Pharmacopuncture Improves the Lipid Profile in Patients under Statins: Retrospective Study at a Korean Medicine Clinic.

Objective: To assess the efficacy of pharmacopuncture (PA) in improving lipid profiles of patients under statin therapy. Design and Setting: Single-center retrospective study. Interventions: Fifty-nine patients who were previously under statins were retrospectively analyzed. We injected 10 cc of PA twice or thrice a week for 12 to 16 weeks at the acupoint (CV5). The PA solution was based on aqueous extracts of various herbs: Taraxaci Herba, Artemisiae Annuae Herba, Elsholtziae Herba, Acanthopanacis Cortex, and Rumecis Radix. Main Outcome Measures: Lipid profiles, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels, were compared before and after PA treatment within patients. Results: The mean age was 59.03 ± 19.82 years, and 50.8% were women (n=30). TC and LDL-C levels decreased from 233.6 ± 54.6 mg/dL to 202.0 ± 26.4 mg/dL (P = 1.27×10-6) and from 175.1 ± 46.2 mg/dL to 133.1 ± 21.6 mg/dL (P = 1.37×10-10), respectively. Interestingly, HDL-C level increased from 30.4 ± 14.6 mg/dL to 43.1 ± 12.1 mg/dL (P = 4.39×10-10), where men demonstrated better improvement than women (P = 1.73×10-3). Conclusion: Our findings highlight the adjuvant effects of PA treatment on the lipid profile in patients under statins and the sex interaction in HDL-C improvement, which provides a clinical foundation for future clinical trials with personalized treatment strategies to establish the clinical benefits of PA treatment with statins.

Proliferative hepatocellular carcinomas in cirrhosis: patient outcomes of LI-RADS category 4/5 and category M.

OBJECTIVES: We aimed to compare Liver Imaging Reporting and Data System (LI-RADS) category 4/5 and category M (LR-M) of proliferative hepatocellular carcinomas (HCCs) in cirrhotic patients and evaluate their impacts on prognosis. METHODS: This retrospective multi-reader study included cirrhotic patients with single treatment-naïve HCC ≤ 5.0 cm who underwent contrast-enhanced CT, MRI, and subsequent hepatic resection within 2 months. The percentages of CT/MRI LR-4/5 and LR-M in proliferative and non-proliferative HCCs were compared. Univariable and multivariable Cox proportional hazards regression analyses were performed to assess the association of LI-RADS categories (LR-4/5 vs. LR-M) and pathologic classification (proliferative vs. non-proliferative) with overall survival (OS) and recurrence-free survival (RFS). Subgroups of patients with proliferative and non-proliferative HCCs were analyzed to compare OS and RFS between LR-4/5 and LR-M. RESULTS: Of the 204 included patients, 38 were classified as having proliferative HCC. The percentages of LR-M were higher in proliferative than non-proliferative HCC on both CT (15.8% vs. 3.0%, p = 0.007) and MRI (26.3% vs. 9.6%, p = 0.016). Independent of pathologic classification, CT and MRI LR-M were significantly associated with poorer OS (hazard ratio (HR) = 4.58, p = 0.013, and HR = 6.45, p < 0.001) and RFS (HR = 3.66, p = 0.005, and HR = 6.44, p < 0.001) than LR-4/5. MRI LR-M was associated with significantly poorer OS (p ≤ 0.003) and RFS (p < 0.001) than MRI LR-4/5 in both proliferative and non-proliferative HCCs. CONCLUSIONS: This multi-reader study showed that the percentages of LR-M were significantly higher in proliferative than non-proliferative HCCs. CT/MRI LR-M was significantly associated with poor OS and RFS, independent of the pathologic classification of proliferative versus non-proliferative HCCs. CLINICAL RELEVANCE STATEMENT: CT and MRI LI-RADS category M can be clinically useful in predicting poor outcomes in patients with proliferative and non-proliferative hepatocellular carcinomas. KEY POINTS: • The percentages of LR-M tumors on both CT and MRI were significantly higher in proliferative than non-proliferative hepatocellular carcinomas. • Independent of pathologic classification, CT/MRI LR-M categories were correlated with poor overall survival and recurrence-free survival. • Patients with both proliferative and non-proliferative hepatocellular carcinomas categorized as MRI LR-M had significantly poorer overall survival and recurrence-free survival than those categorized as MRI LR-4/5.

Antitumor effects of IL-12 and GM-CSF co-expressed in an engineered oncolytic HSV-1.

Oncolytic viruses selectively replicate and destroy cancer cells while sparing normal cells, prompting their recognition as promising antitumor agents. Herpes simplex virus (HSV) is suitable as an anticancer agent, given its considerable therapeutic gene capacity and excellent safety profile in clinical trials. Interleukin (IL)-12 induces a Th1-type immune response that mediates interferon (IFN)-γ release from natural killer (NK), CD4+ and CD8+ T cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the generation of antigen-presenting cells and promotes dendritic cell differentiation. We established a novel oncolytic HSV-1 (∆6/GM/IL12) co-expressing IL-12 and GM-CSF and tested its effects against a B16-F10 murine melanoma model. ∆6/GM/IL12 administration diminished tumor growth and prolonged survival compared to treatment with ∆6/GM or ∆6/IL12 expressing each individual cytokine. Flow cytometry and histological analysis showed increased activation of CD4+ and CD8+ T cells in ∆6/GM/IL12-treated mice. Enzyme-linked immunosorbent spot assay showed an increase in the phenotypically characterized IFN-γ-producing cell population in ∆6/GM/IL12-treated mice. Moreover, ∆6/GM/IL12 induced a B16-F10-specific cytotoxic immune response that enhanced IFN-γ production by CD3+CD8+ T cells. Therefore, IL-12 and GM-CSF from an engineered oncolytic HSV have a synergistic effect, boosting the immune response to increase their antitumor effects.

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor-induced interleukin 12 synthesis.

Src-kinase inhibitors hold great potential as targeted therapy against malignant cells. However, such inhibitors may also affect nonmalignant cells and cause pronounced off-target effects. We investigated the role of the dual kinase inhibitor dasatinib on human myeloid cells. Dasatinib is clinically used for the treatment of bcr/abl⁺ leukemias because it blocks the mutated tyrosine kinase abl. To understand its effect on the development of antigen-specific T-cell responses, we assessed antigen-specific priming of human, naïve T cells. In surprising contrast to the direct inhibition of T-cell activation by dasatinib, pretreatment of maturing dendritic cells (DCs) with dasatinib strongly enhanced their stimulatory activity. This effect strictly depended on the activating DC stimulus and led to enhanced interleukin 12 (IL-12) production and T-cell responses of higher functional avidity. Src-kinase inhibitors, and not conventional tyrosine kinase inhibitors, increased IL-12 production in several cell types of myeloid origin, such as monocytes and classical or nonclassical DCs. Interestingly, only human cells, but not mouse or macaques DCs, were affected. These data highlight the potential immunostimulatory capacity of a group of novel drugs, src-kinase inhibitors, thereby opening new opportunities for chemoimmunotherapy. These data also provide evidence for a regulatory role of src kinases in the activation of myeloid cells.

Proposed diagnostic and prognostic markers of primary malignant hepatic vascular neoplasms.

INTRODUCTION: Primary malignant hepatic vascular tumors with various malignant potentials include epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), which may overlap pathologically. This study aimed to compare the pathological findings of hepatic EHE with those of AS, in association with patient outcomes. METHODS: Fifty-nine histologically confirmed patients with 34 EHE and 25 AS were admitted to a tertiary hospital from 2003 to 2020. Their EHE and AS pathological features were compared. Immunohistochemistry for CD31, ERG, CAMTA-1, TFE3, P53, and Ki-67 labeling was performed on paraffin-embedded blocks. Markers, along with histological findings, were analyzed for the purposes of diagnostic and prognostic significance by multivariate analysis. RESULTS: CAMTA-1 was 91.2% positive in EHE, but negative in AS (p = < 0.001). AS was significantly correlated to an aberrant p53 expression, high Ki-67 labeling, and high mitotic activity, compared to EHE (all, p = < 0.001). EHE can be classified as low grade (LG) and high grade (HG) using the prognostic values of mitotic activity and ki-67 labeling (sensitivity = 1, specificity = 1). Low grade-EHE showed significantly better overall survival than high grade-EHE (p = 0.020). CONCLUSIONS: Immunohistochemistry for CAMTA-1, P53, and Ki-67 labeling may help distinguish EHE and AS in histologically ambiguous cases, especially small biopsied tissue. Moreover, the combination of mitotic activity and Ki-67 labeling can be a prognostic factor for EHE with various clinical features.

Prognostic value of isolated tumor cells and micrometastasis of lymph nodes in invasive urinary bladder cancer.

INTRODUCTION: The prognostic significance of nodal micrometastasis and isolated tumor cells (ITC) in urinary bladder cancer (UBC) is unknown. We aimed to evaluate the prevalence, clinical impact, and clinicopathological characteristics of nodal micrometastasis and ITC in UBC. MATERIALS AND METHODS: A total of 124 patients with UBC undergoing surgery were investigated. Detection of micrometastasis and ITC was performed using pancytokeratin immunohistochemistry (IHC). Histopathologic and clinical findings were correlated with patients' outcome. RESULT: IHC detected nodal micrometastasis and ITC (pNmi group) in 12.9% (13/101) of originally node-negative patients and in 26.1% (6/23) of originally node-positive patients (pN+ group). The remaining 88 were truly node-negative patients (pN0 group). After IHC, all 13 patients in the pNmi group were upstaged from pN0 to pN1-2 and one patient in the pN+ group was changed from pN1 to pN2. Nodal micrometastasis and ITC were significantly associated with mixed urothelial carcinoma (UC) (p = 0.002), UC with discohesive pattern (p = 0.006), glandular differentiation (p = 0.043), lymphovascular invasion (p = 0.009), and budding-like tumor cell clusters (p = 0.002). The pNmi group had significantly worse cancer-specific survival than the pN0 group in univariate (p = 0.004) and multivariate (p = 0.040) analysis. CONCLUSION: IHC frequently identified nodal micrometastasis and ITC in originally node-negative UBC patients on routine pathological examination. Nodal micrometastasis and ITC were independently associated with cancer-related mortality in UBC. IHC might be selectively used to detect micrometastasis and ITC in UBC having specific pathological features.

Comparison of clinical and MRI features of hepatic angiosarcoma and epithelioid hemangioendothelioma.

OBJECTIVE: Differentiating hepatic epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), the two most common vascular tumors in the liver, is important due to disparities in their prognosis and treatment. We aimed to compare clinical and MRI features of the two tumors. METHODS: This retrospective study included patients with pathologically-confirmed AS or EHE who underwent MRI using gadoxetate disodium between 2008 and 2023. Two radiologists independently reviewed MR images. Wilcoxon rank sum and Fisher's exact tests were used to compare clinical and imaging features. Overall survival was compared using restricted mean survival time at 3 years. RESULTS: 32 patients with AS (18 women [56.3%]; median age, 68 years) and 38 with EHE (24 women [63.2%]; 51 years) were included. Patients with AS were generally older (81.3% ≥ 60 years; P < 0.001), had more frequent laboratory abnormalities (P ≤ 0.018), and poorer overall survival (11.2 vs. 31.8 months; P < 0.001) than those with EHE. On MRI, a large dominant mass accompanied by smaller nodules (14/32, 43.8%), often with ill-defined margins (15/32, 46.9%) was prevalent in AS; compared with nodules of similar sizes (24/38, 63.2%; P = 0.015) with well-defined margin (30/38, 78.9%; P = 0.002) in EHE. Cirrhotic appearance of the liver was more frequent in AS (62.5%, P < 0.001), along with decreased parenchymal enhancement on hepatobiliary phase (31.3%, P < 0.001) and ascites (37.5%, P = 0.010). AS frequently presented with avid enhancement of bizarrely-shaped foci, with a centrifugal enhancement pattern. In comparison, targetoid appearance was characteristic of EHE (78.9% on T2-weighted, 54.1% on diffusion-weighted, 65.8% on multiphase images) (P ≤ 0.002), with enhancement degree typically lower than that of the aorta. On hepatobiliary phase, all the AS exhibited hypointensity, while 39.5% of EHE showed targetoid appearance (P < 0.001). CONCLUSION: Patients aged ≥ 60 years presenting with laboratory abnormalities, typically with a large dominant mass accompanied by smaller nodules, exhibiting avid, bizarre, and centrifugal enhancement-particularly in the cirrhotic-appearing liver-suggests the likelihood of AS over EHE.

Transmission-type photonic crystal structures for color filters.

A transmission-type structure based on woodpile photonic crystal layers is proposed for use in color filters. Selective bandpass filters for red, green, and blue wavelength bands are constructed using optimally designed multilayered woodpile photonic crystals. The R/G/B color filtering for a wide range of incidence angles of light is demonstrated numerically, and the operation principle and design method are described.

The Effect of Complete Prostate Examination of Radical Cystoprostatectomy Specimen on the Final Stage of Urothelial Carcinoma of the Urinary Bladder and the Detection of Prostate Cancer.

CONTEXT.­: The prostate sampling methods for radical cystoprostatectomy (RCP) specimens may affect pathologic results. OBJECTIVE.­: To investigate the impact on the tumor stage and clinicopathologic features according to the prostate sampling method for RCP specimens. DESIGN.­: From 2016 to 2017, the prostate in RCP was minimally and conventionally embedded (group 1, n = 98). From 2017 to 2018, it was completely embedded (group 2, n = 102). RESULTS.­: Group 2 was more likely to have prostatic ducts or acini involvement by urothelial carcinoma in situ component (27% versus 10%, P = .002) and prostate involvement (30% versus 13%, P = .003) than group 1. Although there were cases with prostatic stromal invasion in group 2 (14% versus 7%, P = .13), this was not statistically significant. In all, 6 cases were upstaged by subepithelial prostatic stromal invasion through intraurethral extension according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system. Tumor location and the presence of concurrent carcinoma in situ were strongly associated with prostate involvement of urothelial carcinoma. Prostatic adenocarcinoma (PA) was incidentally identified in 47 cases (23.5%). Incidental PA and clinically significant PA were more often identified in group 2 than group 1 (38% versus 8%, P < .01 and 15% versus 6%, P = .048, respectively). CONCLUSIONS.­: A complete prostate examination in RCP specimens can be suggested, since the final pathologic stage can be changed through a thorough prostate examination especially in accord with the AJCC staging manual 8th edition. In addition, the complete prostate analysis could detect more incidental and clinically significant PA.

Using a Deep Learning Model to Address Interobserver Variability in the Evaluation of Ulcerative Colitis (UC) Severity.

The use of endoscopic images for the accurate assessment of ulcerative colitis (UC) severity is crucial to determining appropriate treatment. However, experts may interpret these images differently, leading to inconsistent diagnoses. This study aims to address the issue by introducing a standardization method based on deep learning. We collected 254 rectal endoscopic images from 115 patients with UC, and five experts in endoscopic image interpretation assigned classification labels based on the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scoring system. Interobserver variance analysis of the five experts yielded an intraclass correlation coefficient of 0.8431 for UCEIS scores and a kappa coefficient of 0.4916 when the UCEIS scores were transformed into UC severity measures. To establish a consensus, we created a model that considered only the images and labels on which more than half of the experts agreed. This consensus model achieved an accuracy of 0.94 when tested with 50 images. Compared with models trained from individual expert labels, the consensus model demonstrated the most reliable prediction results.

A Study on Emotions to Improve the Quality of Life of South Korean Senior Patients Residing in Convalescent Hospitals.

This study examined the occurrence of emotion types and the contents and meanings of individual emotion types to improve the quality of life of South Korean senior patients in convalescent hospitals. This research is a sequential mixed study in which we conducted emotion frequency and content analyses with 20 elderly resident patients in a convalescent hospital. In the emotion frequency analysis, we performed emotion occurrence frequency analysis and clustering to create groups of subjects that showed similar distributions of emotions. The study results found that South Korean senior patients displayed six major emotions: joy, sorrow, anger, surprise, fear, and tranquility, including mixed emotional states. In the emotion content analysis, we used NVivo to categorize and analyze the interview contents based on emotion types. The study results show the characteristics of emotions according to patients' treatment and recovery, life within narrow boundaries, relationships with new people and family, and the appearances of themselves that they could not easily but must accept. In addition, these characteristics appeared in health, environment, relationships, and psychological structures. Ultimately, the study results suggest that improving the quality of life of South Korean senior patients requires understanding of their emotions and examining diverse emotions in multiple dimensions.

Clinical Significance of Variable Histomorphologic Findings Related to Mucosal Inflammation in Negative Appendectomy.

The aim of the study was to investigate the clinical significance of various histomorphologic findings related to mucosal inflammation in negative appendectomy. We reviewed histopathologic findings of 118 negative appendectomies and correlated them with the appendicitis inflammatory response (AIR) score and appendiceal diameter. Among 118 patients with negative appendectomy, 94 (80%), 73 (78%) and 89 (75%) patients displayed mucosal inflammation, high neutrophil score (neutrophil count ≥10/5 high power field and surface epithelial flattening, respectively. Out of 118 patients with negative appendectomy, mucosal inflammation, high neutrophil score and surface epithelial flattening were associated with higher risk group according to the appendicitis inflammatory response (AIR) score (p < 0.05, respectively). In addition, mucosal inflammation, high neutrophil score and surface epithelial flattening were frequently detected in 118 negative appendectomies, compared with 24 incidental appendectomies (p < 0.05, respectively). In an analysis of 77 negative appendectomy patients with appendiceal diameter data available, increased appendiceal diameter was positively correlated with luminal inflammation, high neutrophil score and surface epithelial flattening (p < 0.05, respectively). In conclusion, mucosal inflammation, high neutrophil score and surface epithelial flattening in negative appendectomy may be relevant to patients' signs and symptoms, especially in cases with no other cause of the abdominal pain.

Diagnostic value of urine cytology in detecting histologic variants of urothelial carcinomas in the urinary bladder: Cytopathologic correlation of 72 cases.

BACKGROUND: Precise identification of histologic variants in urothelial carcinoma (UC) is important because some histologic types have a poor prognosis and clinical management varies. Urine cytology is used for bladder cancer screening, but the cytomorphologic features of histologic variants have not been well described. In the current study, we evaluate the effectiveness of urine cytology in detecting histologic variants of UC in the urinary bladder. METHODS: Seventy-two urine cytology specimens from patients diagnosed with high-grade UCs by radical cystectomy were retrospectively reviewed and correlated with histopathologic findings of subsequent radical cystectomy specimens. RESULTS: Of 72 total cases, 24 (33%) cases showed six histologic variants in corresponding surgical specimens, including squamous differentiation (13 cases), plasmacytoid variant (3 cases), micropapillary variant (3 cases), sarcomatoid variant (3 cases), giant cell variant (1 case), and glandular differentiation (1 case). Histopathology and cytomorphology were well correlated in 13 cases (54%), with squamous differentiation in 11 of 13 cases (85%), micropapillary features in 1 out of 3 cases (33%), and spindle cell/sarcomatoid features in 1 of 3 cases (33%). Furthermore, mucosal involvement by histologic variants, not amount of histologic variant, was related to high concordance rates between cytology and histology diagnosis. CONCLUSIONS: The morphologic features of some histologic variants of high-grade UCs, such as squamous differentiation, micropapillary variant, and sarcomatoid variant, are partially reflected on urine cytology. In addition, mucosal involvement by histologic variants was associated with a higher detection rate of histologic variants in urine cytology.

Histologically confirmed distant metastatic urothelial carcinoma from the urinary bladder: a retrospective review of one institution's 20-year experience.

BACKGROUND: Urothelial carcinoma (UC) accounts for roughly 90% of bladder cancer, and has a high propensity for diverse differentiation. Recently, certain histologic variants of UC have been recognized to be associated with unfavorable clinical outcomes. Several UC studies have also suggested that tumor budding is a poor prognostic marker. Distant metastasis of UC after radical cystectomy is not uncommon. However, these metastatic lesions are not routinely confirmed with histology. METHODS: We investigated the histopathologic features of 13 cases of UC with biopsy-proven distant metastases, with a special emphasis on histologic variants and tumor budding. RESULTS: Lymph nodes (6/13, 46%) were the most common metastatic sites, followed by the lung (4/13, 31%), liver (4/13, 31%), and the adrenal gland (2/13, 15%). The histologic variants including squamous (n=1), micropapillary (n=4), and plasmacytoid (n=1) variants in five cases of UC. Most histologic variants (4/5, 80%) of primary UCs appeared in the metastatic lesions. In contrast, high-grade tumor budding was detected in six cases (46%), including one case of non-muscle invasive UC. Our study demonstrates that histologic variants are not uncommonly detected in distant metastatic UCs. Most histologic variants seen in primary UCs persist in the distant metastatic lesions. In addition, high-grade tumor budding, which occurs frequently in primary tumors, may contribute to the development of distant metastasis. CONCLUSIONS: Therefore, assessing the presence or absence of histologic variants and tumor budding in UCs of the urinary bladder, even in non-muscle invasive UCs, may be useful to predict distant metastasis.

Double cocktail immunostains with high molecular weight cytokeratin and GATA-3: useful stain to discriminate in situ involvement of prostatic ducts or acini from stromal invasion by urothelial carcinoma in the prostate.

BACKGROUND: Distinguishing prostatic stromal invasion (PSI) by urothelial carcinoma (UC) from in situ UC involving prostatic ducts or acini with no stromal invasion (in situ involvement) may be challenging on hematoxylin and eosin stained sections. However, the distinction between them is important because cases with PSI show worse prognosis. This study was performed to assess the utility of double cocktail immunostains with high molecular weight cytokeratin (HMWCK) and GATA-3 to discriminate PSI by UC from in situ UC involvement of prostatic ducts or acini in the prostate. METHODS: Among 117 radical cystoprostatectomy specimens for bladder UCs, 25 cases showed secondary involvement of bladder UC in prostatic ducts/acini only or associated stromal invasion and of these 25 cases, seven cases revealed equivocal PSI. In these seven cases with equivocal PSI, HMWCK, and GATA-3 double immunohistochemical stains were performed to identify whether this cocktail stain is useful to identify the stromal invasion. RESULTS: In all cases, basal cells of prostate glands showed strong cytoplasmic staining for HMWCK and UC cells showed strong nuclear staining for GATA-3. In cases with stromal invasion of UC, GATA-3-positive tumor cells in the prostatic stroma without surrounding HMWCK-positive basal cells were highlighted and easily recognized. Among seven equivocal cases, two cases showed PSI and five in situ UC in the prostate. In two cases, the original diagnoses were revised. CONCLUSIONS: Our study suggested that HMWCK and GATA-3 double stains could be utilized as an adjunct method in the distinction between PSI by UC from in situ UC involving prostatic ducts or acini.

Human Epidermal Growth Factor Receptor 2-Subtype Invasive Ductal Carcinoma Recurring as Basal-Human Epidermal Growth Factor Receptor 2-Subtype Squamous Cell Carcinoma.

Squamous cell carcinoma of the breast and its subtype, basal-human epidermal growth factor receptor 2 (HER2) phenotype, are very rare. Herein, we report a patient who developed recurrence of squamous cell carcinoma of the breast with basal-HER2 subtype 6 years after the initial diagnosis of invasive ductal carcinoma of the HER2 subtype. To the best of our knowledge, recurrence of invasive ductal carcinoma in the form of metaplastic squamous cell carcinoma of basal-HER2 subtype has not been reported previously. We present a pathological perspective of our experience.

Pitfalls of Frozen Section Diagnosis for Paraganglioma: A Clinicopathologic Analysis and Review of the Literature.

Few paraganglioma (PG) cases include frozen section diagnoses, and therefore, the accuracy of frozen section diagnosis for PG remains unknown. To better understand the histologic characteristics and pitfalls of frozen section findings for PG, 15 PG cases with frozen section diagnoses were selected from 12 articles through PubMed (1984-2015). In addition, we included 3 cases of PG for which intraoperative consultations were requested during a 5-year period (2012-2016) in 2 hospitals. Seven PGs were from the thyroid; 2 from the pancreas; 4 from the mediastinum, retroperitoneum, or mesentery; 1 from the middle ear; and 4 from the urinary bladder (UB). Out of 18 PGs, correct diagnoses were rendered in only 2 cases, and no thyroid or UB PGs were correctly diagnosed on intraoperative consultation. Thyroid PGs were frequently misdiagnosed as medullary thyroid carcinomas (4/7, 57%) and UB PGs were frequently misdiagnosed as malignancies.

IL12-mediated sensitizing of T-cell receptor-dependent and -independent tumor cell killing.

Interleukin 12 (IL12) is a key inflammatory cytokine critically influencing Th1/Tc1-T-cell responses at the time of initial antigen encounter. Therefore, it may be exploited for cancer immunotherapy. Here, we investigated how IL12, and other inflammatory cytokines, shape effector functions of human T-cells. Using a defined culture system, we followed the gradual differentiation and function of antigen-specific CD8(+) T cells from their initial activation as naïve T cells through their expansion phase as early memory cells to full differentiation as clonally expanded effector T cells. The addition of IL12 8 days after the initial priming event initiated two mechanistically separate events: First, IL12 sensitized the T-cell receptor (TCR) for antigen-specific activation, leading to an approximately 10-fold increase in peptide sensitivity and, in consequence, enhanced tumor cell killing. Secondly, IL12 enabled TCR/HLA-independent activation and cytotoxicity: this "non-specific" effect was mediated by the NK cell receptor DNAM1 (CD226) and dependent on ligand expression of the target cells. This IL12 regulated, DNAM1-mediated killing is dependent on src-kinases as well as on PTPRC (CD45) activity. Thus, besides enhancing TCR-mediated activation, we here identified for the first time a second IL12 mediated mechanism leading to activation of a receptor-dependent killing pathway via DNAM1.

Iron enhances NGF-induced neurite outgrowth in PC12 cells.

Rat pheochromocytoma 12 (PC12) cells undergo neuronal differentiation in response to nerve growth factor (NGF). NGF-induced differentiation involves a number of protein kinases, including extracellular signal-regulated kinase (ERK). We studied the effect of iron on neuronal differentiation, using as model the neurite outgrowth of PC12 cells triggered by NGF when the cells are plated on collagen-coated dishes in medium containing 1% serum. The addition of iron enhanced NGF-mediated cell adhesion, spreading and neurite outgrowth. The differentiation-promoting effect of iron seems to depend on intracellular iron, since nitrilotriacetic acid (an efficient iron-uptake mediator) enhanced the response to iron. In agreement with this, intracellular, but not extracellular, iron enhanced NGF-induced neurite outgrowth in pre-spread PC12 cells, and this was correlated with increased ERK activity. Taken together, these data suggest that intracellular iron promotes NGF-stimulated differentiation of PC12 cells by increasing ERK activity.