Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases

Neurodegenerative diseases, such as Alzheimer＇s, Parkinson＇s and Huntington＇s diseases, are all character- ized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.

MicroRNAs as emerging biomarkers and therapeutic targets for pancreatic cancer

Despite tremendous efforts from scientists and clinicians worldwide, pancreatic adenocarcinoma(PDAC) remains a deadly disease due to the lack of early diagnostic tools and reliable therapeutic approaches. Consequently, a majority of patients(80%) display an advanced disease that results in a low resection rate leading to an overall median survival of less than 6 months. Accordingly, robust markers for the early diagnosis and prognosis of pancreatic cancer, or markers indicative of survival and/or metastatic disease are des-perately needed to help alleviate the dismal prognosis of this cancer. In addition, the discovery of new therapeutic targets is mandatory to design effective treatments. In this review, we will highlight the translational studies demonstrating that microRNAs may soon translate into clinical applications as long-awaited screening tools and therapeutic targets for PDAC.

Spontaneous conception after autologous hematopoietic stem cell transplantation： a case report

Dear Editor, Allogeneic or autologous hematopoietic stem cell transplantation （HSCT） allows many patients with hematological malignancies to obtain prolonged survival and often disease cure. Autologous HSCT is particularly effective in acute promyelocytic leukemia （APL）, a subtype of acute myeloid leukemia （AML） after relapse with conventional treatment. However, iatrogenic endocrine disturbances and reproductive failure are frequently-encountered late effects, which have a major impact on the quality oflife.l Conditioning regimens with total body irradiation （TBI） and intensive chemotherapy before autologons or allogeneic HSCT are known to cause permanent infertility, a risk that can be prevented by sperm banking.2

Copy Mean: A New Method to Impute Intermittent Missing Values in Longitudinal Studies

Longitudinal studies are those in which the same variable is repeatedly measured at different times. These studies are more likely than others to suffer from missing values. Since the presence of missing values may have an important impact on statistical analyses, it is important that they should be dealt with properly. In this paper, we present “Copy Mean”, a new method to impute intermittent missing values. We compared its efficiency in eleven imputation methods dedicated to the treatment of missing values in longitudinal data. All these methods were tested on three markedly different real datasets (stationary, increasing, and sinusoidal pattern) with complete data. For each of them, we generated nine types of incomplete datasets that include 10%, 30%, or 50% of missing data using either a Missing Completely at Random, a Missing at Random, or a Missing Not at Random missingness mechanism. Our results show that Copy Mean has a great effectiveness, exceeding or equaling the performance of other methods in almost all configurations. The effectiveness of linear interpolation is highly data-dependent. The Last Occurrence Carried Forward method is strongly discouraged.

Development of NK cell-based cancer immunotherapies through receptor engineering

Natural killer(NK)cell-based immunotherapies are attracting increasing interest in the field of cancer treatment.Early clinical trials have shown promising outcomes,alongside satisfactory product efficacy and safety.Recent developments have greatly increased the therapeutic potential of NK cells by endowing them with enhanced recognition and cytotoxic capacities.This review focuses on surface receptor engineering in NK cell therapy and discusses its impact,challenges,and future directions.Most approaches are based on engineering with chimeric antigen receptors to allow NK cells to target specific tumor antigens independent of human leukocyte antigen restriction.This approach has increased the precision and potency of NK-mediated recognition and elimination of cancer cells.In addition,engineering NK cells with T-cell receptors also mediates the recognition of intracellular epitopes,which broadens the range of target peptides.Indirect tumor peptide recognition by NK cells has also been improved by optimizing immunoglobulin constant fragment receptor expression and signaling.Indeed,engineered NK cells have an improved ability to recognize and destroy target cells coated with specific antibodies,thereby increasing their antibodydependent cellular cytotoxicity.The ability of NK cell receptor engineering to promote the expansion,persistence,and infiltration of transferred cells in the tumor microenvironment has also been explored.Receptor-based strategies for sustained NK cell functionality within the tumor environment have also been discussed,and these strategies providing perspectives to counteract tumor-induced immunosuppression.Overall,receptor engineering has led to significant advances in NK cell-based cancer immunotherapies.As technical challenges are addressed,these innovative treatments will likely reshape cancer immunotherapy.

MACS-annexin V cell sorting of semen samples with high TUNEL values decreases the concentration of cells with abnormal chromosomal content:a pilot study

We question whether,in men with an abnormal rate of sperm DNA fragmentation,the magnetic-activated cell sorting(MACS)could select spermatozoa with lower rates of DNA fragmentation as well as spermatozoa with unbalanced chromosome content.Cryopreserved spermatozoa from six males were separated into nonapoptotic and apoptotic populations.We determined the percentages of spermatozoa with(i)externalization of phosphatidylserine(EPS)by annexin V-Fluorescein isothiocyanate(FITC)labeling,(ii)DNA fragmentation by TdT-mediated-dUTP nick-end labeling(TUNEL),and(iii)numerical abnormalities for chromosomes X,Y,13,18,and 21 by fluorescence in situ hybridization(FISH),on the whole ejaculate and selected spermatozoa in the same patient.Compared to the nonapoptotic fraction,the apoptotic fraction statistically showed a higher number of spermatozoa with EPS,with DNA fragmentation,and with numerical chromosomal abnormalities.Compared to the whole ejaculate,we found a significant decrease in the percentage of spermatozoa with EPS and decrease tendencies of the DNA fragmentation rate and the sum of disomy levels in the nonapoptotic fraction.Conversely,we observed statistically significant higher rates of these three parameters in the apoptotic fraction.MACS may help to select spermatozoa with lower rates of DNA fragmentation and unbalanced chromosome content in men with abnormal rates of sperm DNA fragmentation.

Cell therapy for the treatment of reproductive diseases and infertility:an overview from the mechanism to the clinic alongside diagnostic methods

Infertility is experienced by 8%–12%of adults in their reproductive period globally and has become a prevalent concern.Besides routine therapeutic methods,stem cells are rapidly being examined as viable alternative therapies in regenerative medicine and translational investigation.Remarkable progress has been made in understanding the biology and purpose of stem cells.The affected pluripotent stem cells(iPSCs)and mesenchymal stem cells(MSCs)are further studied for their possible use in reproductive medicine,particularly for infertility induced by premature ovarian insufficiency and azoospermia.Accordingly,this study discusses current developments in the use of some kinds of MSCs such as adipose-derived stem cells,bone marrow stromal cells,umbilical cord MSCs,and menstrual blood MSCs.These methods have been used to manage ovarian and uterine disorders,and each technique presents a novel method for the therapy of infertility.

Concurrent PIEZO1 activation and ATP2B4 blockade effectively reduce the risk of cerebral malaria and inhibit in vitro Plasmodium falciparum multiplication in red blood cells

Malaria caused by the Plasmodium falciparum parasite is responsible for more than 240 million cases per year and killed 627,000 people in 2020,mostly African children.The malaria parasite is transmitted by mosquitos belonging to the genus Anopheles.After an asymptomatic liver stage,the parasite is released into the bloodstream to invade red blood cells(RBCs)and replicate asexually.This erythrocytic phase is associated with a variety of clinical manifestations,including mild and severe malaria.Cerebral malaria(CM)is one of the most severe forms,characterized by the sequestration of parasitized RBCs in the small capillaries of the brain and the local development of cytokine-mediated inflammation.Genetic variants in genes encoding proteins involved in red blood cell physiology are protective factors against severe malaria,as clearly demonstrated for the sickle cell variant of hemoglobin(HbS).

Expert group syndrome at high altitude

During a training session for the university diploma of Mountain medicine delivered by University Sorbonne Paris Nord for medical doctors,one of the participants developed signs of maladaptation to high altitude at 3600 m,the severity of which was incorrectly interpreted.Information was sparingly given by the patient(an anesthetist)to several of his colleagues and no one was in charge to collect clinical data,take a history,and provide appropriate treatment.The combination of the absence of designation of a supervising doctor and the difficulty of communicating with the patient led to a lack of coordinated management and to an evolution of the symptoms towards severe acute mountain sickness.Fortunately,the very rapid management of the patient and a rapid helicopter evacuation,as soon as the symptoms worsened towards the onset of a suspected high altitude cerebral and/or pulmonary edema,allowed rapid resolution without sequelae.Environmental,medical,psychological,and managerial factors led to this Expert Group Syndrome.