Microglia and Astrocytes in Amyotrophic Lateral Sclerosis: Disease-Associated States, Pathological Roles, and Therapeutic Potential.

Microglial and astrocytic reactivity is a prominent feature of amyotrophic lateral sclerosis (ALS). Microglia and astrocytes have been increasingly appreciated to play pivotal roles in disease pathogenesis. These cells can adopt distinct states characterized by a specific molecular profile or function depending on the different contexts of development, health, aging, and disease. Accumulating evidence from ALS rodent and cell models has demonstrated neuroprotective and neurotoxic functions from microglia and astrocytes. In this review, we focused on the recent advancements of knowledge in microglial and astrocytic states and nomenclature, the landmark discoveries demonstrating a clear contribution of microglia and astrocytes to ALS pathogenesis, and novel therapeutic candidates leveraging these cells that are currently undergoing clinical trials.

Synthetic Strategies for Improving Solubility: Optimization of Novel Pyrazolo[1,5-a]pyrimidine CFTR Activator That Ameliorates Dry Eye Disease.

Dry eye disease (DED) is one of the most prevalent ocular diseases but has limited treatment options. Cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel that stimulates fluid secretion in the ocular surface, may pave the way for new therapeutic strategies for DED. Herein, we report the optimization of Cact-3, a potent CFTR activator with poor solubility, to 16d, a potent CFTR activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of 16d significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, 16d significantly reduced mRNA expression of pro-inflammatory cytokines including IL-1ß, IL-17, and TNF-α and MMP2 in cornea and conjunctiva of DED mice.

Selective Loss of MATR3 in Spinal Interneurons, Upper Motor Neurons and Hippocampal CA1 Neurons in a MATR3 S85C Knock-In Mouse Model of Amyotrophic Lateral Sclerosis.

The neuropathological hallmark of amyotrophic lateral sclerosis (ALS) is motor neuron degeneration in the spinal cord and cortex. Accumulating studies report that other neurons in the central nervous system (CNS) are also affected in ALS. Mutations in Matr3, which encodes a nuclear matrix protein involved in RNA splicing, have been linked to ALS. Previously, we generated a MATR3 S85C knock-in (KI) mouse model that recapitulates early-stage features of ALS. We reported that MATR3 S85C KI mice exhibit defects in lumbar spinal cord motor neurons and in cerebellar Purkinje cells, which are associated with reduced MATR3 immunoreactivity. Here, we show that neurons in various other regions of the CNS are affected in MATR3 S85C KI mice. Using histological analyses, we found selective loss of MATR3 staining in α-motor neurons, but not γ-motor neurons in the cervical and thoracic spinal cord. Loss of MATR3 was also found in parvalbumin-positive interneurons in the cervical, thoracic and lumbar spinal cord. In addition, we found the loss of MATR3 in subsets of upper motor neurons and hippocampal CA1 neurons. Collectively, our findings suggest that these additional neuronal types may contribute to the disease process in MATR3 S85C KI mice.

Using Social Media Data to Understand Consumers' Information Needs and Emotions Regarding Cancer: Ontology-Based Data Analysis Study.

BACKGROUND: Analysis of posts on social media is effective in investigating health information needs for disease management and identifying people's emotional status related to disease. An ontology is needed for semantic analysis of social media data. OBJECTIVE: This study was performed to develop a cancer ontology with terminology containing consumer terms and to analyze social media data to identify health information needs and emotions related to cancer. METHODS: A cancer ontology was developed using social media data, collected with a crawler, from online communities and blogs between January 1, 2014 and June 30, 2017 in South Korea. The relative frequencies of posts containing ontology concepts were counted and compared by cancer type. RESULTS: The ontology had 9 superclasses, 213 class concepts, and 4061 synonyms. Ontology-driven natural language processing was performed on the text from 754,744 cancer-related posts. Colon, breast, stomach, cervical, lung, liver, pancreatic, and prostate cancer; brain tumors; and leukemia appeared most in these posts. At the superclass level, risk factor was the most frequent, followed by emotions, symptoms, treatments, and dealing with cancer. CONCLUSIONS: Information needs and emotions differed according to cancer type. The observations of this study could be used to provide tailored information to consumers according to cancer type and care process. Attention should be paid to provision of cancer-related information to not only patients but also their families and the general public seeking information on cancer.

Understanding the Public's Emotions about Cancer: Analysis of Social Media Data.

Cancer survivors suffer from emotional distress, which varies depending on several factors. However, existing emotion management programs are insufficient and do not take into consideration all of the factors. Social media provides a platform for understanding the emotions of the public. The aim of this study was to explore the relationship between the public's emotions about cancer and factors affecting emotions using social media data. We used 321,339 posts on cancer and emotions relating to cancer extracted from 22 social media channels between 1 January 2014, and 30 June 2017. The factors affecting emotions were analyzed using association rule mining and social network analysis. Hope/gratitude was the most frequently mentioned emotion group on social media followed by fear/anxiety/overwhelmed, sadness/depression/loneliness/guilt, and anger/denial. Acute survival stage, treatment method, and breast cancer were associated with hope/gratitude. Early stage, gastrointestinal problems, fatigue/pain/fever, and pancreatic cancer were associated with fear/anxiety/overwhelmed. Surgery, hair loss/skin problems, and fatigue/pain/fever were associated with sadness/depression/loneliness/guilt. Acute survival stage and hair loss/skin problems were associated with anger/denial. We found that emotions concerning cancer differed depending on the cancer type, cancer stage, survival stage, treatment, and symptoms. These findings could guide the development of tailored emotional management programs for cancer survivors that meet the public's needs more effectively.

Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS.

A missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research.

Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease-linked MATR3 mutations in Drosophila.

Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild-type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild-type MATR3, demonstrating that the disease-linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis.

Tyrosinase-Targeting Gallacetophenone Inhibits Melanogenesis in Melanocytes and Human Skin-Equivalents.

Demands for safe depigmentation compounds are constantly increasing in the pharmaceutical and cosmetic industry, since the numerous relevant compounds reported to date have shown undesirable side effects or low anti-melanogenic effects. In this study, we reported three novel inhibitors of tyrosinase, which is the key enzyme in melanogenesis, identified using docking-based high throughput virtual screening of an in-house natural compound library followed by mushroom tyrosinase inhibition assay. Of the three compounds, gallacetophenone showed high anti-melanogenic effect in both human epidermal melanocytes and a 3D human skin model, MelanoDerm. The inhibitory effect of gallacetophenone on tyrosinase was elucidated by computational molecular modeling at the atomic level. Binding of gallacetophenone to the active site of tyrosinase was found to be stabilized by hydrophobic interactions with His367, Ile368, and Val377; hydrogen bonding with Ser380 and a water molecule bridging the copper ions. Thus, our results strongly suggested gallacetophenone as an anti-melanogenic ingredient that inhibits tyrosinase.

Novel tacrine-pyridinium hybrid reactivators of organophosphorus-inhibited acetylcholinesterase: Synthesis, molecular docking, and in vitro reactivation study.

First-line medical treatment against nerve agents consists of co-administration of anticholinergic agents and oxime reactivators, which reactivate inhibited AChE. Pralidoxime, a commonly used oxime reactivator, is effective against some nerve agents but not against others; thus, new oxime reactivators are needed. Novel tacrine-pyridinium hybrid reactivators in which 4-pyridinealdoxime derivatives are connected to tacrine moieties by linear carbon chains of different lengths (C2-C7) were prepared (Scheme 1, 5a-f). Their binding affinities to electric eel AChE were tested because oximes can inhibit free AChE, and the highest AChE activity (95%, 92%, and 90%) was observed at 1 µM concentrations of the oximes (5a, 5b, and 5c, respectively). Based on their inhibitory affinities towards free AChE, 1 µM concentrations of the oxime derivatives (5) were used to examine reactivation of paraoxon-inhibited AChE. Reactivation ability increased as the carbon linker chains lengthened (n = 2-5), and 5c and 5d showed remarkable reactivation ability (41%) compared to that of 2-PAM (16%) and HI-6 (4%) against paraoxon-inhibited electric eel AChE at 1 µM concentrations. Molecular docking simulation showed that the most stable binding free energy was observed in 5c at 73.79 kcal⋅mol-1, and the binding mode of 5c is acceptable for the oxygen atom of oximate to attack the phosphorus atom of paraoxon and reactivate paraoxon-inhibited eel AChE model structure.

A novel anti-melanogenic agent, KDZ-001, inhibits tyrosinase enzymatic activity.

BACKGROUND: The demand for anti-melanogenic agents is increasing due to the unwanted side effects of current treatments. To find an effective anti-melanogenic agent, we used zebrafish as a whole animal model for phenotype-based drug and cosmetic discovery screening. OBJECTIVES: The aim of this study was to identify and explore a small molecule that could be used for skin-whitening cosmetics. METHODS: Using zebrafish embryos, we examined the effects of 1000 compounds on zebrafish development and pigmentation. Pigmentation production was assessed by tyrosinase (TYR) enzymatic activity and melanin contents. Pigmentation marker expression in the human melanoma cell line HMV-II was analyzed by western blot. We also tested reconstituted human skin tissue and analyzed KDZ-001 with computational molecular modeling. RESULTS: We identified three compounds that affected the pigmentation of developing melanophores in zebrafish. Among them, we identified KDZ-001, a novel anti-melanogenic agent, which strongly inhibits melanin synthesis in the developing melanophores of zebrafish, HMV-II cells, and reconstituted human skin with no toxicity. We found that KDZ-001 directly inhibits TYR enzymatic activity. Notably, computational molecular modeling of KDZ-001 suggested that its interaction with copper ions in the active site of TYR is essential for melanin synthesis, further demonstrating that KDZ-001 mainly acts as a TYR inhibitor to synthesize melanin. CONCLUSION: KDZ-001 inhibits melanin synthesis and has a potential for use in skin-whitening cosmetics.

Discovery of novel [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment.

Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay. The substantial antiproliferative activities in human cancer cell lines, promising drug-like properties, and the selectivity for the BET family make the lead compound (13) as a novel BRD4 inhibitor motif for anti-cancer drug discovery.

A Phase I study of cabazitaxel in patients with advanced gastric cancer who have failed prior chemotherapy (GASTANA).

PURPOSE: This Phase I dose-escalation study (GASTANA) evaluated the safety, tolerability, pharmacokinetics and preliminary antitumor activity of cabazitaxel in Asian patients with advanced gastric adenocarcinoma failing two prior chemotherapy regimens. METHODS: Cabazitaxel safety/tolerability was determined using a standard 3 + 3 dose-escalation design based on dose-limiting toxicities (DLTs) in Cycle 1. Three dose levels (DL) were planned: 20, 25 and 15 mg/m(2) (DL 1, DL 2 and DL -1). RESULTS: Fifteen patients were evaluable for DLTs. At DL 1, no DLTs occurred in three patients. At DL 2, four patients were enrolled (one patient discontinued), with only one DLT observed [Grade 4 febrile neutropenia (FN)]; however, all four patients experienced FN, hence three more patients were enrolled at DL 1 who experienced two DLTs (Grade 4 neutropenia >7 days). In response, DL -1 was opened, with no DLTs observed in six patients. In the total population (n = 16), frequent Grade 3/4 toxicities included neutropenia (63%) and FN (38%), best overall responses included one partial response (6.3%; DL -1) and eight stable disease (50%), and median progression-free survival was 83 days. CONCLUSIONS: No unexpected safety findings were observed. Significant toxicities included neutropenia and FN, potentially due to patients being heavily pretreated and the accumulated toxicity of prior taxane therapy.

Are patients with POEMS syndrome at increased risk of Salmonella aortitis?

We report a case of Salmonella infectious aortitis in a patient with POEMS (peripheral neuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome, possibly indicating that vasculopathy associated with POEMS syndrome may increase the risk of Salmonella endovascular infection.

Pharmacodynamics of doxycycline for chemoprophylaxis of Lyme disease: preliminary findings and possible implications for other antimicrobials.

The purpose of this study was to begin to characterise the pharmacodynamic parameters of single-dose doxycycline for the prevention of Lyme disease following a tick bite. Based on limited data from published human and murine studies, it was found that there is a direct correlation between efficacy rate and the area under the time-concentration of free antibiotic curve divided by the minimum inhibitory concentration (fAUC/MIC) (R(2)=0.74, using Pearson correlation), but not the maximum concentration of free drug in serum divided by the MIC (fC(max)/MIC) or the time that the free drug concentration remains above the MIC (fT>MIC). To determine the possible implications of these findings for other antimicrobials, it was assumed that the pharmacodynamic properties of doxycycline would be pertinent to azithromycin, an antibiotic whose activity is known to correlate with AUC/MIC. By making such an extrapolation and using pharmacokinetic modelling with conservative assumptions on MIC values against Borrelia burgdorferi, it is hypothesised that a single 500 mg dose of azithromycin in humans should have comparable efficacy to doxycycline for the prevention of Lyme disease. Additional experimental studies are needed to clarify more precisely the pharmacodynamic properties of doxycycline and to validate the accuracy of this hypothesis.

Conversion of intermittent exotropia types subsequent to part-time occlusion therapy and its sustainability.

PURPOSE: To evaluate the effects of part-time occlusion therapy on types of intermittent exotropia and sustainability of converted types. METHODS: Forty-four and 26 children with basic-type and convergence-insufficiency-type intermittent exotropia, respectively, were evaluated in this study. Upon initial examination, we obtained both distant and near deviating angles using prism cover tests, after correcting for refractive errors. We conducted occlusion of the nondeviating eye for 3 months at 3 h/day and assessed the changes in types of intermittent exotropia. We also observed the changes of deviating angles and sustainability of types after 3 months of cessation of part-time occlusion in patients who did not undergo surgery. RESULTS: Preocclusion deviating angles (mean +/- SD) were determined to be 27.1+/-7.46 prism diopters (PD) on distant measurements and 30.6+/-7.92 PD on near measurements. After 3 months of occlusion, the deviating angles were 25.9+/-9.10 PD on distant measurements and 21.4+/-11.00 PD on near measurements, corresponding to a significant reduction (p=0.005 and p<0.001, respectively). Fourteen patients (32%) suffering from basic type of intermittent exotropia converted to the pseudodivergence excess type. In patients suffering from the basic type who exhibited no changes in type, 9 patients (20%) exhibited reductions on both near and distant angle measurements. Among the convergence insufficiency type of patients, 18 (69%) converted to basic type and 2 patients (7%) converted to the pseudodivergence excess type. In the 15 patients who did not undergo surgery, the converted types were maintained in 6 patients, though the other 9 patients showed regression to the prepatching types after cessation of patching for 3 months. CONCLUSION: Part-time occlusion therapy resulted in the conversion of the basic and convergence insufficiency types to pseudodivergence excess and basic types in more than half of the intermittent exotropes. Future studies on correlation between type conversion and surgical outcome would be necessary.

Primary facial skin cancer: clinical characteristics and surgical outcome in Chungbuk Province, Korea.

Clinical features of facial skin cancer in Asian population including Korean are not readily available. In the present study, we analyzed the clinical characteristics and the surgical results of primary facial skin cancer in Chungbuk Province, Korea. Eighty-six cases of primary facial skin cancer collected during a 10-yr period (1994-2003) were retrospectively reviewed about the clinical characteristics including age, sex, annual diagnostic rate, types of tumor, specific sites of occurrence, and the surgical results. The average age at the diagnosis was 67 and male to female ratio was 1 to 1.05. The average annual diagnostic rate was 0.73% and the rate surged during the period 2001-2003 compared with the period 1994 to 2000. Basal cell carcinoma was the most common tumor and the nose was the most frequent site. Traditional surgical excision with immediate reconstruction was performed in 81 cases. During the 23 months of average follow-up, three patients had recurrences (3.7%) and three patients had secondary skin cancers. Facial skin cancer is increasing in the province and basal cell carcinoma is most frequent. Traditional surgical excision and immediate reconstruction with local flap are a good therapeutic modality with an acceptable recurrence rate.