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Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.

Competing Interests: Conflicts of interest Dr Heberton has served on an advisory board for Blueprint Medicines.

Melanin synthesis involves the successful coordination of metabolic pathways across multiple intracellular compartments including the melanosome, mitochondria, ER/Golgi, and cytoplasm. While pigment production offers a communal protection from UV damage, the process also requires anabolic and redox demands that must be carefully managed by melanocytes. In this report we provide an updated review on melanin metabolism, including recent data leveraging new techniques, and technologies in the field of metabolism. We also discuss the many aspects of melanin synthesis that intersect with metabolic pathways known to impact melanoma phenotypes and behavior. By reviewing the metabolism of melanin synthesis, we hope to highlight outstanding questions and opportunities for future research that could improve patient outcomes in pigmentary and oncologic disease settings., (© 2024 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Importance: Melanoma in Black individuals has an annual incidence of approximately 1 in 100 000 people. Most studies of melanoma in Black patients have used population databases, which lack important, precise clinical details., Objective: To identify patient-level and tumor-level characteristics of melanoma in Black patients., Design, Setting, and Participants: This case series included Black patients with melanoma at 2 tertiary care centers (University of Texas Southwestern [UTSW] Medical Center and Parkland Health), affiliated with a single institution, UTSW in Dallas, Texas. Self-reported Black patients with a histopathologic diagnosis of melanoma were identified between January 2006 and October 2022., Main Outcomes and Measures: The main variables were demographics, clinical characteristics, personal and family medical history, immunosuppression history, comorbidities, histopathology reports, molecular/genetic studies, imaging reports, melanoma treatments and responses, time to progression, metastatic sites, and survival rates., Results: A total of 48 Black patients with melanoma (median [range] age at diagnosis, 62 [23-86] years; 30 [63%] female) were included in the study. Of 40 primary cutaneous melanomas, 30 (75%) were located on acral skin, despite only 10 of 30 (33%) being histologically classified as acral lentiginous melanomas. Compared with those with acral disease, patients with nonacral cutaneous melanomas were more likely to be immunocompromised (4 of 10 [40%] vs 2 of 30 [7%]) or have a personal history of cancer (6 of 10 [60%] vs 5 of 30 [17%]), with all 3 patients with superficial spreading melanoma having a history of both. No patients had more than 1 confirmed primary melanoma. Overall, 13 Black patients (27%) with melanoma developed stage IV disease, of whom 12 died because of disease progression. Those diagnosed with advanced acral melanoma, mucosal/ocular melanoma, or melanoma of unknown primary lacked actionable sequence variations, were nonresponsive to immunotherapy, and had the poorest outcomes. No patients with nonacral cutaneous melanomas developed distant metastases or died of melanoma., Conclusions and Relevance: This single-institution case series highlights several features of melanoma in Black patients that have not been captured in existing population-level registries, including precise anatomic sites, immune status, family and personal cancer history, and genetics. Multi-institutional registries would improve understanding of melanoma in Black patients.

The SKIV2L RNA exosome is an evolutionarily conserved RNA degradation complex in the eukaryotes. Mutations in the SKIV2L gene are associated with a severe inherited disorder, trichohepatoenteric syndrome (THES), with multisystem involvement but unknown disease mechanism. Here, we reported a THES patient with SKIV2L mutations showing severe primary B cell immunodeficiency, hypogammaglobulinemia, and kappa-restricted plasma cell dyscrasia but normal T cell and NK cell function. To corroborate these findings, we made B cell-specific Skiv2l knockout mice ( Skiv2l fl/fl Cd79a-Cre ), which lacked both conventional B-2 and innate-like B-1 B cells in the periphery and secondary lymphoid organs. This was linked to a requirement of SKIV2L RNA exosome activity in the bone marrow during early B cell development at the pro-B cell to large pre-B cell transition. Mechanistically, Skiv2l -deficient pro-B cells exhibited cell cycle arrest and DNA damage. Furthermore, loss of Skiv2l led to substantial out-of-frame V(D)J rearrangement of immunoglobulin heavy chain and severely reduced surface expression of μH, both of which are crucial for pre-BCR signaling and proliferative burst during early B cell development. Together, our data demonstrated a crucial role for SKIV2L RNA exosome in early B cell development in both human and mice by ensuring proper V(D)J recombination and Igh expression, which serves as the molecular basis for immunodeficiency associated with THES.

Despite being the leading cause of cancer deaths, metastasis remains a poorly understood process. To identify novel regulators of metastasis in melanoma, we performed a large-scale RNA sequencing screen of 48 samples from patient-derived xenograft (PDX) subcutaneous melanomas and their associated metastases. In comparison with primary tumors, expression of glycolytic genes was frequently decreased in metastases, whereas expression of some tricarboxylic acid (TCA) cycle genes was increased in metastases. Consistent with these transcriptional changes, melanoma metastases underwent a metabolic switch characterized by decreased levels of glycolytic metabolites and increased abundance of TCA cycle metabolites. A short isoform of glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) lacking the N-terminal domain suppressed metastasis and regulated this metabolic switch. GAPDHS was downregulated in metastatic nodules from PDX models as well as in human patients. Overexpression of GAPDHS was sufficient to block melanoma metastasis, whereas its inhibition promoted metastasis, decreased glycolysis, and increased levels of certain TCA cycle metabolites and their derivatives including citrate, fumarate, malate, and aspartate. Isotope tracing studies indicated that GAPDHS mediates this shift through changes in pyruvate carboxylase activity and aspartate synthesis, both metabolic pathways critical for cancer survival and metastasis. Together, these data identify a short isoform of GAPDHS that limits melanoma metastasis and regulates central carbon metabolism., Significance: This study characterizes metabolic changes during cancer metastasis and identifies GAPDHS as a novel regulator of these processes in melanoma cells., (©2022 American Association for Cancer Research.)

Marine microbes provide the backbone for pelagic ecosystems by cycling and fixing nutrients and establishing the base of food webs. Microbial communities are often assumed to be highly connected and genetically mixed, with localized environmental filters driving minor changes in structure. Our study applied high-throughput Illumina 16S ribosomal RNA gene amplicon sequencing on whole-community bacterial samples to characterize geographic, environmental, and stochastic drivers of community diversity. DNA was extracted from seawater collected from the surface ( N = 18) and at depth just below the deep chlorophyll- a maximum (DCM mean depth = 115.4 m; N = 22) in the Sargasso Sea and adjacent oceanographic regions. Discrete bacterioplankton assemblages were observed at varying depths in the North Sargasso Sea, with a signal for distance-decay of bacterioplankton community similarity found only in surface waters. Bacterial communities from different oceanic regions could be distinguished statistically but exhibited a low magnitude of divergence. Redundancy analysis identified temperature as the key environmental variable correlated with community structuring. The effect of dispersal limitation was weak, while variation partitioning and neutral community modeling demonstrated stochastic processes influencing the communities. This study advances understanding of microbial biogeography in the pelagic ocean and highlights the use of high-throughput sequencing methods in studying microbial community structure., Competing Interests: The authors declare that they have no competing interests., (© 2022 Gill et al.)

The pentose phosphate pathway is a major source of NADPH for oxidative stress resistance in cancer cells but there is limited insight into its role in metastasis, when some cancer cells experience high levels of oxidative stress. To address this, we mutated the substrate binding site of glucose 6-phosphate dehydrogenase (G6PD), which catalyzes the first step of the pentose phosphate pathway, in patient-derived melanomas. G6PD mutant melanomas had significantly decreased G6PD enzymatic activity and depletion of intermediates in the oxidative pentose phosphate pathway. Reduced G6PD function had little effect on the formation of primary subcutaneous tumors, but when these tumors spontaneously metastasized, the frequency of circulating melanoma cells in the blood and metastatic disease burden were significantly reduced. G6PD mutant melanomas exhibited increased levels of reactive oxygen species, decreased NADPH levels, and depleted glutathione as compared to control melanomas. G6PD mutant melanomas compensated for this increase in oxidative stress by increasing malic enzyme activity and glutamine consumption. This generated a new metabolic vulnerability as G6PD mutant melanomas were more dependent upon glutaminase than control melanomas, both for oxidative stress management and anaplerosis. The oxidative pentose phosphate pathway, malic enzyme, and glutaminolysis thus confer layered protection against oxidative stress during metastasis., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA-mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a SKIV2L-deficient patient. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. Moreover, Skiv2l-deficient T cells were chronically hyperactivated and these T cells attacked lesional skin as well as hair follicles. Mechanistically, SKIV2L loss activated the mTORC1 pathway in both keratinocytes and T cells. Both systemic and topical rapamycin treatment of Skiv2l-deficient mice ameliorated epidermal hyperplasia and skin inflammation. Together, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We also propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy.

Eligible for 1 MOC SA Credit From the ABD This Photo Challenge in our print edition is eligible for 1 self-assessment credit for Maintenance of Certification from the American Board of Dermatology (ABD). After completing this activity, diplomates can visit the ABD website (http://www.abderm.org) to self-report the credits under the activity title "Cutis Photo Challenge." You may report the credit after each activity is completed or after accumulating multiple credits.

Understanding the electrochemical behaviors of Ce(III)/Ce(IV) ions is essential for better treatment, separation, and recycling of lanthanide (Ln) and actinide (An) elements. Herein, electrochemical redox behavior and interconversion of Ce(III)/Ce(IV) ions and their recoveries were demonstrated over newly developed thio-terpyridine-functionalized Au-modified carbon paper electrodes in acidic and neutral electrolytes. Cyclic voltammetry and amperometry were performed for the electrodes with and without thio-terpyridine functionalization. Ce oxide nanostructure recovery was successfully conducted by amperometry, and the electrodeposited nanostructured Ce materials were fully characterized by scanning electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction crystallography, and X-ray photoelectron spectroscopy. Geometry optimization and the electronic energy state calculations were conducted by density functional theory at the B3LYP/GENECP level for the complexes of Ce(III) and Ce(IV) ions with the thio-terpyridine in an aqueous state. The present unique results provide valuable information on understanding redox behaviors of Ln and An ions for their recycling and treatment processes.

Introduction: PCSK9 inhibitors lower low-density lipoprotein (LDL) cholesterol and are efficacious at reducing vascular disease, however questions remain about potential effects on cognitive function., Methods: We examined the association of genetic variants in PCSK9 with continuous measures of cognitive ability in UK Biobank. Six independent polymorphisms in PCSK9 were used in up to 337,348 individuals., Results: The PCSK9 allele score was associated with a lower risk of CHD, and weakly with worse log reaction time., Conclusions: We are unable to rule out meaningful associations of PCSK9 genetic variants with cognition, emphasising the potential need for continued pharmacovigilance for patients currently treated with PCSK9 inhibitors., Competing Interests: The Clinical Trial Service Unit and Epidemiological Studies Unit at the University of Oxford (MVH) has received research grants from Abbott/Solvay/Mylan, AstraZeneca, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, and Schering. MVH has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of the Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. NS has consulted for AstraZeneca, Bristol-Myers Squibb, Amgen, Sanofi, and Boehringer Ingelheim. All other authors have nothing to report., (Copyright: © 2021 Termedia & Banach.)

Background: General anesthesia (GA) has been considered the anesthetic technique which most frequent leads to phantom limb pain (PLP) after a limb amputation. However, these prior reports were limited by small sample sizes. The aims of this study were to evaluate the incidence of PLP according to the various anesthetic techniques used for limb amputation and also to compare the occurrence of PLP according to amputation etiology using the Korean Health Insurance Review and Assessment Service for large-scale demographic information., Methods: The claims of patients who underwent limb amputation were reviewed by analyzing the codes used to classify standardized medical behaviors. The patients were categorized into three groups-GA, neuraxial anesthesia (NA), and peripheral nerve block (PNB)-in accordance with the anesthetic technique. The recorded diagnosis was confirmed using the diagnostic codes for PLP registered within one year after the limb amputation., Results: Finally, 7,613 individuals were analyzed. According to the recorded diagnoses, 362 patients (4.8%) developed PLP after amputation. Among the 2,992 patients exposed to GA, 191 (6.4%) were diagnosed with PLP, whereas 121 (4.3%) of the 2,840 patients anesthetized with NA, and 50 (2.8%) of the 1,781 patients anesthetized under PNB developed PLP. The relative risks were 0.67 (95% confidence interval [CI], 0.53-0.84; P < 0.001) for NA and 0.43 (95% CI, 0.32-0.59; P < 0.001) for PNB., Conclusions: In this retrospective cohort study, using large-scale population-based databases, the incidence rates of PLP after limb amputations were, in the order of frequency, GA, NA, and PNB.

Background: The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function., Results: Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory., Conclusion: We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.

A blue fluorophore of Schiff base zinc complex is prepared by a hydrolysis-free solution-based synthetic method. Under ultraviolet (UV) excitation, the complex produces blue emission with a quantum yield ( Q) of 42.6% in methylene chloride and 24.0% in standalone powder form. Quantum mechanical calculations show that the blue emission is generated by the change in the chemical state of the ligand associated with the complexation with Zn cations. Thin films of Zn complexes incorporated in polymethylmethacrylate (PMMA) and cellulose acetate butyrate (CAB) polymers are also prepared by dispersing the complexes into the polymer matrices. These hybrid polymer films exhibit several notable features, particularly enhanced luminescence efficiency (with maximum Q of 85.8% for PMMA and 30.0% for CAB) and scalability for fabrication over a large area while retaining the original properties of the host polymers. Light-emitting diodes are also fabricated using the CAB hybrid thin films, and they show a Q of 43.2% with excellent photostability. The complex and its hybrid films demonstrate their great potential for such applications as UV-to-blue conversion devices in photoelectronics, solar-cell concentrators, solid-state lighting and display, and greenhouse agriculture.

Objectives: The efficacy of radioiodine remnant ablation (RRA) for patients with differentiated thyroid carcinoma (DTC) with gross extrathyroidal extension (ETE) is well described in observational studies. However, its role in gross ETE invading only strap muscles, T3b category in the newly proposed eighth edition of the TNM staging system, is currently unknown., Methods: This study retrospectively analyzed 260 DTC patients with ETE invading only strap muscles who underwent thyroidectomy at a tertiary Korean hospital between 1994 and 2005. Cancer-specific survival (CSS) and recurrence-free survival (RFS) in the no RRA (n = 13), low RRA activity (<3.7 GBq, n = 80), and high RRA activity (≥3.7 GBq, n = 167) groups were studied., Results: No significant differences were observed between low and high activity RRA groups in terms of 10-year CSS (97.3% versus 99.3%; HR 0.23, 95% CI 0.02-2.57; p = .235) and RFS (86.8% versus 88.8%; 0.90, 0.40-2.03; p = .804). In the no RRA group, no patients died of cancer, and only one developed structural recurrence. In Cox regression analyses with inverse probability of treatment weighting adjusted for clinicopathologic risk factors, high activity RRA was not related to recurrence outcomes compared to low activity (HR 0.60, 95% CI 0.26-1.35; p = .214)., Conclusions: Long term oncologic outcomes did not significantly differ between low versus high activity RRA groups, which suggests that low activity RRA might be sufficient in patients with DTC with gross ETE invading only strap muscles. Further studies are needed to clarify the optimal activity of RRA in these patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

To gain better optical and optoelectrical properties, doping trivalent lanthanide cations into host materials is a very attractive approach in nanoscience. Here, we use a transparent conducting oxide, zinc oxide, as the host material to directly embed trivalent terbium cations without the need for any postgrowth treatment, and we investigate the photophysical effect of the dopant. Trivalent Tb cations embedded in ZnO nanowalls produce hypersensitive green emission (at 545 nm, corresponding to the 5 D 4 → 7 F 5 transition) and convert the emission color of ZnO from yellow into white. Evidently, the photoluminescence emission intensity of Tb(III) is further increased by close to 10-fold due to the plasmonic effect introduced by noble metal (Ag and Pt) nanoparticles. The characteristic Tb(III) emission is found to be tunable from white to red and is examined for its potential chemosensing application for rhodamine B involving a plausible cascade energy transfer mechanism from ZnO to rhodamine B via Tb(III) cations.

Peroxyacetic acid mixture Perosan, composed of peroxyacetic acid, hydrogen peroxide and acetic acid, was evaluated for eco-friendly management of tomato bacterial wilt by Ralstonia pseudosolanacearum . Perosan drastically suppressed in vitro growth of R. pseudosolanacearum in liquid cultures in dose- and incubation time-dependent manners. Higher perosan doses (0.1 and 1%) caused lowered pH and phytotoxicity to detached leaves of two tomato cultivars Cupirang and Benekia 220 in aqueous solution. Treatment with 0.01% of Perosan delayed wilting symptom significantly in the detached leaves of two cultivars inoculated with R. pseudosolanacearum (10 7 cfu/ml). Soil drenching of 5% Perosan solution in pots caused severe tissue collapse of tomato seedlings at the four-week-old stage of two tomato cultivars. Treatment with 1% Perosan by soil-drenching significantly reduced bacterial wilt in the tomato seedlings of two cultivars. These findings suggest that Perosan treatment can be applied to suppress bacterial wilt during tomato production.

Fusarium root rot is a major pea disease in Canada and only partial tolerance exists in germplasm. Transgenic technologies may hold promise but the economic benefits of genetically modified (GM) pea will need to surpass the regulatory costs, time and labor involved in bringing a GM crop to market. European pea (Pisum sativum L.) cultivars expressing four antifungal genes, 1-3 β glucanase (G), endochitinase (C) (belonging to PR proteins family), polygalacturonase inhibiting proteins (PGIPs) (P) and stilbene synthase (V) have been transformed for disease tolerance and showed disease tolerance under laboratory conditions. Transgenic lines with four antifungal genes inserted either individually or stacked through crossing were tested for their efficacy against Fusarium root rot (Fusarium avenaceum) in confined trials over three years (2013 to 2015) in comparison with two parental German lines and three Canadian lines. Superior emergence, higher fresh weight or lower disease ratings above and below ground, of transgenic lines in presence of disease inoculum were not observed consistently in the three years of field experiments when compared to the parental and Canadian lines in the presence of disease inoculum. No indication of an advantage of stacked genes over single genes was observed. Most transgenic lines had lower relative gene expression in the roots than in the leaves in greenhouse trials suggesting a possible explanation for poor tolerance to Fusarium root rot. Field trials are necessary to verify the agronomic performance and ecological relevance of the promising effects detected under laboratory conditions.

Genetically modified crops have raised concerns about unintended consequences on non-target organisms including beneficial soil associates. Pea transformed with four antifungal genes 1-3 β glucanase, endochitinase, polygalacturonase-inhibiting proteins, and stilbene synthase is currently under field-testing for efficacy against fungal diseases in Canada. Transgenes had lower expression in the roots than leaves in greenhouse experiment. To determine the impact of disease-tolerant pea or gene products on colonization by non-target arbuscular mycorrhizae and nodulation by rhizobium, a field trial was established. Transgene insertion, as single gene or stacked genes, did not alter root colonization by arbuscular mycorrhiza fungus (AMF) or root nodulation by rhizobium inoculation in the field. We found no effect of transgenes on the plant growth and performance although, having a dual inoculant with both AMF and rhizobium yielded higher fresh weight shoot-to-root ratio in all the lines tested. This initial risk assessment of transgenic peas expressing antifungal genes showed no deleterious effect on non-target organisms.

Background: The prognostic value of the proposed eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) classification is currently unclear. The aim of the study was to evaluate the prognostic value of the eighth edition of the AJCC TNM classification., Methods: We retrospectively assessed 3176 patients with differentiated thyroid carcinoma (DTC) who underwent thyroidectomy at a tertiary Korean hospital from 1996 to 2005. Cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method and compared using the log-rank test. Performance of the eighth edition TNM with respect to prediction of CSS was assessed against the current seventh edition., Results: Upon reclassification according to the eighth edition, 37.6% of patients were down-staged. The proportions of stage I and II tumors increased from 61.9% to 81.1% and from 1.7% to 16.0%, respectively, whereas those of stage III and IVB (formerly IVC in the seventh edition) decreased from 27.6% to 2.3% and 0.8% to 0.5%, respectively. The proportions of variance explained (PVEs) for the ability of the eighth and the seventh edition to predict CSS were 3.9% and 2.9%, respectively. The C-index values were 0.765 (95% confidence interval 0.764-0.766) for the eighth edition and 0.736 (0.735-0.737) for the seventh edition., Conclusion: Our results demonstrate that the eighth edition TNM more accurately predicts CSS for patients with DTC than does the seventh edition., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy., Key Points: Digoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Postherpetic neuralgia (PHN) is a common and painful complication of acute herpes zoster. In some cases, it is refractory to medical treatment. Preventing its occurrence is an important issue. We hypothesized that applying nerve blocks during the acute phase of herpes zoster could reduce PHN incidence by attenuating central sensitization and minimizing nerve damage and the anti-inflammatory effects of local anesthetics and steroids., Methods: This systematic review and meta-analysis evaluates the efficacy of using nerve blocks to prevent PHN. We searched the MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov and KoreaMed databases without language restrictions on April, 30 2014. We included all randomized controlled trials performed within 3 weeks after the onset of herpes zoster in order to compare nerve blocks vs active placebo and standard therapy., Results: Nine trials were included in this systematic review and meta-analysis. Nerve blocks reduced the duration of herpes zoster-related pain and PHN incidence of at 3, 6, and 12 months after final intervention. Stellate ganglion block and single epidural injection did not achieve positive outcomes, but administering paravertebral blockage and continuous/repeated epidural blocks reduced PHN incidence at 3 months. None of the included trials reported clinically meaningful serious adverse events., Conclusions: Applying nerve blocks during the acute phase of the herpes zoster shortens the duration of zoster-related pain, and somatic blocks (including paravertebral and repeated/continuous epidural blocks) are recommended to prevent PHN. In future studies, consensus-based PHN definitions, clinical cutoff points that define successful treatment outcomes and standardized outcome-assessment tools will be needed.

New therapies are required for melanoma. Here, we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human melanoma cells than normal human cells. This reflects on-target inhibition of the ATP1A1 Na(+)/K(+) pump, which is highly expressed by melanoma. MEK inhibitor and/or BRAF inhibitor additively or synergistically combined with digitoxin to induce cell death, inhibiting growth of patient-derived melanomas in NSG mice and synergistically extending survival. MEK inhibitor and digitoxin do not induce cell death in human melanocytes or haematopoietic cells in NSG mice. In melanoma, MEK inhibitor reduces ERK phosphorylation, while digitoxin disrupts ion gradients, altering plasma membrane and mitochondrial membrane potentials. MEK inhibitor and digitoxin together cause intracellular acidification, mitochondrial calcium dysregulation and ATP depletion in melanoma cells but not in normal cells. The disruption of ion homoeostasis in cancer cells can thus synergize with targeted agents to promote tumour regression in vivo.

A silica (SiO2) nanoparticle matrix was codoped with luminescent Eu(III) and Tb(III) ions using a modified Stöber method. The effects of fast and slow thermal annealing on photoluminescence profile imaging were examined. Slow annealing treatment suppressed more quenching sites than fast thermal annealing to further increase the photoluminescence signals. The photoluminescence signals observed between 450 and 720 nm were assigned to the (5)D(0)  → (7)F(J) (J = 0,1,2,3,4) of Eu(III) and the (5)D(4)  → (7)F(J) (J = 6,5,4,3) transitions of Tb(III). Photoluminescence was largely sensitized by indirect excitation and was much stronger than that generated by direct excitation. The Eu(III) and Tb(III) ions were doped at lower symmetry sites in the silica matrix., (Copyright © 2015 John Wiley & Sons, Ltd.)

Reactive oxygen species (ROS) are highly reactive molecules that arise from a number of cellular sources, including oxidative metabolism in mitochondria. At low levels they can be advantageous to cells, activating signaling pathways that promote proliferation or survival. At higher levels, ROS can damage or kill cells by oxidizing proteins, lipids, and nucleic acids. It was hypothesized that antioxidants might benefit high-risk patients by reducing the rate of ROS-induced mutations and delaying cancer initiation. However, dietary supplementation with antioxidants has generally proven ineffective or detrimental in clinical trials. High ROS levels limit cancer cell survival during certain windows of cancer initiation and progression. During these periods, dietary supplementation with antioxidants may promote cancer cell survival and cancer progression. This raises the possibility that rather than treating cancer patients with antioxidants, they should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance., (© 2016 Gill et al; Published by Cold Spring Harbor Laboratory Press.)

Proton-substitution effects of 4-hydroxy-5-phenyl-6H-pyrido[3,2,1-jk]carbazol-6-one (HPPCO) on structural and photophysical properties were presented. HPPCO crystallized in the orthorhombic space group Pbca with an intermolecular hydrogen bonding between OH and oxygen atom of the carbonyl. The proton-substituted derivatives, 6-oxo-5-phenyl-6H-pyrido[3,2,1-jk]carbazol-4-yl acetate (OPPCA) and 6-oxo-5-phenyl-6H-pyrido[3,2,1-jk]carbazol-4-yl benzoate (OPPCB), crystallized in the monoclinic P2₁/c space group. For OPPCA and OPPCB, a weak interaction between carbonyl oxygen atom in the substituted group and carbon atom in the fused ring was responsible for three-dimensional arrangements. In addition, 6-oxo-5-phenyl-6H-pyrido[3,2,1-jk]carbazol-4-yl furan-2-carboxylate (OPPCF), and 6-oxo-5-phenyl-6H-pyrido[3,2,1-jk]carbazol-4-yl naphthoate (OPPCN) were also synthesized. HPPCO and the four derivatives excited by ultraviolet (UV) light produced blue emission. Proton substitution of the OH group significantly increased the radiative transitions and moderately decreased the non-radiative transitions. Consequently the luminescence quantum yields of the derivatives enhanced more than 4.6-fold, no matter what the groups were substituted. Structural and optical properties were further determined using density functional theory (DFT) and ZINDO calculations. The planar structure of the pyridocarbazole-fused ring resulted in π→π(*) electronic transitions within the main frame, with an additional transition from the n(O) of carbonyl to the π(*) of the main frame. The three excited states that arose from these transitions were responsible for the blue luminescence., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A tetrakis(dibenzylmethanido) Eu(III) complex as a ultraviolet (UV) excited phosphor was synthesized, and incorporated with mesoporous silica as core-shell (CS), outer-shell (OS) and intermediate-shell (IS) architectures, using a combination of the self-organization process and the Stöber method. Exciting the Eu(III) complex at UV light produced a strong sensitized red-emission from Eu(III) by energy transfer from the ligand. Phosphor-converted light-emitting diodes (pc-LEDs) were fabricated by casting the powdered complex and the incorporated silica nanoparticles onto a 365-nm InGaN chip, and their optical properties and thermal stability were investigated in terms of the chromaticity index and the intensity decay, respectively. The CS silica nanoparticle casted UV-LED exhibited the best perfomence with strong intensity and excellent thermal stability., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The synthesis and characterization of two europium(III) complexes, [Eu(L)(H2O)]Cl and [Eu(L)(phen)(H2O)]Cl (L=N,N'-bis(salicylidene)-3,6-dioxa-1,8-diaminooctanato and phen=1,10-phenanthroline) are reported. Exciting the Eu(III) complexes with near-UV light resulted in sensitized red luminescence by a transfer of energy from the triplet excited states of L to the Eu(III) ion. Introducing phen to the complex increased the quantum yield of the L-sensitized luminescence of [Eu(L)(phen)(H2O)](+) by more than 18 times relative to [Eu(L)(H2O)](+). The optimized structures and the configurational interaction singles (CIS) of the [Eu(L)(phen)(H2O)](+) and [Eu(L)(H2O)](+) molecules were theoretically studied using ab initio Hartree-Fock (HF). The theoretical calculations showed that the first nearly degenerate 1A and 2A excited states, more specifically the π→π(*) transitions of the two phenolate terminals, contributed significantly to the energy transfer process. Although the phen excitation route was forbidden in [Eu(L)(phen)(H2O)](+), the coordination of phen enhanced the absorbing ability of L markedly and caused the energy transfer from the 1A and 2A states to the (5)D1 and (5)D0 states of Eu(III) to predominate over any radiative and nonradiative processes occurring between the excited states and the ground states of the L moiety. Consequently, the quantum yield of the sensitized luminescence was enhanced significantly in [Eu(L)(phen)(H2O)](+)., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Epidural fibrosis is a contributing factor to the persistent pain that is associated with failed back surgery syndrome (FBSS) and other pathophysiologies, particularly as it inhibits the passage of regional medications to areas responsible for pain. Therefore, effective mechanical detachment of epidural fibrosis can contribute to pain reduction and improve function in FBSS patients. In this report, we describe the successful treatment of FBSS patients with epidural adhesiolysis using a Fogarty catheter via the transforaminal approach.

Conventional transcrural CPB via the "walking off" the vertebra technique may injure vital organs while attempting to proximally spread injectate around the celiac plexus. Therefore, we attempted the CT-simulated fluoroscopy-guided transdiscal approach to carry out transcrural CPB in a safer manner, spreading the injectate more completely and closely within the celiac plexus area. A 54-year-old male patient with pancreatic cancer suffered from severe epigastric pain. The conventional transcrural approach was simulated, but the needle pathway was impeded by the kidney on the right side and by the aorta on the left side. After simulating the transdiscal pathway through the T11-12 intervertebral disc, we predetermined the optimal insertion point (3.6 cm from the midline), insertion angle (18 degrees), and advancement plane, as well as the proper depth. With the transdiscal approach, we successfully performed transcrural CPB within a narrow angle, and the bilateral approach was not necessary as we were able to achieve the bilateral spread of the injectate with the single approach.

Background: Although paclitaxel is a widely used chemotherapeutic agent for the treatment of solid cancers, side effects such as neuropathic pain lead to poor compliance and discontinuation of the therapy. Ethyl pyruvate (EP) is known to have analgesic effects in several pain models and may inhibit apoptosis. The present study was designed to investigate the analgesic effects of EP on mechanical allodynia and apoptosis in dorsal root ganglion (DRG) cells after paclitaxel administration., Methods: Rats were randomly divided into 3 groups: 1) a control group, which received only vehicle; 2) a paclitaxel group, which received paclitaxel; and 3) an EP group, which received EP after paclitaxel administration. Mechanical allodynia was tested before and at 7 and 14 days after final paclitaxel administration. Fourteen days after paclitaxel treatment, DRG apoptosis was determined by activated caspase-3 immunoreactivity (IR)., Results: Post-treatment with EP did not significantly affect paclitaxel-induced allodynia, although it tended to slightly reduce sensitivities to mechanical stimuli after paclitaxel administration. After paclitaxel administration, an increase in caspase-3 IR in DRG cells was observed, which was co-localized with NF200-positive myelinated neurons. Post-treatment with EP decreased the paclitaxel-induced caspase-3 IR. Paclitaxel administration or post-treatment with EP did not alter the glial fibrillary acidic protein IRs in DRG cells., Conclusions: Inhibition of apoptosis in DRG neurons by EP may not be critical in paclitaxel-induced mechanical allodynia.

Background: It has been demonstrated that the expression of tumor necrosis factor-α (TNF-α) and apoptotic cell death in the dorsal root ganglion (DRG) following spinal nerve constriction injury play a role in the initiation and continuation of hyperalgesia and allodynia. The present study was designed to investigate the effects of ethyl pyruvate (EP) on mechanical and cold allodynia, TNF-α expression, and apoptosis in DRG after spinal nerve ligation injury., Methods: Rats were divided into 3 groups: control, pre-EP, and post-EP. EP (50 mg/kg) was intraperitoneally injected 30 minutes before (pre-EP) or after (post-EP) surgery. Behavioral tests to determine mechanical and cold allodynia were conducted before surgery and 4 and 7 days after surgery. Seven days after surgery, TNF-α protein levels in DRG were evaluated by enzyme-linked immunosorbent assay, and DRG apoptosis was determined by immunohistochemical detection of activated caspase-3., Results: Treatment with EP significantly reduced mechanical and cold allodynia following spinal nerve ligation injury. TNF-α protein levels in the pre-EP (4.7 ± 1.2 pg/200 µg; P < 0.001) and post-EP (6.4 ± 1.8 pg/200 µg; P < 0.001) groups were 2-3 times lower than the control group (14.4 ± 1.2 pg/200 µg). The percentages of neurons and satellite cells that co-localized with caspase-3 were also significantly lower in the pre-EP and post-EP groups than the control group., Conclusions: These results demonstrate that EP has a strong anti-allodynic effect that acts through the inhibition of TNF-α expression and apoptosis in DRG after spinal nerve ligation injury.

Background: Elderly patients visiting pain clinic may be at greater risk of misunderstanding the explanation because of age-related cognitive decline. Video instruction may provide a consistent from of teaching in a visual and realistic manner. We evaluated the effect of educational video on the patient understanding and satisfaction in a group of geriatric patients visiting pain clinic., Methods: Ninety two patients aged more than 60 years old who were scheduled for transforaminal epidural block were recruited. After exposure to either video or paper instruction process, each patient was asked 5-item comprehension questions, overall satisfaction and preference question. During follow-up period, number of outpatient referral-line call for further explanation was counted., Results: We observed significantly better comprehension in the video education compared with paper instruction (P < 0.001). Patient satisfaction was also higher in the video group (P = 0.015), and patients visiting pain clinic were more preferred video instruction (P < 0.001). Proportion of referral-line call for further explanation were similar (P = 0.302)., Conclusions: Video approach to instruction process before consent improves treatment comprehension in geriatric patient visiting pain clinic.

Myeloid ecotropic viral integration site 1 (Meis1) forms a heterodimer with Pbx1 that augments Hox-dependent gene expression and is associated with leukemogenesis and HSC self-renewal. Here we identified 2 independent actions of Meis1 in hematopoietic development: one regulating cellular proliferation and the other involved in megakaryocyte lineage development. First, we found that endogenous Mesp1 indirectly induces Meis1 and Meis2 in endothelial cells derived from embryonic stem cells. Overexpression of Meis1 and Meis2 greatly enhanced the formation of hematopoietic colonies from embryonic stem cells, with the exception of erythroid colonies, by maintaining hematopoietic progenitor cells in a state of proliferation. Second, overexpression of Meis1 repressed the development of early erythroid progenitors, acting in vivo at the megakaryocyte-erythroid progenitor stage to skew development away from erythroid generation and toward megakaryocyte development. This previously unrecognized action of Meis1 may explain the embryonic lethality observed in Meis1(-/-) mice that arises from failure of lymphatic-venous separation and can result as a consequence of defective platelet generation. These results show that Meis1 exerts 2 independent functions, with its role in proliferation of hematopoietic progenitors acting earlier in development from its influence on the fate choice at the megakaryocyte-erythroid progenitor between megakaryocytic and erythroid development.

A novel Eu(II) complex with 2-ethylhexyl hydrogen 2-ethylhexyl phosphonate (EHHEHP or PC88A) was synthesized and blended with polystyrene polymer (PS). Both an independent complex and the Eu(II)/PS blend excited by near-UV light produced blue luminescence, arising from the 5d→ 4f transitions of Eu(II). Time-dependent density functional theory (TD-DFT) calculations on electronic structures of the complex molecule indicated that the absorbing and emitting center was associated with the (2)A(d(z(2))) state under the C(2) crystal field. We also synthesized silver nanoparticles (Ag NPs) with an average particle size of 4.48 nm (σ = 0.91 nm) using EHHEHP as a stabilizer. The effects of Ag NPs as a colloidal suspension and an interfacial layer on the luminescence intensity of the blend were investigated as functions of the concentration of Ag NPs and the thickness of the Ag NP layer, respectively. The critical concentration of the colloidal Ag NPs and the critical thickness of the interfacial Ag NP layer were ∼355 ppm and ∼0.16 μm, respectively. Under critical conditions, the Ag NPs increased the luminescence intensity by 4.4 times as a colloidal suspension in CH(2)Cl(2) and 2.2 times as an interfacial-layer state.

Opioid analgesia is the primary pharmacologic intervention for managing pain. However, opioids can cause various adverse effects including pruritus, nausea, constipation, and sedation. Respiratory depression is the most fatal side effect. Therefore, cautious monitoring of respiratory status must be done after opioid administration. Here, we report a patient who suffered from respiratory depression with deep sedation and aspiration pneumonitis after intrathecal morphine administration.