Background: Mental synthesis is the conscious purposeful process of synthesizing a novel mental image from objects stored in memory. In our everyday use of language, we rely on mental synthesis to communicate an infinite number of images with a finite number of words. In typical children, the timeline of mental synthesis acquisition is highly correlated with an increasing vocabulary. Children with ASD, on the other hand, may learn hundreds of words but never acquire mental synthesis. In these individuals, tests assessing vocabulary comprehension may fail to demonstrate the profound deficit in mental synthesis and the resulting inability to understand flexible syntax and spatial prepositions. Objective: We developed a 20-question parent-reported evaluation tool designed to quantitatively assess mental synthesis ability and to serve as a complimentary scale for Autism Treatment Evaluation Checklist (ATEC). Results: Internal reliability was good (Cronbach’s alpha > .9), and the MSEC exhibited adequate test-retest reliability after a three- and nine-months follow up period. The MSEC results positively correlated with the ATEC communication subscale, providing support for construct validity. Moreover, MSEC scores were significantly different for children of different ASD severity levels confirming the known groups validity. Conclusions: This study represents the first step toward the development of an instrument to measure mental synthesis in children with ASD. Although the current empirical evaluation demonstrated strong evidence of excellent psychometric properties, such as validity and reliability, additional studies should be performed to replicate these findings.

Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and treatment of the disease remain a key research endeavor in advancing scientific understanding and clinical applications. In particular, cell-based regenerative medicine, specifically stem cells transplantation, may hold promise as stroke therapy because grafted cells and their components may recapitulate the growth and function of the neurovascular unit, which arguably represents the alpha and omega of stroke brain pathology and recovery. Recent evidence has implicated mitochondria, organelles with a central role in energy metabolism and stress response, in stroke progression. Recognizing that stem cells offer a source of healthy mitochondria, potentially transferrable into ischemic cells, may provide a new therapeutic tool. To this end, deciphering cellular and molecular processes underlying dysfunctional mitochondria may reveal innovative strategies for stroke therapy. Here, we review recent studies capturing the intimate participation of mitochondrial impairment in stroke pathology, and showcase promising methods of healthy mitochondria transfer into ischemic cells, to critically evaluate the potential of mitochondria-based stem cell therapy for stroke.

Understanding the biology underlying the mechanisms and pathways regulating pancreatic β-cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin producing β-cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β-cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β-cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive toβ-cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1⁺/NKX6.1⁺), warrants their future commitment to monohormonal β-cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1⁺/NKX6.1^-) results in an undesirable generation of non-functional polyhormonal β-cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β-cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a mean to increase β-cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β-cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

The past decade has witnessed enormous progress, which has seen the noncoding RNAs (ncRNAs) turn from the so called dark matter RNA to critical functional molecules, influencing most physiological processes in development and disease contexts. Many ncRNAs interact with each other and are part of networks that influence the cell transcriptome and proteome and consequently the outcome of biological processes. The regulatory circuits controlled by ncRNAs have become increasingly more relevant in cancer. Further understanding of these complex network interactions and how ncRNAs are regulated, is paving the way for the identification of better therapeutic strategies in cancer.

In this study, 6 residents of a long-term care facility were asked to try on Virtual Reality glasses and report their first experiences with Virtual Reality. The results show that Virtual Reality is of great interest to elderly residents of in-patient long-term care facilities. The wearing period was longer than expected and no symptoms of cyber sickness occurred. For the residents it was exciting to explore the virtual environments. Austrian destinations, nature scenes in the mountains and forests but also trips to the zoo, the museum, in churches or even densely populated areas like shopping streets or train stations would be places for the residents, they would like to explore virtually. Far-off destinations such as Rio de Janeiro or the Caribbean are more of an exception. Biographically relevant places such as the parental home or the location of their wedding were not named. Concerning the usability, an adjustment of the VR glasses is necessary for a longer-term use in any case.

1) Introduction: Negative pressure wound therapy (NPWT) is a frequently applied open abdomen (OA) treatment. There are only a few experimental data supporting this method and describing the optimal settings and pressure distribution in the abdominal cavity during this procedure. The aim of our study was to evaluate pressure values at different points of the abdominal cavity during NPWT in experimental abdominal compartment syndrome (ACS) animal model. 2) Methods: In this study (permission Nr. 13/2014/UDCAR) 27 Hungahib pigs (15.4- 20.2 kg) were operated. ACS was generated by implanting a plastic bag in the abdomen through mini-laparotomy and filled with 2100- 3300 ml saline solution (37 C°) to an intraabdominal pressure (IAP) of 30 mmHg. After 3 hours, NPWT (Vivano Med ® Abdominal Kit, Paul Hartmann AG, Germany) or Bogota bag was applied. NPWT group was divided into -50, -100 and 150 mmHg suction group. Pressure distribution to the abdominal cavity was monitored at 6 different points of the abdomen via a multichannel pressure monitoring system. 3) Results: The absolute pressure levels were significantly higher above than below the layer. The values of the pressure were similar in the midline than laterally. Amongst the bowels, the pressure values changed periodically between 0 and -12 mmHg which might be caused by the peristaltic movements. 4) Conclusions: The porcine model of the present study seems to be well applicable for investigating ACS and NPWT. It was possible to provide valuable for clinicians. The pressure was well distributed by the protective layer to the lateral parts of the abdomen and this phenomenon did not change considerably during the therapy.

Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.

The morbidity and mortality caused by invasive fungal infections is increasing across the globe due to developments in transplant surgery, the use of immunosuppressive agents, and the emergence of drug-resistant fungal strains, which has led to a challenge in terms of treatment due to the limitations of three classes of drugs. Hence, it is imperative to establish effective strategies to identify and design new antifungal drugs. Drug repurposing is an effective way of expanding the application of existing drugs. In the last years, various existing drugs have been shown to be useful in the prevention and treatment of the invasive fungi. In this review, we summarize the currently used antifungal agents. In addition, the most up to date information on the effectiveness of existing drugs with antifungal activity is discussed. Moreover, the antifungal mechanisms of existing drugs are highlighted. These data will provide valuable knowledge to stimulate further investigation and clinical application in this field.

Purpose: Dysarthria, a neurological injury of the motor component of the speech circuitry, is of common consequences of traumatic brain injury (TBI). Palilalia is a speech disorder characterized by involuntary repetition of words, phrases, or sentences. Based on the evidence supporting the effectiveness of transcranial direct current stimulation (tDCS) in some speech and language disorders, we hypothesized that using tDCS would enhances the effectiveness of speech therapy in a client with chronic dysarthria following TBI. Method: We applied the constructs of the “Be Clear” protocol, a relatively new approach in speech therapy in dysarthria, together with tDCS on a chronic subject who affected by dysarthria and palilalia after TBI. Since there was no research on the use of tDCS in such cases, regions of interest (ROIs) were identified based on deviant brain electrophysiological patterns in speech tasks and resting state compared with normal expected patterns using the Quantitative Electroencephalography (QEEG) analysis. Results: Measures of perceptual assessments of intelligibility, an important index in the assessment of dysarthria, ​​were superior to the primary protocol results immediately and 4 months after intervention. We did not find any factor other than the use of tDCS to justify this superiority. The percentage of repeated words, an index in palilalia assessment, had a remarkable improvement immediately after intervention but fell somewhat after 4 months. We justified this case with subcortical origins of palilalia. Conclusion: Our present case-based findings suggested that applying tDCS together with speech therapy may improve intelligibility in similar case profiles as compared to traditional speech therapy. To reconfirm the effectiveness of the above approach in cases with dysarthria following TBI, more investigation need to be pursued.

DNA origami has emerged in recent years as a powerful technique for designing and building 2D and 3D nanostructures. While the breadth of structures that have been produced is impressive, one of the remaining challenges, especially for DNA origami structures intended to carry out useful biomedical tasks in vivo, is to endow them with the ability to detect and respond to molecules of interest. Target molecules may be disease indicators or cell surface receptors, and the responses may include conformational changes leading to release of therapeutically relevant cargo. Nucleic acid aptamers are ideally suited to this task and are beginning to be used in DNA origami designs. In this review we consider examples of uses of DNA aptamers in DNA origami structures and summarise what is currently understood regarding aptamer-origami integration. We review three major roles for aptamers in such applications: protein immobilisation, triggering of structural transformation, and cell targeting. Finally, we consider future perspectives for DNA aptamer integration with DNA origami.

This paper is an interdisciplinary study of novel applications of techniques and tools of an area of brain science, known as Synesthesia (involving associations and/or confusion between distinct senses), to area of Computer Science known as Immersive Virtual Reality (VR), that makes the subject’s awareness of physical self be diminished by being surrounded in an engrossing artificial environment. Natural Synesthesia has for the last decade been an important emerging area in brain science but is present in only a small proportion of the population. For example a person with Natural Synesthesia, when viewing a grapheme, may perceive a color additionally to be associated to the grapheme. In contrast, Artificial synesthesia (also known as virtual synesthesia or synthetic synesthesia) has been defined as the sensory joining due a cross-modal mapping device, where information of one sense is accompanied by an induced perception in another sense. In particular, we propose use of a multimodal manner of displaying information in VR to increase and concentrate attention. Artificial Synesthesia to synthetically create induced associations between senses, allowing Artificial Synesthesia to be experienced by anyone using a VR system. The paper describes the enhancement of immersive VR by use of Artificial Synesthesia to improve the system’s performance at steering and directing the attention of the user. We describe techniques for an enhanced immersive VR that displays associations between a variety of senses: between colors and characters, also between colors and sounds, and between sounds and the position of tactile sensations. The sense association provided by Artificial Synesthesia allows the system to better capture the user’s attention and better direct that attention. A major application of our work in VR-induced Artificial Synesthesia is to provide an enhanced methodology for controlling the attention of the subject, and to improve the direction of attention of subjects undergoing guided imagery therapies for pain relief. Other potential high-impact applications include improved immersive VR, more programmable human/computer interfaces and other medical therapies.

The research and development of non-viral gene therapy has been extensive over the past decade and has received a big push thanks to the successful approval of non-viral gene therapy products in recent times. Despite these developments, gene therapy applications in cancer have been limited. One of the main causes of this has been the imbalance in development of delivery vectors as compared to nucleic acid payloads. This paper reviews non-viral vectors that can be used to deliver nucleic acids for cancer treatment. It discusses various types of vectors and highlights their current applications. Additionally, it also discusses perspective on regulatory landscape to facilitate commercial translation of gene therapy.

The World Anti-Doping Agency has prohibited gene doping in the context of progress in gene therapy. There is a risk that the artificial regulation of genes using plasmids could be applied for gene doping. However, no gold standard method to detect this has been established. Here, we aimed to develop a method to detect multiple transgene fragments as proof of gene doping. First, gene delivery model mice as a mimic of gene doping were created by injecting firefly luciferase plasmid with polyethylenimine (PEI) into the abdominal cavity. The results confirmed successful establishment of the model, with sufficient luminescence upon in vivo imaging. Next, multiple transgene fragments in the model were detected in plasma cell-free (cf)DNA, blood-cell-fraction DNA, and stool DNA using the TaqMan-qPCR assay, with the highest levels in plasma cfDNA. Using just a single drop of whole blood from the model, we also attempted long-term detection. The results showed that multiple transgene fragments were detected until 11 days. These findings indicate that the combination of plasma cfDNA or just one drop of whole blood with TaqMan-qPCR assay is feasible to detect plasmid-PEI-based gene doping. Our findings could accelerate the development of methods for detecting gene doping in humans.

Photodynamic therapy (PDT) of cancer is dependent on three primary components: photosensitizer (PS), light, and oxygen. Because these components are interdependent and vary during the dynamic process of PDT, assessing PDT efficacy may not be trivial. Therefore, it has become necessary to develop pre-treatment planning, on-line monitoring and dosimetry strategies during PDT, which become more critical for two or more chromophore systems, e.g. PS-CD conjugates developed in our laboratory for fluorescence-imaging and PDT of cancer. In this study, we observed a significant impact of variable light dosimetry; (i) high light fluence and fluence rate (light dose: 135 J/cm², fluence rate: 75 mW/cm²) and (ii) low light fluence and fluence rate (128 J/cm² and 14 mW/cm² and 128 J/cm² and 7 mW/cm²) in photobleaching of the individual chromophores and their long-term tumor response. The fluorescence at the near-infrared (NIR) region of the PS-NIR fluorophore conjugate was assessed intermittently via fluorescence imaging. The loss of fluorescence, photobleaching, caused by singlet oxygen from the PS was mapped continuously during PDT. The tumor responses (BALB/c mice bearing Colon26 tumors) were assessed after PDT by measuring tumor sizes daily. Our results showed distinctive photobleaching kinetics rates between the PS and CD. Interestingly, compared to higher light fluence, the tumors exposed at low light fluence showed reduced photobleaching and enhanced long-term PDT efficacy. The presence of NIR fluorophore in PS-CD conjugates provides an opportunity of fluorescence imaging and monitoring the photobleaching rate of the CD moiety for large and deeply seated tumors and assessing PDT tumor response in real-time.

With the rapid progress of genetic engineering and gene therapy, World Anti-Doping Agency has alerted to gene doping and prohibited its use in sports. However, there is no standard method available yet for detection of transgenes delivered by recombinant adenoviral (rAdV) vectors. Here we aimed to develop a detection method for transgenes delivered by rAdV vectors in a mouse model that mimics gene doping. rAdV vectors containing mCherry gene was delivered in mice through intravenous injection or local muscular injection. After five days, stool and whole blood samples were collected, and total DNA was extracted. As additional experiments, whole blood was also collected from mouse tail tip until 15 days from injection of the rAdv vector. Transgene fragments from different DNA samples were analyzed using semi-quantitative PCR (sqPCR), quantitative PCR (qPCR), and droplet digital PCR (ddPCR). In the results, transgene fragments could directly be detected from blood cell fraction-DNA, plasma-cell free DNA and stool-DNA by qPCR and ddPCR, depending on specimen type and injection methods. We observed that a combination of blood cell fraction-DNA and ddPCR was more sensitive than other combinations used in this model. These results could accelerate the development of detection methods for gene doping.

The purpose of this study is to develop a cranial traction therapy program to help correct facial asymmetry of the hard tissues through the means of the treatment of soft tissues—a non-surgical therapeutic method for the correcting of facial asymmetry. We have formed a group of experts who have agreed to the study. In the primary survey, open questions were used. In the second survey, the results of the first survey were summarized and the degree of agreement was presented to the questions in each category. In the third survey, we conducted a statistical analysis of the degree of agreement on each item of question. All surveys also performed email. The distribution was calculated using the SPSS (ver.23.0) program, and the mean difference between the result and X² was calculated. The significance level was set to p<.05. Most of the questions attained a certain level of consensus by the experts (average of 4.0 or higher), it can be said that most are important and suitable questions. the results regarding the degree of importance for each of the points of evaluation made by the groups of experts in both the second and third stage of the cranial traction therapy program were verified using content validity ratio (CVR 77). The ratio for the cranial traction 13 points of evaluation was within the range of 0.40∼1.00, so the Delphi program for the cranial traction therapy verified that the content was valid.

Background: Acute injuries of the hamstring muscle complex (HMC) Type 3b (interfascicle / bundle-tear) are frequently observed in various sports disciplines both in elite and recreational sport. The treatment of choice of acute HMC injuries Type 3b is a progressive physiotherapeutic exercise program. Besides this, there is currently only insufficient scientific evidence to support other treatment methods, including local infiltrations and injections of platelet-rich-plasma. Very recently it was demonstrated that extracorporeal shock wave therapy (ESWT) may accelerate regeneration after acute skeletal muscle injury. The aim of the present study is to test the hypothesis that the combination of radial ESWT (rESWT) and a specific rehabilitation program (RP) is effective and safe in treatment of acute HMC injury Type 3b in athletes, and is statistically significantly more effective than the combination of sham-rESWT and RP. Methods/Design: We will perform a double blind, randomized, sham-controlled clinical trial at the clinic KinEf Kinesiología Deportiva, Ciudad Autónoma de Buenos Aires, Argentina. Fourty patients with acute HMC injury Type 3b will be randomly allocated to receive either rESWT (nine rESWT sessions; three sessions per week; 2500 radial extracorporeal shock waves (rESWs) per session; energy density depending on what the patient tolerates) or sham-rESWT. In addition, all patients will receive a specific rehabilitation program that will last for eight weeks. The primary outcome measure will be the individual time (days) necessary to return to play. Secondary outcomes will include the presence or absence of reinjury during a time period of six months after inclusion into the study. Discussion: Because of the lack of adequate treatment options for acute HMC injury Type 3b in athletes and particularly the high reinjury rate, we hypothesize that the results of this trial will be of importance and have impact on clinical practice. Trial registration: ClinicalTrials.gov ID NCT03473899. Registered March 22, 2018.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of a timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including an angiogenic switch, immune escape, cancer stem cells, extra cellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced-p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer, and discuss the implications of such approaches in cancer treatment.

Cell death resistance is a key feature of tumor cells. One of the main anti-cancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells.

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has re-emerged in recent decades, causing large-scale epidemics in many parts of the world. CHIKV infection leads to a febrile disease known as chikungunya fever (CHIKF), which is characterised by severe joint pain and myalgia. As many patients develop a painful chronic stage and neither antiviral drugs nor vaccines are available, the development of a potent CHIKV inhibiting drug is crucial for CHIKF treatment. A comprehensive summary of current antiviral research and development of small-molecule inhibitor against CHIKV is presented in this review. We highlight different approaches used for the identification of such compounds and further discuss the identification and application of promising viral and host targets.

The prolonged lockdown imposed to contain the COVID-19 pandemic prevented many people from direct contact with nature and greenspaces, raising alarms for a possible worsening of mental health. This study investigates the effectiveness of a simple and affordable remedy for improving psychological well-being, based on audio-visual stimuli brought by a short computer video showing forest environments, with an urban video as a control. Randomly selected participants were assigned the forest or urban video, to look at and listen early in the morning, and filled questionnaires. In particular, the State-Trait Anxiety Inventory (STAI) Form Y, collected in baseline condition and at the end of the study, and the Part II of the Sheehan Patient Rated Anxiety Scale (SPRAS), collected every day immediately before and after watching the video. The virtual exposure to forest environments showed effective to reduce perceived anxiety levels in in people forced by lockdown in limited spaces and environmental deprivation. Although significant, the effects were observed only in the short term, highlighting the limitation of the virtual experiences. The reported effects might also represent a benchmark to disentangle the determinants of health effects due to real forest experiences, for example, the inhalation of biogenic volatile organic compounds (BVOC).

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of a timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including an angiogenic switch, immune escape, cancer stem cells, extra cellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced-p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer, and discuss the implications of such approaches in cancer treatment.

Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ERBB4 is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM. Using RT-qPCR, we quantified mRNA encoding total ERBB4 and known ERBB4 variants in GBM and non-neoplastic normal brain (NNB) samples. Using immunohistochemistry, we characterized the localization of total and phosphorylated ERBB4 (p-ERBB4) and EGFR protein in archived GBM samples and assessed their association with patient survival. Furthermore, we evaluated the effect of ERBB4 phosphorylation on angiogenesis and tumorigenicity in GBM xenograft models. Total ERBB4 mRNA was significantly lower in GBM than NNB samples, with the JM-a and CYT-2 variants predominating. ERBB4 protein was ubiquitously expressed in GBM but was not associated with patient survival. However, high p-ERBB4 in 11% of archived GBM samples, independent of p-EGFR, was associated with shorter patient survival (12.0±3.2 months) than was no p-ERBB4 (22.5±9.5 months). Increased ERBB4 activation was also associated with increased proliferation, angiogenesis, tumorigenicity and reduced sensitivity to anti-EGFR treatment in xenograft models. Despite low ERBB4 mRNA in GBM, the functional effects of increased ERBB4 activation identify ERBB4 as a potential prognostic and therapeutic target.

Patients with underlying health conditions are at risk for a poor outcome from Coronavirus disease 2019 (COVID-19). Using machine reasoning by the sci.AI system, we investigated the pathobiochemistry of this observation to generate therapeutic guidelines. Facts were extracted and linked from publications available in nlm.nih.gov and Europe PMC to form the dataset which was validated by medical experts. Previously we described how preexisting chronic inflammation renders the acute inflammatory response to Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) excessive translating the SARS-CoV-2 infection into the clinical COVID-19 syndrome. Herein we focus on therapeutic interventions that mitigate the immune response. In essence, from bench to bedside, as depicted in the Graphical Abstract, the clinical management of COVID-19 should aim at: A. Control of excessive oxidant production. B. Neutralization of excessive oxidants. C. Upregulation of nitric oxide (NO) production.

Background: To prioritize the development of antiviral compounds, it is necessary to compare their relative preclinical activity and clinical efficacy. Methods: We reviewed in vitro, animal model, and clinical studies of candidate anti-coronavirus compounds and placed extracted data in an online relational database. Results: As of July 2020, the Coronavirus Antiviral Research Database (CoV-RDB; covdb.stanford.edu) contained >2,400 cell culture, entry assay and biochemical experiments, 240 animal model studies, and 56 clinical studies from >300 published papers. SARS-CoV-2, SARS-CoV, and MERS-CoV account for approximately 85% of the data. Approximately 75% of experiments involved compounds with a known or likely mechanism of action, including receptor binding inhibitors and monoclonal antibodies (20%); viral protease inhibitors (18%); polymerase inhibitors (9%); interferons (8%); fusion inhibitors (8%); host endosomal trafficking inhibitors (7%); and host protease inhibitors (5%). For 724 compounds with a known or likely mechanism, 95 (13%) are licensed in the US for other indications, 72 (10%) are licensed outside the US or are in human trials, and 557 (77%) are pre-clinical investigational compounds. Conclusion: CoV-RDB facilitates comparisons between different candidate antiviral compounds, thereby helping scientists, clinical investigators, public health officials, and funding agencies prioritize the most promising compounds and repurposed drugs for further development.

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-Sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update of NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

Mesenchymal stem cells (MSCs) have emerged as a promising treatment for inflammatory diseases. It is described that the immunomodulatory effect of MSCs takes place both by direct cell-to-cell contact and by means of soluble factors that leads to an increased accumulation of regulatory immune cells at the sites of inflammation. Similar efficacy of MSCs has been described regardless the route of administration used, the inflammation conditions and the MHC context. These observations arise the question as to whether the migration of the MSCs to the inflamed tissues is a pre-requisite to achieve their beneficial effect. To address this, we examined the biodistribution and the efficacy of intraperitoneal luciferase-expressing human expanded adipose derived stem cells (Luci-eASCs) in a mouse model of colitis. Luci-eASC-infused mice were stratified according to their response to the Luci-eASC treatment. According to the stratification criteria, there was a tendency to increase the bioluminescence signal in the intestine at the expense of a decrease in the bioluminescence signal in the liver in the `responder´ mice. These data thus suggest that the accumulation of the eASCs to the inflamed tissues is beneficial to achieve an optimal modulation of inflammation.

In December 2019 a novel human-infecting coronavirus, named SARS-CoV-2 has been recognized to cause a pneumonia epidemic outbreak with different degree of severity in Wuhan, Hubei Province in China. Since then this epidemic spread worldwide an in the last week Europe and Italy also have been involved. Effective preventive and therapeutic strategies are absolutely required to block this serious public health concern. Unfortunately, SARS-CoV-2 has been isolated only recently, therefore a few studies concerning its immunopathogenesis and tretament are available. Therefore, on the basis of the assumption that the SARS-CoV-2 is genetically related to SARS-CoV (about 82% of genome homology) and that its characteristics, like the modality of transmission, the route of infection, the organ localization, the type of the immune response it may stimulate, the morbidity and the mortality rates are still poor-known, a literature search was performed to identify the reports assessing these elements in patients with SARS-CoV-induced infection. Therefore, we have analysed: 1) the structure of SARS CoV-2 and SARS CoV; 2) the clinical signs and symptoms and pathogenic mechanisms observed during the development of acute respiratory syndrome and the Cytokine Release Syndrome; 3) the modification of the cell microRNome and of the immune response in patients with SARS infection; 4) the possible role of some liposoluble compounds (such as vitamin A, D and E) in modulating directly or indirectly the replication ability of SARS-CoV-2 and host immune response.

In the modern world, the problem of antibiotic therapy is acute. Despite the diversity of existing antibiotic drugs, their efficacy decreases as new, resistant forms of pathogenic microorganisms emerge. It is extremely difficult to control such processes and even more difficult to treat severe bacterial infections. In such situations, an individual approach to each patient is required and physicians need parameters to estimate the efficacy of antibiotic therapy. This review discusses the significance of monitoring the content of antibiotics in the blood for this purpose, in combination with the content of inflammatory markers, such as C-reactive protein and procalcitonin. The basic principles of antibiotic therapy, and factors in the resistance of microorganisms to antibiotics, are examined. Approaches to assess the efficacy of antibiotic therapy, as well as methods to detect antibiotics and inflammatory markers in the blood of patients, and comparative assessment of their capabilities and limitations, are described.

Animal-assisted interventions (AAI) use human-animal interactions to positive effect in various contexts including cancer care. This systematic literature review is the first part of a two-part paper series focusing on the research methods and quantitative results of AAI studies in oncology. We find methodological consistency in the use of canines as therapy animals, in the types of high-risk patients excluded from studies, and in the infection precautions taken with therapy animals throughout cancer wards. The investigated patient endpoints are not significantly affected by AAI, with the exceptions of improvements in oxygen consumption, quality of life, depression, mood, and satisfaction with therapy. The AAI field in oncology has progressed significantly since its inception and has great potential to positively impact future patient outcomes. To advance the field, AAI research in oncology should consistently improve the methodological design of studies, report data more completely, and focus on the therapy animal’s well-being.

I Introduction: Pneumothorax is a pathological condition characterized by the presence of air between the visceral and parietal pleura. Objectives: To investigate incidence, clinical characteristics, risk factors, management and perinatal outcome among newborns with pneumothorax in a tertiary care center. Materials and Methods: A prospective observational study was conducted in Maternity hospital with tertiary NICU from 2015-2019. We included all neonates with pneumothorax born in our hospital and compared demographic characteristics, perinatal risk factors, anthropometric parameters, concurrent diseases, clinical course and method of chest drainage between full term (≥37 GW) and preterm (<37GW) newborns. Results: Mong 30.378 neonates, 74 developed pneumothorax (2, 4/1000 newborns). The incidence of neonatal pneumothorax (NP) was higher in preterm group (59, 5%), with a mean age 34,62 GW in whole group. The mode of delivery was c. section in 68.9%. NP occurred mostly on the right side (47,3%), on the second day of life , in males (67,6%). Chest drainage was performed in 64,9% of cases. Of 74 NP cases, 64 (85.1%) recovered, 6 (8,1%) died. Conclusion: Pneumothorax is a pathological condition of the newborn, which, if not diagnosed in time and treated adequately, leads to a fatal outcome.ads to a

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from serosal surface of abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within 3 years. The dismal survival makes DSRCT an orphan disease with urgent need of new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors have been evaluated in small studies. Recent works using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.

Music has the ability to evoke a wide variety of emotions in human listeners. Research has shown that treatment for depression and mental health disorders is significantly more effective when it is complemented by music therapy. However, because each human experiences music-induced emotions differently, there is no systematic way to accurately predict how people will respond to different types of music at an individual level. In this experiment, a model is created to predict humans’ emotional responses to music from both their electroencephalographic data (EEG) and the acoustic features of the music. By using recursive feature elimination (RFE) to extract the most relevant and performing features from the EEG and music, a regression model is fit and accurately correlates the patient’s actual music-induced emotional responses and model’s predicted responses. By reaching a mean correlation of r = 0.788, this model is significantly more accurate than previous works attempting to predict music-induced emotions (e.g. a 370% increase in accuracy as compared to Daly et al. (2015)). The results of this regression fit suggest that accurately predicting how people respond to music from brain activity is possible. Furthermore, by testing this model on specific features extracted from any musical clip, music that is most likely to evoke a happier and pleasant emotional state in an individual can be determined. This may allow music therapy practitioners, as well as music-listeners more broadly, to select music that will improve mood and mental health.

In this review, we highlight new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in APL. PML-RARa sets the cellular landscape of Acute promyelocytic leukemia (APL) by repressing transcription of RARa target genes and disrupting PML-NBs. RAR receptors control the homeostasis of tissue growth, modeling and regeneration, PML NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. Additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. Treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. Resistance to ATRA and ATO may derive from mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or induction of apoptosis in APL cells.

Ucuùba fat is fat obtained from a plant found in South America, mainly in Amazonian Brazil. Due to its biocompatibility and bioactivity, the Ucuùba fat was used for production of ketoconazole-loaded nanostructured lipid carriers (NLC) in view of an application for the treatment of onychomycosis and other persistent fungal infections. The development and optimization of the Ucuùba fat based NLC were performed using a Box-Behnken design of experiment. The independent variables were surfactant concentration (% w/v), liquid lipids concentration (% w/v), solid lipids concentration (% w/v), while the outputs of interest were particle size, polydispersity index (PDI) and drug encapsulation efficiency (EE). The Ucuùba fat based NLC were produced and the process optimized determining a predictive mathematical model. Applying the model, two formulations with the pre-required particle size, i.e., 30 and 85 nm, were produced for further evaluation. The optimized formulations were characterized and showed a particle size in agreement to the predicted value, i.e. 33.6 nm and 74.6 nm, respectively. The optimized formulations were also characterized using multiple techniques in order to investigate the solid state of drug and excipients (DSC and XRD), particle morphology (TEM) and interactions between the formulation components (FTIR). Furthermore, particle size and surface charge of the formulations was studied during a one-month stability study and did not evidence any significative modification during storage.

Radiotherapy using accelerated charged particles is rapidly growing worldwide. About 85% of the cancer patients receiving particle therapy is irradiated with protons, which have physical advantages compared to X-rays but similar biological response. In addition to the ballistic advantages, heavy ions present specific radiobiological features that can make them attractive for treating radioresistant, hypoxic tumors. An ideal heavy ion should have lower toxicity in the entrance channel (normal tissue), and being exquisitely effective in the target region (tumor). Carbon ions have been chosen because they represent the best combination in this direction. Normal tissue toxicities and second cancer risk are similar to those observed in conventional radiotherapy. In the target region, they have increased relative biological effectiveness and reduced oxygen enhancement ratio compared to X-rays. Some radiobiology properties of densely ionizing carbon ions are so distinct from X-rays and protons that they can be considered as a different “drug” in oncology, and may elicit favorable responses such as increased immune response and reduced angiogenesis and metastatic potential. The radiobiological properties of carbon ions should guide patient selection and treatment protocols to achieve optimal clinical results.

Liquid biopsy, based on the circulating tumor cells (CTCs) and cell-free nucleic acids has potential applications at multiple points throughout the natural course of cancer, from diagnosis to follow-up. The advantages of doing ctDNA assessment vs. tissue-based genomic profile are the minimal procedural risk, the possibility to serial testing in order to monitor disease-relapse and response to therapy over time and to reduce hospitalization costs during the entire process. However some critical issues related to ctDNA assays should be taken in consideration. The sensitivity of ctDNA assays depends on the assessment technique and genetic platforms used, on tumor-organ, stage, tumor heterogeneity, tumor clonality. The specificity is usually very high, whereas the concordance with tumor-based biopsy is generally low. In patients with renal cell carcinoma (RCC) qualitative analyses of ctDNA have been performed with interesting results regarding selective pressure from therapy, therapeutic resistance, exceptional treatment response to everolimus and mutations associated with aggressive behavior. Quantitative analyses showed variations of cfDNA levels at different tumor stage. Compared to CTC assay, ctDNA is more stable than cells and easier to isolate. Splice variants, information at single-cell level and functional assays along with proteomics, transcriptomics and metabolomics studies can be performed only in CTCs.

Phenotypic switching in cancer cells has been found to be present across tumor types. Recent studies on Glioblastoma report a remarkably common architecture of four well-defined phenotypes coexisting within high levels of intra-tumour genetic heterogeneity. Tumours grown from any cell type recapitulate the original phenotypic composition. Similar dynamics have been shown to occur in breast cancer, melanoma and likely across further cancer types. Given the adaptive potential of phenotypic switching (PHS) strategies, understanding how it drives tumour evolution and how to break down these architectures is a major priority. Here we model the ecological dynamics behind PHS. The model is able to reproduce experimental results, and specific conditions for cancer progression and clearance reveal novel features of plastic tumours and its direct consequences on therapy resistance. Following our results we discuss \textit{transition} therapy as a novel scheme to target not only combined cytotoxicity but also the rates of phenotypic switching.

Film therapy, the therapeutic use of movies in psychological therapies, is a growing area of interest to therapists and researchers. This paper presents the MOVIE model of film therapy, a widely applicable, trauma-informed framework for working with film imagery and themes in individual or group therapy, counsellor education and self-help. Film or cinema therapy is a highly accessible and relatable method for many diverse client and student groups with benefits that include, catharsis and emotional processing, greater ease of dialogue around issues, increased empathy, and interpersonal learning, engaging with new perspectives and learning skills. Following the model clients mindfully observe and voice their emotional and psychological responses to movie watching, identify how the imagery, characters, themes, and narrative symbolise personal experience and consider any new possibilities that emerged through re-authoring personal narratives. The model is informed by a practice focused review of literature.

Background: CD169 has been found overexpressed in the blood of COVID-19 patients and identified as a biomarker in the early disease. We have analysed CD169 in blood cells of COVID-19 patients to assess its role as predictive marker of the disease. Methods : The ratio of the CD169 Median median Fluorescence fluorescence Intensity intensity of CD169 between monocytes and lymphocytes (CD169 RMFI ) was analysed by flow cytometry in blood samples of COVID-19 patients (COV) and healthy donors (HD ) and correlated with immunophenotyping, inflammatory markers, cytokines mRNA expression, pulmonary involvement and disease progression. Results: CD169 RMFI increased in COV but not in HD. CD169 RMFI correlated with T-cell differentiation and exhaustion markers as well as with B cells maturation and differentiation. In vitro stimulation of PBMCs of HD with SARS-CoV-2 Spike spike protein induced CD169 RMFI together with IL-6 and IL-10 gene expression. Likewise, CD169 RMFI correlated with blood cytokine mRNA levels, inflammatory markers, and pneumonia severity in patients which that had not received any treatment at sampling. Notably, in untreated patients, CD169 RMFI reflected the respiratory outcome during hospitalization. Conclusion : Considering the immunological role of CD169 and its involvement during the infection and the progression of COVID-19, it could be considered as an early biomarker to evaluate disease progression and clinical outcome.

Objective: To evaluate the effect of rectal Ozone (O3) in severe COVID-19 pneumonia in two different cohorts differing in location (Madrid vs Zilina), ethnicity (Slovakian vs Spanish cohorts) and age. Material and Methods: In a multicenter-study, 32 severe bilateral-COVID-19-pneumonia patients and (+) RT-PCR (reverse transcriptase polymerase chain reaction) SARS-CoV-2 were evaluated (16 from each cohort). Primary outcomes: a) clinical (O2-saturation); b) biochemical (Lymphocyte-count, Fibrinogen, D-Dimer, Urea, Ferritin, LDH [lactate dehydrigenase], IL-6 and CRP [c-reactive protein]); and c) radiological improvement. Secondary outcomes: a) days-of-hospitalization, b) mortality-rate before discharge. The Ozone-protocol consisted of 10 sessions of intra-rectal Ozone, total dose 5.25 mg (150 mL volume, 35 g/ml concentration). The Standard-of-care protocol included O2 supply, antivirals (Remdesivir / Isoprinosine), corticosteroids (Dexamethasone / Metilprednisolone), monoclonal antibodies (Anakinra / Tocilizumab), antibiotics (Azytromicine), anticoagulants (Enoxaparine / Fraxiparine). Protocol was approved by Health Care Ethics Committee (Report 15/4/2020) of our Hospital and by Ethics Committee for Medical Investigation of La Princesa’s Hospital (ACTA CEIm 12/20, 28/5/20, Registry 4146). Results: Patients in Slovakian cohort were younger (53.38 vs 84.69 years). Grade of severity was worse in Spanish-cohort (4.78 vs 3.30 points). Length of stay was superior in Spanish-cohort (27.38 vs 10.07 days). Both cohorts improved O2-saturation and Lymphocyte-count. Inflammation biomarkers (Fibrinogen, D-Dimer, Urea, Ferritin, LDH, CRP and IL-6) decreased in both cohorts. In Spanish-cohort, Urea and Ferritin improvement was not significant (p>0.05), while in Slovakian-cohort, Urea, Fibrinogen and LDH were not significant (p>0.05) Radiological signs of bilateral pneumonitis decreased on both cohorts. Mortality was similar (12.5%). Conclusion: After Standard of care protocol, Rectal Ozone improved O2-saturation, decreased inflammation biomarkers and improved Taylor’s radiological scale in both cohorts. Although age, grade of severity and days of hospitalization were inferior in Slovakian cohort, mortality was similar in both cohorts, but inferior if compared to an external control cohort.

Endocrine therapy (ET) has established itself as an efficacious treatment for estrogen receptor-positive (ER+) breast cancers, with a reduction in recurrence rates and increased survival rates. The pre-surgical approach with chemotherapy (NCT) has become a common form of management for large, locally advanced or high-risk tumors. However, a good response to NCT is not usually expected in ER+ tumors. Good results with primary ET, mainly in elderly women, have encouraged studies in other stages of life, and nowadays neoadjuvant endocrine treatment (NET) has become a useful approach to many ER+ breast cancers. The aim of this review is to provide an update on the current state of art regarding the present and the future role of NET.

Cystic Fibrosis (CF) is an inherited monogenic disorder, amenable to gene based therapies. Because CF lung disease is currently the major cause of mortality and morbidity, and lung airway is readily accessible to gene delivery, the major CF gene therapy effort at present is directed to the lung. Although airway epithelial cells are renewed slowly, permanent gene correction through gene editing or targeting in airway stem cells is needed to perpetuate the therapeutic effect. Transcription activator-like effector nuclease (TALEN) has been utilized widely for a variety of gene editing applications. The stringent requirement for nuclease binding target sites allows for gene editing with precision. In this study, we engineered helper-dependent adenoviral (HD-Ad) vectors to deliver a pair of TALENs together with donor DNA targeting the human AAVS1 locus. With homology arms of 4 kb in length, we demonstrated precise insertion of either a LacZ reporter gene or a human CFTR minigene into the target site. Using the LacZ reporter, we determined the efficiency of gene integration to be about 5%. In the CFTR vector transduced cells, we have detected both CFTR mRNA and protein expression by qPCR and Wetern analysis, respectively. We have also confirmed CFTR function correction by flurometric Image Plate Reader (FLIPR) and iodide efflux assays. Taking together, these findings suggest a new direction for future in vitro and in vivo studies in CF gene editing.

The emergence of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment landscape for patients with metastatic non-small cell lung cancer (NSCLC). These achievements inspired investigators and pharmaceutical companies to conduct clinical trials in patients with early-stage NSCLC because both adjuvant and neoadju-vant platinum-based doublet chemotherapies (PT-DCs) showed only a 5% improve-ment in the 5-year overall survival. IMpower010, a phase 3 trial (P3), showed that ad-juvant PT-DC followed by maintenance atezolitumab significantly prolonged dis-ease-free survival than adjuvant PT-DC alone (hazard ratio, 0.79; stage II to IIIA). Since conventional therapies, including chemotherapy and radiotherapy, can promote im-munogenic cell death, which releases tumour antigens from dead tumour cells, ICI combination therapies with conventional therapies are widely proposed. Checkmate 816 trial (P3) indicated a significantly higher pathological complete response rate of neoadjuvant nivolumab/PT-DC combination therapy than neoadjuvant PT-DC alone (odds ratio, 13.9, for stage IB to IIIA). Detection of circulating tumour DNA is highly anticipated for the evaluation of minimal residual disease. Multimodal approaches and new ICI agents are being attempted to improve the efficacy of ICI treatment in phase 2 trials. This review presents the development of perioperative treatment using ICIs in patients with NSCLC while discussing problems and perspectives.

Background: This retrospective study evaluates the survival effects of metronomic maintenance therapy with fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. Methods: We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockdout of EGFR gene, we analyzed the capacities of cell proliferation and migration. Results: Postoperative relapse and mortality were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent predictive factor of postoperative relapse and mortality, as well as a prognostic factor of disease-free survival and overall survival. The significant differences of survival between the two groups were only observed in patients with positive EGFR expression. Conclusions: The present study suggested EGFR expression as the prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. By analyzing EGFR expression, we can identify the potential candidates with optimal survival benefit from metronomic maintenance therapy in patients with stage III CRC.

Malawi has developed an excellent, nation-wide system for monitoring people infected with HIV and keeping track of key epidemic markers. Their success lies in two things: the focus on simplicity and the use of data collection not only to track the epidemic and identify problems but also to give regular feedback and support to every clinic in the country. This achievement is the more remarkable given that Malawi is one of the poorest countries in the world, ranking 190 out of 194 countries by GDP, but has one of the most severe epidemics of HIV in the world, ranking 9th out of 168 countries by HIV prevalence. We first discuss the current state and likely future epidemic trends in Malawi: unless we know where we are and where we are going we cannot decide what to do or how to do it to in order to achieve a better outcome. We then discuss the history and development of Malawi’s patient monitoring system, as reported in their Integrated HIV Program Reports,ix which have been published quarterly since the beginning of 2004. We consider the current state of patient monitoring and support as reflected in the most recent report for the third quarter (Q3) of 2016 and comment on some of the questions that this raises. Finally, we consider ways in which the current system could be improved by strengthening Malawi’s analytical capacity and making better use of this unique data set. The focus here is on HIV in adultsv because if ART is initiated early in all adults living with HIV this should include testing all pregnant women for HIV and starting them on treatment immediately. However, PMTCT is especially important and care must be given to reducing MTCT and identifying the long-term child survivors of mother-to-child transmission and this demands a complementary assessment. There is an ongoing debate about the relative merits of treatment and prevention in reducing transmission and it should be made clear that the primary reason for starting people on treatment early is that it is in the best interest of the individual patient to start treatment as soon as possible after becoming infected. Allowing a person’s immune system to deteriorate to any degree is not consistent with the clinician’s commitment to ‘first do no harm’ and even those with the highest CD4⁺ cell count are at a substantially increased risk of death. What matters, therefore, is to get as many people as possible onto ART, ensure that they remain virally suppressed, and consider prevention in this context.

The kinetics and optimal efficacy conditions of photoinitiated polymerization are theoretically presented. Analytic formulas are derived for the crosslink time, crosslink depth and efficacy function. The roles of photosensitizer (PS) concentration, diffusion depth and light intensity on the polymerization spatial and temporal profiles, for both uniform and non-uniform cases, are presented . For optimal efficacy, a strategy via controlled PS concentration is proposed, where re-supply of PS in high light intensity may achieve a combined-efficacy similar to low light intensity, but has a much faster procedure. A new criterion of efficacy based on the polymerization (crosslink) [strength] and [depth] is introduced.

Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by the impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degree of mental retardation, autism, ataxia and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential use of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between the researchers and the patients.

Extracorporeal shock wave therapy (ESWT) is a safe and effective treatment option for various pathologies of the musculoskeletal system. Many studies addressed the molecular and cellular mechanisms of action of ESWT. However, no uniform concept could be established in this matter until now. We performed a systematic review of the effects of exposure of musculoskeletal tissue to extracorporeal shock waves (ESWs) reported in the literature. The key results were as follows: (i) compared to the effects of many other forms of therapy, the clinical benefit of ESWT does not appear to be based on a single mechanism; (ii) different tissues respond to the same mechanical stimulus in different ways; (iii) just because a mechanism of action of ESWT was described in a study does not automatically mean that this mechanism was relevant to the observed clinical effect; (iv) focused ESWs and radial ESWs seem to act in a similar way; and (v) even the most sophisticated research into the effects of exposure of musculoskeletal tissue to ESWs cannot substitute clinical research in order to determine the optimum intensity, treatment frequency and localization of ESWT.

Lipofuscin is indigestible garbage that accumulates in the autophagic vesicles and cytosol of post-mitotic cells with age. Drs. Brunk and Terman postulated that lipofuscin accumulation is the main or at least a major driving factor in aging. They even posited that the evolution of memory is the reason why we get lipofuscin at all, as stable synaptic connections must be maintained over time, meaning that the somas of neurons must also remain in the same locale. In other words, they cannot dilute out their garbage over time through cell division. Mechanistically, their position certainly makes sense given that rendering a large percentage of a post-mitotic cell’s lysosomes useless must almost certainly negatively affect that cell and the surrounding microenvironment. Here, I explore the possibility that the accumulation of lipofuscin to some extent underlies all other categories of age-related damage as defined by Dr. Aubrey de Grey. I do not think that lipofuscin removal will reverse/prevent all forms of aging, just the major component facing us currently. In this piece, I will review what is known about lipofuscin accumulation from evolutionary and mechanistic standpoints and discuss ways of removing it from non-dividing (or slowly-dividing) cells.

Background: In the midst of a worldwide COVID-19 pandemic music therapists previously not involved in telehealth had to develop effective remote forms of music therapy. The objective of this review was to systematically explore how music therapists previously working in-person adapted to the transfer to remote forms of therapy in the context of the coronavirus outbreak. Methods: We searched Scopus, Web of Science Core Collection, CINAHL, Medline, ProQuest Central, PubMed, EMBASE, PsycINFO and PsyARTICLES, grey literature (October 2020), and websites of professional organizations. We followed the JBI methodology for scoping reviews. Results: Out of the 194 screened texts, we included ten very heterogenous articles with an overall very low quality. Most texts described remote therapy in the form of synchronous video calls using the Internet, one paper described a concert in a patio of a residential home. We report the authors´ experience with the adaptation and activities, challenges and benefits of remote forms of therapy, recommendations of organizations, and examples and tips for online therapies. Conclusions: Music therapists have adapted the musical instruments, the hours, the technology used, the therapeutic goals, the way they prepared their clients for sessions, and other aspects. They needed to be more flexible, consult with colleagues more, and mind the client-therapist relationship's boundaries. It seems, when taken as a necessary short-term measure, online music therapy works sufficiently well. The majority of papers stated that benefits outweighed the challenges, although many benefits were directly linked with the pandemic context.

Conventional radiation therapy uses white X-rays that consist of a mixture of X-ray waves with various energy levels. In contrast, a monochromatic X-ray (monoenergetic X-ray) has a single energy level. Irradiation of high Z elements with a synchrotron generated monochromatic X-ray with the energy at or higher than the K-edge energy of the element results in the production of the Auger electrons that cause DNA damage leading to cell killing. Delivery of high Z elements into cancer cells and tumor mass can be facilitated by the use of nanoparticles. Mesoporous silica nanoparticles (MSNs) have been shown to be effective in delivering high Z elements to cancer cells. A proof of principle experiment was reported that demonstrated the feasibility of this approach. This opens up a possibility to pursue the Auger cancer therapy by the combined use of MSNs loaded with high Z elements and monochromatic X-rays. Similar cancer therapies using other types of quantum beams such as neutron, proton and carbon ion beams can be envisioned.

A single-site, randomized clinical trial was designed to determine the efficacy of regular home use of Lumoral® dual-light antibacterial aPDT in periodontitis patients. For the study, 200 patients are randomized to receive non-surgical periodontal treatment (NSPT), including standardized hygiene instructions and electric toothbrush, and scaling and root planing, or NSPT with adjunctive Lumoral® treatment. A complete clinical intraoral examination is conducted in the beginning, at three months, and at six months. This report presents the three-month results of the first 59 consecutive randomized subjects. At three months, bleeding on probing (BoP) was lower in the NSPT+Lumoral®-group than in the NSPT group (p=0.045), and more patients in the NSPT+Lumoral®-group had their BoP below 10% (52% vs. 29%, respectively, p=0.008). Patients in the NSPT+Lumoral®-group improved their oral hygiene by visible-plaque-index (p=0.0002), while the NSPT group showed no statistical improvement as compared to baseline. Both groups significantly reduced the number of deep periodontal pockets, but more patients with a reduction in their deep pocket number were found in the NSPT+Lumoral® group (92% vs. 63%, p=0.01). Patients whose number of deep pockets was reduced by 50% or more were also more frequent in the NSPT+Lumoral®-group (70% vs. 33%, p=0.01). Patients with initially less than ten deep pockets had fewer deep pockets at three-month follow-up in the Lumoral® group (p=0.02). In conclusion, adjunctive use of Lumoral® in NSPT results in improved treatment outcomes at three months post-therapy.

The World Anti-Doping Agency (WADA) has prohibited gene doping in the context of progress in gene therapy. In addition, there is a risk of the EPO gene being applied in gene doping among athletes. Along with this, development of a gene-doping test has been underway in worldwide. Here, we had two purposes: to develop a robust gene doping mouse model using the human EPO gene (hEPO) transferred using recombinant adenovirus (rAdV) as a vector and to develop a detection method to prove gene doping using this model. The rAdV including the hEPO gene were injected intravenously to transfer the gene to the liver. After injection, the mice developed significantly increased red blood cell counts in whole blood and increased gene expressions of hematopoietic markers in the spleen, indicating successful development of the gene doping model. Next, we detected direct and indirect proof of gene doping in whole blood DNA and RNA using qPCR assay and RNA sequencing. Proof was detected in one drop of whole blood DNA and RNA over a long period; furthermore, the overall RNA expression profiles significantly changed. Therefore, we have advanced detection of hEPO gene doping in humans.

Boron Neutron Capture Therapy (BNCT) is a promising binary disease-targeted therapy, as neutrons preferentially kill cells labeled with boron (¹⁰B), which makes it a precision medicine treatment modality that provides a therapeutic effect exclusively on patient-specific tumor spread. Contrary to what is usual in radiotherapy, BNCT proposes cell-tailored treatment planning rather than to the tumor mass. The success of BNCT depends mainly on the sufficient spatial biodistribution of ¹⁰B located around or within neoplastic cells to produce a high-dose gradient between the tumor and healthy tissue. However, it is not yet possible to precisely determine the concentration of ¹⁰B in a specific tissue in real-time using noninvasive methods. Critical issues remain to be resolved if BNCT is to become a valuable, minimally invasive, and efficient treatment. Moreover, functional imaging technologies such as PET can be applied to determine biological information that can be used for the combined-modality radiotherapy protocol for each specific patient. Anyway, not only imaging methods but also proteomics and gene expression methods will facilitate BNCT becoming a modality of personalized medicine. This work provides an overview of the fundamental principles, recent advances, and future directions of BNCT as cell-targeted cancer therapy for personalized radiation treatment.

Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer deaths worldwide. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with metastatic CRC (mCRC) were accepted as the main therapeutic strategies until the early 2000s, when targeted drugs, like cetuximab and bevacizumab were developed. The use of targeted drugs in clinical practice has significantly increased patients’ overall survival. To date, the emergence of several types of targeted drugs has opened new possibilities and revealed new prospects for mCRC treatment. Therapeutic strategies are continually being updated to select the most suitable targeted drugs based on the results of clinical trials that are currently underway. This review discusses the up-to date molecular evidence of targeted therapy for mCRC and summarizes the Food and Drug Administration-approved targeted drugs including the results of clinical trials. We also explain their mechanisms of action and how these affect the choice of a suitable targeted therapy.

Worldwide, one of the main causes of death among young adults is multiple trauma. In these pa-tients hemorrhagic shock represents the leading cause for worsening of the clinical status and for increased morbidity and mortality. This is due to a multifactorial complex involving cellular, bi-ological, and biophysical mechanisms. The most important mechanisms affecting clinical out-come are oxidative stress, the augmentation of pro-inflammatory status, immune deficiency, dis-ruptions in the coagulation cascade, imbalances in electrolyte and acid-base homeostasis. Poly-trauma patients in hemorrhagic shock need adequate fluid management to ensure hemodynamic stability that must consider not only the maintenance of adequate blood pressure, but also the ad-equate oxygenation of tissues for optimal cellular function. In the current clinical practice, fluid resuscitation in polytrauma patients uses a variety of widely studied pharmacological products, such as crystalloids, colloids, blood transfusions, and the infusion of other blood products. Alt-hough these products exist, an agreement was not reached on a standard administration protocol that could be generally applied for all patients. Moreover, numerous studies have reported a se-ries of adverse events related to fluid resuscitation and to the inadequate use of these products. This review aims at describing the impact the administration of all the solutions used in fluid re-suscitation might have on the cellular and pathophysiological mechanisms in the case of poly-trauma patients suffering from hemorrhagic shock.

As a result of the cancer immunotherapy revolution hundreds of clinical trials of the newly approved immunotherapies are now under way to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by blockade of co-inhibitory signals. While success stories of terminal cancer patients achieving complete remissions are accumulating, not enough research has been done into the risks of the new therapies. Since the use of immunotherapy is becoming more common, and is expected to develop into first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the nemesis of immunotherapy. Immune-related adverse events (IrAEs) could affect any tissue, their incidence may reach up to 90% of patients and toxicity is dose-dependent. While the combination of two immune checkpoint inhibitors (ICIs) increased efficacy, the incidence of severe adverse events was also increased. Apparently, ICIs cannot be restricted to the targeted anti-tumor T cell population. The long lasting objective of cancer regression can only be achieved by paying a price: tolerance to healthy self tissues is compromised. In the face of an ipilimumab induced pan-lymphocytic activation, a therapeutic paradigm shift is required. The task is not desperately trying to put the genie back in the bottle by immune suppressive treatments, but instead harnessing the autoimmune forces by an off label low-dose combined anti-CTLA-4 and anti-PD1 antibody blockade, which is supplemented with conventional interleukin-2 stimulation and hyperthermia. The proof-of-principle of the low-dose-combination therapy was demonstrated in a heavily pre-treated triple negative breast cancer (TNBC) patient with far advanced pulmonary metastases and severe shortness of breath, who had exhausted all conventional treatment. Her pulmonary metastases went into complete remission with transient WHO I-II diarrhea and skin rash. She lived for 27 months after starting the low-dose-combination therapy. She had recurrence as a sternal mass and pleural metastases up to 3 cm. Since the low-dose-combination protocol consists only of approved drugs and treatments, this exceptional response should instigate further research efforts.

Background: Although rarely indicated, antibiotics are commonly used for acute diarrhoea in China. We conducted a randomized, double blind exploratory clinical trial of loperamide, berberine and turmeric for treatment of acute diarrhoea. Methods: Adults with acute uncomplicated diarrhoea were randomized to 4 groups: (A) loperamide; (B) loperamide and berberine; (C) loperamide and turmeric; (D) loperamide, berberine and turmeric. All participants were given rescue ciprofloxacin for use after 48 hours if symptoms worsened or were unimproved. Primary endpoints were feasibility and ciprofloxacin use during the 2 week follow-up period. Semi-structured interviews were conducted following recruitment. Results: Only 21.5% (278/1295) of patients screened were deemed eligible, and 49% (136/278) of these consented and entered into the final analysis. Most participants had mild symptoms, because most patients with moderate or severe symptoms wanted to be given antibiotics. Follow-up was good (94% at 2 weeks). Only two participants used rescue antibiotics compared to 65% of acute diarrhoea patients in the hospital during the recruitment period. The median symptom duration was: 14 hours in group B (IQR 10-22), 16 hours in group D (IQR 10-22), 18 hours in group A (IQR 10-33), 20 hours in group C (IQR 16-54). Re-consultation rates were low. There were no serious treatment-related adverse events. Most interviewed participants said the treatment was effective. Conclusion: Although recruitment was challenging because of widespread expectations for antibiotics, patients with mild diarrhoea accepted to try an alternative. This therapy requires further evaluation in a fully powered, randomised controlled trial among a broader sample.

Forest recreation can be successfully conducted for the purpose of psychological relaxation, as has been proven in previous scientific studies. During the winter in many countries, when snow cover occurs frequently, forest recreation (walking, relaxation, photography, etc.) is common. Nevertheless, whether forest therapy conducted in a forest environment with a snow cover will also have a positive effect on psychological indicators remains unknown. Furthermore, male subjects frequently participate in forest therapy experiments, whereas females are rarely involved. Thus, in this study, the effectuality of forest recreation during winter and with snow cover was tested on 32 young females. For these reasons, the experiment involved 15-minute periods of relaxation in a forest environment or in an urban environment, in addition to a pre-test under indoor conditions. Four psychological questionnaires (POMS, PANAS, ROS, SVS) were administered to participants before and after interventions. Results showed that participants’ levels of negative mood, as measured by different aspects of the POMS questionnaire (tension-anxiety, anger-hostility, depression-dejection, confusion, fatigue), decreased after exposure to the forest environment. In contrast, both tension-anxiety and anger-hostility increased in the urban environment. The indicator of negative affect from the PANAS questionnaire also increased after exposure to the urban environment, whereas the indicator of positive affect based on PANAS was higher in the forest environment than in the urban environment. Restorativeness and subjective vitality exhibited higher values after exposure to the forest environment in comparison to those from the control and pre-test. The changes in these indicators demonstrates that forest recreation in the snow during winter can significantly increase psychological relaxation in young females, as well as showing that recreation can be successfully conducted under these winter conditions.

Currently, in the scientific literature there is a great interest on the study of strategies to implement patient-centered care. One of the main tools for this is the therapeutic relationship. Some studies suggest that the perception of the environment in which the physical therapy treatment takes place can influence the perception of its quality. A qualitative study using focus groups was performed. Two researchers conducted the focus groups, using a topic guide with predetermined questions. The focus group discussions were audio-recorded, transcribed verbatim and analyzed thematically using a modified grounded theory approach. The setting was three hospitals and six public health centers located in Spain. The inclusion criteria were patients who had received a minimum of 15 physical therapy sessions and with no communication impairments. Thirty-one participants in four focus groups. Participants described a series of specific experiences relating to the environment, which they felt were influential in the establishment of therapeutic patient-centered relationships, including eight physical factors and five organizational factors. The results of this study highlight environmental factors that affect the quality of the therapeutic patient-centered relationship in physical therapy and emphasize the need for physical therapists and administrators to rethink the situation and propose strategies for improvement.

In this study, the effects of music therapy on anxiety for patients undergoing regional anaesthesia in an operating room was succinctly investigated. This investigation was largely based on the adapted Hospital Anxiety and Depression Score (HADS) and Spielberger State-Trait Anxiety Inventory (STAI-S), of patients undergoing regional anaesthesia in an operating room. A randomized control trial was performed on 90 patients due for surgery. The selected patients for regional anaesthesia were allocated to either the music therapy group who listened to music using headphones for the entire surgery or the no-treatment control group. Based on the findings, it has been conclusively demonstrated that music can decrease the patient's anxiety level. According to the socio-demographic evaluation, elderly patients have the highest stress hormones levels when compared to young patients. Although elderly patients are more likely to choose religious songs to help them relax, cortisol analysis revealed an increase in cortisol levels among the elderly compared with younger patients. As a result, music is especially important to be delivered to elderly patients. Nonetheless, there is no restriction against administering music to elderly patients because evidence from the Hospital Anxiety and Depression Score (HADS) and State-Trait Anxiety Inventory (STAI-S) has shown that music helps to shift their attention away from pain and complications and makes them feel tranquil. Similarly, the HADS and modified Spielberger STAI (STAI-S) analyses demonstrate a substantial outcome for both groups, with respondents responding positively. The study found that listening to music during regional anaesthesia might help people feel less worried.

Head and neck cancer is the sixth most frequent cancer type. Drug resistance and toxicity are common challenges of the existing therapies, making the development of reliable preclinical models essential for the study of the involved molecular mechanisms as well as for eventual intervention approaches that improve the clinical outcome. Preclinical models of head and neck squamous cell carcinoma have been traditionally based in cell lines and murine models. In this review, we will go over the most frequently used preclinical models, from immortalized-cell and primary tumour cultures in monolayer or 3D, to the currently available animal models. We will scrutinize their efficiency in mimicking the molecular and cellular complexity of head and neck squamous cell carcinoma. Finally, the challenges and opportunities of other envisaged putative approaches, as well as the potential of the preclinical models to further develop customized therapies will be discussed.

Pharmacological treatment is not very effective for neuropathic pain (NP). A progressive decrease in the estimated effect of NP drugs has been reported, giving rise to an increase in the use of the multimodal analgesic approach. We performed a new, independent review to assess whether more evidence and of better-quality has become available since the last systematic review. We evaluated the efficacy, tolerability, and safety of double-blinded, randomized, controlled trials involving only adult participants and comparing combination therapy (CT: ≥ 2 drugs) to a placebo and/or at least one other comparator with an NP indication. The primary outcome assessed was the proportion of participants reporting ≥50% pain reductions from baseline. The secondary outcome assessed was the proportion of drop-outs due to treatment-emergent adverse events. After removing duplicates, 2323 citations were screened, with 164 articles assessed for eligibility, from which 16 were included for qualitative analysis. From the latter, only five lasted for at least 12 weeks and only six complied with the required data for complete analysis. CT has been adopted for years without robust evidence. Efforts have been made to achieve better-quality evidence, but the quality has not improved over the years. In this regard, guidelines for NP should attempt to make recommendations about CT research, prioritizing which combinations to analyze.

Background: Recently we demonstrated that Astragalus polysaccharide (PG2), the active ingredient in dried roots of astragalus membranaceus, ameliorates cancer symptom clusters and improve quality of life (QoL) in patients with metastatic disease by modulating inflammatory cascade, against the background that inflammatory cells including macrophages, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in tumor initiation, metastasis, and progression. Nevertheless, the role of PG2 in the modulation of anticancer immunogenicity and therapeutic response remains relatively underexplored and unclear. Purpose: The present study investigates how and to what extent PG2 modulates cellular and biochemical components of the inflammatory cascade, enhance anticancer immunity, and the therapeutic implication of same in patients with lung cancer. Methods and Results: Herein, we demonstrated that PG2 significantly increased the M1/M2 macrophage polarization ratio in non-small cell carcinoma (NSCLC) H441 and H1299 cells. This PG2-induced preferential pharmacologic up-regulation of tumoral M1 population in vitro, positively correlated with the downregulation of tumor-promoting IL-6 and IL-10 expression in NSCLC cell-conditioned medium, with concomitant marked inhibition of cell proliferation, clonogenicity and tumorsphere formation. Our ex vivo results, using clinical sample from our NSCLC cohort, demonstrated that PG2 also promoted the functional maturation of DCs with consequent enhancement of T cell-mediated anticancer immune responses. Consistent with the in vitro and ex vivo results, our in vivo studies showed that mice treated with PG2 exhibited significant time-dependent depletion of the tumor-associated M2 population, synergistically enhanced the anti-M2-based anticancer effect of cisplatin, and inhibition of xenograft tumor growth in the NSCLC mice models. Moreover, in the presence of PG2, cisplatin-associated dyscresia and weight-loss was markedly suppressed. Conclusion: These results do indicate a therapeutically-relevant role for PG2 in modulating the M1/M2 macrophage pool, facilitating DC maturation, and synergistically enhancing the anticancer effect of conventional chemotherapeutic agent, cisplatin; thus laying the foundation for further exploration of the curative relevance of PG2 as surrogate immunotherapy and/or clinical feasibility of its use for maintenance therapy in patients with lung cancer.

BODIPY dyes have recently raised attention as potential photosensitizers. In this work, commercial and novel photosensitizers (PSs) based on BODIPY chromophores (haloBODIPYs and orthogonal dimers strategically designed with intense bands in the blue, green or red region of the Visible spectra and high singlet oxygen production) were covalently linked to mesoporous silica nanoparticles (MSNs) further functionalized with PEG and folic acid (FA). MSNs of approximately 50 nm in size with different functional groups were synthesized to allow multiple alternatives of PS-PEG-FA decoration of their external surface. Different combinations varying the type of PS (commercial Rose Bengal, Thionine and Chlorine e6 or custom-made BODIPY-based), the linkage design and the length of PEG are detailed. All the nanosystems were physicochemically characterized (morphology, diameter, size distribution and PS loaded amount) and photophysically studied (absorption capacity, fluorescence efficiency, and singlet oxygen production) in suspension. For the most promising PS-PEG-FA silica nanoplatforms, the biocompatibility in dark conditions and the phototoxicity under suitable irradiation wavelengths (blue, green, or red) at regulated light doses (10-15 J/cm2) were compared with PSs free in solution in HeLa cells in vitro.

The potential of Neural Stem Cells (NSCs) to provide therapeutic benefit for a variety of neurological disorders, including brain malignancies, has been long recognized and has inspired many scientists to design, test and successfully demonstrate that NSCs are efficient and effective therapeutic agents. Glioblastoma, the deadliest form of primary brain tumor, despite extensive and sustained efforts to find better therapies, remains a disease without cure, with a median survival after diagnosis of less than two years. Treatment resistance in glioblastoma is in large part attributed to limitations in the delivery and distribution of therapeutic agents administered either systemically or directly into the tumor due to the highly invasive nature of this cancer and its abnormal intratumoral vasculature. Stem Cells (SCs) have an innate tumor-tropic migratory behavior, can be modified to deliver a variety of therapeutic agents and efficiently distribute their cargo into brain tumors, pursuing invading streams of tumor cells, deep into the brain parenchyma. Over the last twenty years, numerous preclinical trials have demonstrated the feasibility and efficacy of SCs as antiglioma agents, leading to the development of trials to test these therapies in the clinic. In this review we present and analyze these studies and discuss mechanisms underlying their beneficial effect, highlighting experimental progress, limitations and the emergence of promising new therapeutic avenues. We hope to increase awareness of the advantages of using SCs for the treatment of glioblastoma and inspire further studies that will lead to accelerated implementation of effective therapies.

Premature ovarian insufficiency (POI) is a highly prevalent disorder, characterized by the development of menopause before age of 40. Most cases are idiopathic; however, in some women the cause of this condition (e.g. anticancer treatment, genetic disorders, and enzymatic defects) may be identified. Although hormone replacement therapy, the principal therapeutic approach for POI, helps to alleviate the related symptoms, this does not effectively solve the issue of fertility. Assisted reproductive techniques also lack efficacy in these women. Thus, the effective approach to manage the patients with POI is highly warranted. Several mechanisms, associated with POI, have been identified, including lack of FSH receptor functioning, alterations in the apoptosis control, mutations in Sal-like 4 genes, thymulin or basonuclin-1 deficiency etc. The above-mentioned may be good targets for gene therapy in order to correct defects, leading to POI. The goal of this review is to summarize the current experience on the POI studies, that employed gene therapy, and to discuss the possible future directions in this field.

Female infertility is a global medical condition that can be caused by various disorders of the reproductive system, including premature ovarian failure (POF), polycystic ovary syndrome (PCOS), endometriosis, Asherman syndrome, and preeclampsia. It affects the quality of life of both patients and couples. Mesenchymal stem cells (MSCs) have received increasing attention as a potential cell-based therapy with several advantages over other cell sources, including greater abundance, fewer ethical considerations, and high capacity for self-renewal and differentiation. Clinical researchers have examined the therapeutic use of MSCs in female infertility. In this review, we discuss recent studies on the use of MSCs in various reproductive disorders that lead to infertility. We also describe the role of microRNAs (miRNAs) and exosomal miRNAs in controlling MSC gene expression and driving MSC therapeutic outcomes. The clinical application of MSCs holds great promise for the treatment of infertility or ovarian insufficiency and to improve reproductive health for a significant number of women worldwide.

Background: This retrospective study evaluate the survival effects of metronomic maintenance therapy with fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. Methods: We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockdout of EGFR gene, we analyzed the capacities of cell proliferation and migration. Results: Postoperative relapse and mortality were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent predictive factor of postoperative relapse and mortality, as well as a prognostic factor of disease-free survival and overall survival. We also demonstrated that EGFR-knockout Caco2 cells are more sensitive to the inhibition effect of fluoropyrimidine than the control those. Conclusions: The present study suggested EGFR expression as the prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. By analyzing EGFR expression and treatment strategies, we can identify the potential candidates with optimal survival benefit from metronomic maintenance therapy in patients with stage III CRC.

Epigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage. Combining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy. Thus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in-depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.

The ketogenic diet and walking exercise training activity are two key public health lifestyle factors. The potential of combined lifestyle factors interventions focused on getting to compliance in forced exercise. A balanced ketogenic diet and regular exercise activity is a key modifiable factor to the prevention and management of chronic diseases. Influence health across the lifespan and reduction of the risk of premature death through several biological mechanisms. Community older group’s lifestyle factors interventions contribute identity in their natural living environment. While the older health benefits of walking exercise training strategies are commonly to study, combined ketogenic diet and walking exercise interventions have induced greater benefits in community older groups.

CD15 (Lewis X/Lex) is a fucosyl (3-fucosly-N-acetyl-lactosamine) moiety found on membrane proteins of various cancer cells. These include renal cancer, prostate and bladder cancers, acute leukemias, hepatocellular carcinoma, breast cancer and melanoma. The antigen plays an espe-cially significant role in renal cell carcinoma. Its high expression serves as a good prognostic marker for patients and high hopes are related to its use in the immunotherapy of the tumor. The biological role of CD15 is the interaction with E-, L- and P-selectins (adhesion molecules) and al-lowing for the adhesion with the endothelial cells. In this way, cancer cells start to interact with the endothelium of blood vessels and consequently move out from the blood flow to the sur-rounding tissues. The blockage of antigen’s function results in reduced metastatic potential. Moreover, the molecule may be a therapeutic target against cancer in monoclonal antibod-ies-based therapies. CD15s is a sialyl derivative of CD15, that possess its own unique characteris-tics. Unlike high expression of CD15, which is a prognostic factor in Hodgkin lymphoma, CD15s relate to poor prognosis for the patients. Due to the high abundance in cancer cells, CD15 is con-sidered as a marker of Cancer Stem Cells. This review presents a comprehensive description of the role of CD15 and CD15s in cancer development and metastasis and overviews the clinical appli-cations of the anti-CD15 therapy.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC, by lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is unresponsive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment but, despite an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.

Oncology clinical pharmacists are uniquely positioned to make interventions to increase patient activation and engagement. To accomplish this goal, pharmacists can target health system-related, provider-related, and patient-related factors to help enhance patient-centered care and drive behavioral health changes. Interventions that pharmacists must tackle include educating team members and patients on the medication acquisition process, communicating urgency of treatment, optimizing workflows, facilitating guideline recommendations, preventing, and managing treatment toxicities, and promoting patient self-advocacy through education and shared decision-making. As crucial members of the healthcare team, oncology clinical pharmacists can simplify highly complex treatment regimens to facilitate and optimize patients’ ownership of their care. This review will focus on the example of venetoclax treatment in acute myeloid leukemia to demonstrate the impact that pharmacists provide that leads to behavioral change of patients and clinicians.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator ok NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

Evolutionary medicine argues that disease can arise because modern conditions do not match those in which we evolved. For example, a decline in exposure to commensal microbes and gastrointestinal helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders (the hygiene hypothesis). Accordingly, microbial and helminthic probiotic therapies have been explored as Darwinian treatments for these disorders. A further possibility is that loss of old friend commensals also increases the sterile, aging-associated inflammation known as inflammaging, that contributes to a range of age-related diseases, including cardiovascular disease, dementia and cancer. Interestingly, Crowe et al. (2020) recently reported that treatment with a secreted glycoprotein from a parasitic nematode can protect against murine aging by induction of anti-inflammatory mechanisms. Here, we explore the hypothesis that restorative helminth therapy would have anti-inflammaging effects. Could worm infections provide broad-spectrum protection against age-related disease?

Binge-eating disorder (BED) and bulimia nervosa (BN) have adverse psychological and medical consequences. Novel interventions, like the integration of virtual reality (VR) with cue-exposure therapy (VR-CET), enhance outcomes for refractory patients compared to cognitive behavior therapy (CBT). Little is known about the feasibility and acceptability of translating VR-CET into real-world settings. To investigate this question, adults previously treated for BED or BN with at least one objective or subjective binge episode/week were recruited from an outpatient University eating disorder clinic to receive up to eight weekly one-hour VR-CET sessions. Eleven of 16 (68.8%) eligible patients enrolled; nine (82%) completed treatment; 82% (9/11) provided follow-up data 7.1 (SD=2.12) months post-treatment. Overall, participant and therapist acceptability of VR-CET was high. Intent-to-treat objective binge episodes (OBEs) decreased significantly from 3.3 to 0.9/week (p &lt; .001). Post-treatment OBE 7-day abstinence rate for completers was 56%, with 22% abstinent for 28 days at follow-up. Among participants purging at baseline, episodes decreased from a mean of one to zero/week, with 100% abstinence maintained at follow-up. The adoption of VR-CET into real-world clinic settings appears feasible and acceptable, with a preliminary signal of efficacy. Findings, including some loss of treatment gains during follow-up may inform future treatment development.

Focal vibration therapy can provide neurophysiological benefits. Unfortunately, standardized protocols are non-existent. Previous research presents a wide range of protocols with a wide range of effectiveness. This paper is part of a broader effort to identify effective, standardized protocols for focal vibration therapy. The vibration characteristics of four commercially available focal vibration devices that have been used for research and clinically were measured. An accelerometer was used for the measurements. Frequency and peak-to-peak amplitude were measured. Measurements were made when the devices were free and then again when they were strapped to the human body. Vibration frequency ranged from 120 to 225 Hz. Free vibration amplitude ranged from 2.0 to 7.9 g’s (peak-to-peak). When the devices were strapped to the body (constrained), vibration amplitude decreased by up to 65.7%. These results identify effective ranges of focal vibration frequency and amplitude. They illustrate the importance of identifying vibration environment, free or constrained, when quoting vibration characteristics. Finally, the inconsistency of multi-actuator devices is discussed. These results will guide protocol development for focal vibration and potentially better focal vibration devices.

In western societies about one in six employees works in shifts. Shiftwork is associated with a number of poor somatic and psychological health outcomes, especially sleep issues. Higher rates of absenteeism and accidents in the workplace are possible consequences. Still, prevention programs and treatment options that are specifically tailored to shift workers’ needs are rare. We devised a 4-week online sleep intervention (n = 21) and compared treatment outcomes to our outpatient treatment for shift workers (n = 12). Measures included the WHO-5, ISI, and ESS scales as well as sleep diaries. Shift workers reported worse symptoms of insomnia than other participants. Results show significant average increases in sleep efficiency (+ 7%) and total sleep time (+ 25 min.), as well as significant improvements regarding insomnia symptoms and wellbeing in the online sample. Rates of improvement did not differ between the online and outpatient samples. Sleep disorders affect a relevant part of the working population, especially shift workers. Online approaches to treatment of these issues seem feasible and effective. Randomized controlled trials are needed.

Eating Disorders (ED) constitute a serious public health issue affecting predominantly women and appearing typically in adolescence or early adulthood. EDs are extremely difficult to treat as these disorders are ego-syntonic and many patients do not seek treatment. It is vital to focus on the development of successful early-intervention programs for individuals presenting at-risk and are on a trajectory towards developing EDs. This study is a randomized controlled trial evalu-ating an innovative digital gamified Acceptance and Commitment early-intervention program (AcceptME) for young females showing signs and symptoms of an ED and at high-risk for an ED. Participants (N=92; Mage=15.30 years, SD=2.15) received either AcceptME (N=62) or a waitlist control (N=30). Analyses indicated that the AcceptME program effectively reduced weight and shape concerns, with large effects when compared to waitlist controls. Most participants scored below the at-risk cut-off (WCS score<52) in the AcceptME at end-of-intervention (57.1%) com-pared to controls (7.1%) with odds of falling into the at-risk group being 14.5 times higher for participants in the control group. At follow-up, 72% of completers reported scores below the at-risk cut-off in the AcceptME group. The intervention also resulted in a decrease in ED symp-tomatology and increased body image flexibility. Overall, results suggest that the AcceptME program holds promise for early-intervention of young women at-risk for developing an ED.

Human pluripotent stem cells (hPSCs) have become a powerful tool to generate various kinds of cell types comprising the human body. Recently, organoid technology emerged as a platform to build a physiologically relevant tissue-like structure from the PSCs, which provides a more relevant three-dimensional microenvironment to the actual human body than the conventional monolayer culture system for transplantation, disease modeling, and drug development. Although it holds so many advantages, the organoid culture system still has various problems related to culture methods, which became a challenge to get similar physiological properties to their original tissue counterparts. Here, we discuss the current development of organoid culture methods, including the problem that may arise from the currently available culture systems as well as the possible approach to overcoming the current limitation and improving their optimum utilization for translational application purposes.

Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production, or oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of turning these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and /or response to anticancer treatments. Additionally, the iron addiction of cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we selected relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides, we discuss some co-existing discrepant findings. We will also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anti-cancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy will also be reported.

In healthy adult brain, glial cell line-derived neurotrophic factor (GDNF) is exclusively expressed by neurons and in some instances, it has furthermore been shown to derive from a single neuronal subpopulation. Secreted GDNF acts in a paracrine fashion by forming a complex with GDNF family receptor α1 (GFRα1) which is mainly expressed by neurons and can act in cis as a membrane-bound or in trans as a soluble factor. The GDNF/GFRα1 complex signals through interaction with RET (“rearranged during transfection”) or with a lower affinity with neural cell adhesion molecule (NCAM). GDNF can also signal independently from GFRα1 via interaction with syndecan-3. RET being expressed by neurons involved in several pathways: nigro-striatal dopaminergic neurons, motor neurons, enteric neurons, sensory neurons, etc. could be the main determinant of the specificity of GDNF pro-survival effect. In injured brain, de novo expression of GDNF occurs in glial cells. Neuroinflammation has been reported to induce GDNF expression in activated astrocytes and microglia, infiltrating macrophages, nestin-positive neural stem cells and neuron/glia (NG2) progenitors. This disease-related GDNF overexpression can be either beneficial or detrimental depending on the localization in the brain and the level and duration of glial cells activation. Some reports also describe upregulation of RET and GFRα1 in glial cells, suggesting that GDNF could modulate neuroinflammation.

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intra-cranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2 treated NK cells as compared to those subjected to non-treated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2 treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.

Nowadays, the uses of laser and optics in the medical areas are extremely vivid, especially low-level laser therapy. The light with the wavelength of 633 nm to 1200 nm could penetrate and propagate deep in biological tissue. To develop the low-level laser therapy device, optimizing light delivery is critical to accurately stimulate the biological effects inside the biological tissue. Nevertheless, each form of the tissues at each zone on the body had various refractive optic, absorption, scattering, and anisotropy coefficients. This paper describes the simulation results of low-level laser propagation from skin surface at the lower spine, the knee, the femur and the prostate gland with four wavelengths (633 nm, 780 nm, 850 nm, and 940 nm) by the Monte Carlo method. These simulation results are the base for developing the low-level laser therapy device, that could be used in clinical for treating the fracture, knee osteoarthritis, spinal degeneration, and benign prostatic hypertrophy.

Background: At present, the treatments for patients with advanced lung cancer focus on chemotherapy, targeted therapy, immunotherapy, or a combination of multiple treatments. Purpose: The main purpose of this study is to compare the various chemotherapy-based combination therapies and find the best one for patients with advanced lung cancer. Methods: Based on database (PubMed, EMBASE and Medline) for randomized controlled trials of advanced lung cancer with combination therapy from 2008 to 2020, we searched literatures with overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse as outcome indicators and established a Bayesian mesh meta-analysis for multiple treatment strategies. Then, we combined the results of four outcome indicators to find out the best chemotherapy-based combination therapy strategy for patients with advanced lung cancer, further, we tried to screen out the best drugs of which were commonly used now. Results: It contained a total of 51 studies, including five combination therapies: Chemotherapy/Chemotherapy plus placebo (CT), chemotherapy plus one targeted therapy drug (CT+T), chemotherapy plus two targeted therapy drugs (CT+T+T), chemotherapy combined with immunotherapy (CT+I) or chemotherapy combined with biotherapy (CT+B). In terms of four outcome indicators, CT+I showed the best therapeutic benefits. In the comparison of immunotherapy drugs, pembrolizumab showed the best effect. Conclusion: Our results showed that, among the multiple chemotherapy-based combination therapy strategies, chemotherapy combined with immunotherapy is the best choice for patients with advanced lung cancer, and pembrolizumab combined with chemotherapy has the best effect.

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF-5-FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the 1) induction of cell cycle arrest in the S phase and 2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both c-mesenchymal–epithelial transition (MET)/ Kirsten Rat Sarcoma virus (KRAS)/ extracellular signal-regulated kinase (ERK) and c-MET/ phosphatidyl-inositol 3-kinases (PI3K)/ protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/ matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required to validate the results of the present study.

Psychotherapy is one of the evidence-based clinical interventions for the treatment of depression in older adults with dementia. Randomized Controlled Trials are often the first methodological choice to gain evidence, yet they are not applicable to a wide range of humanistic psychotherapies. Amongst all, the efficacy of the Gestalt therapy (GT) is under-investigated. The purpose of this paper is to present a research protocol aiming to assess the effects of a GT-based intervention on people with dementia (PWD) and the indirect influence on their family carers. The study implements the Single-Case Experimental Design with Time-Series Analysis that will be carried out in Italy and Mexico. Ten people in each country, who received a diagnosis of dementia and present depressive symptoms, will be recruited. Eight or more GT sessions will be provided whose fidelity will be assessed by the GT Fidelity Scale. Quantitative outcome measures are foreseen for monitoring participants’ depression, anxiety, quality of life, carers’ burden, and the caregiving dyad mutuality, at baseline and follow-up. The advantages and limitations of the research design are considered. If GT will result effective in the treatment of depression in PWD, it could enrich the range of evidence-based interventions provided by healthcare services.

Mycobacterium abscessus is a non-tuberculous mycobacteria notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or acquired resistance of M. abscessus to multiple antibiotics. Despite prolonged poly-antimicrobial therapy, treatment of M. abscessus infections often fails, leading to progressive morbidity and eventual mortality. Great research efforts are invested in finding new therapeutic options for M. abscessus. Clofazimine and rifabutin are known anti-mycobacterial antibiotics, repurposed for use against M. abscessus. Novel antimicrobials active against M. abscessus include delamanid, pretomanid and PIPD1 and the recently approved beta-lactamase inhibitors avibactam, relebactam and vaborbactam. Previously unused antimicrobial combinations e.g. vancomycin-clarithromycin and dual beta-lactam therapy have been shown to have synergistic effect against M. abscessus in experimental models, suggesting their possible use in multiple-drug regimens. Finally, engineered phage therapy has been reported to be clinically successful in a severe case of disseminated M. abscessus infection. While many of these experimental therapeutics have shown activity against M. abscessus in vitro, as well as intracellular and/or animal models, most have little if any evidence of effect in humans infections. Clinical studies of M. abscesssus treatments are needed in order to reliably determine the value of their incorporation in therapeutic regimens.

The purpose of our study is to determine the effectiveness of various types of psychocorrection measures: social and psychological training, a method of biological feedback and Sandplay for the indicators of childhood anxiety among younger schoolchildren. The study was conducted in the school of Magadan, North East of Russia (9-10 year old students, n = 43). We used a standardized method of Multidimensional Assessment of Child Anxiety which included 10 scales. The correction methods were used: socio-psychological training (SPT), biofeedback method (BFB), individual and group Sandplay. Students of group I (n = 12) participated only in the SPT. Students of group II (n = 11) participated in the SPT and underwent a course of training in self-regulation using the BFB method. In correction work with the students of group III (n = 20), the SPT, BFB, individual and group Sandplay were used. In group I, after the correction activities, a significant decrease in anxiety was observed in 3 of 10 scales (2, 6, 7; (p <0.05). In group II it was seen in 5 scales (1, 3, 6, 7, 8; p <0.05). In group III, a significant improvements took place in 7 scales (1, 2, 5, 6, 7, 9, 10; p <0.01–p <0.05). The present study has shown the different efficacy of applying the remedial techniques separately and in combination. The use of methods in the complex enhances the impact on the types of the child anxiety.

Low back pain is a common problem in the active population, and the second reason for visiting a physician. In patients with lumbar disc protrusion, the nucleus pulposus bulges against the disc and the latter protrudes into the spinal column, but the annulus fibrosus remains intact. The purpose of this study was to prove that starting an early complex rehabilitation treatment results into pain and disability reduction, and increased muscle strength and mobility in patients with lumbar disc protrusions. We performed a prospective cohort study, enrolling 60 patients (25 men and 35 women) aged between 26 to 76 years, diagnosed with lumbar disc protrusion. Patients in the experimental group registered significant improvements in all studied variables (pain, mobility, muscle strength, disability) after 6 months of treatment. The results of our study suggest that, in the lumbar disc disease, a combined rehabilitation program may be more effective in terms of pain and disability reduction, if it starts early after diagnosis. The current study proves the importance of combining electrotherapy with hydrotherapy and physical therapy. Patients who received this treatment combination showed an extremely significant improvement in pain relief, and reduction of functional disability after 6 months of treatment.

Nonpharmacological therapeutic interventions in elderly may lead to the reduction of cognitive and depressive symptoms. The aim of the study was to evaluate changes in cognitive functions and mood er or not. in older adults participating in therapy, conducted in the community day-care center (CD-CC). 46 elderly adults (21 M, 25 W) (SG) were examined. The control group (CG) included 45 adults (12 M, 33 W), who participated in the activities of the University of the Third Age (U3A). The following measuring tools were used: Mini-Mental State Examination (MMSE), Clock-Drawing Test (CDT), Verbal Fluency Test (VFT), Digit Span Test (DST), Stroop Color and Word Test (SCWT), Beck's Depression Inventory (BDI), and Hospital Anxiety and Depression Scale (HADS). The intervention consisted of CD-CC 6-month complex therapy. In the SG, compared to the CG, the scores on the: MMSE, CDT, VFT, DST, and SCWT were significantly lower (p<0,05), and BDI was significantly higher (p<0,05). After intervention, the SG and the CG, did not show substantial differences in their scores on the: MMSE, CDT, and BDI. In the SG, a significant improvement (p<0,05) was reported on the: VFT, BDI, and HADS scores. The CD-CC complex therapy can be helpful for the cognitive and emotional elderly functioning.

Interdisciplinary research into the underlying neural processes of music therapy (MT) and subjective experiences of patients and therapists are largely lacking. The aim of the current study was to assess the feasibility of newly developed procedures (including EEG/ECG hyperscanning, synchronous audio-video monitoring, and qualitative interviews) to study the personal experiences and neuronal dynamics of moments of interest during MT with stroke survivors. The feasibility of our mobile set-up and procedures as well as their clinical implementation in a rehabilitation centre and an acute hospital ward were tested with four phase C patients. Protocols and interviews were used for the documentation and analysis of the feasibility. Recruiting patients for MT sessions was feasible, although data collection on three consecutive weeks was not always possible due to organisational constraints, especially in the hospital with acute ward routines. Research procedures were successfully implemented, and according to interviews, none of the patients reported any burden, tiredness or increased stress due to the research procedures, which lasted approx. 3 hours (ranging from 135min to 209min) for each patient. Implementing the research procedures in a rehabilitation unit with stroke patients was feasible and only small adaptations were made for further research.

Asthma is the most common chronic disease in children. It is characterized by difficulty in breathing and chronic airway inflammation associated with narrowing of the airways, and airway hyperresponsiveness. If left untreated, asthma can lead to respiratory distress and even death. A number of medications are available and prescribed to manage asthma. Yet despite that, only half of the asthmatic patients are able to control their condition. Extracellular vesicles (EVs) play an important role in transporting contents such as nucleic acids, proteins, and lipids to other cells. While EVs have been extensively studied as biomarkers of various pathological states, evidence indicates that they can play protective and therapeutic roles in mitigating diseases such as cancer, cardiovascular disease and asthma. Here we propose to conduct a systematic review that provides a detailed analysis of the therapeutic effect of EVs in mitigating the primary (inflammation, airway hyperresponsiveness) and secondary outcomes (airway remodelling, molecular indices of cellular signalling, and inflammatory mediators in serum) associated with asthma in preclinical studies.

Colorectal cancer (CRC) is considered as one of the leading types of cancer in the world. CD133, as a cancer stem cell marker, has a pivotal role in the development of drug resistance, migration, and stemness properties of CRC cells. This study designed to check the combined effect of CD133siRNA and Oxaliplatin on proliferation, migration, apoptosis, and stemness properties of CRC cells in HT-29 cell line.MTT assay was performed to define the combined effect of CD133siRNA and Oxaliplatin on the viability of HT-29 cells. In order to figure out the effect of this combination therapy on CD133 expression at the gene and protein level, qRT-PCR and western blot were exploited, respectively. The ability of cell migration was tested by wound healing assay as well. Also, colony formation and sphere formation were conducted to assess the stemness properties in the combination group. Flow cytometry was conducted to investigate the apoptosis, cell cycle, and surface expression of CD133 in different groups. Finally, the expression of migration-, and stemness-associated genes were measured by qRT-PCR. We indicated that silencing of CD133 reduces the migration and stemness properties of colorectal cancerous cells. This suppression makes HT-29 cells more sensitive to Oxaliplatin and reduces the effective dose of this chemical drug. Therefore, the suppression of CD133 in combination with Oxaliplatin treatment might be a promising therapeutic approach in the treatment of colorectal cancer.

Cellular immunotherapy has recently emerged as a fourth pillar in cancer treatment co-joining surgery, chemotherapy and radiotherapy. Where, the discovery of immune checkpoint blockage or inhibition (ICB/ICI), anti-PD-1/PD-L1 and anti-CTLA4-based, therapy has revolutionized the class of cancer treatment at a different level. However, still some cancer patient escape this immune surveillance mechanism and become resistant to ICB-therapy. Therefore, a more advanced or an alternative treatment is required instantly. Despite the functional importance of epitranscriptomics in diverse clinico-biological practices, its role in improving the efficacy of ICB therapeutics has been limited. Consequently, our study encapsulates the evidences, as a possible strategy, to improve the efficacy of ICB-therapy by co-targeting molecular checkpoints especially N6A-modification machineries which could be reformed into RNA modifying drugs (RMD). Here, we have explained the mechanism of individual RNA-modifiers (editor/writer, eraser/remover and effector/reader) in overcoming the issues associated with high-dose antibody toxicities and drug-resistance. Moreover, we have shed light on the importance of suppressor of cytokine signalling (SOCS/CISH) and microRNAs in improving the efficacy of ICB-therapy, with brief insight on the current monoclonal antibodies undergoing clinical trials or already approved against several solid tumor and metastatic cancers. We anticipate our investigation will encourage researchers and clinicians to further strengthen the efficacy of ICB-therapeutics by considering the importance of epitranscriptomics as a personalized medicine.

Background: Boron Neutron Capture Therapy (BNCT) is an emerging radiotherapy. There are ongoing efforts to develop a Canadian accelerator-based BNCT center. However, it remains unclear how Canadian radiation oncologists (RO), medical physicists (MP), and their trainees perceive BNCT and its impact on radiation oncology as a discipline. Methods: A survey was created to explore knowledge of BNCT, its clinical role, and support for Canadian research. It was distributed through the Canadian Association of Radiation Oncology (CARO) and Canadian Organization of Medical Physicists (COMP). Results: We received 118 valid responses from all 10 provinces, from 70 RO (59.3%) and 48 MP (40.7%), including 9 residents. Most knew of BNCT and its indications (60.2%). Although many were unaware of reasons behind early failures (44.1%), common reasons were lack of clinical trials and inaccessibility of neutron sources (42.4%) and reactor unsuitability (34.7%). Additionally, 90.6% showed definite (66.9%) or possible (23.7%) support for Canadian BNCT research, while 89% indicated definite (56.8%) or possible (32.2%) willingness for BNCT referrals. Conclusions: Most RO and MP supported Canadian BNCT research and would refer patients. However, limited awareness and lack of experiences remain a challenge. Educational sessions are needed to realize this innovative cancer treatment in Canada.

Background: Metastatic cancer is associated with an invariably fatal outcome. However, DeltaRex-G, a tumor- targeted retrovector encoding a CCNG1 inhibitor gene, has induced long term (>10 years) survival of patients with chemo-resistant metastatic pancreatic adenocarcinoma, MPNST, osteosarcoma, B-cell lymphoma, and breast carcinoma. Objective: To evaluate the level of CCNG1 expression in tumors as a potential biomarker for CCNG1 inhibitor therapy. Methods: CCNG1 RNA expression levels were measured in tumors (TCGA, N=9161), adjacent “tissues” (TCGA, N=678) and GTEx normal tissues (N=7187) across 22 organ sites. Differential expression of CCNG1 and Ki-67 in primary (N= 9161) vs metastatic (N= 393) tumors were also compared and particularly in primary (N=103) vs. metastatic (N=367) skin cancer (i.e., melanoma). Results: Enhanced CCNG1 RNA and protein expression were noted in tumors compared to normal analogous counterparts, and CCNG1 expression correlated significantly with that of Ki-67. Further, CCNG1 expression tended to be higher than that of Ki-67 in metastatic vs primary tumors, particularly in skin cancer (melanoma). Conclusions: Taken together, these data indicate that (1) CCNG1 expression is frequently enhanced in tumors when compared to their normal analogous counterparts, (2) CCNG1 and Ki-67 expressions are higher in metastatic vs primary tumors, (3) CCNG1 expression is significantly correlated with that of Ki-67, and (4) CCNG1 may be a stronger marker of metastasis than Ki-67. Phase 2 studies are planned to identify patients who are likely to respond favorably to CCNG1 inhibitor therapy by correlating treatment outcome parameters with CCNG1 expression levels in various cancer types.

It is well known that the event of hepatitis B virus reactivation can occur among patients undergoing treatment for hematological malignancies. In this paper we will present the available data regarding the risk of hepatitis B virus reactivation in this special population of immunosuppressed patients and explore the relevance of an accurate prevention and management of this condition. A computerized literature search was performed using appropriate terms arrangement, including English-written literature only or additional relevant articles. The evaluation of hepatitis B reactivation risk is a multidimensional process, which includes conducting an accurate clinical and physical history, considering the virological categories, the knowledge of the medication chosen to treat these hematological malignancies and the induced grade of immunosuppression. Adopting adequate preventive strategies and surveillance according to the current international recommendations is crucial to prevent HBVr and its dire clinical consequences (hepatitis, liver failure, interruption of lifesaving anti-neoplastic treatments). Universal HBV screening of patients scheduled to undergo treatment for hematological malignancies should be the chosen policy, and clinicians should be aware of the inherent risk of viral reactivation among the different virological categories and the classes of immunosuppressive drugs.