Molecular Biomarkers Correlate with Disease-Free Survival in Patients with Anal Canal Carcinoma Treated with Chemoradiation

Large primary tumor and clinical nodal involvement in patients with anal carcinoma treated with chemoradiation are associated with poor disease-free survival (DFS). However, the outcome in individual patient is unpredictable. We hypothesized that biomarkers related to chemotherapy and/or radiation resistance would be associated with DFS. We analyzed clinical and biomarker data in 30 patients with anal carcinoma who had chemoradiation. Patient selection was based on the availability of untreated cancer for biomarkers, completion of prescribed chemoradiation, and patient outcomes (~50% disease-free) nonrepresentative of published cohorts but conducive to biomarker discovery. Ten biomarkers, Ki67, human telomerase (hTERT), epidermal growth factor receptor (EGFR), p53, p16, Bcl-2, vascular endothelial growth factor (VEGF), nuclear factor kappa-B (NF-κB), SHH, and Gli-1, were studied. Raw data as continuous variable (only EGFR was trichotomized) were analyzed. Univariate and multivariate Cox models were utilized to assess relationship between DFS and biomarkers. Twenty-three of 30 patients were women, tumor diameter was >5 cm in 30, and 37% had clinically positive nodes. Fourteen (30%) patients had a DFS event after chemoradiation. In univariate analysis, NF-κB (P = 0.01), SHH (P = 0.02), Gli-1 (P = 0.02), and tumor diameter (P = 0.03) were significantly associated with DFS, and Ki67 (P = 0.07) was marginally significant. In multivariate analysis, tumor diameter (P = 0.003), Ki67 (P = 0.005), NF-κB (P = 0.002), SHH (P = 0.02), and Gli-1 (P = 0.02) were significantly associated with DFS. Our data, albeit preliminary, suggest that several biomarkers (Ki67, NF-κB, SHH, and Gli-1) are associated with DFS. Upon further expansion and validation, these results may provide a biomarker-based understanding of heterogeneous clinical biology of patients with anal carcinoma.     

Arthritic presentation of acute leukemia in children: experience from a tertiary care centre in North India

The objectives of this study are to highlight the arthritic presentation of acute lymphoblastic leukemia (ALL) in children and to delineate features that could help differentiate it from juvenile idiopathic arthritis (JIA). We present a retrospective case control study based on records of the Pediatric Rheumatology Clinic, Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India for the period January 2005–October 2008. We compared the clinical profile of 11 children referred to us with musculoskeletal complaints who were ultimately diagnosed to have ALL, with the clinical profile of an equal number of age and sex matched children with JIA. Important features that predicted a diagnosis of ALL and differentiated it from JIA were history of night pain (P = 0.001), non-articular bony pain (P = 0.001), presence of joint pain out of proportion to physical findings (P = 0.0001), anemia (P = 0.004), leucopenia (P = 0.045), lymphocytic predominance (P = 0.002) and thrombocytopenia (P = 0.012). In conclusion, children with musculoskeletal complaints are often referred to the rheumatologist for evaluation. The treating physician should always exclude the possibility of an underlying ALL especially if there are atypical clinical features or subtle hematological abnormalities.     

The design and cytotoxic evaluation of some 1-aryl-3-isopropylamino-1-propanone hydrochlorides towards human Huh-7 hepatoma cells

A series of 1-aryl-3-isopropylamino-1-propanone hydrochlorides 1 and a related heterocyclic analog 2 as candidate antineoplastic agents were prepared and the rationale for designing these compounds is presented. A specific objective in this study is the discovery of novel compounds possessing growth-inhibiting properties of hepatoma cells. The compounds in series 1 and 2 were prepared and their structures established unequivocally. X-ray crystallography of two representative compounds 1d and 1g were achieved. Over half of the compounds are more potent than 5-fluorouracil which is an established drug used in treating liver cancers. QSAR evaluations and molecular modeling studies were undertaken with a view to detecting some physicochemical parameters which govern cytotoxic potencies. A number of guidelines for amplification of the project have been formulated.     

Prenatal cocaine exposure and childhood obesity at nine years

Little is known about the association between prenatal cocaine exposure and obesity. We tested whether prenatal cocaine exposure increases the likelihood of obesity in 561 9-year-old term children from the Maternal Lifestyle Study (MLS). Overall, 21.6% of children met criterion for obesity (body mass index [BMI] ≥ 95th percentile, age and sex-specific). While there was no overall cocaine effect on obesity, multivariate logistic analysis revealed that children exposed to cocaine but not alcohol were 4 times more likely to be obese (OR 4.11, CI 2.04-9.76) than children not exposed to either drug. No increase in obesity prevalence was found in children exposed to alcohol but not cocaine (OR 1.08, CI .59-1.93) or both (OR 1.21, CI 0.66-2.22). Alcohol exposure may attenuate the effect of cocaine exposure on obesity. Increased obesity associated with cocaine but not alcohol exposure was first observed at 7 years. BMI was also elevated from 3 to 9 years in children exposed to cocaine but not alcohol, due to increasing weight but normal height. Prenatal exposure to cocaine may alter the neuroendocrine system and metabolic processes resulting in increased weight gain and childhood obesity.     

Identification of protein targets of reactive metabolites of tienilic acid in human hepatocytes

Tienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [(14)C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty-one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 nonredundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 additional proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2 to 4 identifiable proteins, many of which are known targets of other chemically reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approximately 16 previously reported protein targets of TA in rat liver ( Methogo, R., Dansette, P., and Klarskov, K. ( 2007 ) Int. J. Mass Spectrom. , 268 , 284 -295 ), only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e., rat vs human), and still another may be the method of detection of adducted proteins (i.e., Western blot vs C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from humans, and only 21 of these are known to be targets for more than one chemical. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future.     

Phytochemicals from plants to combat cardiovascular disease

For many decades, the use of synthetic chemicals as drugs has been effective in the treatment of most diseases. Moreover, from ancient to modern history, many traditional plant based medicines are playing an important role in health care. Phytochemicals are natural bioactive compounds found in vegetables, fruits, medicinal plants, aromatic plants, leaves, flowers and roots which act as a defense system to combat against diseases. The phytochemicals from natural products cover a diverse range of chemical entities such as polyphenols, flavonoids, steroidal saponins, organosulphur compounds and vitamins. A number of bioactive compounds generally obtained from terrestrial plants such as isoflavones, diosgenin, resveratrol, quercetin, catechin, sulforaphane, tocotrienols and carotenoids are proven to reduce the risk of cardiovascular diseases and aid in cardioprotection which is the leading cause of death globally. The cardioprotective effects of the various phytochemicals are perhaps due to their antioxidative, antihypercholesteroemic, antiangiogenic, anti-ischemic, inhibition of platelet aggregation and anti inflammatory activities that reduce the risk of cardiovascular disorders. The multi-faceted role of the phytochemicals is mediated by its structure-function relationship and can be considered as leads for cardiovascular drug design in future. This review summarizes the findings of recent studies on selected phytochemicals as prophylactic and therapeutic agents in cardioprotection.