Citrate is essential to biomineralization of the bone especially as an integral part of apatite nanocomposite. Citrate precipitate of apatite is hypothesized to be derived from mesenchymal stem/stromal cells (MSCs) upon differentiation into mature osteoblasts. Based on 13C‐labeled signals identified by solid‐state multinuclear magnetic resonance analysis, boosted mitochondrial activity and carbon‐source replenishment of tricarboxylic acid cycle intermediates coordinate to feed forward mitochondrial anabolism and deposition of citrate. Moreover, zinc (Zn2+) is identified playing dual functions: (i) Zn2+ influx is influenced by ZIP1 which is regulated by Runx2 and Osterix to form a zinc‐Runx2/Osterix‐ZIP1 regulation axis promoting osteogenic differentiation; (ii) Zn2+ enhances citrate accumulation and deposition in bone apatite. Furthermore, age‐related bone loss is associated with Zn2+ and citrate homeostasis; whereas, restoration of Zn2+ uptake alleviates age‐associated declining osteogenic capacity and amount of citrate deposition. Together, these results indicate that citrate is not only a key metabolic intermediate meeting the emerging energy demand of differentiating MSCs but also participates in extracellular matrix mineralization, providing mechanistic insight into Zn2+ homeostasis and bone formation.
Two hallmarks for cancer cells are the accelerated cell cycle progression as well as the altered metabolism, however, how these changes are coordinated to optimize the growth advantage for cancer cells are still poorly understood. Here we identify that Polo-like kinase 1 (Plk1), a key regulator for cell mitosis, plays a critical role for biosynthesis in cancer cells through activating pentose phosphate pathway (PPP). We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules. Importantly, we further demonstrate that Plk1-mediated activation of G6PD is critical for its role to promote cell cycle progression and cancer cell growth. Collectively, these findings establish a critical role for Plk1 in regulating biosynthesis in cancer cells, exemplifying how cell cycle progression and metabolic reprogramming are coordinated for cancer progression.
Using bioinformatics, we have identified a novel tumor-specific gene BJ-TSA-9, which has been validated by Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). BJ-TSA-9 mRNA was expressed in 52.5% (21 of 40) of human lung cancer tissues and was especially higher in lung adenocarcinoma (68.8%). To explore the potential application of BJ-TSA-9 for the detection of circulating cancer cells in lung cancer patients, nested RT-PCR was performed. The overall positive detection rate was 34.3% (24 of 70) in peripheral blood mononuclear cells (PBMCs) of patients with various types of lung cancers and was 53.6% (15 of 28) in PBMCs of lung adenocarcinoma patients. In combination with the detection of two known marker genes SCC and LUNX, the detection rate was increased to 81.4%. A follow-up study was performed in 37 patients after surgical removal of tumor mass. Among nine patients with persistent detection of two to three tumor marker transcripts in PBMCs, six patients had recurrence/metastasis. In contrast, 28 patients with transient detection of one tumor marker or without detection of any tumor marker were all in remission. Thus, BJ-TSA-9 may serve as a marker for lung cancer diagnosis and as a marker, in combination with two other tumor markers, for the prediction of the recurrence and prognosis of lung cancer patients.
Purpose To investigate the diagnostic performance of two-dimensional (2D) shear-wave elastography (SWE) in chronic hepatitis B. Materials and Methods This prospective multicenter study from January 2015 to January 2016 was conducted at 12 hospitals and included 654 participants with chronic hepatitis B who had undergone liver biopsy and 2D SWE examination. Participants were divided into chronic infection and chronic hepatitis groups. The diagnostic performance of 2D SWE was compared with the aspartate amino transferase-to-platelet ratio index (APRI), the Fibrosis-4 index (FIB-4), and transient elastography (TE) by using a DeLong test and was also compared between two subgroups. Dual cutoff values for cirrhosis were determined with multilevel likelihood ratio analysis. Results Overall, 402 participants with chronic hepatitis B were enrolled (154 with chronic infection and 248 with chronic hepatitis). The areas under the receiver operating characteristic curve of 2D SWE (0.87; 95% confidence interval [CI]: 0.83, 0.90) were higher than those of TE (0.80; 95% CI: 0.68, 0.88), APRI (0.70; 95% CI: 0.65, 0.74), and FIB-4 (0.73; 95% CI: 0.69, 0.78) in cirrhosis. The high area under the receiver operating characteristic curve (0.92; 95% CI: 0.87, 0.96) was achieved in the chronic infection group and was significantly higher than that of the chronic hepatitis group (0.84; 95% CI: 0.78, 0.88; P = .017). Dual cutoff values with the likelihood ratios below 0.1 and above 10 (8.4 kPa and 11.0 kPa to rule out and rule in a diagnosis of cirrhosis, respectively) were effectively determined in chronic infection; a total of 81.2% (125 of 154) participants with cirrhosis were definitively diagnosed. Conclusion The performance of two-dimensional (2D) shear-wave elastography (SWE) was higher than that of other noninvasive methods. 2D SWE was most effective in ruling in and ruling out cirrhosis in participants with chronic infection, which may prompt antiviral treatment. © RSNA, 2018 Online supplemental material is available for this article.
T cells modified with anti-CD19 chimeric antigen receptor (CAR) containing either CD28 or 4-1BB (also termed TNFRSF9, CD137) costimulatory signalling have shown great potential in the treatment of acute lymphoblastic leukaemia (ALL). However, the difference between CD28 and 4-1BB costimulatory signalling in CAR-T treatment has not been well elucidated in clinical trials. In this study, we treated 10 relapsed or refractory ALL patients with the second generation CD19 CAR-T. The first 5 patients were treated with CD28-CAR and the other 5 patients were treated with 4-1BB CAR-T. All the 10 patients were response-evaluable. Three patients achieved complete remission and 1 patient with extramedullary disease achieved partial response after CD28-CAR-T treatment. In the 4-1BB CAR-T treatment group, 3 patients achieved complete remission. Furthermore, FLT-3 ligand (FLT3LG) was highly correlated with response time and may serve as a prognosis factor. No severe adverse events were observed in these 10 treated patients. Our study showed that both CD28 CAR-T and 4-1BB CAR-T both worked for response but they differed in response pattern (peak reaction time, reaction lasting time and reaction degree), adverse events, cytokine secretion and immune-suppressive factor level.
remains the major concern of anti-CD19 CAR-T cell therapy. One mechanism for relapse is the development of humoral and/or cellular immune responses against some specific epitopes of scFv in the CAR structure, which are derived from a murine antibody. In this investigator-initiated trial, we developed a humanized anti-CD19 scFv CAR-T (hCAR-T) cells and infused these cells to patients with r/r ALL. Sustained B cell aplasia and long-term persistence of hCAR-T cells were observed in these patients. Moreover, four patients with high tumor burden and rapidly progressive disease experienced grade 3-4 of cytokine release syndrome (CRS). These severe CRSs were successfully controlled by tocilizumab, glucocorticoid and plasma exchange (PE). Our data provide a potential method to reduce the relapse rate for patients accepting CAR-T cell therapy.Research.
The two known DP proteins, TFDP1 and -2, bind E2Fs to form heterodimers essential for high affinity DNA binding and efficient transcriptional activation/repression. Here we report the identification of a new member of the DP family, human TFDP3. Despite the high degree of sequence similarity, TFDP3 is apparently distinct from TFDP1 in function. Although TFDP3 retained the capacity to bind to E2F proteins, the resulting heterodimers failed to interact with the E2F consensus sequence. In contrast to the stimulatory effect of TFDP1, TFDP3 inhibited E2F-mediated transcriptional activation. Consistent with this observation, we found that ectopic expression of TFDP3 impaired cell cycle progression from G 1 to S phase instead of facilitating such a transition as TFDP1 does. Sequence substitution analysis indicated that the DNA binding domain of TFDP3 was primarily responsible for the lack of DNA binding ability of E2F-TFDP3 heterodimers and the inhibition of E2F-mediated transcriptional activation. Fine mapping further revealed four amino acids in this region, which were critical for the functional conversion from activation by TFDP1 to suppression by TFDP3. In conclusion, these studies identify a new DP protein and a novel mechanism whereby E2F function is regulated.
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