Impact of CD151 overexpression on prognosis and therapy in non-small cell lung cancer patients lacking EGFR mutations.

This study investigates CD151, a protein linked to cancer progression, in non-small cell lung cancer (NSCLC) patients without epidermal growth factor receptor (EGFR) mutations. These patients often have limited treatment options. The study used retrospective analysis to examine 157 adenocarcinoma biopsy specimens and 199 patient cases from The Cancer Genome Atlas, correlating CD151 expression with patient survival. Cellular studies revealed that CD151 interacts with EGFR, influencing epidermal growth factor (EGF)-induced cell proliferation and the effectiveness of the EGFR inhibitor, erlotinib. A strong association was found between CD151 expression and EGFR mutation status. High CD151 expression in the absence of EGFR mutations is correlated with poorer survival outcomes. Biological assays showed that CD151 colocalizes and associates with EGFR, playing a crucial role in regulating EGF-induced cell proliferation via the AKT and ERK1/2 pathways. Importantly, CD151 expression was found to influence the anti-proliferative effects of the EGFR tyrosine kinase inhibitor, erlotinib. High CD151 expression, in the absence of EGFR mutations, was associated with poorer survival outcomes. It could serve as a potential prognostic marker and influence cellular responses to EGFR-targeted treatments. This study highlights CD151 as a potential novel target for therapeutic intervention in NSCLC, especially in populations lacking EGFR mutations.

Secretome from Magnetically Stimulated Muscle Exhibits Anticancer Potency: Novel Preconditioning Methodology Highlighting HTRA1 Action.

Briefly (10 min) exposing C2C12 myotubes to low amplitude (1.5 mT) pulsed electromagnetic fields (PEMFs) generated a conditioned media (pCM) that was capable of mitigating breast cancer cell growth, migration, and invasiveness in vitro, whereas the conditioned media harvested from unexposed myotubes, representing constitutively released secretome (cCM), was less effective. Administering pCM to breast cancer microtumors engrafted onto the chorioallantoic membrane of chicken eggs reduced tumor volume and vascularity. Blood serum collected from PEMF-exposed or exercised mice allayed breast cancer cell growth, migration, and invasiveness. A secretome preconditioning methodology is presented that accentuates the graded anticancer potencies of both the cCM and pCM harvested from myotubes, demonstrating an adaptive response to pCM administered during early myogenesis that emulated secretome-based exercise adaptations observed in vivo. HTRA1 was shown to be upregulated in pCM and was demonstrated to be necessary and sufficient for the anticancer potency of the pCM; recombinant HTRA1 added to basal media recapitulated the anticancer effects of pCM and antibody-based absorption of HTRA1 from pCM precluded its anticancer effects. Brief and non-invasive PEMF stimulation may represent a method to commandeer the secretome response of muscle, both in vitro and in vivo, for clinical exploitation in breast and other cancers.

Quality assurance for mixed electron-photon beam radiation therapy using treatment log files and MapCHECK.

BACKGROUND: Mixed photon-electron beam radiotherapy (MBRT) is a technique that combines the use of both photons and electrons in one single treatment plan to exploit their advantageous and complimentary characteristics. Compared to other photon treatment modalities, it has been shown that the MBRT technique contributes to better target coverage and organ-at-risk (OAR) sparing. However, the use of combined photons and electrons in one delivery makes the technique more complex and a well-established quality assurance (QA) protocol for MBRT is essential. PURPOSE: To investigate the feasibility of using MapCHECK and log file-dose reconstruction for MBRT plan verification and to recommend a patient-specific quality assurance (PSQA) protocol for MBRT. METHODS: MBRT plans were robustly optimized for five soft-tissue sarcoma (STS) patients. Each plan comprised step-and-shoot deliveries of a six MV photon beam and a combination of five electron beam energies at an SAD of 100 cm. The plans were delivered to the MapCHECK device with collapsed gantry angle and the 2D dose distributions at the detector depth were measured. To simulate the expected dose distribution delivered to the MapCHECK, a MapCHECK computational phantom was modeled in EGSnrc based on vendor-supplied blueprint information. The dose to the detectors in the model was scored using the DOSXYZnrc user code. The agreement between the measured and the simulated dose distribution was evaluated using 2D gamma analysis with a gamma criterion of 3%/2 mm and a low dose threshold of 10%. One of the plans was selected and delivered with a rotating gantry angle for trajectory log file collection. To evaluate the potential interlinac and intralinac differences, the plan was delivered repeatedly on three linacs. From the collected log files, delivery parameters were retrieved to recalculate the 3D dose distributions in the patient's anatomy with DOSXYZnrc. The recalculated mean dose to the clinical target volume (CTV) and OARs from all deliveries were computed and compared with the planned dose in terms of percentage difference. To validate the accuracy of log file-based QA, the log file-recalculated dose was also compared with film measurement. RESULTS: The agreement of the total dose distribution between the MapCHECK measurement and simulation showed gamma passing rates of above 97% for all five MBRT plans. In the log file-dose recalculation, the difference between the recalculated and the planned dose to the CTV and OARs was below 1% for all deliveries. No significant inter- or intralinac differences were observed. The log file-dose had a gamma passing rate of 98.6% compared to film measurement. CONCLUSION: Both the MapCHECK measurements and log file-dose recalculations showed excellent agreement with the expected dose distribution. This study demonstrates the potential of using MapCHECK and log files as MBRT QA tools.

The Developmental Implications of Muscle-Targeted Magnetic Mitohormesis: A Human Health and Longevity Perspective.

Muscle function reflects muscular mitochondrial status, which, in turn, is an adaptive response to physical activity, representing improvements in energy production for de novo biosynthesis or metabolic efficiency. Differences in muscle performance are manifestations of the expression of distinct contractile-protein isoforms and of mitochondrial-energy substrate utilization. Powerful contractures require immediate energy production from carbohydrates outside the mitochondria that exhaust rapidly. Sustained muscle contractions require aerobic energy production from fatty acids by the mitochondria that is slower and produces less force. These two patterns of muscle force generation are broadly classified as glycolytic or oxidative, respectively, and require disparate levels of increased contractile or mitochondrial protein production, respectively, to be effectively executed. Glycolytic muscle, hence, tends towards fibre hypertrophy, whereas oxidative fibres are more disposed towards increased mitochondrial content and efficiency, rather than hypertrophy. Although developmentally predetermined muscle classes exist, a degree of functional plasticity persists across all muscles post-birth that can be modulated by exercise and generally results in an increase in the oxidative character of muscle. Oxidative muscle is most strongly correlated with organismal metabolic balance and longevity because of the propensity of oxidative muscle for fatty-acid oxidation and associated anti-inflammatory ramifications which occur at the expense of glycolytic-muscle development and hypertrophy. This muscle-class size disparity is often at odds with common expectations that muscle mass should scale positively with improved health and longevity. Brief magnetic-field activation of the muscle mitochondrial pool has been shown to recapitulate key aspects of the oxidative-muscle phenotype with similar metabolic hallmarks. This review discusses the common genetic cascades invoked by endurance exercise and magnetic-field therapy and the potential physiological differences with regards to human health and longevity. Future human studies examining the physiological consequences of magnetic-field therapy are warranted.

Brief, weekly magnetic muscle therapy improves mobility and lean body mass in older adults: a Southeast Asia community case study.

Brief (10 min) weekly exposure to low energy pulsed electromagnetic fields (PEMFs) has been shown to improve human muscle mitochondrial bioenergetics and attenuate systemic lipotoxicity following anterior cruciate ligament surgical reconstruction. Here we present data generated from 101 participants, 62% female, aged 38-91 years, recruited from the QuantumTx Demo Centre in Singapore, wherein 87% of participants (n = 88) presented with pre-existing mobility dysfunction and 13% (n = 13) were healthy volunteers. Participants were recruited if: (i) not pregnant; (ii) above 35 years of age and; (iii) without surgical implants. All participants completed mobility testing, pre- and post- PEMF intervention for 12 weeks, whereas bioelectrical impedance analysis was conducted in a subgroup of 42 and 33 participants at weeks 4 and 8, respectively. Weekly PEMF exposure was associated with significant improvements in mobility (Timed Up and Go, 5 times Sit-to-Stand, and 4m Normal Gait Speed) and body composition (increased skeletal muscle mass and reduced total and visceral fat mass), particularly in the older participants. Perception of pain was also significantly reduced. PEMF therapy may provide a manner to counteract age-associated mobility and metabolic disruptions and merits future investigation in randomized controlled trials to elucidate its clinical benefits in the frail and older adult populations.

Magnetic field therapy enhances muscle mitochondrial bioenergetics and attenuates systemic ceramide levels following ACL reconstruction: Southeast Asian randomized-controlled pilot trial.

Background: Metabolic disruption commonly follows Anterior Cruciate Ligament Reconstruction (ACLR) surgery. Brief exposure to low amplitude and frequency pulsed electromagnetic fields (PEMFs) has been shown to promote in vitro and in vivo murine myogeneses via the activation of a calcium-mitochondrial axis conferring systemic metabolic adaptations. This randomized-controlled pilot trial sought to detect local changes in muscle structure and function using MRI, and systemic changes in metabolism using plasma biomarker analyses resulting from ACLR, with or without accompanying PEMF therapy. Methods: 20 patients requiring ACLR were randomized into two groups either undergoing PEMF or sham exposure for 16 weeks following surgery. The operated thighs of 10 patients were exposed weekly to PEMFs (1 â€‹mT for 10 â€‹min) for 4 months following surgery. Another 10 patients were subjected to sham exposure and served as controls to allow assessment of the metabolic repercussions of ACLR and PEMF therapy. Blood samples were collected prior to surgery and at 16 weeks for plasma analyses. Magnetic resonance data were acquired at 1 and 16 weeks post-surgery using a Siemens 3T Tim Trio system. Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS) was utilized to monitor changes in high-energy phosphate metabolism (inorganic phosphate (Pi), adenosine triphosphate (ATP) and phosphocreatine (PCr)) as well as markers of membrane synthesis and breakdown (phosphomonoesters (PME) and phosphodiester (PDE)). Quantitative Magnetization Transfer (qMT) imaging was used to elucidate changes in the underlying tissue structure, with T1-weighted and 2-point Dixon imaging used to calculate muscle volumes and muscle fat content. Results: Improvements in markers of high-energy phosphate metabolism including reductions in ΔPi/ATP, Pi/PCr and (Pi â€‹+ â€‹PCr)/ATP, and membrane kinetics, including reductions in PDE/ATP were detected in the PEMF-treated cohort relative to the control cohort at study termination. These were associated with reductions in the plasma levels of certain ceramides and lysophosphatidylcholine species. The plasma levels of biomarkers predictive of muscle regeneration and degeneration, including osteopontin and TNNT1, respectively, were improved, whilst changes in follistatin failed to achieve statistical significance. Liquid chromatography with tandem mass spectrometry revealed reductions in small molecule biomarkers of metabolic disruption, including cysteine, homocysteine, and methionine in the PEMF-treated cohort relative to the control cohort at study termination. Differences in measurements of force, muscle and fat volumes did not achieve statistical significance between the cohorts after 16 weeks post-ACLR. Conclusion: The detected changes suggest improvements in systemic metabolism in the post-surgical PEMF-treated cohort that accords with previous preclinical murine studies. PEMF-based therapies may potentially serve as a manner to ameliorate post-surgery metabolic disruptions and warrant future examination in more adequately powered clinical trials. The Translational Potential of this Article: Some degree of physical immobilisation must inevitably follow orthopaedic surgical intervention. The clinical paradox of such a scenario is that the regenerative potential of the muscle mitochondrial pool is silenced. The unmet need was hence a manner to maintain mitochondrial activation when movement is restricted and without producing potentially damaging mechanical stress. PEMF-based therapies may satisfy the requirement of non-invasively activating the requisite mitochondrial respiration when mobility is restricted for improved metabolic and regenerative recovery.

Channels Adopted for Information Seeking during COVID-19: Comparing Social Media with News Media and Interpersonal Communication in Taiwan.

By adopting niche theory, this study compared social media with news media and interpersonal communication regarding their capabilities in satisfying people's information needs of daily use, surveillance, convenience, and information quality during the outbreak of COVID-19. Two methods were adopted to collect data for this study: the first was to conduct 20 intensive interviews, and the second was to administer an online survey by contracting a professional polling company with a panel of 8.8 million members. The stratified random sampling method was used to acquire a representative sample, from which 1100 valid questionnaires were obtained. The results showed that: (1) Social media were superior to traditional news media in terms of its convenience. However, several new types of online news, such as Yahoo news, were able to compete with social media for convenience. (2) Interpersonal communication did not outperform in satisfying individuals' needs for the four gratifications. Nevertheless, interpersonal communication plays the role of social support for individuals.

Information Seeking and Processing during the Outbreak of COVID-19 in Taiwan: Examining the Effects of Emotions and Informational Subjective Norms.

Adopting the model of risk information seeking and processing (RISP) as a theoretical framework, the objective of this study was to investigate the factors that prompted individuals' information-seeking and -processing behaviors during the COVID-19 pandemic in Taiwan. There were two unique aspects in this study: one was to adopt specific emotions to investigate the impact of negative emotions, and the other was to examine the effect of informational subjective norms (ISNs) on information-seeking and -processing behavior. An online survey was conducted by a professional polling company, and a stratified random sampling method was employed, using gender, age, education, personal income, and residential areas as strata to select participants. This study obtained 1100 valid questionnaires. The results showed that (1) risk perception did not exert any significant impacts on respondents' perceived information insufficiency; (2) risk perception exerted a powerful impact on respondents' ISNs, which, in turn, positively affected their information insufficiency; (3) the respondents who experienced fear were found to have a high probability of using a systematic-processing mode, while the respondents who experienced anger were more likely to adopt a heuristic-processing mode to process information; and (4) the use of a systematic-processing mode was positively associated, while the use of a heuristic-processing mode was negatively associated, with information-seeking behavior.

Brief exposure to directionally-specific pulsed electromagnetic fields stimulates extracellular vesicle release and is antagonized by streptomycin: A potential regenerative medicine and food industry paradigm.

Pulsing electromagnetic fields (PEMFs) have been shown to promote in vitro and in vivo myogeneses via mitohormetic survival adaptations of which secretome activation is a key component. A single 10-min exposure of donor myoblast cultures to 1.5 mT amplitude PEMFs produced a conditioned media (pCM) capable of enhancing the myogenesis of recipient cultures to a similar degree as direct magnetic exposure. Downwardly-directed magnetic fields produced greater secretome responses than upwardly-directed fields in adherent and fluid-suspended myoblasts. The suspension paradigm allowed for the rapid concentrating of secreted factors, particularly of extracellular vesicles. The brief conditioning of basal media from magnetically-stimulated myoblasts was capable of conferring myoblast survival to a greater degree than basal media supplemented with fetal bovine serum (5%). Downward-directed magnetic fields, applied directly to cells or in the form of pCM, upregulated the protein expression of TRPC channels, markers for cell cycle progression and myogenesis. Direct magnetic exposure produced mild oxidative stress, whereas pCM provision did not, providing a survival advantage on recipient cells. Streptomycin, a TRP channel antagonist, precluded the production of a myogenic pCM. We present a methodology employing a brief and non-invasive PEMF-exposure paradigm to effectively stimulate secretome production and release for commercial or clinical exploitation.

Corrigendum: Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach.

[This corrects the article DOI: 10.3389/fonc.2021.783803.].

Exploring Psychological Factors for COVID-19 Vaccination Intention in Taiwan.

To underpin the psychological factors for vaccination intention, we explored the variables related to positive and negative attitudes toward COVID-19 vaccination in Taiwan. The data were collected via an online survey platform with a sample size of 1100 in April 2021. We found that people's interpretations of the origin of the virus were relevant. People who tended to believe that the virus was artificially created felt powerless and were more concerned about the possible side-effects of the vaccines, which was negatively associated with their vaccination intention. The source of vaccine recommendation was found to be relevant to vaccination intention. People's vaccination intention was highest if the vaccines were recommended by health professionals, followed by friends and the government, and then mainstream media and social media. The analysis of the demographic variables showed that men tended to be more receptive to vaccines than women. Our findings should provide insights into developing communication strategies to effectively promote vaccination intentions.

Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach.

Chemotherapy is the mainstream treatment modality for invasive breast cancer. Unfortunately, chemotherapy-associated adverse events can result in early termination of treatment. Paradoxical effects of chemotherapy are also sometimes observed, whereby prolonged exposure to high doses of chemotherapeutic agents results in malignant states resistant to chemotherapy. In this study, potential synergism between doxorubicin (DOX) and pulsed electromagnetic field (PEMF) therapy was investigated in: 1) MCF-7 and MDA-MB-231 cells in vitro; 2) MCF-7 tumors implanted onto a chicken chorioallantoic membrane (CAM) and; 3) human patient-derived and MCF-7 and MDA-MB-231 breast cancer xenografts implanted into NOD-SCID gamma (NSG) mice. In vivo, synergism was observed in patient-derived and breast cancer cell line xenograft mouse models, wherein PEMF exposure and DOX administration individually reduced tumor size and increased apoptosis and could be augmented by combined treatments. In the CAM xenograft model, DOX and PEMF exposure also synergistically reduced tumor size as well as reduced Transient Receptor Potential Canonical 1 (TRPC1) channel expression. In vitro, PEMF exposure alone impaired the survival of MCF-7 and MDA-MB-231 cells, but not that of non-malignant MCF10A breast cells; the selective vulnerability of breast cancer cells to PEMF exposure was corroborated in human tumor biopsy samples. Stable overexpression of TRPC1 enhanced the vulnerability of MCF-7 cells to both DOX and PEMF exposure and promoted proliferation, whereas TRPC1 genetic silencing reduced sensitivity to both DOX and PEMF treatments and mitigated proliferation. Chronic exposure to DOX depressed TRPC1 expression, proliferation, and responses to both PEMF exposure and DOX in a manner that was reversible upon removal of DOX. TRPC1 channel overexpression and silencing positively correlated with markers of epithelial-mesenchymal transition (EMT), including SLUG, SNAIL, VIMENTIN, and E-CADHERIN, indicating increased and decreased EMT, respectively. Finally, PEMF exposure was shown to attenuate the invasiveness of MCF-7 cells in correlation with TRPC1 expression. We thus demonstrate that the expression levels of TRPC1 consistently predicted breast cancer sensitivity to DOX and PEMF interventions and positively correlated to EMT status, providing an initial rationale for the use of PEMF-based therapies as an adjuvant to DOX chemotherapy for the treatment of breast cancers characterized by elevated TRPC1 expression levels.

Cell-Derived Vesicles as TRPC1 Channel Delivery Systems for the Recovery of Cellular Respiratory and Proliferative Capacities.

Pulsed electromagnetic fields (PEMFs) are capable of specifically activating a TRPC1-mitochondrial axis underlying cell expansion and mitohormetic survival adaptations. This study characterizes cell-derived vesicles (CDVs) generated from C2C12 murine myoblasts and shows that they are equipped with the sufficient molecular machinery to confer mitochondrial respiratory capacity and associated proliferative responses upon their fusion with recipient cells. CDVs derived from wild type C2C12 myoblasts include the cation-permeable transient receptor potential (TRP) channels, TRPC1 and TRPA1, and directly respond to PEMF exposure with TRPC1-mediated calcium entry. By contrast, CDVs derived from C2C12 muscle cells in which TRPC1 has been genetically knocked-down using CRISPR/Cas9 genome editing, do not. Wild type C2C12-derived CDVs are also capable of restoring PEMF-induced proliferative and mitochondrial activation in two C2C12-derived TRPC1 knockdown clonal cell lines in accordance to their endogenous degree of TRPC1 suppression. C2C12 wild type CDVs respond to menthol with calcium entry and accumulation, likewise verifying TRPA1 functional gating and further corroborating compartmental integrity. Proteomic and lipidomic analyses confirm the surface membrane origin of the CDVs providing an initial indication of the minimal cellular machinery required to recover mitochondrial function. CDVs hence possess the potential of restoring respiratory and proliferative capacities to senescent cells and tissues.

Magnetic fields modulate metabolism and gut microbiome in correlation with Pgc-1α expression: Follow-up to an in vitro magnetic mitohormetic study.

Exercise modulates metabolism and the gut microbiome. Brief exposure to low mT-range pulsing electromagnetic fields (PEMFs) was previously shown to accentuate in vitro myogenesis and mitochondriogenesis by activating a calcium-mitochondrial axis upstream of PGC-1α transcriptional upregulation, recapitulating a genetic response implicated in exercise-induced metabolic adaptations. We compared the effects of analogous PEMF exposure (1.5 mT, 10 min/week), with and without exercise, on systemic metabolism and gut microbiome in four groups of mice: (a) no intervention; (b) PEMF treatment; (c) exercise; (d) exercise and PEMF treatment. The combination of PEMFs and exercise for 6 weeks enhanced running performance and upregulated muscular and adipose Pgc-1α transcript levels, whereas exercise alone was incapable of elevating Pgc-1α levels. The gut microbiome Firmicutes/Bacteroidetes ratio decreased with exercise and PEMF exposure, alone or in combination, which has been associated in published studies with an increase in lean body mass. After 2 months, brief PEMF treatment alone increased Pgc-1α and mitohormetic gene expression and after >4 months PEMF treatment alone enhanced oxidative muscle expression, fatty acid oxidation, and reduced insulin levels. Hence, short-term PEMF treatment was sufficient to instigate PGC-1α-associated transcriptional cascades governing systemic mitohormetic adaptations, whereas longer-term PEMF treatment was capable of inducing related metabolic adaptations independently of exercise.

Marketing a health Brand on Facebook: Effects of reaction icons and user comments on brand attitude, trust, purchase intention, and eWOM intention.

This study examined effects of Facebook reaction icons and user comments on brand attitude, trust, information seeking, purchase intention, and eWOM intention towards a health brand, as well as potential moderating effects of SNS use. Results of a 3 (reaction icons: positive/neutral/negative) × 3 (valence of comments: positive/neutral/negative) between-subjects experiment (N = 306) indicated that positive Facebook reaction icons significantly influenced brand attitude, trust, purchase intention, and eWOM intention, while neutral comments significantly impacted brand attitude and trust. The degree of SNS use also negatively moderated between reaction icon valence and eWOM intention. Implications for health marketing communication are discussed.

Endoscopic submucosal dissection of colonic lesions: first 50 cases at a local institution.

INTRODUCTION: Endoscopic submucosal dissection (ESD) in the colon and rectum has been developed with good reported outcomes. The main advantage of ESD is the ability to perform en bloc resection, which has implications for complete excision and pathological analysis. Locally, the use of ESD in colonic lesions has seen recent traction. Our study aimed to review the outcomes of the first 50 cases of endoscopic excision of advanced colonic lesions using ESD at our institution. METHODS: This was a retrospective study of all patients who underwent ESD at our institution from September 2010 to October 2016. Data collected included patient demographics, resection technique, conversion rate and morbidity. RESULTS: 51 patients underwent ESD during the study period. All patients were of American Society of Anesthesiologists (ASA) class 1-3. Their median age was 60.0 years and the majority (n = 36) were male. The mean procedure time was 80.9 minutes. 36 (76.6%) of cases underwent en bloc resection. 4 (7.8%) cases required conversion to surgery, mainly due to difficulty in raising the colonic lesions. 3 (5.9%) patients had malignancy as the final histology. 2 (4.3%) patients had recurrence during surveillance scope. No cases of early mortality were reported. CONCLUSION: Our results suggest that ESD for advanced colonic lesions can be safely performed. Expertise needs to be developed to achieve satisfactory en bloc resection rates.

Ambient and supplemental magnetic fields promote myogenesis via a TRPC1-mitochondrial axis: evidence of a magnetic mitohormetic mechanism.

We show that both supplemental and ambient magnetic fields modulate myogenesis. A lone 10 min exposure of myoblasts to 1.5 mT amplitude supplemental pulsed magnetic fields (PEMFs) accentuated in vitro myogenesis by stimulating transient receptor potential (TRP)-C1-mediated calcium entry and downstream nuclear factor of activated T cells (NFAT)-transcriptional and P300/CBP-associated factor (PCAF)-epigenetic cascades, whereas depriving myoblasts of ambient magnetic fields slowed myogenesis, reduced TRPC1 expression, and silenced NFAT-transcriptional and PCAF-epigenetic cascades. The expression levels of peroxisome proliferator-activated receptor γ coactivator 1α, the master regulator of mitochondriogenesis, was also enhanced by brief PEMF exposure. Accordingly, mitochondriogenesis and respiratory capacity were both enhanced with PEMF exposure, paralleling TRPC1 expression and pharmacological sensitivity. Clustered regularly interspaced short palindromic repeats-Cas9 knockdown of TRPC1 precluded proliferative and mitochondrial responses to supplemental PEMFs, whereas small interfering RNA gene silencing of TRPM7 did not, coinciding with data that magnetoreception did not coincide with the expression or function of other TRP channels. The aminoglycoside antibiotics antagonized and down-regulated TRPC1 expression and, when applied concomitantly with PEMF exposure, attenuated PEMF-stimulated calcium entry, mitochondrial respiration, proliferation, differentiation, and epigenetic directive in myoblasts, elucidating why the developmental potential of magnetic fields may have previously escaped detection. Mitochondrial-based survival adaptations were also activated upon PEMF stimulation. Magnetism thus deploys an authentic myogenic directive that relies on an interplay between mitochondria and TRPC1 to reach fruition.-Yap, J. L. Y., Tai, Y. K., Fröhlich, J., Fong, C. H. H., Yin, J. N., Foo, Z. L., Ramanan, S., Beyer, C., Toh, S. J., Casarosa, M., Bharathy, N., Kala, M. P., Egli, M., Taneja, R., Lee, C. N., Franco-Obregón, A. Ambient and supplemental magnetic fields promote myogenesis via a TRPC1-mitochondrial axis: evidence of a magnetic mitohormetic mechanism.

C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy.

Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.

The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy.

Mutations in C9orf72 leading to hexanucleotide expansions are the most common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A phenotype resembling ALS and FTD is seen in transgenic mice overexpressing the hexanucleotide expansions, but is absent in C9orf72-deficient mice. Thus, the exact function of C9orf72 in neurons and how loss of C9orf72 may contribute to neuronal dysfunction remains to be clearly defined. Here, we showed that primary hippocampal neurons cultured from c9orf72 knockout mice have reduced dendritic arborization and spine density. Quantitative proteomic analysis identified C9orf72 as a component of the macroautophagy/autophagy initiation complex composed of ULK1-RB1CC1-ATG13-ATG101. The association was mediated through the direct interaction with ATG13 via the isoform-specific carboxyl-terminal DENN and dDENN domain of C9orf72. Furthermore, c9orf72 knockout neurons showed reduced LC3-II puncta accompanied by reduced ULK1 levels, suggesting that loss of C9orf72 impairs basal autophagy. Conversely, wild-type neurons treated with a ULK1 kinase inhibitor showed a dose-dependent reduction of dendritic arborization and spine density. Furthermore, expression of the long isoform of human C9orf72 that interacts with the ULK1 complex, but not the short isoform, rescues autophagy and the dendritic arborization phenotypes of c9orf72 knockout neurons. Taken together, our data suggests that C9orf72 has a cell-autonomous role in neuronal and dendritic morphogenesis through promotion of ULK1-mediated autophagy.

Randomized Controlled Trial of Preoperative Topical Decolonization to Reduce Surgical Site Infection for Staphylococcus aureus Nasal Swab-Negative Mohs Micrographic Surgery Patients.

BACKGROUND: Surgical site infection (SSI) is mainly due to endogenous bacteria. Topical decolonization is a preoperative intervention currently advised for proven nasal carriers of Staphylococcus aureus (S. aureus). OBJECTIVE: The authors assessed whether topical decolonization could be of benefit for patients who are not nasal carriers of S. aureus. METHODS AND MATERIALS: The authors performed a randomized controlled trial of S. aureus nasal swab-negative patients. Five days before Mohs surgery topical decolonization with nasal mupirocin and chlorhexidine, body wash was started. The control group had no intervention. RESULTS: In the week after Mohs surgery, the infection rate in the intervention group was 2% (n = 661, 14) and that of the control group was 4% (n = 689, 29). CONCLUSION: Topical decolonization reduces SSI in nasal swab-negative Mohs surgery patients.