Challenges and opportunities for cancer stem cell-targeted immunotherapies include immune checkpoint inhibitor, cancer stem cell-dendritic cell vaccine, chimeric antigen receptor immune cells, and modified exosomes.

Cancer stem cells (CSCs) are associated with the tumor microenvironment (TME). CSCs induce tumorigenesis, tumor recurrence and progression, and resistance to standard therapies. Indeed, CSCs pose an increasing challenge to current cancer therapy due to their stemness or self-renewal properties. The molecular and cellular interactions between heterogeneous CSCs and surrounding TME components and tumor-supporting immune cells show synergistic effects toward treatment failure. In the immunosuppressive TME, CSCs express various immunoregulatory proteins, growth factors, metabolites and cytokines, and also produce exosomes, a type of extracellular vesicles, to protect themselves from host immune surveillance. Among these, the identification and application of CSC-derived exosomes could be considered for the development of therapeutic approaches to eliminate CSCs or cancer, in addition to targeting the modulators that remodel the composition of the TME, as reviewed in this study. Here, we introduce the role of CSCs and how their interaction with TME complicates immunotherapies, and then present the CSC-based immunotherapy and the limitation of these therapies. We describe the biology and role of tumor/CSC-derived exosomes that induce immune suppression in the TME, and finally, introduce their potentials for the development of CSC-based targeted immunotherapy in the future.

Nucleic acid-based vaccine for ovarian cancer cells; bench to bedside.

Ovarian cancer continues to be a difficult medical issue that affects millions of individuals worldwide. Important platforms for cancer immunotherapy include checkpoint inhibitors, chimeric antigen receptor T cells, bispecific antibodies, cancer vaccines, and other cell-based treatments. To avoid numerous infectious illnesses, conventional vaccinations based on synthetic peptides, recombinant subunit vaccines, and live attenuated and inactivated pathogens are frequently utilized. Vaccine manufacturing processes, however, are not entirely safe and carry a significant danger of contaminating living microorganisms. As a result, the creation of substitute vaccinations is required for both viral and noninfectious illnesses, including cancer. Recently, there has been testing of nucleic acid vaccines, or NAVs, as a cancer therapeutic. Tumor antigens (TAs) are genetically encoded by DNA and mRNA vaccines, which the host uses to trigger immune responses against ovarian cancer cells that exhibit the TAs. Despite being straightforward, safe, and easy to produce, NAVs are not currently thought to be an ideal replacement for peptide vaccines. Some obstacles to this strategy include selecting the appropriate therapeutic agents (TAs), inadequate immunogenicity, and the immunosuppressive characteristic of ovarian cancer. We focus on strategies that have been employed to increase NAVs' effectiveness in the fight against ovarian cancer in this review.

Safety and efficacy of hybrid vascular closure technique using both a suture- and collagen-mediated closure device after transfemoral transcatheter aortic valve implantation.

OBJECTIVES: To evaluate the clinical utility and feasibility of a hybrid technique for obtaining vascular hemostasis by combining a suture- and a collagen-mediated system after transfemoral transcatheter aortic valve implantation (TF TAVI) in a real-world setting. METHODS: In 75 consecutive TF TAVI procedures, we investigated a hybrid closing method to achieve hemostasis at the large bore puncture site using a combination of one presuture closure system (ProGlide) and one collagen-mediated system (Angio-Seal). Vascular complications at puncture site were recorded until discharge. RESULTS: Successful hemostasis by the hybrid technique was achieved in 74 out of 75 patients, and the method was well tolerated by all patients. In 73 patients, (97.3%) neither puncture site related complications nor serious early or late bleedings were observed during a median hospital stay of 2 days postprocedure. CONCLUSION: This single-center registry study indicates that a percutaneous hybrid closure technique is safe and efficacious in closing large bore arteriotomies. It is an easy and reliable technique that may contribute to simplifying TAVI procedures. STUDY REGISTRATION: The data was collected from an internal quality control registry on treatment of patients with valvular heart disease with or without coronary artery disease, No 2014/17280, Oslo University Hospital, Ullevål.

Catheter-based left atrial appendage closure. / Kateterbasert lukking av venstre atriums aurikkel.

BAKGRUNN: Atrieflimmer er en vanlig tilstand i befolkningen og gir økt risiko for hjerneslag. Antikoagulasjonsbehandling er effektivt for å forebygge tromboembolisme ved atrieflimmer, men av ulike grunner blir mange atrieflimmerpasienter med indikasjon for antikoagulasjonsbehandling ikke behandlet. Kateterbasert lukking av venstre atriums aurikkel er en ny metode for å forebygge hjerneslag ved atrieflimmer. MATERIALE OG METODE: I perioden september 2014-april 2016 gjennomgikk 27 pasienter med atrieflimmer og høy risiko for hjerneslag forsøk på kateterbasert lukking av venstre atriums aurikkel ved Oslo universitetssykehus. Antikoagulasjonsbehandling var vurdert som kontraindisert hos 26 av pasientene. Vi presenterer resultater fra prosedyre, ekkokardiografikontroller og kliniske hendelser i oppfølgingsperioden på ett år. RESULTATER: Aurikkelplugg ble vellykket implantert hos 26 pasienter. To pasienter fikk komplikasjoner i forbindelse med prosedyren: En fikk hjerneslag og en fikk transfusjonskrevende lyskeblødning. En pasient fikk hjertetamponade fem måneder etter prosedyren. En pasient som grunnet anatomisk vanskelige forhold ikke fikk implantert aurikkelplugg, døde av hjerneslag i oppfølgingsperioden. Tre pasienter hadde klinisk transitorisk iskemisk anfall (TIA). Det var ingen forekomst av intrakranial eller gastrointestinal blødning. FORTOLKNING: Kateterbasert lukking av venstre atriums aurikkel er gjennomførbart, men innebærer risiko for komplikasjoner og bør forbeholdes pasienter med høy risiko for hjerneslag og kontraindikasjon mot antikoagulasjonsbehandling.

Echocardiographic evaluation of left ventricular filling pressure in heart transplant recipients.

OBJECTIVES: Diastolic dysfunction is a major cause of morbidity in heart transplant recipients. A reliable, non-invasive marker of left ventricular (LV) filling pressure would simplify follow-up in these patients. We aimed to test the validity of echocardiographic indices of LV filling pressure in a contemporary population of heart transplant recipients. DESIGN: Eighty-three patients were examined by right-sided heart catheterisation and echocardiography one year after heart transplantation. We explored the association between echocardiographic parameters of LV filling pressure and invasively measured pulmonary capillary wedge pressure (PCWP). RESULTS: Peak early mitral flow velocity divided by septal early mitral relaxation velocity (E/e'(septal)) was the echocardiographic parameter that best correlated with PCWP (r = 0.47; p < 0.001). At a cut-off value of 22, E/e'(septal) could identify patients with a PCWP above 12 mm Hg with a sensitivity of 56% and a specificity of 95%. CONCLUSIONS: The E/e' index was moderately associated with LV filling pressure in heart transplant recipients. Echocardiographic parameters of diastolic function should be interpreted with caution when estimating left ventricular filling pressures in this population.

Assessment of Bacterial Load and Post-Endodontic Pain after One-Visit Root Canal Treatment Using Two Types of Endodontic Access Openings: A Randomized Controlled Clinical Trial.

The need for controlling bacteria and pain during root canal therapy is undeniable. This clinical trial aimed to assess whether there is a difference in colony-forming unit (CFU) reduction after instrumentation and post-endodontic pain after root canal treatment (RCT) using a traditional endodontic cavity (TEC) versus a conservative endodontic cavity (CEC). This clinical study was conducted on 89 patients designated for a single-visit RCT. Patients were allocated randomly (TEC n = 45 and CEC n = 44). The access opening was gained accordingly in each group by a single operator. A pre-instrumentation sample of root canal dentin was collected using an endodontic file; the second sample was collected similarly, right after shaping and cleaning the root canal. The CFU was calculated based on the samples collected. The pain level was recorded preoperatively and at 1, 7, and 21 days postoperatively utilizing a visual analog scale (VAS). There were no statistically significant differences in the CFU reduction between the TEC and CEC groups (p > 0.05). Additionally, there were no statistically significant differences found in postoperative pain levels between the TEC and CEC at 1, 7, and 21 days (p > 0.05). Despite the limitations of this study, both the CEC and TEC demonstrate a decrease in bacteria within the root canals and alleviate postoperative pain with no difference between them.

A comprehensive insight into the contribution of epigenetics in male infertility; focusing on immunological modifications.

Numerous recent studies have examined the impact epigenetics-including DNA methylation-has on spermatogenesis and male infertility. Differential methylation of several genes has been linked to compromised spermatogenesis and/or reproductive failure. Specifically, male infertility has been frequently associated with DNA methylation abnormalities of MEST and H19 inside imprinted genes and MTHFR within non-imprinted genes. Microbial infections mainly result in male infertility because of the immune response triggered by the bacteria' accumulation of immune cells, proinflammatory cytokines, and chemokines. Thus, bacterially produced epigenetic dysregulations may impact host cell function, supporting host defense or enabling pathogen persistence. So, it is possible to think of pathogenic bacteria as potential epimutagens that can alter the epigenome. It has been demonstrated that dysregulated levels of LncRNA correlate with motility and sperm count in ejaculated spermatozoa from infertile males. Therefore, a thorough understanding of the relationship between decreased reproductive capacity and sperm DNA methylation status should aid in creating new diagnostic instruments for this condition. To fully understand the mechanisms influencing sperm methylation and how they relate to male infertility, more research is required.

Critical role of exosome, exosomal non-coding RNAs and non-coding RNAs in head and neck cancer angiogenesis.

Head and neck cancer (HNC) refers to the epithelial malignancies of the upper aerodigestive tract. HNCs have a constant yet slow-growing rate with an unsatisfactory overall survival rate globally. The development of new blood vessels from existing blood conduits is regarded as angiogenesis, which is implicated in the growth, progression, and metastasis of cancer. Aberrant angiogenesis is a known contributor to human cancer progression. Representing a promising therapeutic target, the blockade of angiogenesis aids in the reduction of the tumor cells oxygen and nutrient supplies. Despite the promise, the association of existing anti-angiogenic approaches with severe side effects, elevated cancer regrowth rates, and limited survival advantages is incontrovertible. Exosomes appear to have an essential contribution to the support of vascular proliferation, the regulation of tumor growth, tumor invasion, and metastasis, as they are a key mediator of information transfer between cells. In the exocrine region, various types of noncoding RNAs (ncRNAs) identified to be enriched and stable and contribute to the occurrence and progression of cancer. Mounting evidence suggest that exosome-derived ncRNAs are implicated in tumor angiogenesis. In this review, the characteristics of angiogenesis, particularly in HNC, and the impact of ncRNAs on HNC angiogenesis will be outlined. Besides, we aim to provide an insight on the regulatory role of exosomes and exosome-derived ncRNAs in angiogenesis in different types of HNC.

Pregnancy detection and monitoring in cattle via combined foetus electrocardiogram and phonocardiogram signal processing.

BACKGROUND: Pregnancy testing in cattle is commonly invasive requiring manual rectal palpation of the reproductive tract that presents risks to the operator and pregnancy. Alternative non-invasive tests have been developed but have not gained popularity due to poor specificity, sensitivity and the inconvenience of sample handling. Our aim is to present the pilot study and proof of concept of a new non invasive technique to sense the presence and age (limited to the closest trimester of pregnancy) of the foetus by recording the electrical and audio signals produced by the foetus heartbeat using an array of specialized sensors embedded in a stand alone handheld prototype device. The device was applied to the right flank (approximately at the intercept of a horizontal line drawn through the right mid femur region of the cow and a vertical line drawn anywhere between lumbar vertebrae 3 to 5) of more than 2000 cattle from 13 different farms, including pregnant and not pregnant, a diversity of breeds, and both dairy and beef herds. Pregnancy status response is given "on the spot" from an optimized machine learning algorithm running on the device within seconds after data collection. RESULTS: Using combined electrical and audio foetal signals we detected pregnancy with a sensitivity of 87.6% and a specificity of 74.6% for all recorded data. Those values increase to 91% and 81% respectively by removing files with excessive noise (19%).Foetus ageing was achieved by comparing the detected foetus heart-rate with published tables. However, given the challenging farm environment of a restless cow, correct foetus ageing was achieved for only 21% of the correctly diagnosed pregnant cows. CONCLUSIONS: In conclusion we have found that combining ECG and PCG measurements on the right flank of cattle provides a reliable and rapid method of pregnancy testing. The device has potential to be applied by unskilled operators. This will generate more efficient and productive management of farms. There is potential for the device to be applied to large endangered quadrupeds in captive breeding programs where early, safe and reliable pregnancy diagnosis can be imperative but currently difficult to achieve.

Insidious Onset of Incarcerated Parastomal Hernia With Gastric Outlet Obstruction: A Case Report.

Although parastomal hernias have a high incidence in the general population, involvement of the stomach remains rare due to the numerous suspensory structures tethering this organ in its anatomical location. This case details a 75-year-old lady with a painless onset of a gastric parastomal hernia with progressive incarceration over a two-week period. The deteriorating clinical condition of the patient following weeks of stability indicated that the cause of symptoms is likely sinister. Imaging confirmed incarceration of the stomach within a parastomal hernia. Although this has been reported previously, there is little to suggest this condition exists with an insidious onset. Patients who are at high risk of gastric herniation and who fit this clinical vignette with a known parastomal hernia should be offered prompt investigations to ascertain the diagnosis and facilitate further management.

Mechanism to prevent the abuse of IPv6 fragmentation in OpenFlow networks.

OpenFlow makes a network highly flexible and fast-evolving by separating control and data planes. The control plane thus becomes responsive to changes in topology and load balancing requirements. OpenFlow also offers a new approach to handle security threats accurately and responsively. Therefore, it is used as an innovative firewall that acts as a first-hop security to protect networks against malicious users. However, the firewall provided by OpenFlow suffers from Internet protocol version 6 (IPv6) fragmentation, which can be used to bypass the OpenFlow firewall. The OpenFlow firewall cannot identify the message payload unless the switch implements IPv6 fragment reassembly. This study tests the IPv6 fragmented packets that can evade the OpenFlow firewall, and proposes a new mechanism to guard against attacks carried out by malicious users to exploit IPv6 fragmentation loophole in OpenFlow networks. The proposed mechanism is evaluated in a simulated environment by using six scenarios, and results exhibit that the proposed mechanism effectively fixes the loophole and successfully prevents the abuse of IPv6 fragmentation in OpenFlow networks.

Utility of Precision Medicine in the Management of Diabetes: Expert Opinion from an International Panel.

AIM: The primary objective of this review is to develop a practice-based expert group opinion on the role of precision medicine with a specific focus on sulfonylureas (SUs) in diabetes management. BACKGROUND: The clinical etiology, presentation and complications of diabetes vary from one patient to another, making the management of the disease challenging. The pre-eminent feature of diabetes mellitus (DM) are chronically elevated blood glucose concentrations; however, in clinical practice, the exclusion of autoimmunity, pregnancy, pancreatic disease or injury and rare genetic forms of diabetes is crucial. Within this framework, precision medicine provides unique insights into the risk factors and natural history of DM. Precision medicine goes beyond genomics and encompasses patient-centered care, molecular technologies and data sharing. Precision medicine has evolved in the field of diabetology. It has helped improve the efficacy of SUs, a class of drugs, which have been effectively used in the management of diabetes mellitus for decades, and it has enabled the expansion of SUs use in diabetes patients with genetic mutations. REVIEW RESULTS: After due discussions, the expert group analyzed studies that focused on the use of SUs in diabetes patients with genomic variations and rare mutations. The expert group opined that SUs are important glucose-lowering drugs and that precision medicine helps in improving the efficacy of SUs by matching them to those patients who will benefit most. CONCLUSION: Precision medicine opens new vistas for the effective use of SUs in unexpected patient populations, such as those with genetic mutations.

DAD-match; Security technique to prevent denial of service attack on duplicate address detection process in IPv6 link-local network.

An efficiently unlimited address space is provided by Internet Protocol version 6 (IPv6). It aims to accommodate thousands of hundreds of unique devices on a similar link. This can be achieved through the Duplicate Address Detection (DAD) process. It is considered one of the core IPv6 network's functions. It is implemented to make sure that IP addresses do not conflict with each other on the same link. However, IPv6 design's functions are exposed to security threats like the DAD process, which is vulnerable to Denial of Service (DoS) attack. Such a threat prevents the host from configuring its IP address by responding to each Neighbor Solicitation (NS) through fake Neighbor Advertisement (NA). Various mechanisms have been proposed to secure the IPv6 DAD procedure. The proposed mechanisms, however, suffer from complexity, high processing time, and the consumption of more resources. The experiments-based findings revealed that all the existing mechanisms had failed to secure the IPv6 DAD process. Therefore, DAD-match security technique is proposed in this study to efficiently secure the DAD process consuming less processing time. DAD-match is built based on SHA-3 to hide the exchange tentative IP among hosts throughout the process of DAD in an IPv6 link-local network. The obtained experimental results demonstrated that the DAD-match security technique achieved less processing time compared with the existing mechanisms as it can resist a range of different threats like collision and brute-force attacks. The findings concluded that the DAD-match technique effectively prevents the DoS attack during the DAD process. The DAD-match technique is implemented on a small area IPv6 network; hence, the author future work is to implement and test the DAD-match technique on a large area IPv6 network.

Late Pseudoaneurysm After Access Site Closure with Manta in Transfemoral Aortic Valve Implantation.

INTRODUCTION: Access site vascular complications in transfemoral transcatheter aortic valve implantation (TF-TAVI) are still a major concern. Recently, a novel collagen plug based closure device (Manta) was introduced. The results from the first reports on Manta are very promising, but not much is known about the long-term patency. REPORT: A case of late pseudoaneurysm after access site arterial closure with Manta in TF-TAVI is described. The patient presented five weeks after left sided TF-TAVI with pain and claudication like symptoms in the left leg. CT angiography revealed a pseudoaneurysm at the puncture site. The patient was successfully treated by vascular surgery. DISCUSSION: The results from recent peri-operative reports on the Manta vascular closure device (VCD) are promising, but not much is known about the long-term patency. In the present report a patient is described who developed a pseudoaneurysm several weeks after access site closure with Manta. To the authors' knowledge, no such late access site complications after use of the Manta VCD have been reported previously.

Euthymia in Diabetes: Clinical Evidence and Practice-Based Opinion from an International Expert Group.

AIM: To develop an evidence-based expert group opinion on various types of euthymia associated with diabetes mellitus (DM) and its management. BACKGROUND: Diabetes mellitus is a metabolic syndrome characterized by diverse biomedical and psychosocial features. Emotional health disturbances may lead to psychological and psychiatric dysfunction and may negatively influence glycemic control. Patients with DM may experience diabetes distress (DD) associated with burden of self-care, interpersonal issues, and emotional worries regarding the ability to cope with the illness. Euthymia or a state of positive mental health and psychological well-being should be considered a key outcome of diabetes care. Therefore, to achieve optimal outcomes, the consideration and measurement of psychological and psychiatric aspects along with glycemic levels are very important. A group of multidisciplinary clinical experts came together in an international meeting held in India to develop a workable concept for euthymia in diabetes care. A multidisciplinary approach was suggested to enhance the clinical outcomes and facilitate patient-centered care. During the meeting emphasis was given to the concept of a euthymia model in diabetes care. This model focuses on enhancement of self-care skills in diabetic patients and preventative health awareness among diabetes care providers. Euthymia also encompasses patient-provider communication to aid enhancement of coping skills. RESULTS: After due discussions and extensive deliberations, the expert group provided several recommendations on implementing the concept of euthymia in DM care. CONCLUSIONS: Introduction of the concept of euthymia in routine clinical practice is important to improve the quality of life and coping skills in patients with DM. A timely clinical assessment of psychological and psychiatric aspects along with patient-reported outcomes of diabetes contributes to overall health and well-being of affected individuals. FUNDING: Sanofi India.

Glucocrinology of Modern Sulfonylureas: Clinical Evidence and Practice-Based Opinion from an International Expert Group.

AIM: The primary objective of this document is to develop practice-based expert group opinion on certain important but less discussed endocrine and metabolic effects of modern sulfonylureas (SUs) and their usage in the management of diabetes mellitus (DM). BACKGROUND: Modern SUs may be considered a panacea in DM care with their beneficial extra-pancreatic, pleiotropic, and cardiovascular effects. Safe glycemic control with SUs could be achieved with appropriate patient selection, drug and dosage selection, and patient empowerment. Additionally, sulfonylureas also exhibit certain endocrine and metabolic effects, which could be considered beneficial in the management of DM. In this regard, a group of international clinical experts discussed the less known beneficial aspects of SUs and safe and smart prescription of modern SUs in DM care. RESULTS: The concept of glucocrinology or the relationship of glycemia with the endocrine system was emphasized during the meetings. Clinical experts arrived at a consensus for the usage of modern SUs in the presence of other endocrine dysfunction and the impact of these drugs on endocrine health. The beneficial pleiotropic and cardiovascular effects of modern SUs were also discussed. The key discussion points were considered to develop clinical expert opinions for the use of modern SUs in persons with DM. Clinical expert opinions were developed for indications, pleiotropic benefits, cardiovascular outcomes, adherence, and safe use of modern SUs. CONCLUSIONS: Appropriate clinical judgement coupled with a patient-centered approach is crucial to achieve the best outcome in persons with DM. Owing to their safety, efficacy, extra-pancreatic benefits including effects on endocrine and metabolic aspects, and low cost of therapy, modern SUs could be considered as drugs/agents of choice for the treatment of diabetes. FUNDING: Sanofi India.

Feature Selection for the Detection of Sleep Apnea using Multi-Bio Signals from Overnight Polysomnography.

Patients with sleep apnea (SA) are at increased risk of stroke and cardiovascular disease. Diagnosis of sleep apnea depends on the standard overnight polysomnography (PSG). In this study, the DREAM Apnea Database was used to evaluate the importance of the various features proposed in the literature for the analysis of sleep apnea. Various timeand frequency- domain features that include wavelet and power spectral density were extracted from ECG, EMG, EEG, airflow, SaO2, abdominal and thoracic recordings. Evaluation measures of one-way analysis of variance (ANOVA) and Rank-Sum test were used to test the performance of different features. The selected feature subset indicated that frequency-domain features outperform time-domain ones. This study will help in enhancing the detection accuracy of sleep apnea for the various polysomnography signals.

Changes in lower limb muscle synchronisation during walking on high-heeled shoes.

The goal of this research was to investigate the effect of wearing high-heeled shoes (HHS) on lower limb muscle synchronisation during walking, using beta band (15-30 Hz) coherence analysis. Fifteen females with no previous neuromuscular disorders volunteered in this study. Surface electromyography in frequency domain was studied from rectus femoris (RF), vastus lateralis (VL), vastus medialis (VM) and semitendinosus (ST) muscles during walking by subjects wearing HHS of three different heel heights (low - 4 cm, medium - 6 cm and high - 10 cm). Average coherence values were calculated for RF-VL, RF-VM and RF-ST muscles in beta band to analyse muscle pair synchronisation. In this study, significant increase in beta band coherence was found in all three muscle pairs during walking on HHS of different heel heights (p<0.05). Increased beta band coherence obtained from this study suggested that walking on HHS demands higher muscle pair synchronisation, to maintain stability around the knee joint.

Estimating The Quality of Electroconvulsive Therapy Induced Seizures Using Decision Tree and Fuzzy Inference System Classifiers.

Electroconvulsive therapy (ECT) is an effective and widely used treatment for major depressive disorder, in which a brief electric current is passed through the brain to trigger a brief seizure. This study aims to identify seizure quality rating by utilizing a set of seizure parameters. We used 750 ECT EEG recordings in this experiment. Four seizure related parameters, (time of slowing, regularity, stereotypy and post-ictal suppression) are used as inputs to two classifiers, decision tree and fuzzy inference system (FIS), to predict seizure quality ratings. The two classifiers produced encouraging results with error rate of 0.31 and 0.25 for FIS and decision tree, respectively. The classification results show that the four seizure parameters provide relevant information about the rating of seizure quality. Automatic scoring of seizure quality may be beneficial to clinicians working in this field.