Zingiber officinale promotes autophagy and apoptosis in human oral cancer through the C/EBP homologous protein.

The rhizome of Zingiber officinale (Z. officinale), commonly known as ginger, has been characterized as a potential drug candidate due to its antitumor effects. However, the chemotherapeutic effect of ginger on human oral cancer remains poorly understood. In this study, we examined the effects of an ethanol extract of Z. officinale rhizomes (ZOE) on oral cancer and identified the components responsible for its pharmacological activity. ZOE exerts its inhibitory activity in oral cancer by inducing both autophagy and apoptosis simultaneously. Mechanistically, ZOE-induced autophagy and apoptosis in oral cancer are attributed to the reactive oxygen species (ROS)-mediated endoplasmic reticulum stress response. Additionally, we identified two active components of ZOE, 1-dehydro-6-gingerdione and 8-shogaol, which were sufficient to stimulate autophagy initiation and apoptosis induction by enhancing CHOP expression. These results suggest that ZOE and its two active components induce ROS generation, upregulate CHOP, initiate autophagy and apoptosis, and hold promising therapeutics against human oral cancer.

Antitumor activity of afatinib in EGFR T790M-negative human oral cancer therapeutically targets mTOR/Mcl-1 signaling axis.

PURPOSE: This study investigates the role and effectiveness of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in oral cancer, focusing on the clinical relevance of EGFR and myeloid cell leukemia-1 (Mcl-1) in head and neck cancers (HNCs). It aims to explore the molecular mechanism of afatinib, a TKI, in treating human oral cancer. METHODS: We conducted an in silico analysis using databases like The Cancer Genome Atlas, Gene Expression Omnibus, and Clinical Proteomic Tumor Analysis Consortium, along with immunohistochemistry staining, to study EGFR and Mcl-1 expression in HNCs. For investigating afatinib's anticancer properties, we performed various in vitro and in vivo analyses, including trypan blue exclusion assay, Western blotting, 4'-6-diamidino-2-phenylindole staining, flow cytometry, quantitative real-time PCR, Mitochondrial membrane potential assay, overexpression vector construction, transient transfection, and a tumor xenograft model. RESULTS: Higher expression levels of EGFR and Mcl-1 were observed in HNC patient tissues compared to normal tissues, with their co-expression significantly linked to poor prognosis. There was a strong correlation between EGFR and Mcl-1 expressions in oral cancer patients. Afatinib treatment induced apoptosis and suppressed Mcl-1 in oral cancer cell lines without the EGFR T790M mutation. The mechanism of afatinib-induced apoptosis involved the EGFR/mTOR/Mcl-1 axis, as shown by the effects of mTOR activator MHY1485 and inhibitor rapamycin. Afatinib also increased Bim expression, mitochondrial membrane permeabilization, and cytochrome c release. It significantly lowered tumor volume without affecting body, liver, and kidney weights. CONCLUSION: Afatinib, targeting the EGFR/mTOR/Mcl-1 axis, shows promise as a therapeutic strategy for oral cancer, especially in patients with high EGFR and Mcl-1 expressions.

Evaluating the Surgical Outcome of Lymphovenous Anastomosis in Breast Cancer-Related Lymphedema Using Tc-99m Phytate Lymphoscintigraphy: Preliminary Results.

Background: Breast cancer-related lymphedema (BCRL) remains a significant postcancer treatment challenge with no definitive cure. Recent supermicrosurgical treatments, such as lymphovenous anastomosis (LVA), have shown promise but lack established objective indicators for outcome evaluation. We investigated the utility of Technetium-99m (Tc-99m) lymphoscintigraphy, an imaging technique providing objective information on lymphatic fluid flow, for assessing LVA surgical outcomes. Methods and Results: A retrospective cohort analysis of patients undergoing LVA for BCRL was conducted. Lymphoscintigraphy images pre- and 1-year postsurgery were compared to determine changes in lymphatic fluid flow of 18 patients based on newly defined parameters "uptake ratio" and "washout rates." Statistically significant reduction in the uptake ratio was observed in the forearm at 30 and 60 minutes postinjection phases. In addition, the forearm showed higher washout rate, indicating an improved lymphatic function in the forearm. Conclusion: Tc-99m lymphoscintigraphy can provide valuable objective data for evaluating LVA surgical outcomes in BCRL patients. However, site-specific differences in outcomes highlight the need for individualized surgical planning. Further large-scale studies are necessary to validate these preliminary findings and develop a standardized approach for LVA assessment.

Effects of Korean red ginseng on T-cell repopulation after autologous hematopoietic stem cell transplantation in childhood cancer patients.

Background: Although the survival outcomes of childhood cancer patients have improved, childhood cancer survivors suffer from various degrees of immune dysfunction or delayed immune reconstitution. This study aimed to investigate the effect of Korean Red Ginseng (KRG) on T cell recovery in childhood cancer patients who underwent autologous hematopoietic stem cell transplantation (ASCT) from the perspective of inflammatory and senescent phenotypes. Methods: This was a single-arm exploratory trial. The KRG group (n = 15) received KRG powder from month 1 to month 12 post-ASCT. We compared the results of the KRG group with those of the control group (n = 23). The proportions of T cell populations, senescent phenotypes, and cytokine production profiles were analyzed at 1, 3, 6, and 12 months post-ASCT using peripheral blood samples. Results: All patients in the KRG group completed the treatment without any safety issues and showed a comparable T cell repopulation pattern to that in the control group. In particular, KRG administration influenced the repopulation of CD4+ T cells via T cell expansion and differentiation into effector memory cell re-expressing CD45RA (EMRA) cells. Although the KRG group showed an increase in the number of CD4+ EMRA cells, the expression of senescent and exhausted markers in these cells decreased, and the capacity for senescence-related cytokine production in the senescent CD28- subset was ameliorated. Conclusions: These findings suggest that KRG promotes the repopulation of CD4+ EMRA T cells and regulates phenotypical and functional senescent changes after ASCT in pediatric patients with cancer.

CT texture features and lung shunt fraction measured using 99mTc-macroaggregated albumin SPECT/CT before trans-arterial radioembolization for hepatocellular carcinoma patients.

The aim of this study is to determine whether contrast-enhanced computed tomography (CECT)-based texture parameters can predict high (> 30 Gy) expected lung dose (ELD) calculated using 99mTc macroaggregated albumin single-photon emission computed tomography/computed tomography (SPECT/CT) for pre-trans-arterial radioembolization (TARE) dosimetry. 35 patients were analyzed, with a treatable planned dose of ≥ 200 Gy for unresectable hepatocellular carcinoma (HCC). Lung shunt fraction (LSF) was obtained from planar and SPECT/CT scans. Texture features of the tumor lesion on CECT before TARE were analyzed. Univariate and multivariate linear regression analyses were performed to determine potential ELD > 30 Gy predictors. Among the 35 patients, nine (25.7%) had ELD > 30 Gy, and had a higher LSF than the ELD ≤ 30 Gy group using the planar (20.7 ± 8.0% vs. 6.3 ± 3.3%; P < 0.001) and SPECT/CT (12.4 ± 5.1% vs. 3.5 ± 2.0%; P < 0.001) scans. The tumor integral total (HU × L) value was a predictor for high LSF using SPECT/CT, with an area under the curve, sensitivity, and specificity of 0.983 (95% confidence interval: 0.869-1.000, P < 0.001), 100%, and 88.5%, respectively. The tumor integral total value is an imaging marker for predicting ELD > 30 Gy. Applying CECT texture analysis may assist in reducing time and cost in patient selection and modifying TARE treatment plans.

Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

Detection of recurrence sites using 18F-fluorocholine PET/CT in prostate cancer patients with PSA failure.

Background: The optimal condition for the clinical application of 18F-fluorocholine positron emission tomography-computed tomography (FCH-PET/CT) to detect recurrence sites in prostate-specific antigen (PSA) failure remains unclear due to the heterogeneity of prostate cancer failure. We aimed to evaluate the detection rate of FCH-PET/CT in prostate cancer patients with PSA failure and to determine the optimal PSA level for performing FCH-PET/CT. Methods: FCH-PET/CT was conducted in 89 patients diagnosed with PSA failure after radical treatment (radical prostatectomy in 75 and definitive radiotherapy in 14) between November 2018 and May 2021. Detection rates were examined via receiver operating characteristic (ROC) analysis, and multivariable logistic regression was performed to identify factors affecting positive FCH-PET/CT findings. We also conducted subgroup analyses according to the PSA failure patterns after the radical treatment (persistently high PSA [N = 48] and biochemical recurrence [BCR] [N = 41]). Results: FCH-PET/CT demonstrated a 59.6% overall detection rate, and the optimal PSA threshold for detecting positive findings was ≥ 1.00 ng/mL at the time of imaging. On multivariable analysis, PSA > 1.00 ng/mL (P < 0.001) was a significant predictor of positive FCH-PET/CT findings, especially regarding distant bone metastases (P < 0.001) and recurrence outside the pelvis (P < 0.001). In a subgroup analysis of patients with BCR after initial radical treatment, the area under the ROC curve (AUC) was 0.82, and PSA ≥ 1.75 ng/mL was the optimal value for identifying positive FCH-PET/CT findings. This PSA value was also associated with significantly higher detection rates of distant bone metastases and outside-pelvis metastasis (P < 0.001, both). Conclusion: FCH-PET/CT is a clinically useful tool for detecting tumor recurrence sites in prostate cancer patients with PSA failure if PSA has exceeded a certain value at the time of imaging. Particularly, higher AUC values were observed when FCH-PET/CT was performed in patients with BCR after initial treatment.

Serial Quantitative Assessment of Load Redistribution After Medial Open-Wedge High Tibial Osteotomy.

Background: The maximum standardized uptake value (SUVmax), as determined on combined single-photon emission computed tomography and conventional computed tomography (SPECT/CT), can be an indicator of biomechanical changes due to the load redistribution effect after medial open-wedge high tibial osteotomy (MOW-HTO). Purpose/Hypothesis: The purposes of this study were to (1) analyze serial changes in the SUVmax in the medial, lateral, and patellofemoral compartments after MOW-HTO and (2) identify the contributing factors that affect changes in the SUVmax. The hypotheses were that (1) an elevated SUVmax in the medial compartment would be transferred to the lateral compartment because of the load redistribution effect and (2) there would be contributing factors that cause SUVmax changes. Study Design: Case series; Level of evidence, 4. Methods: Included were 67 knees that were treated with biplanar MOW-HTO between March 2019 and December 2020. SPECT/CT was performed immediately after surgery and at 3 months and 1 year postoperatively to determine the serial load redistribution effect of MOW-HTO. The Pearson correlation coefficient was used to evaluate the relationship between SUVmax and radiological parameters, and subgroup analyses were conducted to compare the SUVmax according to associated cartilage procedures and the weightbearing line ratio (WBLR). Results: The SUVmax in the medial and lateral compartments increased at 3 months but decreased at 1 year postoperatively. The load redistribution effect was most prominent in the anterior zones of the femur (medial: P = .041; lateral: P = .012). In the patella, the SUVmax decreased in both the medial and the lateral zones at all follow-up times (P < .001 for all). The SUVmax in the anterolateral and posterolateral articular zones of the femur increased with a greater preoperative WBLR (r = 0.256, P = .039; and r = 0.261, P = .036, respectively). Patients who underwent an associated cartilage procedure had a significantly higher SUVmax in the anteromedial and posteromedial articular zones of both the femur and the tibia at 1 year postoperatively (P ≤ .002 for all). Conclusion: After MOW-HTO, the unloading effect in the anteromedial articular zone of the femur was the most significant. A greater SUVmax in the lateral zones of the femur was observed in cases of overcorrection. The SUVmax in the medial zones was higher postoperatively in patients with associated cartilage procedures.

CT-free quantitative SPECT for automatic evaluation of %thyroid uptake based on deep-learning.

PURPOSE: Quantitative thyroid single-photon emission computed tomography/computed tomography (SPECT/CT) requires computed tomography (CT)-based attenuation correction and manual thyroid segmentation on CT for %thyroid uptake measurements. Here, we aimed to develop a deep-learning-based CT-free quantitative thyroid SPECT that can generate an attenuation map (µ-map) and automatically segment the thyroid. METHODS: Quantitative thyroid SPECT/CT data (n = 650) were retrospectively analyzed. Typical 3D U-Nets were used for the µ-map generation and automatic thyroid segmentation. Primary emission and scattering SPECTs were inputted to generate a µ-map, and the original µ-map from CT was labeled (268 and 30 for training and validation, respectively). The generated µ-map and primary emission SPECT were inputted for the automatic thyroid segmentation, and the manual thyroid segmentation was labeled (280 and 36 for training and validation, respectively). Other thyroid SPECT/CT (n = 36) and salivary SPECT/CT (n = 29) were employed for verification. RESULTS: The synthetic µ-map demonstrated a strong correlation (R2 = 0.972) and minimum error (mean square error = 0.936 × 10-4, %normalized mean absolute error = 0.999%) of attenuation coefficients when compared to the ground truth (n = 30). Compared to manual segmentation, the automatic thyroid segmentation was excellent with a Dice similarity coefficient of 0.767, minimal thyroid volume difference of - 0.72 mL, and a short 95% Hausdorff distance of 9.416 mm (n = 36). Additionally, %thyroid uptake by synthetic µ-map and automatic thyroid segmentation (CT-free SPECT) was similar to that by the original µ-map and manual thyroid segmentation (SPECT/CT) (3.772 ± 5.735% vs. 3.682 ± 5.516%, p = 0.1090) (n = 36). Furthermore, the synthetic µ-map generation and automatic thyroid segmentation were successfully performed in the salivary SPECT/CT using the deep-learning algorithms trained by thyroid SPECT/CT (n = 29). CONCLUSION: CT-free quantitative SPECT for automatic evaluation of %thyroid uptake can be realized by deep-learning.

BRAFV600E and TERT promoter C228T mutations on ThyroSeq v3 analysis of delayed skin metastasis from papillary thyroid cancer: a case report and literature review.

BACKGROUND: Skin metastasis from papillary thyroid cancer (PTC) is a rare entity that can occur up to decades after treatment of the primary tumor. Here, we present a patient who developed skin metastasis 10 years after treatment of her primary tumor and describe the molecular findings of the metastatic lesion. CASE PRESENTATION: A 44-year-old female with a history of PTC who underwent a total thyroidectomy and radioactive iodine (RAI) treatment 10 years ago presented with a 1.3-cm skin lesion along the prior thyroidectomy scar. A biopsy revealed metastatic PTC, and the patient underwent surgical excision of the lesion. ThyroSeq molecular testing showed the copresence of BRAFV600E mutation and TERT promoter C228T mutation. The patient subsequently received one round of adjuvant RAI therapy. CONCLUSIONS: A high index of suspicion is warranted in patients with a history of PTC who develop a skin lesion, even several years after remission of the primary disease. In patients with high-risk mutations, such as BRAFV600E and TERT promoter C228T mutations, long-term surveillance of disease recurrence is particularly important.

Targeting tumor-intrinsic PD-L1 suppresses the progression and aggressiveness of head and neck cancer by inhibiting GSK3ß-dependent Snail degradation.

PURPOSE: PD-L1 is an immune checkpoint protein that allows cells to evade T-cell-mediated immune responses. Herein, we uncover a tumor-intrinsic mechanism of PD-L1 that is responsible for the progression and aggressiveness of HNC and reveal that the extracts of a brown alga can target the tumor-intrinsic signaling pathway of PD-L1. METHODS: The biological functions of PD-L1 in the proliferation and aggressiveness of HNC cells in vitro were examined by metabolic activity, clonogenic, tumorigenicity, wound healing, migration, and invasion assays. The clinical importance of PD-L1 in the prognosis of patients with HNC was analyzed by immunohistochemistry. The relationship between PD-L1 and EMT was confirmed via western blotting, qPCR, and immunocytochemistry. RESULTS: Through our in silico approach, we found that PD-L1 was upregulated in HNC and was correlated with an unfavorable clinical outcome in patients with HNC. PD-L1 was crucial for promoting tumor growth, both in vitro and in vivo. High expression of PD-L1 was closely correlated with LN metastasis in OSCC. PD-L1 facilitated the cytoskeletal reorganization and aggressiveness of HNC cells. Moreover, PD-L1 enhanced the EMT of HNC cells by regulating the Snail/vimentin axis. Consistently, MEIO suppressed the PD-L1/Snail/vimentin axis, thereby inhibiting the aggressiveness of HNC cells. Inhibition of PD-L1 induced by PD-L1 silencing or MEIO treatment caused Snail degradation through a GSK3ß-dependent mechanism. The tumor-intrinsic function of PD-L1 could be attributed to the regulation of the GSK3ß/Snail/vimentin axis. CONCLUSION: The discovery of MEIO targeting the tumor-intrinsic function of PD-L1 may prove particularly valuable for the development of novel and effective anticancer drug candidates for HNCs overexpressing PD-L1.

Comparison of arthroscopic primary and revision Bankart repair for capsulolabral restoration: a matched-pair analysis.

INTRODUCTION: There have been no previous studies comparing serial radiologic results between primary and revision Bankart repair despite the significance of capsulolabral height and slope restoration. The purpose of this study was (1) to compare serially the height and slope of the repaired labrum in the early postoperative period among primary and revision Bankart repair groups, and (2) to compare clinical outcomes between the two groups. MATERIALS AND METHODS: This study included each 24 patients who underwent arthroscopic primary Bankart repair (Group A) and revision Bankart repair (Group B) matched by age, sex, and glenoid defect ratio. Postoperative serial radiologic assessment of the repaired labral height and slope was proceeded using magnetic resonance imaging (MRI) or computed tomographic arthrography (CTA) at 3 weeks and 6 months. RESULTS: There were no significant differences in labral height and slope at 3 weeks and 6 months postoperatively in Group A. However, significant reductions in labral height and slope were evident between 3 weeks and 6 months postoperatively in Group B (P < 0.05). Group A yielded superior results to Group B with respect to labral height and slope at each time point (P < 0.05) in between-group analyses. The clinical outcomes were not significantly different between the two groups except for the patients' return to their premorbid sports activity level (P = 0.024). CONCLUSIONS: The height and slope of the repaired capsulolabral structures in the early postoperative period after arthroscopic revision Bankart repair group were significantly lower than those of the primary Bankart repair group. Also the reduction of labral height and slope was significant in the revision Bankart repair group over time. Nonetheless, clinical outcomes did not differ significantly except return to premorbid sports activity level at final follow-up.

Diagnostic accuracy of F-18-Fluorocholine PET/CT and multiparametric MRI for prostate cancer.

Background: Positron emission tomography (PET) using different positron-emitting radiopharmaceuticals has emerged as a promising new metabolic diagnostic tool for the evaluation of a variety of malignant diseases. Thus, we investigated the diagnostic efficacy of F-18-Fluorocholine positron emission tomography/computed tomography (PET/CT) and multiparametric magnetic resonance imaging (mpMRI) for the detection and localization of tumors within the prostate with the correlating histopathology as the standard of reference. Methods: Forty patients with histologically proven prostate cancer underwent both F-18-Fluorocholine PET/CT and mpMRI before robot-assisted laparoscopic radical prostatectomy (RARP). The maximum standard uptake values and the tumor-to-background ratio were measured on a sextant basis. In brief, the sextants were defined as right apex, right middle, right base, left apex, left middle, and left base. For each tumor region, the correlation of the tumor localization based on the sextant in both F-18-Fluorocholine PET/CT and mpMRI scans with the histopathological results was determined. Results: The correlation between both imaging modalities and RARP pathology representing (1) all cancer and (2) clinically significant cancer defined as a ≥ International Society of Urological Pathology grade of 2 showed that the sensitivity and the area under the curve (AUC) were higher for mpMRI than for F-18-Fluorocholine PET/CT. In contrast, F-18-Fluorocholine PET/CT had relatively higher specificity than mpMRI. Importantly, we found a very high AUC value of over 0.8 in both imaging modalities. Conclusion: mpMRI had results superior to F-18-Fluorocholine PET/CT in assessing intraprostatic tumor localization. However, F-18-Fluorocholine PET/CT showed superiority in terms of specificity. Thus, using both modalities in conjunction could provide better treatment planning.

Cytoplasmic zinc promotes IL-1ß production by monocytes and macrophages through mTORC1-induced glycolysis in rheumatoid arthritis.

The essential micronutrient zinc regulates immune responses by affecting signaling pathways. In activated monocytes and macrophages, signaling networks mediate the metabolic reprogramming that meets the demands of participation in immune responses. Here, we demonstrated that cytoplasmic, bioavailable zinc was essential for promoting IL-1ß production in activated human monocytes and macrophages downstream of glycolysis induced by the kinase-containing multiprotein complex mTORC1. The concentration of cytoplasmic zinc was determined by that of extracellular zinc, which was brought into cells through the zinc-specific importer Zip8. The abundance of Zip8 was increased in monocytes from patients with rheumatoid arthritis (RA), as well as in LPS-stimulated monocytes and macrophages from healthy individuals. The mTORC1-mediated phosphorylation of S6 kinase (S6K) was enhanced by zinc-mediated inhibition of PP2A, a phosphatase that targets S6K. As a result, IL-1ß production was increased due to the activation of mTORC1-induced glycolysis. In monocytes of patients with RA, the expression of Zip8 and the zinc-inducible metallothionein isoform MT2A and the phosphorylation of S6K were enhanced compared with those of healthy controls. Furthermore, Zip8 expression correlated with more severe RA clinical parameters, suggesting that Zip8-mediated zinc influx is related to inflammatory conditions. These results provide insight into the role of cytoplasmic, bioavailable zinc in the metabolic reprogramming of human monocytes and macrophages in inflammatory responses.

Usefulness of Bone SPECT/CT for Predicting Avascular Necrosis of the Femoral Head in Children with Slipped Capital Femoral Epiphysis or Femoral Neck Fracture.

OBJECTIVE: This study aimed to investigate the usefulness of bone single-positron emission tomography/computed tomography (SPECT/CT) of the hip in predicting the later occurrence of avascular necrosis (AVN) after slipped capital femoral epiphysis (SCFE) or femoral neck fracture in pediatric patients. The quantitative parameters of SPECT/CT useful in predicting AVN were identified. MATERIALS AND METHODS: Twenty-one (male:female, 10:11) consecutive patients aged < 18 years (mean age ± standard deviation [SD], 11.0 ± 2.7 years) who underwent surgery for SCFE or femoral neck fracture and postoperative bone SPECT/CT were included. The maximum standardized uptake value (SUV), mean SUV, and minimum SUV of the femoral head were measured. The ratios of the maximum SUV, mean SUV, and minimum SUV of the affected femoral head to the contralateral side were determined. Patients were followed up for > 1 year after the surgery. The SPECT/CT parameters were compared between patients who developed AVN and those who did not. The accuracy of SPECT/CT parameters for predicting AVN was assessed. RESULTS: Six patients developed AVN. There was a significant difference in the ratio of the mean SUV among patients who developed AVN (mean ± SD, 0.8 ± 0.3) and those who did not (1.1 ± 0.2, p = 0.018). However, there were no significant differences in the ratios of the maximum and minimum SUV between the groups (all p = 0.205). For the maximum, mean, and minimum SUVs, no significant differences were observed between the groups (p = 0.519, 0.733, and 0.470, respectively). The cutoff mean SUV ratio of 0.87 yielded a 66.7% sensitivity and 93.2% specificity for predicting AVN. CONCLUSION: Quantitative bone SPECT/CT is useful for evaluating femoral head viability in pediatric patients with SCFE or femoral neck fractures. Clinicians should consider the high possibility of later AVN development in patients with a decreased mean SUV ratio.

Induction of Unique STAT Heterodimers by IL-21 Provokes IL-1RI Expression on CD8+ T Cells, Resulting in Enhanced IL-1ß Dependent Effector Function.

IL-1ß plays critical roles in the priming and effector phases of immune responses such as the differentiation, commitment, and memory formation of T cells. In this context, several reports have suggested that the IL-1ß signal is crucial for CTL-mediated immune responses to viral infections and tumors. However, little is known regarding whether IL-1ß acts directly on CD8+ T cells and what the molecular mechanisms underlying expression of IL-1 receptors (IL-1Rs) on CD8+ T cells and features of IL-1R+CD8+ T cells are. Here, we provide evidence that the expression of IL-1R type I (IL-1RI), the functional receptor of IL-1ß, is preferentially induced by IL-21 on TCR-stimulated CD8+ T cells. Further, IL-1ß enhances the effector function of CD8+ T cells expressing IL-21-induced IL-1RI by increasing cytokine production and release of cytotoxic granules containing granzyme B. The IL-21-IL-1RI-IL-1ß axis is involved in an augmented effector function through regulation of transcription factors BATF, Blimp-1, and IRF4. Moreover, this axis confers a unique effector function to CD8+ T cells compared to conventional type 1 cytotoxic T cells differentiated with IL-12. Chemical inhibitor and immunoprecipitation assay demonstrated that IL-21 induces a unique pattern of STAT activation with the formation of both STAT1:STAT3 and STAT3:STAT5 heterodimers, which are critical for the induction of IL-1RI on TCR-stimulated CD8+ T cells. Taken together, we propose that induction of a novel subset of IL-1RI-expressing CD8+ T cells by IL-21 may be beneficial to the protective immune response against viral infections and is therefore important to consider for vaccine design.

Association between Thyroid Function and Heart Rate Monitored by Wearable Devices in Patients with Hypothyroidism.

BACKGROUND: Heart rate (HR) monitored by a wearable device (WD) has demonstrated its clinical feasibility for thyrotoxicosis subjects. However, the association of HR monitored by wearables with hypothyroidism has not been examined. We assessed the association between serum thyroid hormone concentration and three WD-HR parameters in hypothyroid subjects. METHODS: Forty-four subjects scheduled for radioactive iodine therapy (RAI Tx) after thyroid cancer surgery were included. Thirty subjects were prepared for RAI Tx by thyroid hormone withdrawal (hypothyroidism group) and 14 subjects by recombinant human thyrotropin (control group). Three WD-HR parameters were calculated from the HR data collected during rest, during sleep, and from 2:00 AM to 6:00 AM, respectively. We analyzed the changes in conventionally measured resting HR (On-site rHR) and WDHR parameters relative to thyroid hormone levels. RESULTS: Serum free thyroxine (T4) levels, On-site rHR, and WD-HR parameters were lower in the hypothyroid group than in the control group at the time of RAI Tx. WD-HR parameters also reflected minute changes in free T4 levels. A decrease in On-site rHR and WD-HR parameters by one standard deviation (On-site rHR, approximately 12 bpm; WD-HR parameters, approximately 8 bpm) was associated with a 0.2 ng/dL decrease in free T4 levels (P<0.01) and a 2-fold increase of the odds ratio of hypothyroidism (P<0.01). WD-HR parameters displayed a better goodness-of-fit measure (lower quasi-information criterion value) than On-site rHR in predicting the hypothyroidism. CONCLUSION: This study identified WD-HR parameters as informative and easy-to-measure biomarkers to predict hypothyroidism.

Zap70 Regulates TCR-Mediated Zip6 Activation at the Immunological Synapse.

The essential microelement zinc plays immunoregulatory roles via its ability to influence signaling pathways. Zinc deficiency impairs overall immune function and resultantly increases susceptibility to infection. Thus, zinc is considered as an immune-boosting supplement for populations with hypozincemia at high-risk for infection. Besides its role as a structural cofactor of many proteins, zinc also acts as an intracellular messenger in immune cell signaling. T-cell activation instructs zinc influx from extracellular and subcellular sources through the Zip6 and Zip8 zinc transporters, respectively. Increased cytoplasmic zinc participates in the regulation of T-cell responses by modifying activation signaling. However, the mechanism underlying the activation-dependent movement of zinc ions by Zip transporters in T cells remains elusive. Here, we demonstrate that Zip6, one of the most abundantly expressed Zip transporters in T cells, is mainly localized to lipid rafts in human T cells and is recruited into the immunological synapse in response to TCR stimulation. This was demonstrated through confocal imaging of the interaction between CD4+ T cells and antigen-presenting cells. Further, immunoprecipitation assays show that TCR triggering induces tyrosine phosphorylation of Zip6, which has at least three putative tyrosine motifs in its long cytoplasmic region, and this phosphorylation is coupled with its physical interaction with Zap70. Silencing Zip6 reduces zinc influx from extracellular sources and suppresses T-cell responses, suggesting an interaction between Zip6-mediated zinc influx and TCR activation. These results provide new insights into the mechanism through which Zip6-mediated zinc influx occurs in a TCR activation-dependent manner in human CD4+ T cells.

Quantitative salivary gland SPECT/CT using deep convolutional neural networks.

Quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) using Tc-99m pertechnetate aids in evaluating salivary gland function. However, gland segmentation and quantitation of gland uptake is challenging. We develop a salivary gland SPECT/CT with automated segmentation using a deep convolutional neural network (CNN). The protocol comprises SPECT/CT at 20 min, sialagogue stimulation, and SPECT at 40 min post-injection of Tc-99m pertechnetate (555 MBq). The 40-min SPECT was reconstructed using the 20-min CT after misregistration correction. Manual salivary gland segmentation for %injected dose (%ID) by human experts proved highly reproducible, but took 15 min per scan. An automatic salivary segmentation method was developed using a modified 3D U-Net for end-to-end learning from the human experts (n = 333). The automatic segmentation performed comparably with human experts in voxel-wise comparison (mean Dice similarity coefficient of 0.81 for parotid and 0.79 for submandibular, respectively) and gland %ID correlation (R2 = 0.93 parotid, R2 = 0.95 submandibular) with an operating time less than 1 min. The algorithm generated results that were comparable to the reference data. In conclusion, with the aid of a CNN, we developed a quantitative salivary gland SPECT/CT protocol feasible for clinical applications. The method saves analysis time and manual effort while reducing patients' radiation exposure.