Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy.

Purpose: This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy. Materials and Methods: We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data. Results: Among 208 consecutively enrolled patients, we selected 84 (41 males; median age 59, range 35 to 90) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, 7 mutations in 5 patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival. Conclusion: While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer's clonal evolution. Additionally, baseline-ctDNA's VAF values were prognostic after treatment.

Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusions: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD. Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Minimal impact of beam projection angle deviations in skyline (Laurin) view and the efficacy of the anterior border of proximal tibia as a guiding landmark.

OBJECTIVE: Obtaining an optimal knee skyline view is challenging due to inaccuracies in beam projection angles (BPAs) and soft tissue obscuring bony landmarks. This study aimed to assess the impact of BPA deviations on patellofemoral index measurements and assessed the anterior border of the proximal tibia as an anatomic landmark for guiding BPAs. MATERIALS AND METHODS: This retrospective study consisted of three parts. The first was a simulation study using 52 CT scans of knees with a 20° flexion contracture to replicate the skyline (Laurin) view. Digitally reconstructed radiographs simulated neutral, 5° downward, and 5° upward tilt BPAs. Five patellofemoral indices (sulcus angle, congruence angle, patellar tilt angle, lateral facet angle, and bisect ratio) were measured and compared. The second part was a proof of concept study on 162 knees to examine patellar indices differences across these BPAs. Lastly, the alignment of the anterior border of the proximal tibia with the BPA tangential to the patellar articular surface was tested from the CT scans. RESULTS: No significant differences in patellofemoral indices were found across various BPAs in both the simulation and proof of concept studies (all p > 0.05). The angle between the anterior border of the proximal tibia and the patellar articular surface was 1.5 ± 5.3°, a statistically significant (p = 0.037) yet clinically acceptable deviation. CONCLUSION: Patellofemoral indices in skyline view remained consistent regardless of BPA deviations. The anterior border of the proximal tibia proved to be an effective landmark for accurate beam projection.

Synthesis of the C13-C27 Fragment of Madeirolide A Using Visible-Light-Promoted Radical Cyclization.

The convergent synthesis of a fully elaborated C13-C27 fragment of madeirolide A has been achieved. The key features of the synthesis include the stereocontrolled construction of both the THF and THP rings via visible-light-induced iridium-catalyzed radical cyclization and the late-stage union of the two oxacyclic subunits through nickel-catalyzed decarboxylative cross-coupling.

Incidence and Clinical Characteristics of Slipped Capital Femoral Epiphysis in Patients with Endocrinopathy: A Population-Based Cohort Study.

BACKGROUND: Endocrinopathy is a risk factor for slipped capital femoral epiphysis (SCFE). We aimed to determine (1) the incidence of endocrinopathy-associated SCFE compared with that of non-endocrinopathy-associated SCFE, (2) whether the incidence of SCFE increases with the number of deficient hormones, and (3) the clinical characteristics of endocrinopathy-associated SCFE. METHODS: We conducted a population-based cohort study using a nationwide database in South Korea. All new diagnoses of endocrinopathy or SCFE between 2002 and 2019 in children born between 2002 and 2005 were identified. The incidence of SCFE was calculated for each type of endocrinopathy. The trend of the incidence of SCFE relative to the number of deficient hormones was analyzed. The male:female ratio was compared between endocrinopathy-associated SCFE and non-endocrinopathy-associated SCFE. For endocrinopathy-associated SCFE, the time between the diagnoses of SCFE and endocrinopathy was evaluated. RESULTS: The incidence of SCFE was higher in children with endocrinopathy than in those without endocrinopathy (37.1/100,000 versus 9.0/100,000 children) (relative risk, 4.1 [95% confidence interval, 2.8-6.1]). Among various endocrinopathies, growth hormone deficiency showed the highest incidence of SCFE (583.8/100,000 children). The Cochran-Armitage test showed a linear trend, with an increased number of deficient hormones being associated with a higher incidence of SCFE (p < 0.001). Male sex was dominant in the non-endocrinopathy-associated SCFE group (73%; 117 of 161), whereas female sex was dominant in the endocrinopathy-associated SCFE group (53%; 16 of 30) (p = 0.009). Twenty-two of the 30 cases of endocrinopathy-associated SCFE were diagnosed after the diagnosis of endocrinopathy, with a median time of 3.6 years between the diagnoses. Six (27%) of these 22 children developed SCFE >5 years after the diagnosis of endocrinopathy. CONCLUSIONS: The incidence of SCFE was approximately 4 times higher in children with endocrinopathy than in those without endocrinopathy. The risk of SCFE increased with an increased number of deficient hormones. Long-term monitoring of SCFE occurrence in children with endocrinopathies is strongly recommended. LEVEL OF EVIDENCE: Diagnostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Concurrent self-assembly of RGB microLEDs for next-generation displays.

MicroLED displays have been in the spotlight as the next-generation displays owing to their various advantages, including long lifetime and high brightness compared with organic light-emitting diode (OLED) displays. As a result, microLED technology1,2 is being commercialized for large-screen displays such as digital signage and active R&D programmes are being carried out for other applications, such as augmented reality3, flexible displays4 and biological imaging5. However, substantial obstacles in transfer technology, namely, high throughput, high yield and production scalability up to Generation 10+ (2,940 × 3,370 mm2) glass sizes, need to be overcome so that microLEDs can enter mainstream product markets and compete with liquid-crystal displays and OLED displays. Here we present a new transfer method based on fluidic self-assembly (FSA) technology, named magnetic-force-assisted dielectrophoretic self-assembly technology (MDSAT), which combines magnetic and dielectrophoresis (DEP) forces to achieve a simultaneous red, green and blue (RGB) LED transfer yield of 99.99% within 15 min. By embedding nickel, a ferromagnetic material, in the microLEDs, their movements were controlled by using magnets, and by applying localized DEP force centred around the receptor holes, these microLEDs were effectively captured and assembled in the receptor site. Furthermore, concurrent assembly of RGB LEDs were demonstrated through shape matching between microLEDs and receptors. Finally, a light-emitting panel was fabricated, showing damage-free transfer characteristics and uniform RGB electroluminescence emission, demonstrating our MDSAT method to be an excellent transfer technology candidate for high-volume production of mainstream commercial products.

Immune response to the mRNA COVID-19 vaccine in hemodialysis patients: cohort study.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: A transcriptomic analysis of the immune response to the Covid-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells (PBMCs) was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and seven days after the second dose (V2D7) using anti-Spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified six months after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with predominant T cell activity in controls one week after the first vaccination dose, compared to predominant myeloid cell activity in HD at this time point. HD demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p < 0.05). Anti-spike IgG remained elevated above baseline at six months in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusion: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance hemodialysis subjects (HD) comparable to healthy controls (HC) and identify transcriptomic and clinical predictors of anti-Spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of end stage renal disease (ESRD). Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Oleic acid from cancer-associated fibroblast promotes cancer cell stemness by stearoyl-CoA desaturase under glucose-deficient condition.

BACKGROUND: Cancer-associated fibroblasts (CAFs) coordinate the malignancy of cancer cells via secretory materials. Reprogrammed lipid metabolism and signaling play critical roles in cancer biology. Oleic acid (OA) serves as a source of energy under glucose-deficient conditions, but its function in cancer progression remains unclear. The present study investigated that CAFs in xenografted tumors had higher amounts of fatty acids, particularly OA, compared to normal fibroblasts, and promoted the cancer cell stemness in lung adenocarcinoma cells under glucose-deficient condition. METHODS: Xenografts were established in immunodeficient mice by injection of NCI-H460 (H460) cells. Lipids and fatty acids were evaluated using the BODIPY staining and fatty-acid methyl esters analysis. The expression levels of markers for lipid metabolism and cancer stemness were determined by western blot, flow cytometry, and real-time PCR. Cancer cell subclones against stearoyl-CoA desaturase (SCD) were produced by lentiviral vector and CRISPR/cas9 systems. The expression of SCD was examined immunochemically in human adenocarcinoma tissues, and its clinical relevance to survival rate in lung adenocarcinoma patients was assessed by Kaplan-Meier analysis. RESULTS: Transferred CAF-derived OA through lipid transporter upregulated SCD in cancer cells under glucose-deficient conditions, resulting in enhanced lipid metabolism and autophagosome maturation. By OA treatment under glucose deficient condition, cancer cell stemness was significantly enhanced through sequential activation of SCD, F-actin polymerization and nuclear translocation of yes-associated protein. These findings were confirmed by experiments using chemical inhibitors, SCD-overexpressing cells and SCD-knockout (KO) cells. When xenografted, SCD-overexpressing cells produced larger tumors compared with parental cells, while SCD-KO cells generated much smaller tumors. Analysis of tumor tissue microarray from lung adenocarcinoma patients revealed that SCD expression was the marker for poor prognosis involving tumor grade, clinical stage and survival rate. CONCLUSION: Our data indicate that CAFs-derived OA activated lipid metabolism in lung adenocarcinoma cells under glucose-deficient conditions, subsequently enhancing stemness and progression toward malignancy.

Serum uromodulin in dogs with chronic kidney disease.

BACKGROUND: Serum uromodulin concentration has been described as a novel biomarker of chronic kidney disease (CKD) in humans but not dogs. OBJECTIVE: To evaluate the serum uromodulin concentration in dogs with CKD and assess its diagnostic performance in distinguishing dogs with CKD from healthy dogs. ANIMALS: Forty-nine dogs with CKD (International Renal Interest Society [IRIS] Stage 1, n = 23; Stage 2, n = 20; Stage 3-4, n = 6) and 25 healthy controls. METHODS: Prospective, observational study. Serum uromodulin concentration was measured using a canine-specific enzyme-linked immunosorbent assay (ELISA), and its correlation with conventional renal markers was analyzed. RESULTS: Serum uromodulin concentrations were significantly lower in the CKD group than in the control group (P < .001), but no significant difference was observed among stages of CKD. A negative correlation was observed between serum uromodulin concentration and conventional renal markers (blood urea nitrogen concentration, r = -.60, P < .0001; serum creatinine concentration, r = -.46, P < .0001; serum symmetric dimethylarginine concentration [SDMA], r = -.65, P < .0001). In receiver operating characteristic analysis, the area under the curve (AUC) of uromodulin (AUC, 0.97; 95% confidence interval [CI], 0.94-1.00) was higher than that of SDMA (AUC, 0.87; 95% CI, 0.79-0.95) for CKD diagnosis (P = .01). The AUC of uromodulin (AUC, 0.95; 95% CI, 0.89-1.00) also was higher than that of SDMA (AUC, 0.72; 95% CI, 0.58-0.87) in distinguishing dogs with Stage 1 CKD from controls (P = .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Serum uromodulin concentration is decreased in dogs with CKD. Thus, serum uromodulin may be a valuable diagnostic marker for CKD in dogs, particularly in identifying early-stage CKD.

A machine-learning model to predict postoperative delirium following knee arthroplasty using electronic health records.

BACKGROUND: Postoperative delirium is a challenging complication due to its adverse outcome such as long hospital stay. The aims of this study were: 1) to identify preoperative risk factors of postoperative delirium following knee arthroplasty, and 2) to develop a machine-learning prediction model. METHOD: A total of 3,980 patients from two hospitals were included in this study. The model was developed and trained with 1,931 patients from one hospital and externally validated with 2,049 patients from another hospital. Twenty preoperative variables were collected using electronic hospital records. Feature selection was conducted using the sequential feature selection (SFS). Extreme Gradient Boosting algorithm (XGBoost) model as a machine-learning classifier was applied to predict delirium. A tenfold-stratified area under the curve (AUC) served as the metric for variable selection and internal validation. RESULTS: The incidence rate of delirium was 4.9% (n = 196). The following seven key predictors of postoperative delirium were selected: age, serum albumin, number of hypnotics and sedatives drugs taken preoperatively, total number of drugs (any kinds of oral medication) taken preoperatively, neurologic disorders, depression, and fall-down risk (all p < 0.05). The predictive performance of our model was good for the developmental cohort (AUC: 0.80, 95% CI: 0.77-0.84). It was also good for the external validation cohort (AUC: 0.82, 95% CI: 0.80-0.83). Our model can be accessed at https://safetka.connecteve.com . CONCLUSIONS: A web-based predictive model for delirium after knee arthroplasty was developed using a machine-learning algorithm featuring seven preoperative variables. This model can be used only with information that can be obtained from pre-operative electronic hospital records. Thus, this model could be used to predict delirium before surgery and may assist physician's effort on delirium prevention.

Subungual Pigmented Squamous Cell Carcinoma in a Dog.

An 11-year-old spayed female Miniature Schnauzer dog was presented with loss of a claw caused by a nail bed mass. Histopathological evaluation revealed that the mass comprised neoplastic squamous cells with abundant cytoplasmic melanin pigment. Immunohistochemically, the neoplastic cells were positive for cytokeratin and negative for vimentin and ionized calcium-binding adaptor molecule 1, supporting a diagnosis of pigmented squamous cell carcinoma. To our knowledge, this is the first report of subungual pigmented squamous cell carcinoma in animals.

Calcifying aponeurotic fibroma on the paw in a dog.

A 12-year-old, spayed female, Maltese dog with a round and firm mass on the dorsal part of the left rear paw and a cervical mass was brought to the clinic. The paw mass was contiguous to the adjacent tendon; it was composed of neoplastic mesenchymal cells and had scattered foci of calcification with chondroid differentiation microscopically. The neoplastic cells were positive for vimentin and S100, but negative for desmin and smooth muscle actin. Microscopic features and immunohistochemistry results were consistent with calcifying aponeurotic fibroma (CAF). The cervical mass was composed of polygonal cells forming acini with marked anisocytosis and anisokaryosis and diagnosed as thyroid follicular carcinoma. No recurrence or metastasis occurred during follow-up. To the best of our knowledge, this is the first case of canine CAF with features identical to its human counterparts. Key clinical message: This report describes the rare case of calcifying aponeurotic fibroma on the paw in a dog. This is apparently the first case in the veterinary literature with identical clinical and pathological features to the human counterpart.

Fibrome aponévrotique calcifiant sur la patte chez un chien. Une chienne maltaise stérilisée âgée de 12 ans avec une masse ronde et ferme sur la partie dorsale de la patte arrière gauche et une masse cervicale a été amenée à la clinique. La masse de la patte était contiguë au tendon adjacent; il était composé de cellules mésenchymateuses néoplasiques et présentait des foyers de calcification dispersés avec une différenciation chondroïde au microscope. Les cellules néoplasiques étaient positives pour la vimentine et le S100, mais négatives pour la desmine et l'actine des muscles lisses. Les caractéristiques microscopiques et les résultats d'immunohistochimie étaient compatibles avec un fibrome aponévrotique calcifiant (CAF). La masse cervicale était composée de cellules polygonales formant des acini avec une anisocytose et une anisocaryose marquées et diagnostiquée comme un carcinome folliculaire de la thyroïde. Aucune récidive ou métastase n'est survenue au cours du suivi. À notre connaissance, il s'agit du premier cas de CAF canin avec des caractéristiques identiques à ses homologues humains.Message clinique clé :Ce rapport décrit le cas rare de fibrome aponévrotique calcifiant sur la patte chez un chien. C'est apparemment le premier cas dans la littérature vétérinaire avec des caractéristiques cliniques et pathologiques identiques à son homologue humain.(Traduit par Dr Serge Messier).

Temozolomide abrogates the aggressiveness of urothelial carcinoma cells by enhancing senescence and depleting the side population.

Patients with advanced urothelial carcinoma (UC) generally have poor prognoses due to therapeutic resistance. Furthermore, there are limited treatment options for advanced UC. Therefore, novel or effective chemotherapeutic agents are needed to improve patient survival. The present study was conducted to investigate the effect of temozolomide (TMZ) on UC cells so as to identify a potential method to overcome therapeutic resistance. TMZ is an alkylating agent with a target different from that of other anticancer drugs used to treat UC, such as cisplatin. TMZ enhanced the autophagic response and senescence, which was mediated via the p53 and p21 pathways. Inhibiting the autophagic response using chloroquine synergistically augmented the cytotoxic effect of TMZ on UC cells. TMZ significantly reduced the invasiveness of UC cells. Notably, the abundance of side population fraction was also significantly reduced following TMZ treatment. Considering that side population fraction is known to confer therapeutic resistance, it is noteworthy that the TMZ treatment markedly decreased side population fraction. Altogether, TMZ may have the potential to be applied as a part of an alternative treatment strategy to reduce the malignancy of UC cells.

Metamaterial-Integrated High-Gain Rectenna for RF Sensing and Energy Harvesting Applications.

This paper presents a metamaterial (MTM)-integrated high-gain rectenna for RF sensing and energy harvesting applications that operates at 2.45 GHz, an industry, science, medicine (ISM) band. The novel MTM superstrate approach with a three-layered integration method is firstly introduced for rectenna applications. The integrated rectenna consists of three layers, where the first layer is an MTM superstrate consisting of four-by-four MTM unit cell arrays, the second layer a patch antenna, and the third layer a rectifier circuit. By integrating the MTM superstrate on top of the patch antenna, the gain of the antenna is enhanced, owing to its beam focusing capability of the MTM superstrate. This induces the increase of the captured RF power at the rectifier input, resulting in high-output DC power and high entire end-to-end efficiency. A parametric analysis is performed in order to optimize the near-zero property of the MTM unit cell. In addition, the effects of the number of MTM unit cells on the performance of the integrated rectenna are studied. A prototype MTM-integrated rectenna, which is designed on an RO5880 substrate, is fabricated and characterized. The measured gain of the MTM-integrated rectenna is 11.87 dB. It shows a gain improvement of 6.12 dB compared to a counterpart patch antenna without an MTM superstrate and a maximum RF-DC conversion efficiency of 78.9% at an input RF power of 9 dBm. This results in the improvement of the RF-DC efficiency from 39.2% to 78.9% and the increase of the output DC power from 0.7 mW to 6.27 mW (a factor of 8.96 improvements). The demonstrated MTM-integrated rectenna has shown outstanding performance compared to other previously reported work. We emphasize that the demonstrated MTM-integrated rectenna has a low design complexity compared with other work, as the MTM superstrate layer is integrated on top of the simple patch antenna and rectifier circuit. In addition, the number of MTM units can be determined depending on applications. It is highly envisioned that the demonstrated MTM-integrated rectenna will provide new possibilities for practical energy harvesting applications with improved antenna gain and efficiency in various IoT environments.

Ovalicin attenuates atopic dermatitis symptoms by inhibiting IL-31 signaling and intracellular calcium influx.

Atopic dermatitis (AD) is a common skin disorder difficult to be treated with medication. This study investigated the potential of ovalicin extracted from Cordyceps militaris for the treatment of AD using in vitro and in vivo models. We found that, in canine macrophage cell line DH82, lipopolysaccharide (LPS) upregulated the expression of genes associated with inflammation and pruritic responses through activating calcium and interleukin-31 (IL-31) signaling, and the upregulation could be suppressed by ovalicin, with an effect significantly stronger than dexamethasone. Ovalicin also reduced the expression of IL-31 downstream genes, including JAK2 (Janus kinase 2), TRPV1 (transient receptor potential vanilloid receptor-1), and HRH2 (histamine receptor H2). Ovalicin significantly alleviated the allergic symptoms in the AD mouse model. Histologically, the number of macrophages and mast cells infiltrated in the dermis was significantly reduced by ovalicin treatment. In the skin tissue of AD mice, reduction of IL-31 receptor was observed in the ovalicin treated group compared to the group without ovalicin treatment. To our knowledge, this is the first study to elucidate the anti-atopic mechanism of ovalicin, which could be an alternative to steroidal drugs commonly used for AD treatment.

Heterogeneous response of cancer-associated fibroblasts to the glucose deprivation through mitochondrial calcium uniporter.

Cancer-associated fibroblasts (CAFs) are an abundant component of the tumor microenvironment and have distinct features from normal fibroblasts (NFs). However, the discriminative nature of heterogeneous CAFs under glucose starvation remains unknown. In this study, we investigated the changes in the mitochondrial calcium concentration and relevant intracellular machinery in CAFs under glucose-deficient conditions. Xenografted tumor masses were dissected into multiple pieces and subjected to the CAF isolation using magnetically activated cell sorting (MACS). NFs were separated from the normal lung and skin. Under glucose starvation, CAFs from the tumor mass exhibited heterogeneity in cell proliferation, ATP production and calcium concentration. Compared to NFs, mitochondrial calcium concentration was significantly higher in glucose-starved CAFs with upregulation of mitochondrial calcium uniporter (MCU) that led to enhancement of ATP production and cell growth. Intriguingly, treatment of glucose-starved CAFs with oligomycin increased apoptosis by disrupted calcium homeostasis following overactivation of the mPTP. Moreover, oligomycin-induced apoptosis was mitigated by calcium chelation. This study demonstrated that the discriminative calcium influx to mitochondria through MCU coordinated cell growth and apoptosis in glucose-starved CAFs but not in NFs.

Reduction in mitochondrial oxidative stress mediates hypoxia-induced resistance to cisplatin in human transitional cell carcinoma cells.

Tumor hypoxia is known to promote the acquisition of more aggressive phenotypes in human transitional cell carcinoma (TCC), including drug resistance. Accumulating evidence suggests that mitochondria play a central role in the chemoresistance of TCC. However, the role of mitochondria in the hypoxia-induced drug resistance in TCC remains elusive. The present study investigated the function of mitochondria in the drug resistance using a TCC cell line under hypoxic conditions. In vitro hypoxia (0.1% O2, 48 h) was achieved by incubating TCC cells in air chamber. Mitochondrial events involving hypoxia-induced drug resistance were assessed. Hypoxia significantly reduced the cisplatin-induced apoptosis of TCC cells. Additionally, hypoxia substantially decreased the level of mitochondrial reactive oxygen species (ROS) generated by cisplatin treatment. Analogously, elimination of mitochondrial ROS significantly rescued cells from cisplatin-induced apoptosis. Hypoxia enhanced mitochondrial hyperpolarization, which was not related to ATP production or the reversal of ATP synthase activity. The mitochondrial DNA (mtDNA) amplification efficiency data illustrated that hypoxia significantly prevented oxidative damage to the mitogenome. Moreover, transmission electron microscopy revealed that cisplatin-induced disruption of the mitochondrial ultrastructure was abated under hypoxic conditions. Notably, depletion of mtDNA by ethidium bromide abrogated hypoxia-induced resistance to cisplatin. Taken together, the present study demonstrated that TCC cells exposed to hypoxic conditions rendered mitochondria less sensitive to oxidative stress induced by cisplatin treatment, leading to enhanced drug resistance.

Thyroglobulin as a negative marker for malignancy in canine and human breast tumors.

Canine mammary gland tumors (CMTs) are the most common tumor type in female dogs. This study evaluated the expression pattern and role of thyroglobulin (Tg) in CMT and in human breast cancer (HBC). CMT samples were subjected to fine-needle aspiration, primary cell culture, and histopathology. The expression level of Tg was higher in benign CMT than in malignant CMT (mCMT) primary cells, particularly in the epithelial lineage. Moreover, treatment with Tg enhanced the sensitivity of doxorubicin in mCMT epithelial cells and mitigated proinflammatory response by increasing nuclear factor erythroid 2-related factor 2 (Nrf2). The proximal region of the Tg promoter was hypermethylated in mCMT epithelial cells, silencing Tg expression with concurrent downregulation of Nrf2-mediated antioxidant signaling. An identical pattern of Tg expression was observed in cytological and tissue samples. Tissue microarray analysis showed that Tg was highly expressed in normal and benign tissues when compared with their malignant counterparts, which was diminished along with higher histological grades. The survival rate was significantly higher in HBC patients with high Tg expression than those with low Tg expression. This study also showed that the progression of HBC is accompanied by the reduction of Tg expression along with augmentation of proinflammatory signaling. Our data suggested that Tg could be a negative indicator of malignancy in canine and human breast neoplasia.

Change in intersegmental foot and ankle motion after a high tibial osteotomy in genu varum patients.

High tibial osteotomy (HTO) is a well-established treatment for medial compartment knee osteoarthritis (OA), which shifts the weight-bearing axis from the medial to the lateral side of the knee. As the adjacent ankle joint may be directly affected by the change in biomechanics, this study aimed to evaluate the change in the intersegmental foot and ankle motion after HTO in patients with genu varum. The study included 24 patients who underwent HTO, and 48 older healthy participants as a control group. Segmental foot kinematics were evaluated using a 3D multisegment foot model, and gait data of temporal and spatial parameters were obtained. After HTO, normalized stride length significantly increased with a tendency for increases in gait speed. In hallux kinematics relative to the forefoot, the sagittal motions of both the patients and the control group were similar throughout the majority of the gait cycle. In forefoot kinematics relative to the hindfoot, the pre-HTO state revealed significant pronation throughout the gait cycle, while the post-HTO state showed a similar position and motion to the control group. In hindfoot kinematics relative to the tibia, coronal motions of the pre-HTO state showed supination throughout the gait cycle, while supination during the stance phase decreased after HTO. Genu varum patients with medial compartment knee OA showed different gait parameters and intersegmental motion during gait when compared with age- and gender-matched controls. The effect of HTO was demonstrated by the normalization of midfoot compensation in patients with genu varum.

Quantified Vascular Calcification at the Dialysis Access Site: Correlations with the Coronary Artery Calcium Score and Survival Analysis of Access and Cardiovascular Outcomes.

Vascular calcification is a major contributor to mortality in end-stage renal disease (ESRD) patients. In this study, we investigated whether there was a correlation between the coronary artery calcium score (CACS) and the vascular calcification score (VCS), and whether higher VCS increased the incidence of interventions and major adverse cardiac and cerebrovascular events (MACCE). ECG-gated CT, including vascular access and the coronary vessel, was taken. CACS and VCS were calculated by the Agatston method. A comparison of CACS and survival analysis according to VCS groups was performed. Using a cutoff of VCS = 500, 77 patients were divided into two groups. The vintage was significantly older in the higher VCS group. The median CACS was higher in the higher VCS group (21 [0, 171] vs. 552 [93, 2430], p < 0.001). The hazard ratio (HR) for interventions and MACCEs in the higher VCS group increased by 3.2 and 2.3, respectively. Additionally, a longer duration of hemodialysis and higher magnesium levels (>2.5 mg/dL) showed lower HRs for interventions (<1). We quantified VCS and found that it was associated with the CACS. Additionally, higher VCS increased the risk of access interventions and MACCE. VCS of the access site may be suggested as a biomarker to predict ESRD patients.