pts had a grade 3/4 peripheral neuropathy during follow-up. Discussion and conclusion: Our results show that ixa-based therapy demonstrated good efficacy with limited toxicity for pts with RRMM in real-life clinical practice. Moreover, in pts with PIs- or len- refractory diseases, ixa-based therapy still showed acceptable effectiveness (ORR: 44.4% and 30.6%; mPFS: 6.7 months and 5.9 months). Although 70.5% pts in our real-life cohort were ineligible for MM1 trial, the efficacy and safety profile is similar to that reported in MM1 China Continuation Study. Ixa-based therapy is a reasonable choice for Chinese RRMM pts. Disclosures No relevant conflicts of interest to declare.