The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this ...inhibitory axis in the suppression of tumour-specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein. Interference with CMTM6 expression results in impaired PD-L1 protein expression in all human tumour cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member, CMTM4, but not by any of the other CMTM members tested. Notably, CMTM6 increases the PD-L1 protein pool without affecting PD-L1 (also known as CD274) transcription levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with the PD-L1 protein, reduces its ubiquitination and increases PD-L1 protein half-life. Consistent with its role in PD-L1 protein regulation, CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.
Autologous transplantation of patient-specific induced pluripotent stem cell (iPSC)-derived neurons is a potential clinical approach for treatment of neurological disease. Preclinical demonstration ...of long-term efficacy, feasibility, and safety of iPSC-derived dopamine neurons in non-human primate models will be an important step in clinical development of cell therapy. Here, we analyzed cynomolgus monkey (CM) iPSC-derived midbrain dopamine neurons for up to 2 years following autologous transplantation in a Parkinson’s disease (PD) model. In one animal, with the most successful protocol, we found that unilateral engraftment of CM-iPSCs could provide a gradual onset of functional motor improvement contralateral to the side of dopamine neuron transplantation, and increased motor activity, without a need for immunosuppression. Postmortem analyses demonstrated robust survival of midbrain-like dopaminergic neurons and extensive outgrowth into the transplanted putamen. Our proof of concept findings support further development of autologous iPSC-derived cell transplantation for treatment of PD.
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•A non-human primate model tests cell transplantation for PD therapy•Autologous iPSC dopamine neurons can provide long-term functional recovery•Transplanted cells survive for up to 2 years and reinnervate the host brain
A pre-clinical test of transplantation of autologous iPSC-derived dopamine neurons in a cynomolgus monkey model of Parkinson’s disease provides proof of principle for long-term innervation and functional benefit without a requirement for immunosuppression.
Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial ...objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.
We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.
Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.
In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).
Stimulation of hMSC differentiation by Sr2+-modifid CaP bone cements.
In the present study, the in vitro effects of novel strontium-modified calcium phosphate bone cements (SrCPCs), prepared using ...two different approaches on human-bone-marrow-derived mesenchymal stem cells (hMSCs), were evaluated. Strontium ions, known to stimulate bone formation and therefore already used in systemic osteoporosis therapy, were incorporated into a hydroxyapatite-forming calcium phosphate bone cement via two simple approaches: incorporation of strontium carbonate crystals and substitution of Ca2+ by Sr2+ ions during cement setting. All modified cements released 0.03–0.07mM Sr2+ under in vitro conditions, concentrations that were shown not to impair the proliferation or osteogenic differentiation of hMSCs. Furthermore, strontium modification led to a reduced medium acidification and Ca2+ depletion in comparison to the standard calcium phosphate cement. In indirect and direct cell culture experiments with the novel SrCPCs significantly enhanced cell proliferation and differentiation were observed. In conclusion, the SrCPCs described here could be beneficial for the local treatment of defects, especially in the osteoporotic bone.
Circular RNAs are generated from many protein-coding genes, but their role in cardiovascular health and disease states remains unknown. Here we report identification of circRNA transcripts that are ...differentially expressed in post myocardial infarction (MI) mouse hearts including circFndc3b which is significantly down-regulated in the post-MI hearts. Notably, the human circFndc3b ortholog is also significantly down-regulated in cardiac tissues of ischemic cardiomyopathy patients. Overexpression of circFndc3b in cardiac endothelial cells increases vascular endothelial growth factor-A expression and enhances their angiogenic activity and reduces cardiomyocytes and endothelial cell apoptosis. Adeno-associated virus 9 -mediated cardiac overexpression of circFndc3b in post-MI hearts reduces cardiomyocyte apoptosis, enhances neovascularization and improves left ventricular functions. Mechanistically, circFndc3b interacts with the RNA binding protein Fused in Sarcoma to regulate VEGF expression and signaling. These findings highlight a physiological role for circRNAs in cardiac repair and indicate that modulation of circFndc3b expression may represent a potential strategy to promote cardiac function and remodeling after MI.
Progesterone is commonly considered as a female reproductive hormone and is well-known for its role in pregnancy. It is less well appreciated that progesterone and its metabolite allopregnanolone are ...also male hormones, as they are produced in both sexes by the adrenal glands. In addition, they are synthesized within the nervous system. Progesterone and allopregnanolone are associated with adaptation to stress, and increased production of progesterone within the brain may be part of the response of neural cells to injury. Progesterone receptors (PR) are widely distributed throughout the brain, but their study has been mainly limited to the hypothalamus and reproductive functions, and the extra-hypothalamic receptors have been neglected. This lack of information about brain functions of PR is unexpected, as the protective and trophic effects of progesterone are much investigated, and as the therapeutic potential of progesterone as a neuroprotective and promyelinating agent is currently being assessed in clinical trials. The little attention devoted to the brain functions of PR may relate to the widely accepted assumption that non-reproductive actions of progesterone may be mainly mediated by allopregnanolone, which does not bind to PR, but acts as a potent positive modulator of γ-aminobutyric acid type A (GABA(A) receptors. The aim of this review is to critically discuss effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABA(A) receptors, with main focus on the brain.
Mesoporous bioactive glasses (MBGs) are promising materials for regenerative medicine, due to their favorable properties including bioactivity and degradability. These key properties, but also their ...surface area, pore structure and pore volume are strongly dependent on synthesis parameters and glass stoichiometry. However, to date no systematic study on MBG properties covering a broad range of possible compositions exists.
Here, 24 MBG compositions in the SiO2–CaO–P2O5 system were synthesized by varying SiO2 (60–90 mol %), CaO and P2O5 content (both 0 to 40 mol-%), while other synthesis parameters were kept constant. Mesopore characteristics, degradability and bioactivity were analysed.
The results showed that, within the tested range of compositions, mesopore formation required a molar SiO2 content above 60% but was independent of CaO and P2O5 content. While mesopore size did not depend on glass stoichiometry, mesopore arrangement was influenced by the SiO2 content. Specific surface area and pore volume were slightly altered by the SiO2 content. All materials were degradable; however, degradation as well as bioactivity, i.e. the ability to form a CaP mineral on the surface, depended on stoichiometry. Major differences were found in early surface reactions in simulated body fluid: where some MBGs induced direct hydroxyapatite crystallization, high release of calcium in others resulted in calcite formation.
In summary, degradation and bioactivity, both key parameters of MBGs, can be controlled by glass stoichiometry over a broad range while leaving the unique structural parameters of MBGs relatively unaffected. This allows targeted selection of material compositions for specific regenerative medicine applications.
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•Mesoporous bioactive glasses can be obtained over a broad range of compositions.•In the SiO2/CaO/P2O5 system up to 15 mol-% P2O5 allow ordered porosity.•In SiO2/P2O5 glasses, up to 30 mol-% P2O5 are possible.•Bioactivity and degradation can be tailored by controlling stoichiometry.
Introduction
State-of-the-art research highlights that borderline personality disorder have high rates of comorbid Axis I disorders, which imply uncertainty in establishing an accurate diagnosis and ...can be some of the most challenging patients for clinicians and researchers.
Objectives
This study seeks to observe the diagnostic stability in borderline personality disorder patients, in order to increase empirical knowledge through a retrospective look at the historical line of diagnoses.
Methods
A twenty-year retrospective study at a psychiatric hospital, searching at the electronic clinical records for all patients with borderline personality disorder diagnosis, under the code 301.83 from World Health Organization’s International Classification of Diseases, 9
th
Revision (WHO ICD9). A 346 patients’ sample was identified aged between 18 and 83 years (
M
age
=44.14 years,
SD
=11.18; predominantly female 73.70%;
M
schooling
=9.31years;
M
admissions
=4.72
times
,
SD
=9.21; 2
nd
-5
th
comorbid diagnosis, a 75.72% sample with three diagnosis); excluding organic cerebral syndrome and no comorbidity besides drug abuse, or no comorbidity at all.
Results
As a general observation, the following diagnoses are indicated: 44.09% major depressive disorder, 33.16% affective disorder, 13.05% schizophrenia, and 9.70% mania. As a spectrums disorders analysis (Figure 1), differential percentage occurrences are identified in patients with borderline personality disorder.
Image:
Conclusions
Based on clinical diagnoses records of borderline personality disorder patients, some spectrums disorders are highlighted, to be reported in descending order of incidence: depressive, affective, schizoaffective and schizophrenia spectrums.
Disclosure of Interest
None Declared
To determine the association between antimüllerian hormone (AMH), a measure of ovarian reserve, and miscarriage among naturally conceived pregnancies.
Prospective cohort study.
Not applicable.
Women ...(n = 533), between 30 and 44 years of age with no known history of infertility, polycystic ovarian syndrome, or endometriosis who conceived naturally.
None.
Miscarriage, defined as an intrauterine pregnancy loss before 20 weeks' gestation.
After adjusting for maternal age, race, history of recurrent miscarriage, and obesity, risk of miscarriage decreased as AMH increased (risk ratio per unit increase in natural log of AMH = 0.83; 95% confidence interval CI, 0.73, 0.94). Women with severely diminished ovarian reserve (AMH ≤ 0.4 ng/mL) miscarried at over twice the rate of women with an AMH ≥ 1 ng/mL (hazard ratio, 2.3; 95% CI, 1.3, 4.3).
AMH levels are inversely associated with the risk of miscarriage. Women with severely diminished ovarian reserve are at an increased risk of miscarriage.
Piezo ion channels are activated by various types of mechanical stimuli and function as biological pressure sensors in both vertebrates and invertebrates. To date, mechanical stimuli are the only ...means to activate Piezo ion channels and whether other modes of activation exist is not known. In this study, we screened ~3.25 million compounds using a cell-based fluorescence assay and identified a synthetic small molecule we termed Yoda1 that acts as an agonist for both human and mouse Piezo1. Functional studies in cells revealed that Yoda1 affects the sensitivity and the inactivation kinetics of mechanically induced responses. Characterization of Yoda1 in artificial droplet lipid bilayers showed that Yoda1 activates purified Piezo1 channels in the absence of other cellular components. Our studies demonstrate that Piezo1 is amenable to chemical activation and raise the possibility that endogenous Piezo1 agonists might exist. Yoda1 will serve as a key tool compound to study Piezo1 regulation and function.
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