A FRAMEWORK OF ADAPTED TRAVEL REFERENCES IN ONLINE SOCIAL MEDIA

Location information collected from mobile users, knowingly and unknowingly, can reveal not only a user’s latitude and longitude. In this paper, we study approximate k nearest neighbor queries where the mobile user queries the area based company about approximate k nearest sights according to his current location. To judge the security within our solutions, we define a crook model internet hosting in queries. The security analysis has shown our solutions ensures both location privacy meaning the client does not reveal any longer understanding about his place for that LBS provider and query privacy meaning the client does not reveal what type of POIs he's interested in the LBS provider. We're feeling the mobile user can purchase his location from satellites anonymously, coupled with base station coupled with LBS provider don't collude to comprise the customer location privacy or susceptible to anonymous funnel. RSA is not a probabilistic file encryption plan. To alter RSA acquiring a probabilistic file encryption plan, we must be adding random bits for your message m before encrypting m with RSA. The goal of transporting this out must be to ensure the mobile user can buy only one in POIs per query. In addition, once the mobile user can buy a string of encrypted k nearest POIs inside the response within the LBS server, they may frequently run the RR formula simply when using the LBS server to get a sequence of k nearest POIs without passion for query generation and response generation. Performance has shown our fundamental protocol performs much well compared to present PIR based LBS query protocols with regards to both parallel computation and communication overhead

Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models

The future paradigm of HMA + VEN or targeted inhibitor approaches: sequencing or triplet combinations in AML therapy

The routine use of next-generation sequencing methods has underscored the genetic and clonal heterogeneity of acute myeloid leukemia (AML), subsequently ushering in an era of precision medicine–based targeted therapies exemplified by the small-molecule inhibitors of FLT3 , IDH1/IDH2 , and BCL2 . This advent of targeted drugs in AML has broadened the spectrum of antileukemic therapies, and the approval of venetoclax in combination with a hypomethylating agent has been a welcome addition to our AML patients unable to tolerate intensive chemotherapy. Mounting evidence demonstrates that molecularly targeted agents combined with epigenetic therapies exhibit synergistic augmented leukemic cell kill compared to single-agent therapy. With such great power comes greater responsibility in determining the appropriate frontline AML treatment regimen in a molecularly defined subset and identifying safe and effective combination therapies with different mechanisms of action to outmaneuver primary and secondary resistance mechanisms in AML

Chronic Neutrophilic Leukemia: Current and Future Perspectives

Chronic neutrophilic leukemia (CNL) is a BCR-ABL1enegative myeloproliferative neoplasm with notably dismal survival. The current 2016 World Health Organization classification of myeloid neoplasms enables clinicians to unequivocally differentiate CNL from its comparable myelodysplastic/myeloproliferative neoplasm overlap syndromes. Additionally, the gradual emergence of next-generation sequencing has progressively expanded our evolving understanding of the molecular pathogenesis of CNL and its therapeutic potential. Hematopoietic stem-cell transplantation remains the primary therapeutic option for the effective treatment of CNL. In this comprehensive review, we highlight the contemporaneous classification, diagnostic criteria, and molecular pathogenesis of CNL. We also discuss the therapeutic implications of the heterogeneous molecular fingerprint of CNL, focusing on emerging targeted therapies, specifically inhibitors of JAK and MAPK signaling pathways

Current State and Future Prospects of Diagnosis and Management of TP53 Mutated Myeloid Neoplasms

TP53 mutated myeloid neoplasms including acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are notoriously treatment resistant with uniformly poor outcomes. TP53 status is an important prognostic indicator and early knowledge of the of TP53 mutation/allelic state may assist in appropriate management including clinical trial enrollment for eligible patients. Thus far, no therapy has shown to demonstrate durable response or incremental survival benefit in TP53 mutated AML or MDS. Therefore, there is an urgent need for innovative therapies to improve the outcomes in this notoriously recalcitrant genomic subset. In this review, we dissect the biology, classification,prognosis, current treatment landscape, and the early phase evaluation of investigational agents in TP53 mutated AML and MDS

Young Adults with Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a disease of older age with a median age of 68 years at diagnosis. This chapter includes answers to practice‐based questions covering the principles of diagnosis, classification, staging, treatment, and outcomes in AML. Advances in next‐generation sequencing and better understanding of the molecular pathogenesis of AML has revealed the existence of age‐related differences in AML biology. Ara‐C is the most active agent in the treatment of AML and the backbone for many of the standard and investigational combination regimens. Measurable residual disease (MRD) indicates the persistence of leukemic cells below the level of routine methods of morphological detection in patients who have achieved morphologic remission. Bulk next‐generation sequencing has also been used for MRD monitoring looking for mutation clearance but has lower sensitivity. Currently, MRD status does not guide treatment decision‐making outside of clinical trials

The odyssey of pacritinib in myelofibrosis

Myelofibrosis (MF) can present with symptomatic splenomegaly and/or cytopenias including thrombocytopenia. Disease-related thrombocytopenia is a poor prognostic factor with a median overall survival of less than 2 years. Currently approved JAK1/2 inhibitors have not been evaluated in patients with platelets <= 50 x 109/L and in fact could potentiate thrombocytopenia because of their combined JAK1/2 inhibitory activity. Pacritinib (PAC), a selective JAK2, fms-like tyrosine kinase 3, interleukin-1 receptor-associated kinase 1 multikinase inhibitor was developed to meet this unmet need. PAC was evaluated in 2 randomized phase 3 trials in the frontline setting (PERSIST-1, PAC 400 mg daily vs best available therapy) and second-line setting in patients with MF with platelets <= 100 x 10(9)/L (PERSIST-2, PAC 400 mg daily or 200 mg twice daily vs best available therapy). PERSIST-1 met its primary end point; however, the development of PAC hit a brief pause because of a US Food and Drug Administration-mandated clinical hold for excess of bleeding and cardiac events in the PAC 400 mg daily arm in the PERSIST-1 study. Although the PERSIST-2 study was terminated abruptly because of this clinical hold, it met its splenic response end point and demonstrated a trend toward symptom improvement. Subsequent, diligent review of the PERSIST-1 and PERSIST-2 studies did not confirm an excess of severe bleeding or cardiac events on the PAC arm. Additionally, the dose finding PAC203 study endorsed the safety and efficacy of 200 mg twice daily, leading to the approval of PAC for the treatment of patients with MF with platelets <= 50 x 10(9)/L