Burn Pit Smoke Condensate-Mediated Toxicity in Human Airway Epithelial Cells.

Burn pits are a method of open-air waste management that was common during military operations in Iraq, Afghanistan, and other regions in Southwest Asia. Veterans returning from deployment have reported respiratory symptoms, potentially from exposure to burn pit smoke, yet comprehensive assessment of such exposure on pulmonary health is lacking. We have previously shown that exposure to condensates from burn pit smoke emissions causes inflammation and cytotoxicity in mice. In this study, we explored the effects of burn pit smoke condensates on human airway epithelial cells (HAECs) to understand their impact on cellular targets in the human lung. HAECs were cultured at the air-liquid interface (ALI) and exposed to burn pit waste smoke condensates (plywood, cardboard, plastic, mixed, and mixed with diesel) generated under smoldering and flaming conditions. Cytotoxicity was evaluated by measuring transepithelial electrical resistance (TEER) and lactate dehydrogenase (LDH) release; toxicity scores (TSs) were quantified for each exposure. Pro-inflammatory cytokine release and modulation of gene expression were examined for cardboard and plastic condensate exposures. Burn pit smoke condensates generated under flaming conditions affected cell viability, with flaming mixed waste and plywood exhibiting the highest toxicity scores. Cardboard and plastic smoke condensates modulated cytokine secretion, with GM-CSF and IL-1ß altered in more than one exposure group. Gene expression of detoxifying enzymes (ALDH1A3, ALDH3A1, CYP1A1, CYP1B1, NQO1, etc.), mucins (MUC5AC, MUC5B), and cytokines was affected by several smoke condensates. Particularly, expression of IL6 was elevated following exposure to all burn pit smoke condensates, and polycyclic aromatic hydrocarbon acenaphthene was positively associated with the IL-6 level in the basolateral media of HAECs. These observations demonstrate that exposure to smoke condensates of materials present in burn pits adversely affects HAECs and that aberrant cytokine secretion and altered gene expression profiles following burn pit material smoke exposure could contribute to the development of airway disease.

Monitoring redox stress in human airway epithelial cells exposed to woodsmoke at an air-liquid interface.

Wildland fires contribute significantly to the ambient air pollution burden worldwide, causing a range of adverse health effects in exposed populations. The toxicity of woodsmoke, a complex mixture of gases, volatile organic compounds, and particulate matter, is commonly studied in vitro using isolated exposures of conventionally cultured lung cells to either resuspended particulate matter or organic solvent extracts of smoke, leading to incomplete toxicity evaluations. This study aimed to improve our understanding of the effects of woodsmoke inhalation by building an advanced in vitro exposure system that emulates human exposure of the airway epithelium. We report the development and characterization of an innovative system that permits live-cell monitoring of the intracellular redox status of differentiated primary human bronchial epithelial cells cultured at an air-liquid interface (pHBEC-ALI) as they are exposed to unfractionated woodsmoke generated in a tube furnace in real time. pHBEC-ALI exposed to freshly generated woodsmoke showed oxidative changes that were dose-dependent and reversible, and not attributable to carbon monoxide exposure. These findings show the utility of this novel system for studying the molecular initiating events underlying woodsmoke-induced toxicity in a physiologically relevant in vitro model, and its potential to provide biological plausibility for risk assessment and public health measures.

Emissions from plastic incineration induce inflammation, oxidative stress, and impaired bioenergetics in primary human respiratory epithelial cells.

Inhalation exposure to plastic incineration emissions (PIEs) is a problem of increasing human relevance, as plastic production and waste creation have drastically increased since mainstream integration during the 20th century. We investigated the effects of PIEs on human nasal epithelial cells (HNECs) to understand if such exposures cause damage and dysfunction to respiratory epithelia. Primary HNECs from male and female donors were cultured at air-liquid interface (ALI), and 16HBE cells were cultured on coverslips. Smoke condensates were generated from incineration of plastic at flaming (640°C) and smoldering (500°C) temperatures, and cells were subsequently exposed to these materials at 5-50 µg/cm2 concentrations. HNECs were assessed for mitochondrial dysfunction and 16HBE cells for glutathione oxidation in real-time analyses. HNEC culture supernatants and total RNA were collected at 4-h postexposure for cytokine and gene expression analysis, and results show that PIEs can acutely induce inflammation, oxidative stress, and mitochondrial dysfunction in HNECs, and that incineration temperature modifies biological responses. Specifically, condensates from flaming and smoldering PIEs significantly increased HNEC secretion of cytokines IL-8, IL-1ß, and IL-13, as well as expression of xenobiotic metabolism pathways and genes such as CYP1A1 and CYP1B1 at 5 and 20 µg/cm2 concentrations. Only 50 µg/cm2 flaming PIEs significantly increased glutathione oxidation in 16HBEs, and decreased respiration and ATP production in HNEC mitochondria. Impact Statement: Our data reveal the impact of incineration temperatures on biological outcomes associated with PIE exposures, emphasizing the importance of temperature as a factor when evaluating respiratory disease associated with PIEs exposure.

Specific transcription factors Ascl1 and Lhx6 attenuate diabetic neuropathic pain by modulating spinal neuroinflammation and microglial activation in mice.

Gamma-aminobutyric acid (GABA) neuronal system-related transcription factors (TFs) play a critical role in GABA production, and GABA modulates diabetic neuropathic pain (DNP). The present study investigated the therapeutic effects of intrathecal delivery of two TFs achaete-scute homolog 1 (Ascl1) and LIM homeobox protein 6 (Lhx6) in a mouse model of DNP and elucidated their underlying mechanisms. GABA-related specific TFs, including Ascl1, Lhx6, distal-less homeobox 1, distal-less homeobox 5, the Nkx2.1 homeobox gene, and the Nkx2.2 homeobox gene, were investigated under normal and diabetic conditions. Among these, the expression of Ascl1 and Lhx6 was significantly downregulated in mice with diabetes. Therefore, a single intrathecal injection of combined lenti-Ascl1/Lhx6 was performed. Intrathecal delivery of lenti-Ascl1/Lhx6 significantly relieved mechanical allodynia and heat hyperalgesia in mice with DNP. Ascl1/Lhx6 delivery also reduced microglial activation, decreased the levels of pro-inflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-1ß, increased the levels of anti-inflammatory cytokines including IL-4, IL-10, and IL-13, and reduced the activation of p38, c-Jun N-terminal kinase, and NF-κB in the spinal cord of mice with DNP, thereby reducing DNP. The results of this study suggest that intrathecal Ascl1/Lhx6 delivery attenuates DNP via upregulating spinal GABA neuronal function and inducing anti-inflammatory effects.

Effect of Thrombin-Containing Local Hemostatics on Postoperative Spinal Epidural Hematoma in Biportal Endoscopic Spinal Surgery.

STUDY DESIGN: Retrospective case-control study. PURPOSE: This study aimed to investigate the preventive effect of thrombin-containing local hemostatics (TCLH) on postoperative spinal epidural hematoma (POSEH) in biportal endoscopic spinal surgery (BESS). This study compared the incidence of morphometric and symptomatic POSEH with or without TCLH in BESS. OVERVIEW OF LITERATURE: POSEH is reported not uncommon in BESS when compared with conventional spine surgery (CSS). TCLH achieves hemostasis with a high success rate in CSS. However, few studies have examined the effect of TCLH on BESS. METHODS: Patients with and without TCLH were assigned to groups A and B, respectively. POSEH between the two groups was compared morphometrically and symptomatically. The risk factors for symptomatic and morphometric POSEH in BESS were identified. RESULTS: The morphometric POSEH was greater in group B, and the difference was significant (p =0.019). The incidence of symptomatic POSEH was lower in group A with 4.6% (5/109) than in group B with 9.5% (9/95); however, the rate was not significantly different (p =0.136). The morphometric POSEH was classified into two small (hG1 and hG2) and large (hG3 and hG4) and were compared between groups A and B, and the difference was significant (p =0.02). In the multivariable logistic regression, nonuse of TCLH (p =0.004) and preoperative diagnosis of stenosis (p =0.016) were variables found to be significant risk factors of morphometric POSEH. CONCLUSIONS: Severe compression of the thecal sac by POSEH is more common in patients without TCLH. The risk of hematoma formation was higher when bilateral decompression was needed and the cut bone surface was more exposed.

Unveiling the potential effects of acetylsalicylic acid: insights into regeneration in endometrial stem cells.

BACKGROUND: Although acetylsalicylic acid has been widely used for decades to treat and prevent various diseases, its potential effects on endometrial receptivity and subsequent pregnancy rates are still controversial due to conflicting data: many reports have shown positive effects of acetylsalicylic acid, whereas others have found that it has no effect. Furthermore, the direct effects of acetylsalicylic acid on various functions of normal endometrial cells, especially endometrial stem cells, and their underlying molecular mechanisms have not yet been proven. Recently, studies have revealed that a reduced number of active stem/progenitor cells within endometrial tissue limits cyclic endometrial regeneration and subsequently decreases pregnancy success rates, suggesting that endometrial stem cells play a critical role in endometrial regeneration and subsequent endometrial receptivity. METHODS: We assessed whether aspirin treatment can inhibit various endometrial stem cell functions related to regenerative capacity, such as self-renewal, migration, pluripotency/stemness, and differentiation capacity, in vitro. Next, we evaluated whether SERPINB2 regulates the effects of aspirin on endometrial stem cell functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. To further investigate whether aspirin also inhibits various endometrial stem cell functions in vivo, aspirin was administered daily to mice through intraperitoneal (i.p.) injection for 7 days. RESULTS: In addition to its previously identified roles, to the best of our knowledge, we found for the first time that acetylsalicylic acid directly inhibits various human endometrial stem cell functions related to regenerative capacity (i.e., self-renewal, migration, differentiation, and capacity) through its novel target gene SERPINB2 in vitro. Acetylsalicylic acid exerts its function by suppressing well-known prosurvival pathways, such as Akt and/or ERK1/2 signaling, through a SERPINB2 signaling cascade. Moreover, we also found that acetylsalicylic acid markedly inhibits regenerative capacity-related functions in endometrial stem cells within tissue. CONCLUSIONS: We have found that acetylsalicylic acid has diverse effects on various endometrial stem cell functions related to regenerative capacity. Our findings are a critical step toward the development of more effective therapeutic strategies to increase the chances of successful pregnancy. Video Abstract.

Peptide-Assembled Single-Chain Atomic Crystal Enhances Pluripotent Stem Cell Differentiation to Neurons.

Nanomaterials hybridized with biological components have widespread applications. among many candidates, peptides are attractive in that their peptide sequences can self-assemble with the surface of target materials with high specificity without perturbing the intrinsic properties of nanomaterials. Here, a 1D hybrid nanomaterial was developed through self-assembly of a designed peptide. A hexagonal coiled-coil motif geometrically matched to the diameter of the inorganic nanomaterial was fabricated, whose hydrophobic surface was wrapped along the axis of the hydrophobic core of the coiled coil. Our morphological and spectroscopic analyses revealed rod-shaped, homogeneous peptide-inorganic nanomaterial complexes. Culturing embryonic stem cells on surfaces coated with this peptide-assembled single-chain atomic crystal increased the growth and adhesion of the embryonic stem cells. The hybridized nanomaterial also served as an ECM for brain organoids, accelerating the maturation of neurons. New methods to fabricate hybrid materials through peptide assembly can be applied.

The Influence of Systolic Blood Pressure at the Time of Extubation on the Development of Postoperative Spinal Epidural Hematoma.

Background: The most common cause of neurological complications after a biportal endoscopic spine surgery (BESS) is postoperative spinal epidural hematomas (POSEH). The objective of this study was to determine the influence of systolic blood pressure at extubation (e-SBP) on POSEH. Methods: A total of 352 patients who underwent single-level decompression surgery including laminectomy and/or discectomy with BESS under the diagnosis of spinal stenosis and herniated nucleus pulposus between August 1, 2018, and June 30, 2021, were reviewed retrospectively. The patients were divided into two, a POSEH group and a normal group without POSEH (no neurological complication). The e-SBP, demographic factors, and the preoperative and intraoperative factors suspected to influence the POSEH were analyzed. The e-SBP was converted to a categorical variable by the threshold level that was decided by maximum area under the curve (AUC) in receiver operating characteristic (ROC) curve analysis. Antiplatelet drugs (APDs) were taken in 21 patients (6.0%), discontinued in 24 patients (6.8%), and not taken in 307 patients (87.2%). Tranexamic acid (TXA) was used in 292 patients (83.0%) in the perioperative period. Results: Of the 352 patients, 18 patients (5.1%) underwent revision surgery for the removal of POSEH. The POSEH and normal groups were homogenous in age, sex, diagnosis, operation segments, operation time, and lab findings that were related to blood clotting, whereas there were differences in e-SBP (163.7 ± 15.7 mmHg in POSEH group and 154.1 ± 18.3 mmHg in normal group), APD (4 takers, 2 stoppers, 12 non-takers in POSEH group and 16 takers, 22 stoppers, 296 non-takers in normal group), and TXA (12 use, 6 not use in POSEH group and 280 use, 54 not use in normal group) in single variable analysis. The highest AUC in the ROC curve analysis was 0.652 for 170 mmHg e-SBP (p < 0.05). There were 94 patients in the high e-SBP group (≥ 170 mmHg) and 258 patients in the low e-SBP group. In multivariable logistic regression analysis, only high e-SBP was a significant risk factor for POSEH (p = 0.013; odds ratio, 3.434). Conclusions: High e-SBP (≥ 170 mmHg) can influence the development of POSEH in biportal endoscopic spine surgery.

Citrous Lime-A Functional Reductive Booster for Oil-Mediated Green Synthesis of Bioactive Silver Nanospheres for Healthcare Clothing Applications and Their Eco-Mapping with SDGs.

Silver nanoparticles (Ag-NPs) are most effective against pathogens and have widely been studied as antibacterial agents in commodity clothing, medical textile, and other hygiene products. However, prolonged utilization of silver and rapid mutation in bacterium stains has made them resistant to conventional silver agents. On the other hand, strict compliance against excessive utilization of toxic reagents and the current sustainability drive is forcing material synthesis toward green routes with extended functionality. In this study, we proposed an unprecedented chemical-free green synthesis of bioactive Ag-NPs without the incorporation of any chemicals. Cinnamon essential oil (ECO) was used as a bio-reducing agent with and without the mediation of lime extract. A rapid reaction completion with better shape and size control was observed in the vicinity of lime extract when incorporated into the reaction medium. The interaction of natural metabolites and citrus compounds with nanoparticles was established using Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy. The application of as-prepared nanoparticles on textiles encompasses extended bioactivity to treated fabric with infused easy-care performance. To the best of our knowledge, this is the first reported instance of utilizing bioactive silver nanoparticles as a functional finish, both as an antimicrobial and as for easy care in the absolute absence of toxic chemicals. The easy-care performance of fabric treated with lime-mediated nanoparticles was found to be 141O, which is around 26% better than bare cotton without any significant loss in fabric strength. Furthermore, to enlighten the sustainability of the process, the development traits were mapped with the United Nations Sustainable Development Goals (SDGs), which show significant influence on SDGs 3, 8, 9, and 14. With the effective suspension of microorganisms, added functionality, and eco-mapping with SDGs with the chemical-free synthesis of nanoparticles, widespread utilization can be found in various healthcare and hygiene products along with the fulfillment of sustainability needs.

Contributions of particulate and gas phases of simulated burn pit smoke exposures to impairment of respiratory function.

OBJECTIVE: Inhalation of smoke from the burning of waste materials on military bases is associated with increased incidences of cardiopulmonary diseases. This study examined the respiratory and inflammatory effects of acute inhalation exposures in mice to smoke generated by military burn pit-related materials including plywood (PW), cardboard (CB), mixed plastics (PL), and a mixture of these three materials (MX) under smoldering (0.84 MCE) and flaming (0.97 MCE) burn conditions. METHODS: Mice were exposed nose-only for one hour on two consecutive days to whole or filtered smoke or clean air alone. Smoldering combustion emissions had greater concentrations of PM (∼40 mg/m3) and VOCs (∼5-12 ppmv) than flaming emissions (∼4 mg/m3 and ∼1-2 ppmv, respectively); filtered emissions had equivalent levels of VOCs with negligible PM. Breathing parameters were assessed during exposure by head-out plethysmography. RESULTS: All four smoldering burn pit emission types reduced breathing frequency (F) and minute volumes (MV) compared with baseline exposures to clean air, and HEPA filtration significantly reduced the effects of all smoldering materials except CB. Flaming emissions had significantly less suppression of F and MV compared with smoldering conditions. No acute effects on lung inflammatory cells, cytokines, lung injury markers, or hematology parameters were noted in smoke-exposed mice compared with air controls, likely due to reduced respiration and upper respiratory scrubbing to reduce the total deposited PM dose in this short-term exposure. CONCLUSION: Our data suggest that material and combustion type influences respiratory responses to burn pit combustion emissions. Furthermore, PM filtration provides significant protective effects only for certain material types.

Computational Approach to Link Chemicals in Anthropogenic Smoke Particulate Matter with Toxicity.

A weighted chemical coexpression network analysis (WCCNA) was utilized to identify chemicals co-modulated to variable burning of anthropogenic materials and to link chemicals to biological responses (lung toxicity and mutagenicity). Polyaromatic hydrocarbons (PAHs) were co-modulated with increased concentrations in flaming smoke particulate matter (PM) from the burning of plastic-containing materials and showed significant association with increased neutrophil influx, cytokine levels, and mutagenicity. Inorganic elements were co-modulated with increased concentrations in flaming plywood and cardboard smoke PM and showed significant association with increased protein and albumin levels. This study shows the potential for using a computational network analysis to identify and prioritize hazardous chemical components within complex environmental mixtures and provides guidance on key chemical tracers required for intervention research to protect public health from the exposure.

Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development.

The transient receptor potential vanilloid 1 (TRPV1) ion channel plays an important role in the peripheral nociceptive pathway. TRPV1 is a polymodal receptor that can be activated by multiple types of ligands and painful stimuli, such as noxious heat and protons, and contributes to various acute and chronic pain conditions. Therefore, TRPV1 is emerging as a novel therapeutic target for the treatment of various pain conditions. Notably, various peptides isolated from venomous animals potently and selectively control the activation and inhibition of TRPV1 by binding to its outer pore region. This review will focus on the mechanisms by which venom-derived peptides interact with this portion of TRPV1 to control receptor functions and how these mechanisms can drive the development of new types of analgesics.

Investigating the Anti-Inflammatory Effects of RCI001 for Treating Ocular Surface Diseases: Insight Into the Mechanism of Action.

The ocular surface is continuously exposed to various environmental factors, and innate and adaptive immunity play crucial roles in ocular surface diseases (OSDs). Previously, we have reported that the topical application of RCI001 affords excellent anti-inflammatory and antioxidant effects in dry eye disease and ocular chemical burn models. In this study, we examined the inhibitory effects of RCI001 on the Rac1 and NLRP3 inflammasomes in vitro and in vivo. Following RCI001 application to RAW264.7 and Swiss 3T3 cells, we measured Rac1 activity using a glutathione-S-transferase (GST) pull-down assay and G-protein activation assay kit. In addition, we quantified the expression of inflammatory cytokines (interleukin [IL]-1ß, IL-6, and tumor necrosis factor [TNF]-α) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells using ELISA and real-time PCR. In the mouse ocular alkali burn model, RCI001 was administered via eye drops (10 mg/mL, twice daily) for 5 days, and 1% prednisolone acetate (PDE) ophthalmic suspension was used as a positive control. Corneal epithelial integrity (on days 0-5) and histological examinations were performed, and transcript and protein levels of Rac1, NLRP3, caspase-1, and IL-1ß were quantified using real-time PCR and western blotting in corneal tissues collected on days 3 and 5. We observed that RCI001 dose-dependently inhibited Rac1 activity and various inflammatory cytokines in LPS-stimulated murine macrophages. Furthermore, RCI001 restored corneal epithelial integrity more rapidly than corticosteroid treatment in chemically injured corneas. Compared to the saline group, activation of Rac1 and the NLRP3 inflammasome/IL-1ß axis was suppressed in the RCI001 group, especially during the early phase of the ocular alkali burn model. Topical RCI001 suppressed the expression of activated Rac1 and inflammatory cytokines in vitro and rapidly restored the injured cornea by inhibiting activation of Rac1 and the NLRP inflammasome/IL-1ß axis in vivo. Accordingly, RCI001 could be a promising therapeutic agent for treating OSDs.

Cerebrospinal Fluid-philic and Biocompatibility-Enhanced Soft Cranial Window for Long-Term In Vivo Brain Imaging.

Soft, transparent poly(dimethyl siloxane) (PDMS)-based cranial windows in animal models have created many opportunities to investigate brain functions with multiple in vivo imaging modalities. However, due to the hydrophobic nature of PDMS, the wettability by cerebrospinal fluid (CSF) is poor, which may cause air bubble trapping beneath the window during implantation surgery, and favorable heterogeneous bubble nucleation at the interface between hydrophobic PDMS and CSF. This may result in excessive growth of the entrapped bubble under the soft cranial window. Herein, to yield biocompatibility-enhanced, trapped bubble-minimized, and soft cranial windows, this report introduces a CSF-philic PDMS window coated with hydroxyl-enriched poly(vinyl alcohol) (PVA) for long-term in vivo imaging. The PVA-coated PDMS (PVA/PDMS) film exhibits a low contact angle θACA (33.7 ± 1.9°) with artificial CSF solution and maintains sustained CSF-philicity. The presence of the PVA layer achieves air bubble-free implantation of the soft cranial window, as well as induces the formation of a thin wetting film that shows anti-biofouling performance through abundant water molecules on the surface, leading to long-term optical clarity. In vivo studies on the mice cortex verify that the soft and CSF-philic features of the PVA/PDMS film provide minimal damage to neuronal tissues and attenuate immune response. These advantages of the PVA/PDMS window are strongly correlated with the enhancement of cortical hemodynamic changes and the local field potential recorded through the PVA/PDMS film, respectively. This collection of results demonstrates the potential for future microfluidic platforms for minimally invasive CSF extraction utilizing a CSF-philic fluidic passage.

Identification of a Novel Geminivirus in Fraxinus rhynchophylla in Korea.

Fraxinus rhynchophylla, common name ash, belongs to the family Oleaceae and is found in China, Korea, North America, the Indian subcontinent, and eastern Russia. It has been used as a traditional herbal medicine in Korea and various parts of the world due to its chemical constituents. During a field survey in March 2019, mild vein thickening (almost negligible) was observed in a few ash trees. High-throughput sequencing of libraries of total DNA from ash trees, rolling-circle amplification (RCA), and polymerase chain reaction (PCR) allowed the identification of a Fraxinus symptomless virus. This virus has five confirmed open reading frames along with a possible sixth open reading frame that encodes the movement protein and is almost 2.7 kb in size, with a nonanucleotide and stem loop structure identical to begomoviruses. In terms of its size and structure, this virus strongly resembles begomoviruses, but does not show any significant sequence identity with them. To confirm movement of the virus within the trees, different parts of infected trees were examined, and viral movement was successfully observed. No satellite molecules or DNA B were identified. Two-step PCR confirmed the virion and complementary strands during replication in both freshly collected infected samples of ash tree and Nicotiana benthamiana samples agro-inoculated with infectious clones. This taxon is so distantly grouped from other known geminiviruses that it likely represents a new geminivirus genus.

Current usage of stereotactic body radiotherapy for oligometastatic prostate cancer in Korea: patterns of care survey (KROG 19-08).

BACKGROUND: Growing evidence suggests that metastasis-directed therapy and/or prostate-directed therapy may benefit patients with oligometastatic prostate cancer (OMPC). Stereotactic body radiotherapy (SBRT) is increasingly used to treat oligometastases in various cancers. The purpose of this study was to investigate the current patterns of curative-intent SBRT for OMPC in Korea. METHODS: A 20-item questionnaire was sent to 326 radiation oncologists in 93 institutions in Korea. Only 1 physician per institution was required to complete the survey. Subsequently, the second survey consisting of 3 clinical scenarios was sent to 64 physicians with clinical experience in SBRT: case 1, cT4N0M1 (direct invasion to two pelvic bones); case 2, cT2N0M1 (three bone metastases); and case 3, solitary spine metastasis after radical prostatectomy. RESULTS: Seventy-six physicians from 93 institutions (82%) answered the first survey. The multidisciplinary team approach was practiced in 16 institutions (21%). Most physicians (75%) agreed on the definition of oligometastases as limited lesions and/or organs ≤5: 25% agreed with low-volume disease according to CHAARTED trial. During the last year, 49 physicians (64%) treated OMPC patients with curative intent. Sixty four physicians (84%) had a clinical experience with SBRT: 48 (75%) stated that both dose and fraction number should be considered when defining SBRT, whereas others (25%) stated that only fraction size should be considered. Fifty-five faculties (86%) answered the second survey. Physicians agreed with oligometastases in 89% for case 1, in 80% for case 2, and in 100% for case 3. The rate of SBRT application was the highest in case 3 (70%). CONCLUSIONS: There was diversity in the patterns of SBRT for OMPC in Korea. Additional prospective studies are necessary to strengthen evidence regarding role of SBRT in OMPC.

Sequence-dependent aggregation-prone conformations of islet amyloid polypeptide.

Amyloid proteins, which aggregate to form highly ordered structures, play a crucial role in various disease pathologies. Despite many previous studies on amyloid fibrils, which are an end product of protein aggregation, the structural characteristics of amyloid proteins in the early stage of aggregation and their related aggregation mechanism still remain elusive. The role of the amino acid sequence in the aggregation-prone structures of amyloid proteins at such a stage is not understood. Here, we have studied the sequence-dependent structural characteristics of islet amyloid polypeptide based on atomistic simulations and spectroscopic experiments. We show that the amino acid sequence determines non-bonded interactions that play a leading role in the formation of aggregation-prone conformations. Specifically, a single point mutation critically changes the population of aggregation-prone conformations, resulting in a change of the aggregation mechanism. Our simulation results were supported by experimental results suggesting that mutation affects the kinetics of aggregation and the structural characteristics of amyloid aggregates. Our study provides an insight into the role of sequence-dependent aggregation-prone conformations in the underlying mechanisms of amyloid aggregation.

Riboflavin Inhibits Histamine-Dependent Itch by Modulating Transient Receptor Potential Vanilloid 1 (TRPV1).

Riboflavin, also known as vitamin B2, isfound in foods and is used as a dietary supplement. Its deficiency (also called ariboflavinosis) results in some skin lesions and inflammations, such as stomatitis, cheilosis, oily scaly skin rashes, and itchy, watery eyes. Various therapeutic effects of riboflavin, such as anticancer, antioxidant, anti-inflammatory, and anti-nociceptive effects, are well known. Although some studies have identified the clinical effect of riboflavin on skin problems, including itch and inflammation, its underlying mechanism of action remains unknown. In this study, we investigated the molecular mechanism of the effects of riboflavin on histamine-dependent itch based on behavioral tests and electrophysiological experiments. Riboflavin significantly reduced histamine-induced scratching behaviors in mice and histamine-induced discharges in single-nerve fiber recordings, while it did not alter motor function in the rotarod test. In cultured dorsal root ganglion (DRG) neurons, riboflavin showed a dose-dependent inhibitory effect on the histamine- and capsaicin-induced inward current. Further tests wereconducted to determine whether two endogenous metabolites of riboflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), have similar effects to those of riboflavin. Here, FMN, but not FAD, significantly inhibited capsaicin-induced currents and itching responses caused by histamine. In addition, in transient receptor potential vanilloid 1 (TRPV1)-transfected HEK293 cells, both riboflavin and FMN blocked capsaicin-induced currents, whereas FAD did not. These results revealed that riboflavin inhibits histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how riboflavin exerts antipruritic effects and suggests that it might be a useful drug for the treatment of histamine-dependent itch.

Stem Cell Therapy for Modulating Neuroinflammation in Neuropathic Pain.

Neuropathic pain (NP) is a complex, debilitating, chronic pain state, heterogeneous in nature and caused by a lesion or disease affecting the somatosensory system. Its pathogenesis involves a wide range of molecular pathways. NP treatment is extremely challenging, due to its complex underlying disease mechanisms. Current pharmacological and nonpharmacological approaches can provide long-lasting pain relief to a limited percentage of patients and lack safe and effective treatment options. Therefore, scientists are focusing on the introduction of novel treatment approaches, such as stem cell therapy. A growing number of reports have highlighted the potential of stem cells for treating NP. In this review, we briefly introduce NP, current pharmacological and nonpharmacological treatments, and preclinical studies of stem cells to treat NP. In addition, we summarize stem cell mechanisms-including neuromodulation in treating NP. Literature searches were conducted using PubMed to provide an overview of the neuroprotective effects of stem cells with particular emphasis on recent translational research regarding stem cell-based treatment of NP, highlighting its potential as a novel therapeutic approach.

Inter-institutional Variation in Intensity-modulated Radiotherapy for Breast Cancer in Korea (KROG 19-01).

BACKGROUND/AIM: To present the variations in the target delineation and the planning results of intensity-modulated radiation therapy (IMRT) for breast cancers. PATIENTS AND METHODS: We requested the target volumes and organs at risk delineation for two cases of left breast cancers, and evaluated the IMRT plans including the supraclavicular and internal mammary node irradiation. RESULTS: Twenty-one institutions participated in this study. Differences in the planning target volume among institutions reached up to three-times for breast-conserving surgery (BCS) case and five-times for mastectomy case. Mean heart doses ranged from 3.3 to 24.1 Gy for BCS case and from 5.0 to 26.5 Gy for mastectomy case. Ipsilateral lung volumes receiving more than 20 Gy ranged from 4.7 to 57.4% for BCS case and from 16.4 to 55.5% for mastectomy case. CONCLUSION: There were large variations in the target delineation and planning results of IMRT for breast cancers among institutions. Considering the increased use of breast IMRT, more standardized protocols are needed.