Recent developments in the immunopathology of COVID-19.

There has been an important change in the clinical characteristics and immune profile of Coronavirus disease 2019 (COVID-19) patients during the pandemic thanks to the extensive vaccination programs. Here, we highlight recent studies on COVID-19, from the clinical and immunological characteristics to the protective and risk factors for severity and mortality of COVID-19. The efficacy of the COVID-19 vaccines and potential allergic reactions after administration are also discussed. The occurrence of new variants of concerns such as Omicron BA.2, BA.4, and BA.5 and the global administration of COVID-19 vaccines have changed the clinical scenario of COVID-19. Multisystem inflammatory syndrome in children (MIS-C) may cause severe and heterogeneous disease but with a lower mortality rate. Perturbations in immunity of T cells, B cells, and mast cells, as well as autoantibodies and metabolic reprogramming may contribute to the long-term symptoms of COVID-19. There is conflicting evidence about whether atopic diseases, such as allergic asthma and rhinitis, are associated with a lower susceptibility and better outcomes of COVID-19. At the beginning of pandemic, the European Academy of Allergy and Clinical Immunology (EAACI) developed guidelines that provided timely information for the management of allergic diseases and preventive measures to reduce transmission in the allergic clinics. The global distribution of COVID-19 vaccines and emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with reduced pathogenic potential dramatically decreased the morbidity, severity, and mortality of COVID-19. Nevertheless, breakthrough infection remains a challenge for disease control. Hypersensitivity reactions (HSR) to COVID-19 vaccines are low compared to other vaccines, and these were addressed in EAACI statements that provided indications for the management of allergic reactions, including anaphylaxis to COVID-19 vaccines. We have gained a depth knowledge and experience in the over 2 years since the start of the pandemic, and yet a full eradication of SARS-CoV-2 is not on the horizon. Novel strategies are warranted to prevent severe disease in high-risk groups, the development of MIS-C and long COVID-19.

Long read genome assemblies complemented by single cell RNA-sequencing reveal genetic and cellular mechanisms underlying the adaptive evolution of yak.

Wild yak (Bos mutus) and domestic yak (Bos grunniens) are adapted to high altitude environment and have ecological, economic, and cultural significances on the Qinghai-Tibetan Plateau (QTP). Currently, the genetic and cellular bases underlying adaptations of yak to extreme conditions remains elusive. In the present study, we assembled two chromosome-level genomes, one each for wild yak and domestic yak, and screened structural variants (SVs) through the long-read data of yak and taurine cattle. The results revealed that 6733 genes contained high-FST SVs. 127 genes carrying special type of SVs were differentially expressed in lungs of the taurine cattle and yak. We then constructed the first single-cell gene expression atlas of yak and taurine cattle lung tissues and identified a yak-specific endothelial cell subtype. By integrating SVs and single-cell transcriptome data, we revealed that the endothelial cells expressed the highest proportion of marker genes carrying high-FST SVs in taurine cattle lungs. Furthermore, we identified pathways which were related to the medial thickness and formation of elastic fibers in yak lungs. These findings provide new insights into the high-altitude adaptation of yak and have important implications for understanding the physiological and pathological responses of large mammals and humans to hypoxia.

Exploring Potential Mechanisms of Fludioxonil Resistance in Fusarium oxysporum f. sp. melonis.

Melon Fusarium wilt (MFW), which is caused by Fusarium oxysporum f. sp. melonis (FOM), is a soil-borne disease that commonly impacts melon cultivation worldwide. In the absence of any disease-resistant melon cultivars, the control of MFW relies heavily on the application of chemical fungicides. Fludioxonil, a phenylpyrrole fungicide, has been shown to have broad-spectrum activity against many crop pathogens. Sensitivity analysis experiments suggest that fludioxonil has a strong inhibitory effect on the mycelial growth of FOM isolates. Five fludioxonil-resistant FOM mutants were successfully generated by repeated exposure to fludioxonil under laboratory conditions. Although the mutants exhibited significantly reduced mycelial growth in the presence of the fungicide, there initially appeared to be little fitness cost, with no significant difference (p < 0.05) in the growth rates of the mutants and wild-type isolates. However, further investigation revealed that the sporulation of the fludioxonil-resistant mutants was affected, and mutants exhibited significantly (p < 0.05) reduced growth rates in response to KCl, NaCl, glucose, and mannitol. Meanwhile, molecular analysis of the mutants strongly suggested that the observed fludioxonil resistance was related to changes in the sequence and expression of the FoOs1 gene. In addition, the current study found no evidence of cross-resistance between fludioxonil and any of the other fungicides tested. These results indicate that fludioxonil has great potential as an alternative method of control for FOM in melon crops.

Safety and effectiveness of an iris hook assisted phacoemulsification in vitrectomized eyes.

AIM: To introduce a simple iris hook assisted phacoemulsification (PE) procedure and evaluate the safety and efficacy of it in completely vitrectomized eyes. METHODS: A single centre study which included 65 previously completely vitrectomized eyes of 62 patients who underwent cataract surgery. Patients were randomly divided into 3 groups. Patients received PE, and intraocular lens (IOL) implantation with the assistance of iris hook (Synergeties™) as group A (25 eyes); patients who received PE assisted with a 25G pars plana irrigation as group B (20 eyes), and patients who received PE performed without the help of any instrument as group C (20 eyes). Main outcome measures were surgery duration, Ultrasound (U/S) total time, endothelial cell density (ECD), cumulative dissipated energy (CDE) and complications of the procedures. RESULTS: With the help of iris hook, the patients in group A had the lowest ECD loss rate (0.07±0.03, 0.09±0.03, and 0.10±0.03, P<0.05), shortest CDE (12.2±4.1, 15.8±6.0, and 16.0±6.0, P<0.05) and U/S total time (36.6±13.0s, 46.3±16.4s, and 47.6±16.1s, P<0.05), and minimal incidence of complications. The longest surgery duration was in group B (19.4±1.6min) and maximum complications rate in group C (20% miosis, 10% posterior capsular tears, 5% zonular dialysis, 5% cystoid macular edema). While best-corrected visual acuity (BCVA), intraocular pressure (IOP) and ECD did not show a significant difference among the three groups. CONCLUSION: Without prolonged surgery duration, the iris hook assistant method can minimize heat generation during surgery and incidence of complications, which transfer the challenged PE in vitrectomized eyes into a regular surgery. It does not need any change in the hydrodynamic parameters and in the bag PE technique, easy to operate even for junior surgeons.

Clinical Evaluation for Sublingual Immunotherapy With Dermatophagoides farinae in Polysensitized Allergic Asthma Patients.

Background: Many studies have demonstrated the efficacy of single-allergen sublingual immunotherapy (SLIT) in polysensitized patients with allergic rhinitis (AR), but less is reported in polysensitized patients with allergic asthma (AS). Method: Data of 133 adult patients with house dust mite (HDM)-induced AS who had been treated for 3 years were collected. These patients were divided into the control group (treated with low to moderate dose of inhaled glucocorticoids and long-acting ß2 agonists, n = 37) and the SLIT group (further treated with Dermatophagoides farinae drops, n = 96). The SLIT group contained three subgroups: the single-allergen group (only sensitized to HDM, n = 35), the 1- to 2-allergen group (HDM combined with one to two other allergens, n = 32), and the 3-or-more-allergen group (HDM combined with three or more other allergens, n = 29). The total asthma symptom score (TASS), total asthma medicine score (TAMS), and asthma control test (ACT) were assessed before treatment and at yearly visits. Forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) was assessed before treatment and at the end of SLIT. Results: TASS and ACT scores in the control group were significantly higher than that in the single-allergen group and the 1- to 2-allergen group after 1, 2, and 3 years of SLIT and significantly higher than that in the 3-or-more-allergen group after 3-year SLIT (all p < 0.05). TAMS of the control group was significantly higher than that of the other three groups after 0.5, 1, 2, and 3 years of SLIT (all p < 0.05). FEV1/FVC in the control group was significantly higher than baseline after 3 years of immunotherapy (p < 0.05). Conclusion: Patients sensitized to HDM with/without other allergens showed similar efficacy after 3 years of SLIT. However, the initial response of patients with three or more allergens was slower during immunotherapy process.

Reduced microbial stability in the active layer is associated with carbon loss under alpine permafrost degradation.

Permafrost degradation may induce soil carbon (C) loss, critical for global C cycling, and be mediated by microbes. Despite larger C stored within the active layer of permafrost regions, which are more affected by warming, and the critical roles of Qinghai-Tibet Plateau in C cycling, most previous studies focused on the permafrost layer and in high-latitude areas. We demonstrate in situ that permafrost degradation alters the diversity and potentially decreases the stability of active layer microbial communities. These changes are associated with soil C loss and potentially a positive C feedback. This study provides insights into microbial-mediated mechanisms responsible for C loss within the active layer in degraded permafrost, aiding in the modeling of C emission under future scenarios.

Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases.

Vital osteocytes have been well known to function as an important orchestrator in the preservation of robustness and fidelity of the bone remodeling process. Nevertheless, some key pathological factors, such as sex steroid deficiency and excess glucocorticoids, and so on, are implicated in inducing a bulk of apoptotic osteocytes, subsequently resulting in resorption-related bone loss. As much, osteocyte apoptosis, under homeostatic conditions, is in an optimal state of balance tightly controlled by pro- and anti-apoptotic mechanism pathways. Importantly, there exist many essential signaling proteins in the process of osteocyte apoptosis, which has a crucial role in maintaining a homeostatic environment. While increasing in vitro and in vivo studies have established, in part, key signaling pathways and cross-talk mechanism on osteocyte apoptosis, intrinsic and complex mechanism underlying osteocyte apoptosis occurs in various states of pathologies remains ill-defined. In this review, we discuss not only essential pro- and anti-apoptotic signaling pathways and key biomarkers involved in these key mechanisms under different pathological agents, but also the pivotal role of apoptotic osteocytes in osteoclastogenesis-triggered bone loss, hopefully shedding new light on the attractive and proper actions of pharmacotherapeutics of targeting apoptosis and ensuing resorption-related bone diseases such as osteoporosis and fragility fractures.

KLF5 and MYC modulated LINC00346 contributes to gastric cancer progression through acting as a competing endogeous RNA and indicates poor outcome.

It was found in this study that long intergenic non-protein coding RNA 346 (LINC00346) was an lncRNA aberrantly expressed in gastric cancer (GC) based on multiple Gene Expression Omnibus (GEO) databases of GC cohorts. The LINC00346 gene was recurrently amplified and upregulated in GC, and its expression was positively correlated with poor pathologic stage, large tumor size, and poor prognosis. In addition, the oncogenic transcription factors KLF5 and MYC could bind to the LINC00346 promoter and enhance its expression. Gene Set Enrichment Analysis (GSEA) in the GEO datasets revealed that cell cycle and focal adhesion genes were enriched in patients with high LINC00346 expression. In vitro and in vivo assays of LINC00346 alterations revealed a complex integrated phenotype affecting cell growth, migration and invasion. Strikingly, high-throughput sequencing analysis after LINC00346 alterations highlighted alterations in cell cycle and focal adhesion pathways in GC cells. Mechanistically, argonaute 2 (Ago2) was recruited by LINC00346, which functioned as a molecular sponge for miR-34a-5p by antagonizing its ability to repress CD44, NOTCH1, and AXL protein translation. Taken together, our findings support a model in which the KLF5, MYC/LINC00346/miR-34a-5p cross-talk served as critical effectors in GC tumorigenesis and progression, suggesting a new therapeutic direction in the treatment of GC.

EZH2-mediated epigenetic suppression of EphB3 inhibits gastric cancer proliferation and metastasis by affecting E-cadherin and vimentin expression.

EphB3 is a member of the EPH family of receptors and has been found to play a role in the carcinogenesis of some human cancers. However, its expression and clinical significance in gastric cancer (GC) have not been well documented. In the present study, we detected the expression of EphB3 in GC and adjacent noncancerous tissues and explored its relationships with the clinicopathological features and prognosis of GC patients. It was found that EphB3 silenced GC cells epigenetically by direct transcriptional repression of GC cells via polycomb group protein EZH2 mediation. EphB3 was downregulated in GC cells and tissues, and EphB3 depletion promoted GC cell growth and invasion, while ectopic overexpression of EphB3 produced a significant anti-tumor effect. EphB3 was found to be involved in epithelial-mesenchymal transition by regulating E-cadherin and vimentin expression. In addition, patients with reduced EphB3 expression had shorter disease-free survival (DFS), indicating that EphB3 may prove to be a biomarker for prognosis of GC. These results demonstrated that EphB3 functioned as a tumor-suppressor and prognostic biomarker in GC.

Upregulation of the long noncoding RNA FOXD2-AS1 promotes carcinogenesis by epigenetically silencing EphB3 through EZH2 and LSD1, and predicts poor prognosis in gastric cancer.

Accumulating data indicate that long noncoding RNAs (lncRNAs) serve as important modulators in biological processes and are dysregulated in diverse tumors. The function of FOXD2-AS1 in gastric cancer (GC) progression and related biological mechanisms remain undefined. A comprehensive analysis identified that FOXD2-AS1 enrichment was upregulated markedly in GC and positively correlated with a large tumor size, a later pathologic stage, and a poor prognosis. Gene-set enrichment analysis (GSEA) in GEO datasets uncovered that cell cycle and DNA replication associated genes were enriched in patients with high FOXD2-AS1 expression. Loss of FOXD2-AS1 function inhibited cell growth via inhibiting the cell cycle in GC, whereas upregulation of FOXD2-AS1 expression promoted cancer progression. The enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins were found to serve as binding partners of FOXD2-AS1 and mediators of FOXD2-AS1 function. Mechanically, FOXD2-AS1 promoted GC tumorigenesis partly through EZH2 and LSD1 mediated EphB3 downregulation. The present results revealed that FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1, and may prove to be a potential biomarker of carcinogenesis.

Retraction Note to: Decreased expression of the long noncoding RNA LINC00261 indicate poor prognosis in gastric cancer and suppress gastric cancer metastasis by affecting the epithelial-mesenchymal transition.

RETRACTION: The authors have retracted this article [1] because of significant overlap of text and some images with a previously published article by Xu et al. [2]. A formal investigation by the 1st Affiliated Hospital of Wenzhou Medical University has found that some panels in Fig. 6b [1] are identical with panels in Fig. 5a [2] and some images of mice lungs in Fig. 6c [1] are identical with images in Fig. 3g [2]. The data reported in this article are therefore unreliable. All authors agree to this retraction.

Downregulation of liver-intestine cadherin enhances cisplatin-induced apoptosis in human gastric cancer BGC823 cells.

Gastric cancer is the fourth most common type of cancer. Liver-intestine cadherin (CDH17) has been found to be involved in the proliferation and apoptosis of gastric cancer cells. Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumor and hematological malignancies. However, the mechanism of enhancing cisplatin-inducing effects on human gastric cancer BGC823 cells by blocking CDH17 gene, both in vitro and in vivo, remains to be clarified. In this study, we investigated the signaling pathway by which cisplatin induces apoptosis by blocking CDH17 gene in gastric cancer BGC823 cells. Our results indicate that down-expression of CDH17 gene can enhance apoptosis-inducing effects of cisplatin on human gastric cancer BGC823 cells. The expression levels of Bax and Cyt-c proteins were upregulated, but the expression levels of Bcl-2 and Bcl-xL proteins were downregulated by blocking CDH17 gene in gastric cancer BGC823 cells after treatment with cisplatin. Moreover, down-expression of CDH17 enhanced the efficacy of cisplatin-induced inhibition of tumor growth in nude mice via apoptosis induction. Down-expression of CDH17 gene can significantly improve apoptosis-inducing effects of cisplatin in vitro and in vivo, which is a new strategy to improve chemotherapeutic effects on gastric cancer.

Taurine­upregulated gene 1: A vital long non­coding RNA associated with cancer in humans (Review).

It is widely reported that long non­coding RNAs (lncRNAs) are involved in regulating cell differentiation, proliferation, apoptosis and other biological processes. Certain lncRNAs have been found to be crucial in various types of tumor. Taurine­upregulated gene 1 (TUG1) has been shown to be expressed in a tissue­specific pattern and exert oncogenic or tumor suppressive functions in different types of cancer in humans. According to previous studies, TUG1 is predominantly located in the nucleus and may regulate gene expression at the transcriptional level. It mediates chromosomal remodeling and coordinates with polycomb repressive complex 2 (PRC2) to regulate gene expression. Although the mechanisms of how TUG1 affects the tumor genesis process remain to be fully elucidated, increasing studies have suggested that TUG1 offers potential as a diagnostic and prognostic biomarker, and as a therapeutic target in certain types of tumor. This review aims to summarize current evidence concerning the characteristics, mechanisms and associations with cancer of TUG1.

KLF16 promotes proliferation in gastric cancer cells via regulating p21 and CDK4.

Krüppel-like factors (KLFs), such as KLF4, KLF2, KLF5 and KLF15, have been extensively investigated in multi-cancers. However, KLF16, a member of KLFs, hasn't been well identified in cancer, especially in gastric cancer (GC). Here, we investigated the roles of KLF16 in GC. In present study, we found that KLF16 expression levels were significantly up-regulated in GC tissues compared to adjacent normal tissues both in protein and mRNA levels by using immunohistochemistry assays (IHC) and real-time quantitative PCR (qPCR). And KLF16 expression levels were positively correlated to tumor size, invasion depth, lymphatic metastasis and TNM stage. Furthermore, KLF16 expression also could predict prognosis in patients with GC. Moreover, the knock-down of KLF16 could significantly suppress proliferation via increasing p21 expression and decreasing CDK4 expression in GC cell lines. In summary, these findings demonstrate that KLF16 plays a significant role in GC progression and could be a new therapeutic target for GC patients.

E2F1 induces TINCR transcriptional activity and accelerates gastric cancer progression via activation of TINCR/STAU1/CDKN2B signaling axis.

Recent evidence indicates that E2F1 transcription factor have pivotal roles in the regulation of cellular processes, and is found to be dysregulated in a variety of cancers. Long non-coding RNAs (lncRNAs) are also reported to exert important effect on tumorigenesis. E2F1 is aberrantly expressed in gastric cancer (GC), and biology functions of E2F1 in GC are controversial. The biological characteristics of E2F1 and correlation between E2F1 and lncRNAs in GC remain to be found. In this study, integrated analysis revealed that E2F1 expression was significantly increased in GC cases and its expression was positively correlated with the poor pathologic stage, large tumor size and poor prognosis. Forced E2F1 expression promotes proliferation, whereas loss of E2F1 function decreased cell proliferation by blocking of cell cycle in GC cells. Mechanistic analyses indicated that E2F1 accelerates GC growth partly through induces TINCR transcription. TINCR could bind to STAU1 (staufen1) protein, and influence CDKN2B mRNA stability and expression, thereby affecting the proliferation of GC cells. Together, our findings suggest that E2F1/TINCR/STAU1/CDKN2B signaling axis contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease.

Blockade of NF-κB and MAPK pathways by ulinastatin attenuates wear particle-stimulated osteoclast differentiation in vitro and in vivo.

Ulinastatin, a urinary trypsin inhibitor (UTI), is widely used to clinically treat lipopolysaccharide (LPS)-related inflammatory disorders recently. Adherent pathogen-associated molecular patterns (PAMPs), of which LPS is the best-studied and classical endotoxin produced by Gram-negative bacteria, act to increase the biological activity of osteopedic wear particles such as polymethyl-methacrylate (PMMA) and titanium particles in cell culture and animal models of implant loosening. The present study was designed to explore the inhibitory effect of UTI on osteoclastogenesis and inflammatory osteolysis in LPS/PMMA-mediated Raw264.7 cells and murine osteolysis models, and investigate the potential mechanism. The in vitro study was divided into the control group, LPS-induced group, PMMA-stimulated group and UTI-pretreated group. UTI (500 or 5000 units/ml) pretreatment was followed by PMMA (0.5 mg/ml) with adherent LPS. The levels of inflammatory mediators including tumour necrosis factor-α (TNF-α), matrixmetallo-proteinases-9 (MMP-9) and interleukin-6 (IL-6), receptor activation of nuclear factor NF-κB (RANK), and cathepsin K were examined and the amounts of phosphorylated I-κB, MEK, JNK and p38 were measured. In vivo study, murine osteolysis models were divided into the control group, PMMA-induced group and UTI-treated group. UTI (500 or 5000 units/kg per day) was injected intraperitoneally followed by PMMA suspension with adherent LPS (2×108 particles/25 µl) in the UTI-treated group. The thickness of interfacial membrane and the number of infiltrated inflammatory cells around the implants were assessed, and bone mineral density (BMD), trabecular number (Tb.N.), trabecular thickness (Tb.Th.), trabecular separation (Tb.Sp.), relative bone volume over total volume (BV/TV) of distal femur around the implants were calculated. Our results showed that UTI pretreatment suppressed the secretion of proinflammatory cytokines including MMP-9, IL-6, TNF-α, RANK and cathepsin K through down-regulating the activity of nuclear factor kappa B (NF-κB) and MAPKs partly in LPS/PMMA-mediated Raw264.7 cells. Finally, UTI treatment decreased the inflammatory osteolysis reaction in PMMA-induced murine osteolysis models. In conclusion, these results confirm the anti-inflammatory potential of UTI in the prevention of particle disease.

Decreased expression of the long noncoding RNA LINC00261 indicate poor prognosis in gastric cancer and suppress gastric cancer metastasis by affecting the epithelial-mesenchymal transition.

BACKGROUND: Recent evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles in the regulation of cellular processes and are found to be dysregulated in a variety of cancers. LINC00261 is an lncRNA that is aberrantly expressed in gastric cancer (GC). The clinical role of LINC00261 in GC and molecular mechanisms remains to be found. METHODS: Real-time polymerase chain reaction (PCR) was used to examine LINC00261 expression in GC cell lines/tissues compared with normal epithelial cells/adjacent non-tumorous tissues. Gain and loss of function approaches were used to investigate the biological role of LINC00261 in GC cells. The effects of LINC00261 on cell viability were evaluated by MTT and colony formation assays. Wound healing assay, cell migration and invasion assays, and nude mice were used to examine the effects of LINC00261 on tumor cell metastasis in vitro and in vivo. Protein levels of LINC00261 targets were determined by western blot and immunohistochemistry. RESULTS: LINC00261 was downregulated in GC cell lines and cancerous tissues, as compared with normal gastric epithelial cells and adjacent noncancerous tissue samples. Low LINC00261 expression was correlated with deeper tumor invasion (P < 0.001), higher tumor stage (P = 0.013), and lymphatic metastasis (P = 0.006). Univariate and multivariate analyses indicated that low LINC00261 expression predicted poor prognosis. Ectopic expression of LINC00261 impaired cell migration and invasion, leading to the inhibition of metastasis in vitro and in vivo. Knockdown of LINC00261 expression promoted cell migration and invasion in vitro. Overexpression of LINC00261 was found to play a key role in epithelial-mesenchymal transition (EMT) through the regulation of E-cadherin, N-cadherin, and Vimentin expression. CONCLUSIONS: Low expression of the lncRNA LINC00261 occurs in GC and is associated with poor prognosis. LINC00261 suppresses GC metastasis by regulating EMT. Thus, LINC00261 plays an important role in the progression and metastasis of GC.

Imaging observations of pulmonary inflammatory myofibroblastic tumors in patients over 40 years old.

Pulmonary inflammatory myofibroblastic tumors (PIMTs) are extremely rare in adults. If occurring in patients >40 years old, PIMT should be rapidly distinguished from lung cancer. The present study aimed to characterize the imaging features of PIMT in patients >40 years old in order to improve the diagnosis of PIMT. The imaging data of 10 patients with PIMT were reviewed retrospectively. Of the patients, eight underwent computed tomography (CT), two underwent positron emission tomography (PET)/CT and four underwent single-photon emission computed tomography (SPECT). Unenhanced CT revealed 10 lesions with a maximum diameter ranging between 5 and 57 mm located in the lower (n=6) or upper (n=4) lobe, in a peripheral (n=9) or central (n=1) region, and that were well- (n=4) or ill-defined (n=6), and round to oval (n=5) or irregular (n=5) in shape. Calcification (n=3), necrosis (n=6), cavity (n=4), air bronchogram (n=6) and obstructive pneumonia (n=1) were also observed in the patients. Contrast-enhanced CT revealed six lesions with moderate to high contrast enhancement in the arterial and venous phases, including four lesions with delayed enhancement. PET/CT identified two lesions with increased tracer uptake that were homogeneous and heterogeneous and each exhibited a maximal standard uptake value (SUVmax) of 6.0 and 5.4, respectively. The delayed PET/CT revealed foci that each exhibited an increased SUVmax of 6.9 and 5.9, respectively. SPECT demonstrated no definitive bone metastases, but did reveal atypical hypertrophic pulmonary osteoarthropathy in one patient. The combined imaging methods may lead to a more precise evaluation of PIMT in patients >40 years old.

Thyroid carcinoma showing thymus-like elements: a clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis.

OBJECTIVES: To investigate the clinicopathologic, immunophenotypic, ultrastructural, and molecular features of thyroid carcinoma showing thymus-like elements (CASTLE). METHODS: We retrospectively analyzed the clinicopathologic data of 10 patients with CASTLE and described the immunophenotypic and ultrastructural features of these tumors. The expression of Epstein-Barr virus-encoded RNA and the gene status of EGFR, C-KIT, and HER-2 were also assessed by molecular techniques. RESULTS: The tumor cells were positive for CD5, CD117, p63, HMWK, EGFR, GLUT-1, Pax8, E-cadherin, bcl-2, and p53 in all cases and for CA-IX, CEA, p16, HER-2, and neuroendocrine markers in some cases. Ultrastructural examination indicated that the tumor cells contained large quantities of tonofilament with abundant intercellular desmosomes, including intracytoplasmic neuroendocrine granules in one case. EGFR gene amplification in two patients and polyploidy of chromosome 7 in one patient were identified by fluorescence in situ hybridization. Sequencing analysis revealed that a synonymous mutation, Q787Q 2363 (G→A), occurred on exon 20 of the EGFR gene in three patients. CONCLUSIONS: GLUT-1 can be used as a novel biomarker for CASTLE, and combined detection of GLUT-1 with CD5 and CD117 aids in the diagnosis of this tumor. Aberrant expression of Bcl-2, p53, p16, E-cadherin, EGFR, C-KIT, and HER-2 may play important roles in the development of CASTLE.

Frequent co-inactivation of the SWI/SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhabdoid tumours.

AIMS: Malignant rhabdoid tumours (MRTs) are highly aggressive malignancies of early infancy characterized by inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodelling complex. The aim of this study was to explore the status of multiple key subunits of the SWI/SNF complex in MRTs. METHODS AND RESULTS: We screened the key subunits of the SWI/SNF complex, including SMARCB1, SMARCA2, PBRM1, SMARCA4, and ARID1A, in four MRTs by immunohistochemistry, sequencing, and fluorescence in-situ hybridization (FISH). Complete loss of SMARCB1, SMARCA2 and PBRM1 expression and corresponding mutations in the same genes were observed in all cases. The mutations included seven missense, three same-sense, four frameshift and two truncating mutations. FISH revealed heterozygous deletion of SMARCB1 in one case, and monoploidy of chromosome 22, which harbours SMARCB1, in another case. Furthermore, trisomy of chromosome 9, which harbours SMARCA2, was observed in two cases. Abnormality of PBRM1 was not found in any case. CONCLUSIONS: We report, for the first time, co-inactivation and frequent mutations of SMARCB1, SMARCA2 and PBRM1 in MRTs. Multiple subunit abnormalities of the SWI/SNF complex potentially act together to contribute to the tumorigenesis of MRTs, which provides unique insights into this disease.