Twice in a Blue Moon (The Jordon Journals: Book 2)

Congratulations to Michael Vance. His novel with R. The link to the ballot follows. They would both appreciate your vote. JKP to publish sequel for Michael Vance. Great article about Michael Vance. Dear Reader, This is your assignment should you choose to accept it…. Be one of the first to own a copy today! Part 2 of our interview with author Michael Vance is now available! Check out Part 2 of our interview with Michael Vance! Michael Vance Book Signing in Ada. Oklahoma authors Michael Vance and R. Jones will sign their novels, comic books, and other non-fiction and fiction on Saturday, February 21 starting at 10 am at Hastings Entertainment in Ada.

Enjoy Part 1 of our interview with author Michael Vance! Part 1 of our interview with author Michael Vance is now available! Popularity Popularity Featured Price: Low to High Price: High to Low Avg. Available to ship in days. Validity of administrative data in recording sepsis: Medicine, Health Care and Philosophy. Administrative registers in psychiatric research: Accuracy of administrative health data for the diagnosis of upper gastrointestinal diseases. The inevitable application of big data to health care.

The Journal of the American Medical Association. Fusing randomized trials with big data. Big data and large sample size: Clinical and Translational Science. The rise of big clinical databases. British Journal of Surgery. Activity-based funding of hospitals and its impact on mortality, readmission, discharge destination, severity of illness, and volume of care: Medical Care Research and Review.

The American Journal of Bioethics. Harnessing the heart of big data. Big Data - and its contributions to peri-operative medicine. Tobias is a third year medical student at UWA, with broad interests in medicine and surgery. He previously completed a degree in Biomedical Science, specialising in cellular and macromolecular biochemistry.

Tobias is passionate about the role of evidence-based research in medicine and plans on being heavily involved in research throughout his medical career. Hepatocellular carcinoma HCC is the sixth most common cancer worldwide contributing to approximately , deaths each year with this number on the rise in the developing world. The aetiology of HCC has been well characterised, including chronic hepatitis B and C infection as well as alcoholic cirrhosis.

Current screening programs for patients at high risk of developing HCC, including ultrasound and alpha-fetoprotein analysis, are neither sufficiently sensitive nor specific to detect early HCC. This reduces the likelihood of detecting HCC when curative treatment is effective. If further research confirms this mutation as a common step in early hepatocarcinogenesis then this maker could be utilised to screen for early HCC lesions in at risk populations.

Further research in this area could facilitate the early diagnosis of HCC, improving the efficacy of treatment. Introduction Liver cancer is the sixth most common cancer worldwide and the second largest cause of cancer mortality [1]. It has several subtypes including hepatocellular carcinoma HCC , bile duct cancer, hepatoblastoma, and various other liver sarcomas and carcinomas [2].

A similar rise in HCC incidence and death rates in Australia have also been identified; possibly linked to the increased prevalence of Hepatitis B and Hepatitis C infection in Australia [6,7]. Moreover, there is evidence that HCC incidence rates in Australia may be up to two-fold higher than the rates reported by cancer registries such as the Victorian Cancer Registry [8]. These features make HCC an insidious and difficult disease to clinically detect and investigate. Patients who develop HCC are usually asymptomatic, mostly displaying symptoms related to their chronic liver disease which can become modified with disease progression [6,12].

Examples of this include signs of decompensation such as ascites, encephalopathy, jaundice, and variceal bleeding [12]. Advanced lesions also can present more conspicuously causing obstructive symptoms such as jaundice, diarrhoea, weight loss, and fatigue [13]. These signs are a result of local tumour invasion and growth inside the liver. However, systemic signs can also occur as a result of metastases which can develop in the lung, portal vein, periportal nodes, bone or brain [13].

The aetiology of HCC is well documented in the literature with high rates linked to both hepatitis B and hepatitis C exposure [9]. Other significant causes that may cause patients to present include alcoholic liver disease, non-alcoholic steatohepatitis as well as hereditary conditions such as haemochromatosis, alpha-1 antitrypsin deficiency, and autoimmune disorders Figure 1 [10,11].

The natural history of HCC growth begins as small asymptomatic nodules which can often take years to develop depending on the aetiological exposure [5]. Small HCCs at detection have relatively long Figure 1. Aetiology of hepatocellular carcinoma. Volume 8, Issue 1 Screening and detection of HCC Accordingly, screening programs for HCC in at risk groups, those with chronic liver disease or chronic hepatitis infection, is recommended with specialist review forming part of a monthly management plan [15]. These programs involve using alpha-fetoprotein AFP and ultrasound to screen for the presence of cancer lesions.

Some studies investigating the clinical utility of AFP have suggested it lacks the sensitivity to be useful, with one study suggesting it rarely assisted in a diagnosis [5,17,18]. As a result of this, it has been suggested that AFP testing alone should only be used if ultrasound is unavailable, with the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver recommending it not be used at all [16,18,20]. Due to these limitations, other serum markers which include plasma microRNAs such as miR and miR, des-gamma-carboxy prothrombin, AFP isoforms and glypican-3 are currently being investigated and evaluated for future use [19,20].

Another modality that is used in HCC screening is ultrasound. Ultrasound can detect large HCCs with high sensitivity and specificity; however, it is less able to reliably identify smaller lesions, which are required if more effective therapy is to be offered [6,19,20].

Combined use of AFP and ultrasound has been shown to increase detection rates, but had a raised combined false positive rate of 7. Despite the limitations of these tests, the Royal Australian College of General Practitioners guidelines suggest that patients with chronic liver disease or chronic hepatitis infection should be considered for monthly AFP and ultrasound screening [15].

The importance of early HCC detection cannot be understated. The natural history of early tumours is poorly known as most are treated upon diagnosis; however, surgical resection, tranplantation and ablation offer high rates of complete responses and a potential cure in all patients with early HCC [22]. Advanced course HCC has a survival of less than six months without treatment with prognostic factors for survival including anatomical extension of the tumour, performance status and functional hepatic reserve based on the Child-Pugh Score [].

It is from this that researchers are currently investigating superior screening techniques which can identify tumours earlier and with greater sensitivity and specificty to enable earlier intervention and better treatment outcomes.

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Cancer biology as the pathway for a HCC screening test One approach that is currently being investigated in the medical literature focusses on the biology of HCC hepatocarcinogenesis to develop a sensitive early screening test that can guide and detect treatment before the cancer can extend and spread. Mature hepatocytes have an average lifespan of between days and rarely proliferate unless stimulated by acute injury [25]. The observation of normally quiescent hepatocytes and cholangiocytes proliferating.

If this regenerative capacity is compromised, the liver has liver progenitor cells LPCs which can expand and regenerate the chronically damaged liver [27,28]. LPCs can propagate and differentiate into two types of liver epithelial cells; hepatocytes and cholangiocytes [27]. These cells have been defined as stem cells because they are clonogenic, with a high growth potential and are able to be induced to differentiate into both types of liver cells and have shown capability in repopulating the liver on transplantation [].

The proliferation and differentiation of LPCs into hepatocytes render them a target population for hepatocarcinogenesis [30]. LPCs have been traced to hepatocytes and are markedly elevated in chronic liver disease [28]. Recent laboratory experimentation has shown a link between induced liver damage in mice and the development of HCC, suggesting a tenable link between LPCs and HCC development [31,32].

LPCs have also been documented in chronic human liver pathologies, such as chronic hepatitis C, which is highly associated with hepatocarcinogenesis [29,]. From a molecular analysis of HCC progression, it has been shown that hepatocarcinogenesis is a multistep process that is heterogeneous and not well understood [40]. Progressive genetic alterations have been shown to cause a spectrum of cellular changes starting from cell hyperplasia, proliferation to dysplasia and eventually cancer [28,40].

This model is widely accepted and has been applied to many types of cancer, including HCC [28]. Multiple studies have demonstrated that two tumour suppressor pathways are important in controlling cell proliferation including the retinoblastoma protein pathway and the p53 pathway [28,41]. Most human tumours have genetic mutations, deletions, deregulated methylation or alterations in microRNA signalling in their Retinoblastoma and p53 pathways; making these genes likely candidates in the transformation of non-tumourigenic LPCs to tumourigenic LPCs [].

The nature of how genes are inactivated in tumourigenesis is biologically complex. While the current screening methods using AFP and ultrasound are considered to be clincially useful in detecting HCC, there exists a space for more accurate modalities to detect early HCC lesions. This could potentially improve the prognosis of patients with HCC development and allow early directed treatment with the possibility of cure.

Thank you to Professor George Yeoh for his assistance in proofreading this article and providing support and advice. References [1] Laursen L. Cancer Australia; [cited April]. Annu Rev Genomics Hum Genet. Guidelines for the diagnosis and treatment of hepatocellular carcinoma HCC in adults. Primary hepatocellular carcinoma in Australia, — Rising incidence of hepatocellular carcinoma in the United States. Novel populationbased study finding higher than reported hepatocellular carcinoma incidence suggests an updated approach is needed.

Incidence, aetiology, and outcomes of cancer in Indigenous peoples in Australia. Pathobiology of liver fibrosis: Clinical features and diagnosis of primary hepatocellular carcinoma. A new prognostic system for hepatocellular carcinoma: Cancer survival and prevalence in Australia period estimates from to Australian Institute of Health and Welfare. Royal Australian College of General Practitioners. Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. American association for the study of liver diseases: Prevention of hepatocellular carcinoma and recommendations for surveillance in adults with chronic liver disease.

Asian pacific association for the study of liver consensus recommendations on hepatocellular carcinoma. Natural history of hepatocellular carcinoma and prognosis in relation to treatment.

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Study of patients. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Prognosis of hepatocellular carcinoma: Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. Liver stem cells and hepatocellular carcinoma. Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy. Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: Cancer stem cells in the development of liver cancer. Invadin macrophages play a major role in liver progenitor cell response to chronic liver injury.

A modified choline-deficient, ethionine-supplemented diet reduces morbidity and retains a liver progenitor cell response in mice. Human liver progenitor cell lines are readily established from non-tumorous tissue adjacent to hepatocellular carcinoma. Hepatic oval cell response to the cholinedeficient, ethionine supplemented model of murine liver injury is attenuated by the administration of a cyclo-oxyenase 2 inhibitor.

Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Hepatic oval cell lines generate hepatocellular carcinoma following transfection with HBx gene and treatment with aflatoxin B1 in vivo. Molecular mechanisms in hepatocellular carcinoma. The RB and p53 pathways in cancer. Alterations of the p14 ARF gene and p53 and p53 status in human hepatocellular carcinoma. MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med. Genes involved in hepatocellular carcinoma: Detection of hypermethylation of the p16 INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus.

Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. CpG island methylator phenotype associated with tumor recurrence in tumor-node-metastasis stage I hepatocellular carcinoma. Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma. Genetic and epigenetic signatures in human hepatocellular carcinoma: This review has taken Sam out of his comfort zones of emergency and cardiovascular medicine and into the world of molecular oncology. Since the introduction of the tyrosine kinase inhibitor TKI , imatinib, in , CML survival rates have increased, to the point where life expectancy is equal to that of the general population.

One obstacle patients face is imatinib resistance. Literature about resistance has mainly focussed on mutations in the Bcr-Abl kinase domain KD , which have been well described. Areas that have not been as well established include the origin of KD mutations and resistance from mechanisms outside of KD mutations.

Experimental therapies to combat imatinib resistance are also mentioned. Using database searches to obtain the current literature, this review attempts to determine the current consensus on these topics and highlight areas where research could be beneficial. While the origin of KDmutations and non-KD resistance is not entirely clear, the many possible causes that have been elucidated thus far have already paved the way for new therapies.

Introduction Chronic myeloid leukaemia CML was the first cancer where the pathological chromosomal abnormality was identified, and is one of the most understood and well-managed cancers [1,2]. CML is a clonal disorder of pluripotent stem cells that results in over-proliferation of mature myeloid cells [3].

Constitutive and aberrant tyrosine kinase activity is responsible for pathological cell proliferation in CML [4]. For patients aged diagnosed in , this jumped to Responsible for these leaps in survival was imatinib mesylate, a TKI approved in [6]. Imatinib antagonises tyrosine kinase activity by competing with ATP binding to the Bcr-Abl protein, reducing unchecked cellcycle progression [3]. Hence, it is important for doctors and medical students alike to understand that resistance occurs, some of the mechanisms behind resistance and how new pharmacotherapies can combat these.

This review summarises the pathophysiology of CML and synthesises the literature around competing theories of imatinib resistance. Pathophysiology of CML CML is a myeloproliferative disease caused by a reciprocal translocation between chromosome 9 and 22 9;22 q34;q This creates an abnormal chromosome 22 called the Philadelphia Ph chromosome, named after the city it was discovered in in [2,8].

Bcr-Abl has constitutive tyrosine kinase activity, causing modulated gene transcription, proliferation, and enforced survival of myeloid progenitor cells [14]. Unregulated cells grow and enter the S-Phase of the cell cycle independently of physiological growth factors and avoid apoptosis [8,14,15].

Abl and Bcr-Abl are non-receptor tyrosine kinases that travel between the nucleus and the cytoplasm and phosphorylate proteins via SH2 and SH3 domains [16]. Targets of increased phosphorylation that have proliferative effects include insulin-like growth factor receptor 1 IGF-1R [17], Ras [16], p27Kip [18], and others. This review will focus on a selection of the most well-known pathways Figure 1.

These three pathways highlight that Bcr-Abl is central. Intracellular pathways influenced by Bcr-Abl Kinase [24,25,26]. Imatinib is shown solely inhibiting Bcr-Abl, however, research shows imatinib therapy also affects Lyn kinase expression and activity. Survival with CML over time [29]. This figure from the German CML-Study group shows patient survival probability as a function of time after diagnosis in five consecutive randomised treatment optimisation studies.

Kindly authorised by R Hehlmann. Gives a good prognostic indicator Normally not achieved until equivalent to 0. As a consequence, pharmacotherapy targeting Bcr-Abl has been developed in the form of imatinib. The current parameters to measure successful treatment outcomes are listed with definitions in Table 1. In the International Randomized Study of Interferon and STI, it was found that complete haematological response CHR , complete cytogenetic response CCyR , and major molecular response MMR scores were superior in imatinib-treated patients compared with interferon-treated patients [30].

Imatinib binds specifically to the ATP-binding sites of Bcr-Abl, c-kit, and platelet-derived growth factor receptors, and inhibits their tyrosine kinase activity by both preventing ATP binding and stabilising the activation loop in an inactive conformation [34,36,37]. Treatment considerations and mechanisms of Imatinib resistance in CML Failure of TKI therapy is caused by a number of factors, including inappropriate drug choice, patient non-adherence, and drug resistance. There are a number of opinions as to what constitutes treatment failure, but the definition used by this paper is the one put forward by the ELN and European Society for Medical Oncology.

Treatment failure depends on which measurement is used; using haematological parameters testing peripheral leukocyte counts , treatment failure is defined as no haematological response by three months, or any loss of CHR. Using cytogenetic response, however, treatment failure is no cytogenetic response within six months, no CCyr by 18 months, or any loss of CCyr, as detected by CBA [38].

While this review focuses on imatinib the gold standard in CML therapy [30], second generation TKIs such as nilotinib, ponatinib, and dasatinib are now also used, both as first line agents and for use in imatinib resistant patients [1,27]. Which TKI to use and at what dose depends on a number of factors, including imatinib sensitivity and which disease phase the patient is in.

Using imatinib inappropriately could cause treatment failure, while immediately using a second generation TKI or increasing TKI dosages has been found to limit adherence, as well as side effects Table 2 , especially for patients who require more potent TKIs and higher doses [40]. The most serious complication in CML treatment is resistance to therapy. This occurs most frequently in the AP and BP stages of the disease Traditionally, resistance is thought to occur from point mutations in the Bcr-Abl kinase domain KD [1,15,34,43].

There are several mutations that can cause mutations in this setting Table 3. Bcr-Abl KD mutations can be intrinsic primary or acquired secondary and interfere with TKI therapy in a number of ways [1]. The most common mechanisms are by directly interfering with TKI binding via amino acid substitutes in the ATP binding site or by preventing the activation loop from adopting the inactive conformational state [34].

Although Abl KD mutations causing TKI resistance were first induced in laboratory cell lines in [44], and detected in vivo clinically in [45], novel mutations are continually being discovered, with two new mutations conferring resistance sequenced in [46]. The discovery and sequencing of mutations has led to individualised therapy and a more accurate prognosis for specific mutations, for instance the TI mutation.

In this common mutation, threonine is replaced with. Volume 8, Issue 1 Table 2. Stages of CML with respective treatment options and side effects[1,27,41,42]. Lower response rates and inferior event free survival if patients have resistance. Overall mutation rate for imatinib was 9. However, this drug is not used as a front line therapy as it has a higher rate of arterial thrombosis and pancreatitis when compared to imatanimb [1].

Another drug, ABL, also acts at another molecular site and thus avoids the resistance caused by KD mutations.

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ABL mimics the autoregulating region of ABL1 that is lost upon fusion of BCR, restoring negative regulation, and has been shown to remain effective against clinically significant mutations in an in vivo model [48]. This example highlights how sequencing mutations can provide valuable, individualised prognostic information and guide future research.

How these mutations arise is not clear; in some patients with secondary resistance pre-therapeutic samples revealed the same KD mutation detected at relapse, consistent with selection of pre-existing resistant clones during therapy giving an evolutionary advantage [52,53]. This discrepancy may be explained by the more recent study utilising more sensitive technology and patients who had CML for a longer period of time, which has been linked to mutagenicity [28]. KD resistance in Bcr-Abl1 CML differs from other diseases in that unlike traditional drug resistance, where treatment resistance arises via positive selection of tumour cells with mechanisms to avoid DNA damage, in CML resistant cells there is a tendency to accumulate more rather than less DNA damage [56].

The mechanism behind this is unknown, but it is an example of how the malignancy directly causes resistance. Nevertheless, the evidence suggests that pre-existing KD mutations in cancer stem cells are more likely to be responsible for secondary resistance. Mutation rate and advanced disease phase were. AM S J correlated, consistent with mutations being related to exposure time to Bcr-Abl activity [34].

One suggested mechanism is production of reactive oxygen species causing genomic instability, shown in vitro and in murine models, but beyond the original studies, no further research has been undertaken [34,57]. While KD mutations are a highly researched area in CML therapy over 60 unique point mutations have been identified , there remains an information deficit, for example, the prevalence of mutations in specific populations, or randomised controlled trials for TKI choice following imatinib failure [1,58].

Non Bcr-Abl kinase domain mediated resistance Recent research adds complexity by suggesting there are a number of mutations and events occurring outside of Bcr-Abl KD that impact drug resistance [43]. This includes mutations of Bcr-Abl1 outside of the kinase domain, such as BCR-ABL1 amplification, and causes outside of the Bcr-Abl1 protein altogether, such as mesenchymal cells, drug transporters and bypass molecular pathways.

However, increased expression is not the sole cause of non-KD mediated resistance as studies have shown that increasing imatinib concentration in non-mutated, sensitive cells with induced BCR-ABL1 amplification still reduces Bcr-Abl activity, whereas some resistant cells without KD mutations remain resistant at any dose [60]. In a study of non-KD mutated resistant cells treated with imatinib, Erk2 was found in the nucleus of resistant cells only, and inhibiting Erk2 caused damage to resistant cells [60].

Mechanisms for how Erk2 could cause primary resistance were then elucidated. To achieve this, mutated Ras which activates Erk2 , was virally transduced into sensitive cells that were cultured and treated with imatinib. Using proliferation assays to determine cell survival, it was discovered activating Erk2 gave previously sensitive cells resistance without any prior exposure to imatinib. Erk2 is a key regulator of the pro-apoptotic molecule Bim and it is proposed interactions between Erk2 and Bcr-Abl over-stimulate Erk2 and reduce CML cell apoptosis [62].

Research in by Wong et al. Drug transporters Alterations in drug transporters are yet another mechanism by which medication resistance can occur and will be mentioned briefly. A drug must both reach the target organ in sufficient amounts and be present at an effective therapeutic concentration for it to exert and effect, and both influx and efflux transporters can interfere with these pharmacokinetics [27]. Radiolabelled imatinib assays have determined that the level of kinase inhibition is dependent on the level of uptake and retention of imatinib achieved [68].

Imatinib enters the circulation from the gastrointestinal tract by a member of the organic cation transporter OCT family, OCT-1, thus mutations in OCT-1 are thought to contribute to treatment failure [68]. In other drugs, MDR1 overexpression has been confirmed to cause drug resistance by increasing efflux before a therapeutic concentration can be reached, and this is a relationship currently under investigation in CML. Non-Bcr-Abl KD resistance is not a well-studied area and much research is yet to be undertaken.

Two recent CML mutation reviews by Jabbour et al. In addition, there was much disagreement among researchers concerning molecular pathways to resistance. Extremely resistant patients require potent TKIs or stemcell transplantation, both of which greatly affect quality of life, which could be avoided if mechanisms behind resistance were uncovered and targeted treatment developed1. Only pathways that have been clearly implicated in CML and imatinib resistance by research literature were included.

Systematic database searches were used to carry out this review. Lyn kinase is a non-receptor tyrosine kinase regulated by Bcr-Abl. Imatinib resistant but Bcr-Abl KD-mutation negative cells were found to overexpress Lyn kinase following treatment with imatinib [64]. In cell lines from these patients, while imatinib effectively inhibited Bcr-Abl activity, Lyn kinase phosphorylation continued, allowing proliferation to continue. Interestingly, prior to imatinib therapy, there was no consistent difference in Lyn expression between sensitive and resistant cells, but afterward there were consistent distinctions in their control of phosphorylation.

This implies imatinib treatment uncouples Lyn expression from Bcr-Abl, leading to resistance. Lyn overexpression can induce a three to fourfold resistance, equal to some KD mutations, yet the mechanisms of its overexpression and how it worsens CML are not yet known [65]. One theory is that because silencing of Lyn kinase induces apoptosis in CML cells, overexpression causes cell survival, signalled through via Gab2 [66,67]. This article holds a number of clinical implications for all medical students, not just the aspiring oncologist.

For instance, the prevailing view in oncology is that mutations that confer imatinib resistance occur in the kinase domain. With the explosion of advances in genome sequencing, it is becoming possible to prospectively genetically screen patients to determine whether resistance will occur. By investigating and becoming aware of the role of non-KD mutations, doctors could also give more accurate prognoses to patients with these mutations and begin studies looking at the best treatment for these cases for example, randomised controlled trials comparing current therapy to higher doses of imatinib, or new pharmacological agents altogether.

This review also provides a general overview into CML pathophysiology, imatinib pharmacology and chemotherapy resistance, topics every medical practitioner should be very familiar with. Imatinib is a TKI that revolutionised leukaemia treatment and increased the length and quality of life of CML patients. While it has been known for many years that primary and secondary resistance to imatinib exist, the mechanisms have not been fully explained. While mutations in the Bcr-Abl KD account for the majority of resistance and are well known, what remains unclear is the origin of these mutations, and how resistance occurs without KD mutations.

Stem cell mutations and self-mutagenesis are possible explanations for how KD mutation occurs, and gene amplification, Lyn kinase and Erk2 for resistance occurring outside of the KD. Further research identifying key events in downstream pathways will offer new approaches for overcoming all forms of imatinib resistance. The author would also like to thank Dr. Donna Rigano and Miss Shalisa Maisrikrod for their assistance and editing help.

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Diagnosis and treatment of chronic myeloid leukemia in A minute chromosome in human chronic granulocytic leukemia. Jabbour E, Kantarjian H. Trends in all-cause mortality among patients with chronic myeloid leukemia: Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. A new consistent chromosomal abnormality in chromc myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining.

Clinical and laboratory haematology. A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia. Bcr-Abl kinase promotes cell cycle entry of primary myeloid CML cells in the absence of growth factors. British journal of haematology. Inhibition of Rasmediated signaling pathways in CML stem cells. Inhibition of IGF-IR tyrosine kinase induces apoptosis and cell cycle arrest in imatinib-resistant chronic myeloid leukaemia cells. Journal of cellular and molecular medicine. Bcr-Abl induces autocrine IGF-1 signaling. Zha J, Lackner MR.

Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Bhatia R, Verfaillie CM. Inhibition of BCR-ABL expression with antisense oligodeoxynucleotides restores beta1 integrin-mediated adhesion and proliferation inhibition in chronic myelogenous leukemia hematopoietic progenitors. A common phosphotyrosine signature for the Bcr-Abl kinase. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.

CML—where do we stand in ? Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. The New England journal of medicine. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: Characterisation, mechanism of action and therapeutic interests for bone cancers. Journal of bone oncology. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative.

Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: Suboptimal response to or failure of Imatinib treatment for chronic myeloid leukemia: Australian public assessment report for Imatinib, Nilotinib and Dastinib. Woden, ACT, Australia Subdural hematomas during CML therapy with imatinib mesylate. Induction of resistance to the Abelson inhibitor STI in human leukemic cells through gene amplification. BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients-Frequency and clinical outcome.

ABL, a potent allosteric inhibitor of BCR-ABL, prevents emergence of resistant disease when administered in combination with Nilotinib in an in vivo murine model of chronic myeloid leukemia. Imatinib-resistant chronic myeloid leukemia CML: J Manag Care Spec Pharm. Kinase domain mutations of BCR-ABL identified at diagnosis before imatinib-based therapy are associated with progression in patients with high Sokal risk chronic phase chronic myeloid leukemia.

Genomic instability in myeloid malignancies: Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: Single-cell analysis of K cells: Journal of cancer research and clinical oncology. Journal of the National Cancer Institute. OCT-1— mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib AMN P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphiapositive patients: Abl-kinase-sensitive levels of ERK5 and its intrinsic basal activity contribute to leukaemia cell survival.

1. Twice in a Blue Moon by Patricia Moyes?
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Blockade of the ERK or PI3K-Akt signaling pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib. Biochemical and biophysical research communications. To ascertain the function of miRNAa in hepatocellular carcinoma HCC and to assess its use as a therapeutic agent through the analysis of pre-clinical and clinical trials.

Multiple studies found that miRNAa was downregulated in the majority of human HCC samples and subsequently had a tumour suppressor role via the inhibition of a number of target genes essential for carcinogenesis. There are some characters who re-appear every now and then, such as the Manciples who make almost a cameo in this one.

A few locations are revisited, such as the fictitious Tampica and British Seawards. And she usually makes a dig at mystery books: In this one, on p 96 Henry replies to someone: It's only in works of fiction that people have curiously vivid mem So many of the modern "cozy" series are somewhat formulaic and predictable.

It's only in works of fiction that people have curiously vivid memories stretching back over years.

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One off-putting aspect in this book is the first person narrator. But despite that, I enjoyed it. Also happens in Murder Fantastical, and maybe another? Jun 30, Nancy rated it really liked it Shelves: Even though it was pretty clear from the beginning who was behind several murders, the how and why seemed impossible so one did keep guessing how so many seemingly unrelated events were connected.

I enjoyed the voice of the narrator so rounded my 3. Oct 29, Susan rated it liked it Shelves: When her reclusive great-uncle dies, Susan Gardiner learns that he's left the bulk of his estate to her hitherto unknown cousin James--but he's left Susan a derelict pub in the East Anglian countryside. James suggests she sell, not knowing that Susan has been trained as a hotelier and loves living in the country. Soon the remodeled Blue Moon is a success--until a patron dies after eating a poison mushroom. Henry Tibbett and his wife Emmy come to investigate, with Henry's favorite assistant, Dere When her reclusive great-uncle dies, Susan Gardiner learns that he's left the bulk of his estate to her hitherto unknown cousin James--but he's left Susan a derelict pub in the East Anglian countryside.

Henry Tibbett and his wife Emmy come to investigate, with Henry's favorite assistant, Derek Reynolds, along to help. The criminal seems apparent, at first, until there's a second death. Jan 21, Teri Koll rated it liked it. I guessed the killer during the first half of the book. Not intriguing, but an easy read it you're pressed for time. Nov 24, JZ marked it as 4-maybe Shelves: Feb 20, Shannon rated it liked it.

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Her books are solid, comforting standard British Police Procedurals, with a big dose of Cozy thrown in for charm. This particular book is about two distant cousins who are strangers but both heirs to a great-uncle's estate, who meet over the reading of his will and discover a great interest in each other. The female half inherits a broken-down inn called "The Blue Moon. It is a great success until a dinner guest dies from ingesting poison mushrooms.

The mystery is on, now involving an old murder as well as another new one. Suspects abound from the nasty owner of a rival establishment, to an unsavory faux foreign waiter. Chief Inspector Henry Tibbet is on hand, but acts much more like an old friend of the family than a Scotland Yard upper police officer! It was disappointing that the murderer was so easily figured out; I kept waiting for a surprise element which never developed.

James Patterson Womens Murder Club: Twice in a Blue Moon (PC Longplay)

Still, it soothed my jaded reading sensibilities. Patricia Moyes is pretty much my go-to fix for reading indigestion! For various reasons not able to read a book in 6 weeks, I wanted an easy return to a practice I very much enjoy. This book was a good choice. My copy was remaindered, then bought by me in a charity store for a dollar and worth it. This is a regular small English village mystery about murder featuring Patricia Moyes' famous character, Inspector Henry Tibbet and his wife Emmy.

Susan Gardiner has inherited an Inn from her great-uncle Sebastian Gardiner, a recluse living in a large run-down London h For various reasons not able to read a book in 6 weeks, I wanted an easy return to a practice I very much enjoy. Susan Gardiner has inherited an Inn from her great-uncle Sebastian Gardiner, a recluse living in a large run-down London home. The inn is even more run down than the old house but Susan, having received first class training in hotel and restaurant management, decides to resurrect it and run it as an upscale restaurant, which she does with the help f her second cousin, James.

Then someone dies of eating a poison mushroom which grows in the area and the chase is on for the killer. A pleasant little English murder drama as told by Susan herself. It is an easy read with lots of plot twists as one would hope for. I enjoyed it as an example of the genre. And a good story only partly predictable. May 20, Avid Series Reader rated it liked it Shelves: