Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, ...glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer.
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•GDH1 contributes to anoikis resistance and tumor metastasis by activating CamKK2•α-KG binds to CamKK2 and recruits AMPK to CamKK2•In LKB1 null lung cancer, GDH1-induced CamKK2 substitutes for LKB1 to activate AMPK•PLAG1 induces GDH1 expression upon cell detachment from the matrix
Although elevated glutaminolysis has been demonstrated in cancer cells, the precise mechanism by which glutaminolysis promotes tumor metastasis remains unclear. In this article, Jin et al. demonstrate a mechanism by which GDH1 provides anti-anoikis and pro-metastatic signals through activating CamKK2 and AMPK that promotes tumor metastasis in LKB1-deficient lung cancer.
Toll-like receptors (TLRs) activation enables host to recognize a large number of pathogen-associated molecule patterns (PAMPs), ignite immune cells to discriminate between self and non-self, and ...then promote the following innate and adaptive immune responses. Accumulated clinical/preclinical evidences have proven TLRs to be critical role in the autoimmune diseases, including inflammatory and tumor-associated diseases. Activation of TLRs is becoming or has been a target for cancer treatment. It is shown that TLRs can induce preferable anti-tumor effect by eliciting inflammatory cytokines expression and cytotoxic T lymphocytes (CTLs) response. As adjuvant, TLRs agonists can launch a strong immune response to assist cancer radiotherapy and bio-chemotherapy. On the other hand, tumor-associated antigens acting as PAMPs, can also activate TLRs and induce tumor gene-related programmed cell death, including apoptosis, autophagy and programmed necrosis. While there are also arguments that the excessive TLRs expression will promote tumor deterioration in various organisms, as the TLR-induced inflammation will accelerate the cancer cells boost in the tumor microenvironment (TME). However, the effect of TLRs acting on cancers is still not quite clear today. In this review, we will summarize the recent researches of TLRs in cancer treatment and their role in TME, giving a brief overview on future expectation.
Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. ...These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.
Tell me which you want: Catalytic asymmetric 4+2 cycloadditions of β,γ‐unsaturated α‐ketophosphonates with allenic esters catalyzed by organocatalysts derived from different cinchona alkaloids have ...been developed, affording phosphonate‐substituted functionalized pyran and dihydropyran derivatives in excellent yields with high enantioselectivities under mild conditions. The choice of product is controlled by the hydrogen bonding characteristics of the chosen catalyst.
Adopting learning management systems to support teaching has become the norm in education field. Therefore, huge amount of data about the learning history of students has been accumulated. Educators, ...therefore, can use data mining techniques to evaluate students' learning performance. Fuzzy association rule mining is one of the techniques used to investigate the correlation between teaching means or students' characteristics and their performance. For instance, the rule Gender = Male∧Attendance = Low∧Final Report = Middle→Semester = Middle states that a student's semester grade is in Middle if his gender is male, attendance rate is Low, and final report score is Middle, where Middle and Low are predetermined linguistic terms given by educators. The information shown in this example reveals general and concise knowledge for educators, allowing them to adjust their teaching strategies and pedagogies. However, no studies, to our knowledge, have yet to assess changes by applying this type of rule in the education field. For example, say that the above rule became available in the last semester; however, is not a trend this semester, and has been substituted by "Gender = Female∧Attendance = High∧Final Report = Middle→Semester = Middle". Without updates in knowledge and belief, educators might adopt inappropriate teaching strategies and pedagogies for students who are learning in different time-periods. To deal with this problem, this study proposes a change mining model to detect changes in students' learning performance. We also carry out experiments to evaluate the proposed model. We empirically demonstrate how the model helps educators to understand the changing characteristics of students and to improve their teaching practice.
Flavonoids, commonly found in various plants, are a class of polyphenolic compounds having a basic structural unit of 2-phenylchromone. Flavonoid compounds have attracted much attention due to their ...wide biological applications. In order to facilitate further research on the biomedical application of flavonoids, we surveyed the literature published on the use of flavonoids in medicine during the past decade, documented the commonly found structures in natural flavonoids, and summarized their pharmacological activities as well as associated mechanisms of action against a variety of health disorders including chronic inflammation, cancer, cardiovascular complications and hypoglycemia. In this mini-review, we provide suggestions for further research on the biomedical applications of flavonoids.
Incorrect decision-making in financial institutions is very likely to cause financial crises. In recent years, many studies have demonstrated that artificial intelligence techniques can be used as ...alternative methods for credit scoring. Previous studies showed that prediction models built using hybrid approaches perform better than single approaches. In addition, feature selection or instance selection techniques should be incorporated into building prediction models to improve the prediction performance. In this study, we integrate feature selection, instance selection, and decision tree techniques to propose a new approach to predicting credit approval. Experimental results obtained using the survey data show that our proposed approach is superior to the other five traditional machine learning approaches in the measures. In addition, our approach has a lower cost effect than the traditional five methods. That is, the proposed approach generates fewer costs, such as money loss, than the traditional five approaches.
•Ni-Co NWAs electrode was fabricated by polycarbonate template.•Ni-Co NWAs electrode with 10% of Co molar ratio shows best catalytic activity.•Direct urea/H2O2 fuel cell shows high output performance ...with Ni-Co NWAs anode.
Nickel-cobalt nanowire arrays (Ni-Co NWAs) electrode is prepared by one-step galvanostatic electrodeposition with a polycarbonate membrane as the template. By adjusting the Co proportion in the Ni and Co bath solution into 10%, the optimal Ni-Co NWAs electrode in terms of relatively lower onset potential and highest current density towards urea electro-oxidation is obtained. Its catalytic performance is investigated by constructing single direct urea/hydrogen peroxide (H2O2) fuel cell. Results show that a peak power density of 7.4mWcm−2 and an open circuit voltage of 0.92V are achieved at room temperature when 9.0molL−1 KOH and 0.33molL−1 urea are used as the anolyte, H2SO4 and H2O2 as the catholyte. Additionally, the urea/H2O2 fuel cell also demonstrates excellent stability during short term duration test.
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is crucial in controlling cellular activities in response to extracellular cytokines. Dysfunctions of the ...JAK/STAT pathway result in various hematopoietic and immune disorders. The central events in regulating this pathway are tyrosine phosphorylation and dephosphorylation of the signaling components, which are carried out by protein tyrosine kinases and protein tyrosine phosphatases (PTP), respectively. Here, we review recent advances in the regulatory roles of PTPs, in particular, SHP2 phosphatase, in the JAK/STAT signaling pathway.
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•Both indirect oxidation and direct urea electro-oxidation paths exist on nickel.•Rate determining step depends on polarization potential and KOH concentration.•Nickel catalyst is ...poisoned by the CO2 intermediate.
Urea electro-oxidation reaction in alkaline medium is systematically analyzed by electrochemical impedance spectroscopy (EIS). The effects of polarization potential and KOH concentration on the impedance appearance are investigated. In the presence of urea, it is found that Nyquist plots exhibit two depressed semicircles, with one at higher frequencies stably locating in the first quadrant while the other’s location at lower frequencies varying between the first and second quadrant as the polarization potential changes. Results show both indirect and direct pathways proceed in urea electro-oxidation reaction. A mathematical model indicates the reverse loop in the Nyquist plots is attributed to CO2 poisoning on the catalyst, which is also validated by the followed chronoamperometric method. Moreover, the rate determining steps of urea electro-oxidation reaction is dependent on KOH concentration. The EIS technique gives a new sight to interpret the poor stability of urea electro-oxidation on nickel catalyst, and thus helps to explore a CO2-insensitive catalyst.
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