18F-FDG PET/CT findings in a patient with blastic plasmacytoid dendritic cell neoplasm and post-transplant lymphoproliferative disorder after hematopoietic stem cell transplantation: a case report.

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare hematopoietic malignancy, which originating from precursors of plasmacytoid dendritic cells. Allogeneic hematopoietic stem cell transplantation (HSCT) is normally considered in the treatment of BPDCN patients to acquire sustained remission. Post-transplant lymphoproliferative disorder (PTLD) is a group of conditions involving abnormal lymphoid cells proliferation in the context of extrinsic immunosuppression after solid organ transplantation (SOT) or HSCT. Herein, we report a patient with BPDCN, who suffered from PTLD after allogeneic HSCT. Case presentation: A 66-year-old man was diagnosed with BPDCN, confirmed by pathologic examination after splenectomy. The post-surgery 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (18F-FDG PET/CT) showed multifocal 18F-FDG avidity in the left cheek, lymph nodes and bone marrow. The patient started chemotherapy, followed by allogeneic HSCT and immunosuppressive therapy. Four months after the HSCT, the patient developed intermittent fever and recurrent lymphadenopathy, accompanied with progressively elevated Epstein-Barr virus (EBV)-DNA both in serum and lymphocytes. 18F-FDG PET/CT was performed again and found multiple new enlarged 18F-FDG-avid lymph nodes, while the previous hypermetabolic lesions all disappeared. The pathology of mesenteric lymph node indicated a monomorphic PTLD (diffuse large B-cell lymphoma). Then the immunosuppressive medications were stopped and two cycles of Rituximab were given, and the follow-up CT scan indicated a complete response. Conclusion: When patients with BPDCN recurred new enlarged lymph nodes after allogeneic HSCT and immunosuppressive therapy, PTLD should be taken into consideration. 18F-FDG PET/CT may provide additional evidence for supporting or refuting the suspicion of PTLD, and suggest lesions accessible for biopsy.

Generalized Muscular Uptake of 99m Tc-MDP on Bone Scan in a Patient With Scleromyxedema-Associated Myopathy.

ABSTRACT: A 62-year-old man presented with a 5-year history of progressive myasthenia, myalgia, and skin changes. Upon laboratory testing, elevated serum creatine kinase and lactate dehydrogenase, as well as monoclonal immunoglobulin Gκ, were observed. A bone scan revealed generalized muscular uptake of 99m Tc-MDP, whereas 18 F-FDG PET/CT demonstrated only mild hypermetabolism of the muscles. A muscle biopsy showed myofibrillary vacuolar degeneration, and a skin biopsy indicated scleromyxedema. Based on these findings, the patient was diagnosed with scleromyxedema-associated myopathy.

Dengue Virus 2 NS2B Targets MAVS and IKKε to Evade the Antiviral Innate Immune Response.

Dengue virus (DENV) is a widespread arbovirus. To efficiently establish infection, DENV evolves multiple strategies to hijack the host innate immune response. Herein, we examined the inhibitory effects of DENV serotype 2 (DENV2) nonstructural proteins on RIG-I-directed antiviral immune response. We found that DENV2 NS2A, NS2B, NS4A, and NS4B significantly inhibited RIG-I-mediated IFN-ß promoter activation. The roles of NS2B in RIG-I-directed antiviral immune response are unknown. Our study further showed that NS2B could dose-dependently suppress RIG-I/MAVS-induced activation of IFN-ß promoter. Consistently, NS2B significantly decreased RIG-I- and MAVS-induced transcription of IFNB1, ISG15, and ISG56. Mechanistically, NS2B was found to interact with MAVS and IKKε to impair RIG-I-directed antiviral response. Our findings demonstrated a previously uncharacterized function of NS2B in RIG-I-mediated antiviral response, making it a promising drug target for anti-DENV treatments.

PET/CT molecular imaging in the era of immune-checkpoint inhibitors therapy.

Cancer immunotherapy, especially immune-checkpoint inhibitors (ICIs), has paved a new way for the treatment of many types of malignancies, particularly advanced-stage cancers. Accumulating evidence suggests that as a molecular imaging modality, positron emission tomography/computed tomography (PET/CT) can play a vital role in the management of ICIs therapy by using different molecular probes and metabolic parameters. In this review, we will provide a comprehensive overview of the clinical data to support the importance of 18F-fluorodeoxyglucose PET/CT (18F-FDG PET/CT) imaging in the treatment of ICIs, including the evaluation of the tumor microenvironment, discovery of immune-related adverse events, evaluation of therapeutic efficacy, and prediction of therapeutic prognosis. We also discuss perspectives on the development direction of 18F-FDG PET/CT imaging, with a particular emphasis on possible challenges in the future. In addition, we summarize the researches on novel PET molecular probes that are expected to potentially promote the precise application of ICIs.

Diagnostic performance and prognostic value of preoperative 18F-FDG PET/CT in renal cell carcinoma patients with venous tumor thrombus.

BACKGROUND: To observe the diagnostic efficacy of preoperative fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) upon venous tumor thrombus (VTT) in patients with renal cell carcinoma (RCC), and investigate the prognostic value of imaging parameters integrated with clinicopathological characteristics in patients with VTT after nephrectomy with tumor thrombectomy. METHODS: Patients with newly diagnosed RCC who underwent 18F-FDG PET/CT were reviewed retrospectively. The diagnostic efficacy of 18F-FDG PET/CT in VTT was analyzed. Logistic regression analysis was carried out to identify the clinical variables and PET/CT variables (including maximum standardized uptake value (SUVmax) of primary tumor, VTT SUVmax and primary tumor size) for differentiating early VTT (Mayo 0-II) from advanced VTT (Mayo III-IV). Cox proportional hazard analyses were used to evaluate clinicopathological factors and PET/CT factors (including distant metastasis, primary tumor SUVmax, VTT SUVmax and primary tumor size) for disease-free survival (DFS) in patients with VTT after operation. RESULTS: A total of 174 eligible patients were included in this study, including 114 men (65.5%) and 60 women (34.5%), with a median age of 58 years (range, 16-81 years). The distribution of pathological tumor stage (T stage) was 56 (T1), 17 (T2), 95 (T3), and 6 cases (T4), respectively. According to WHO/ISUP grade, except for 4 cases of chromophobe cell RCC, there were 14 patients (8.0%) of grade 1, 59 patients (33.9%) of grade 2, 74 patients (42.5%) of grade 3 and 23 patients (13.2%) of grade 4. The median maximum diameter of the primary tumor on PET/CT was 7.3 cm (5.0-9.5 cm). The distal metastasis was observed in 46 patients (26.4%). Sixty-one cases (35.1%) were confirmed with VTT by pathology. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 18F-FDG PET/CT imaging were 96.7, 99.1, 98.3, 98.3, and 98.2%, in detecting VTT, respectively, and 70.0, 100.0, 94.9, 100.0, and 94.2%, in evaluating the level of VTT, respectively. Elevated VTT SUVmax (≥5.20) could significantly distinguish the early VTT group and advanced VTT group (P = 0.010). In the prognosis analysis, elevated VTT SUVmax (≥4.30) (P = 0.018, HR 3.123, 95% CI 1.212-8.044) and distant metastasis (P = 0.013, HR 3.344, 95% CI 1.293-8.649) were significantly independent predictors for DFS. CONCLUSION: Preoperative 18F-FDG PET/CT has a high diagnostic efficacy in detecting VTT and evaluating its level in RCC patients. Those patients with elevated VTT SUVmax should be carefully monitored to detect the possibility of disease progression after operation.

Emerging roles of growth differentiation factor-15 in brain disorders (Review).

Brain disorders, such as Alzheimer's and Parkinson's disease and cerebral stroke, are an important contributor to mortality and disability worldwide, where their pathogenesis is currently a topic of intense research. The mechanisms underlying the development of brain disorders are complex and vary widely, including aberrant protein aggregation, ischemic cell necrosis and neuronal dysfunction. Previous studies have found that the expression and function of growth differentiation factor-15 (GDF15) is closely associated with the incidence of brain disorders. GDF15 is a member of the TGFß superfamily, which is a dimer-structured stress-response protein. The expression of GDF15 is regulated by a number of proteins upstream, including p53, early growth response-1, non-coding RNAs and hormones. In particular, GDF15 has been reported to serve an important role in regulating angiogenesis, apoptosis, lipid metabolism and inflammation. For example, GDF15 can promote angiogenesis by promoting the proliferation of human umbilical vein endothelial cells, apoptosis of prostate cancer cells and fat metabolism in fasted mice, and GDF15 can decrease the inflammatory response of lipopolysaccharide-treated mice. The present article reviews the structure and biosynthesis of GDF15, in addition to the possible roles of GDF15 in Alzheimer's disease, cerebral stroke and Parkinson's disease. The purpose of the present review is to summarize the mechanism underlying the role of GDF15 in various brain disorders, which hopes to provide evidence and guide the prevention and treatment of these debilitating conditions.

Determination and comparison of the Francisella tularensis subsp.novicida U112 proteome to other bacterial proteomes.

The proteins expressed by Francisella tularensis subsp. novicida U112 grown to midexponential phase were surveyed by nanoLC-tandem mass spectrometry (LC-MS/MS). To improve annotation of the genome and develop a technology to provide high-throughput analysis of the Francisella proteome in multiple conditions, we sought to establish a fast and simple analysis that would reduce as much as possible the false discovery rate. Our survey detected expression of 63.0% of the predicted proteome from the stable condition of growth in rich medium available at (www.francisella.org). On the basis of detection of essential proteins, we estimated coverage to be approximately 80% of the actual expressed proteome. This suggests that no less than 70% of the proteins could be expressed in this condition. This analysis revealed two previously unidentified protein coding open reading frames and validated 50% of the proteins annotated as hypothetical. On the basis of results of the screen to detect essential proteins, not all proteins expressed provide a measurable contribution to F.t. novicida growth in this condition. Comparison of this protein profile with other profiles previously published suggested that the genome size and number of genes involved in regulation have little effect on the number of proteins expressed in a given stable condition.

Systematic investigation of lycopene effects in LNCaP cells by use of novel large-scale proteomic analysis software.

Lycopene, the red pigment of tomatoes, is a carotenoid with potent antioxidant properties. Although lycopene might function as a prostate cancer chemoprevention agent, little is known about its effects at the cellular level. To define general changes induced by treatment of cells with lycopene, and to gain insights into the possible chemoprevention properties of lycopene, we investigated changes in protein expression after lycopene treatment in human LNCaP cells. The high throughput proteomics data were then visualized and analyzed by novel biological protein pathway modeling software. Differentially expressed proteins were identified, and the data were analyzed by protein pathway simulation software without need for specialized programming by importing pathway models from a number of sources or creating their own. One notable outcome was the identification of a group of upregulated proteins involved in detoxification of reactive oxygen species. This finding suggests that a possible mechanism of lycopene chemoprevention is the stimulation of detoxification enzymes associated with the antioxidant response element. Novel biological pathway modeling software enhances analysis of large proteomics data. When applied to the analysis of proteins differentially expressed in prostate cancer cells upon treatment with lycopene, the upregulation of detoxification enzymes was identified.

Mining the acute respiratory distress syndrome proteome: identification of the insulin-like growth factor (IGF)/IGF-binding protein-3 pathway in acute lung injury.

To obtain a more complete protein profile of the airspace milieu in acute respiratory distress syndrome (ARDS) and to identify new mediators, we analyzed bronchoalveolar lavage fluid (BALF) by shotgun proteomics. Using BALF from three patients, we identified a total of 870 different proteins, a nearly 10-fold increase from previous reports. Among the proteins identified were known markers of lung injury, such as surfactant, proteases, and serum proteins. We also identified several biologically interesting proteins not previously identified in patients with ARDS, including insulin-like growth factor-binding protein-3 (IGFBP-3). Because of the known role of IGFBP-3 in regulating cell survival, we measured IGFBP-3 levels by enzyme-linked immunosorbent assay in ARDS BALF. Normal controls had low levels of IGFBP-3, whereas patients with early ARDS had a significant increase in IGFBP-3. The IGF pathway, acting through the type 1 IGF-receptor, repressed apoptosis of lung fibroblasts but not lung epithelial cells. Furthermore, depletion of IGF in ARDS BALF led to enhanced fibroblast apoptosis. Our data suggest that the IGFBP-3/IGF pathway is involved in the pathogenesis of lung injury, illustrating the power of shotgun proteomics to catalog proteins present in complex biological fluids, such as BALF, from which hypotheses can be developed and tested.

Membrane-based nanoscale proteolytic reactor enabling protein digestion, peptide separation, and protein identification using mass spectrometry.

A miniaturized trypsin membrane reactor housed inside a commonly used capillary fitting is developed and demonstrated for enabling rapid and sensitive protein identification by on-line proteolytic digestion and analysis of protein digests using nano-ESI-MS and MALDI-MS. The design and assembly of the capillary fitting-based trypsin membrane reactor are straightforward and highly robust, without the need for expensive fabrication technology and procedures. The resultant protein digests can also be further concentrated and resolved using capillary reversed-phase liquid chromatography or transient capillary isotachophoresis/zone electrophoresis prior to the mass spectrometric analysis in an integrated platform. By comparing these results with the results obtained from our previous studies using plastic microfluidics (Gao et al., Anal. Chem. 2001, 73, 2648-2655), significant reduction in dead volume and sample consumption can be achieved using this newly developed tryptic digestion station. This nanoscale reaction system enables rapid proteolytic digestion in seconds instead of hours for a protein concentration of less than 10(-8) M, consumes very little sample (< or = 5 fmol), and offers capillary interfaces with various separation and mass spectrometry techniques. The ultrafast enzymatic turnover for attaining complete peptide coverage in protein identification is contributed by the highly porous structure of the membrane media, providing excessive trypsin loading while eliminating the constraints of diffusion-limited reaction kinetics.