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1.  The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia 
Blood Cancer Journal  2012;2(8):e81-.
Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nℳ), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μℳ). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).
doi:10.1038/bcj.2012.28
PMCID: PMC3432483  PMID: 22864397
acute myeloid leukemia; drug development; tyrosine kinase inhibitor; signal transduction; FLT3
2.  Regulation of gastric function by endogenous gastrin releasing peptide in humans: studies with a specific gastrin releasing peptide receptor antagonist 
Gut  2001;49(1):23-28.
BACKGROUND AND AIMS—The main goal of our study was to characterise the activity of BIM26226 as a peripheral gastrin releasing peptide (GRP) receptor antagonist in healthy human subjects and to determine if endogenous GRP is a physiological regulator of gastric acid secretion and gastrin release.
METHODS—Our study consisted of three parts. In part I, subjects received saline or BIM26226 followed by graded doses of intravenous human GRP in a four period crossover design. In part II, subjects received BIM26226 or saline during oral meal ingestion or modified sham feeding. In part III, subjects received an acidified meal in the presence and absence of BIM26226 in a two period crossover design. In addition, gastrin and somatostatin mRNA were measured in biopsy specimens during saline and BIM26226 infusion.
RESULTS—BIM26226 dose dependently inhibited GRP induced acid output. Acid secretion after oral liquid meal intake and sham feeding was significantly inhibited by BIM26226 (p<0.01) whereas plasma gastrin release remained unchanged. Gastrin and somatostatin mRNAs were not significantly different after saline or BIM26226.
CONCLUSIONS—BIM26226 is a potent GRP antagonist in humans. Endogenous GRP may be a physiological regulator of gastric acid secretion. Gastrin release does not seem to be under the control of GRP.


Keywords: gastrin; gastric acid secretion; gastrin releasing peptide; gastric function; BIM26226
doi:10.1136/gut.49.1.23
PMCID: PMC1728358  PMID: 11413106
3.  Iron deficiency anemia in 1-year-old children of disadvantaged families in Montreal. 
OBJECTIVES: To determine the prevalence of iron deficiency anemia among 1-year-old infants of disadvantaged families in Montreal as well as certain predictors of this condition. DESIGN: Cohort study. SETTING: Five poorest health districts in Montreal. PARTICIPANTS: Infants 10 to 14 months of age were identified from registration lists of births from May 1988 to August 1989. Those whose mother had less than 11 years of schooling and a family income below the government-defined low-income cutoff point were eligible. INTERVENTION: During a home visit capillary blood samples were obtained from the child, and the mother answered a questionnaire about infant-feeding practices. Infants with a serum ferritin level of 10 micrograms/L or less and either a hemoglobin level of 115 g/L or less or a mean corpuscular volume of 72 fL or less were considered as having iron deficiency anemia. RESULTS: Of the 299 mothers who were eligible and could be located 220 (74%) agreed to participate; 218 blood samples were available. Iron deficiency anemia was found in 25% of the infants (95% confidence interval [CI] 19% to 31%). The mean hemoglobin level was 115 (standard deviation 11) g/L. The serum ferritin level, assessed routinely in the last 62 infants, was 10 micrograms/L or less in 37% of the infants. The factors that were found to be predictors of iron deficiency anemia included the use of whole cow's milk before 6 months of age (odds ratio [OR] 3.56 [95% CI 1.07 to 11.26]) and the use of iron-fortified infant cereal for less than 6 months (OR 3.15 [95% CI 1.25 to 7.96]). A low birth weight and the use of iron-fortified formula for less than 6 months were associated with iron deficiency anemia. CONCLUSIONS: Despite a decrease in the prevalence of iron deficiency anemia among children of disadvantaged families in the United States socioeconomically disadvantaged infants in Montreal are at risk. Preventive measures must be taken to ensure adequate iron status in the first year of life.
PMCID: PMC1488517  PMID: 1571868
6.  Carcinoma of the Breast 
British Medical Journal  1958;1(5078):1066.
PMCID: PMC2028646
7.  The Case for Rational Surgery in Cancer 
Postgraduate Medical Journal  1955;31(351):11-15.
PMCID: PMC2501450  PMID: 14371159
9.  Theory of Cancer Treatment 
British Medical Journal  1952;2(4790):940-941.
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PMCID: PMC2021817
10.  Cancer Treatment 
British Medical Journal  1952;1(4771):1301.
PMCID: PMC2023738
11.  Nature Cure 
British Medical Journal  1952;1(4759):653-654.
PMCID: PMC2023174

Results 1-12 (12)