Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the ...pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo‐planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta‐analysis, using standardized means and a random‐effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta‐analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I2 = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools.
Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we ...investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4
+
T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases.
Key messages
MSCs can spontaneously take up the ATP-competitive kinase inhibitor Ro-31-8425.
Ro-31-8425-loaded MSCs gradually release Ro-31-8425 and exhibit sustained suppression of T cells.
Ro-31-8425-loaded MSCs have more sustained serum levels of Ro-31-8425 than free Ro-31-8425.
Ro-31-8425-loaded MSCs are more effective than MSCs and free Ro-31-8425 for EAE therapy.
PRX302 is a highly potent, mutant bacterial pore-forming biologic protoxin engineered for selective activation by PSA, a serine protease expressed by benign and malignant prostate epithelial cells. ...Although being developed as a local therapy for benign prostatic hyperplasia and localized prostate cancer, PRX302 cannot be administered systemically as a treatment for metastatic disease due to binding to ubiquitously expressed glycosylphosphatidylinositol (GPI)-anchored proteins, which leads to poor accumulation within the tumor microenvironment. To overcome this limitation, poly-lactic-co-glycolic acid (PLGA) microparticles encapsulating the protoxin were developed, which are known to accumulate in the liver, a major site of metastasis for prostate cancer and other solid tumors. A highly sensitive and reproducible sandwich ELISA to quantify PRX302 released from microparticles was developed. Utilizing this assay, PRX302 release from different microparticle formulations was assessed over multiple days. Hemolysis assays documented PSA-dependent pore formation and lytic potential (i.e., function) of the released protoxin. MTT assays demonstrated that conditioned supernatant from PRX302-loaded, but not blank (i.e., unloaded), PLGA microparticles was highly cytotoxic to PC3 and DU145 human prostate cancer cells in the presence of exogenous PSA. Microparticle encapsulation prevented PRX302 from immediately interacting with GPI-anchored proteins as demonstrated in a competition assay, which resulted in an increased therapeutic index and significant antitumor efficacy following a single dose of PRX302-loaded microparticles in a preclinical model of prostate cancer liver metastasis with no obvious toxicity. These results document that PRX302 released from PLGA microparticles demonstrate
antitumor efficacy in a clinically relevant preclinical model of metastatic prostate cancer.
The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA
and human
associate with ...phenylalanine hydroxylase (PAH).
-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU.
depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically,
modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-
mimics reduced excessive Phe in
and
mice and improved the Phe tolerance of these mice.
Vitamin A deficiency increases susceptibility to skin infection. However, the mechanisms by which vitamin A regulates skin immunity remain unclear. Here, we show that resistin-like molecule α ...(RELMα), a small secreted cysteine-rich protein, is expressed by epidermal keratinocytes and sebocytes and serves as an antimicrobial protein that is required for vitamin-A-dependent resistance to skin infection. RELMα was induced by microbiota colonization of the murine skin, was bactericidal in vitro, and was protected against bacterial infection of the skin in vivo. RELMα expression required dietary vitamin A and was induced by the therapeutic vitamin A analog isotretinoin, which protected against skin infection in a RELMα-dependent manner. The RELM family member Resistin was expressed in human skin, was induced by vitamin A analogs, and killed skin bacteria, indicating a conserved function for RELM proteins in skin innate immunity. Our findings provide insight into how vitamin A promotes resistance to skin infection.
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•Skin microbiota induces epidermal RELMα, which kills bacteria via membrane disruption•RELMα-deficient mice have altered skin microbiota and are more susceptible to infection•Dietary vitamin A is required for RELMα expression•RELMα is required for vitamin-A-dependent resistance to skin infection
Vitamin A regulates skin immunity via unknown mechanisms. Harris et al. show that RELMα is an antimicrobial protein expressed by epidermal cells that shapes resident skin bacterial communities and limits skin infection. RELMα is induced by dietary vitamin A and mediates vitamin-A-dependent resistance to skin infection.
Background
Patients with heart failure (HF) have increased risk for thromboembolic events. Real‐world incidences of efficacy and safety outcomes of direct oral anticoagulants (DOACs) in patients with ...left ventricular systolic dysfunction (LVSD) are of growing clinical interest.
Hypothesis
Real‐world efficacy and safety outcomes of DOACs in patients with LVSD will be similar to those of LVSD or HF subgroups in the RE‐LY, ROCKET‐AF, and ARISTOTLE trials.
Methods
We performed a retrospective review of adult patients with LVSD (left ventricular ejection fraction ≤40%) on DOAC therapy between 2010 and 2016. Incidences of safety and efficacy outcomes of anticoagulation with DOACs were extracted from primary and secondary hospital discharge diagnoses.
Results
DOACs were prescribed to 287 patients with LVSD over a mean follow‐up of 313.3 ± 52.3 days. Many patients had moderate and severe chronic kidney disease (28.9% and 10.1%, respectively) and indications for anticoagulation therapy other than atrial fibrillation (19.9%). For efficacy outcomes, the calculated incidence rates of ischemic stroke and systemic embolism were 1.2 (95% confidence interval CI: 0.25‐3.56) and 0.81 (95% CI: 0.10‐2.94) events per 100 person‐years, respectively. For the safety outcomes, incidence rates of GI bleeding and intracranial hemorrhage were 2.4 (95% CI: 0.8‐5.3) and 0.41 (95% CI: 0.1‐2.2) events per 100 patient‐years, respectively.
Conclusions
Our findings are largely compatible with the results of LVSD or HF subgroups in RE‐LY, ROCKET‐AF, and ARISTOTLE trials and add to increasing confidence that DOACs can be safely used for stroke and systemic embolism prevention in patients with LVSD.
The clinical efficacy of epidermal growth factor receptor (EGFR)–targeted therapy in
-mutant non–small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR ...inhibitor resistance occurs through amplification of the human growth factor receptor (
) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent
mutation and
amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of
-mutant,
-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced
mRNA expression stoichiometry as associated with
oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor–resistant
-mutant,
-amplified patients also exhibited a reduced
mRNA ratio. Our findings reveal that a subset of
-mutant,
-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.
OBJECTIVE: To determine the adherence by laboratories across the United States to the standard semen analysis guidelines and parameter reference ranges 10 years after being set by the World Health ...Organization (WHO) in 1999 and to compare compliance between regional laboratories vs. specialty assisted reproductive technology (ART) laboratories. DESIGN: Observational study. SETTING: Regional clinical and reproductive endocrinology andrology laboratories. INTERVENTION(S): Blank or deidentified semen analysis reports were collected from laboratories through direct contact or from reports received as part of clinical care for male infertility. MAIN OUTCOME MEASURE(S): Adherence to semen analysis reference range reporting as recommended by the 1999 WHO guidelines. RESULT(S): Semen analyses reports were collected from 111 laboratories from 31 different states. Of 111 laboratories, 26 (23%) reported all reference range parameters in accordance with the guidelines. Of 65 ART laboratories, 21 (32%) complied with all reference range parameters as outlined by the guidelines, vs. 5 of 46 non-ART laboratories (11%). Seventy percent of laboratories that did not report 1999 WHO parameters did so because of differences in reference values for normal morphology. CONCLUSION(S): Adherence to WHO 1999 semen analysis reference range guidelines has not been achieved by ART and non-ART laboratories 10 years after being introduced. Non-ART laboratories report reference ranges less accurately than ART laboratories.
Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI ...patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.
A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.
All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.
Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.
Sinus venosus atrial septal defect (SVASD) differs from secundum atrial septal defect by its atrial septal location and its association with anomalous pulmonary venous connection (APVC). Data on ...long-term outcome after surgical repair are limited.
We reviewed outcomes of 115 patients (mean age+/-SD 34+/-23 years) with SVASD who had repair from 1972 through 1996. APVC was present in 112 patients (97%). Early mortality was 0.9%. Complete follow-up was obtained for 108 patients (95%) at 144+/-99 months. Symptomatic improvement was noted in 83 patients (77%), and deterioration was noted in 17 patients (16%). At follow-up, 7 (6%) of 108 patients had sinus node dysfunction, a permanent pacemaker, or both, and 15 (14%) of 108 patients had atrial fibrillation. Older age at repair was predictive of postoperative atrial fibrillation (P=0.033). No reoperations were required during follow-up. Survival was not different from expected for an age- and sex-matched population. Clinical improvement was more common with older age at surgery (P=0.014). Older age at repair (P=0.008) and preoperative New York Heart Association class III or IV (P=0.038) were independent predictors of late mortality.
Operation for SVASD is associated with low morbidity and mortality, and postoperative subjective clinical improvement occurs irrespective of age at surgery. Postoperative atrial fibrillation appears to be related to older age at operation. SVASD repair achieves survival similar to that of a matched population and should be considered whenever repair may impact survival or symptoms.
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