Malaria parasite genome scan: insights into antimalarial resistance

Genome scan and genotype-phenotype association study offer excellent opportunities to unearth drug/vaccine targets in human pathogens including malaria parasites. A recently conducted such study in worldwide isolates in the most devastating malaria parasite Plasmodium falciparum has reported important genomic information on genetic basis of antimalarial resistance. Several unknown genes were also found to be under strong influence of natural selection. The findings provide important insights into the malaria parasite genome evolution in general and to use this information to develop more focused malaria control strategies, in particular.     

Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer

Purpose

Cetuximab (C), a chimeric monoclonal antibody that binds epidermal growth factor receptor (EGFR), is active against androgen-independent prostate cancer cell lines and might enhance the activity of chemotherapy. The efficacy of combining cetuximab with mitoxantrone (M) plus prednisone (MP) was evaluated in progressive metastatic castrate-resistant prostate cancer (CRPC) after receiving docetaxel.

Materials and Methods

Patients with progression after receiving docetaxel were eligible and randomized 2:1 to CMP or MP. Therapy was mitoxantrone 12 mg/m² intravenously (I.V.) on day 1, oral prednisone 10 mg daily in both arms, and cetuximab 250 mg/m² I.V. (400 mg/m² day 1, cycle 1) on days 1, 8, and 15 in the CMP arm. Cycles were repeated every 21 days. Radiologic assessments of disease and PSA (prostate-specific antigen) occurred every 4 cycles. The primary endpoint was time to progression (TTP).

Results

A total of 115 patients were enrolled, 75 in the CMP and 40 in the MP arm: the median TTP was 4.9 and 6.6 months, respectively; the measurable disease response rate was 2% and 4%, the PSA response rate 7.7% and 17.6%, and median survival 11.9 and 15.7 months, respectively. Key grade 3-4 toxicities were neutropenia 44% and 25.6%, anemia 6.7% and 7.7%, thrombocytopenia 6.7% and 2.6%, and fatigue 8% in both arms. In an unplanned exploratory analysis, median TTP with (n = 24) and without rash (n = 51) in the CMP arm was 10.3 months vs. 2.8 months (P = .004). On multivariable analysis,rash was significantly associated with TTP (hazard ratio [HR] = 0.43; P = .01).

Conclusions

The treatment with CMP is not recommended in unselected men with docetaxel-treated CRPC, although rash might help develop tailored therapy.     

Lymphocytic thrombophilic arteritis presenting as localized livedo racemosa

A 28-year-old Costa Rican woman presented with a 6-year history of an asymptomatic progressive localized livedo racemosa on her limbs. Histological examination revealed a lymphocytic vasculitis targeting the arterioles in the deep dermis. In addition, a distinct hyalinised fibrin ring was noted at the periphery of the vessel lumen. These findings were consistent with the recently described entity known as lymphocytic thrombophilic arteritis. An extensive array of investigations did not show any underlying systemic disease, and the patient has remained in good health without treatment.     

Racial Disparities in Stage-Specific Colorectal Cancer Mortality: 1960�C2005

Objectives. We examined whether racial disparities in stage-specific colorectal cancer survival changed between 1960 and 2005.Methods. We used US Mortality Multiple-Cause-of-Death Data Files and intercensal estimates to calculate standardized mortality rates by gender and race from 1960 to 2005. We used Surveillance, Epidemiology, and End Results (SEER) data to estimate stage-specific colorectal cancer survival. To account for SEER sampling uncertainty, we used a bootstrap resampling procedure and fit a Cox proportional hazards model.Results. Between 1960–2005, patterns of decline in mortality rate as a result of colorectal cancer differed greatly by gender and race: 54% reduction for White women, 14% reduction for Black women, 39% reduction for White men, and 28% increase for Black men. Blacks consistently experienced worse rates of stage-specific survival and life expectancy than did Whites for both genders, across all age groups, and for localized, regional, and distant stages of the disease.Conclusions. The rates of stage-specific colorectal cancer survival differed among Blacks when compared with Whites during the 4-decade study period. Differences in stage-specific life expectancy were the result of differences in access to care or quality of care. More attention should be given to racial disparities in colorectal cancer management.Although colorectal cancer mortality rates have declined since 1960, these declines have been uneven,^1–3 and racial disparities in mortality rates have increased. Factors contributing to increased mortality rates among Blacks include racial differences in risk factors, prevention, detection, and treatment.⁴ Blacks receive less colorectal screening,⁵ and their cancer is detected at more advanced stages.^6,7 Important differences exist in how colorectal cancer is detected, but not necessarily in how it is treated once detected. Significant improvements have occurred in colorectal cancer treatment through time, yet these improvements may not be distributed equally across all racial groups. Previous research has also found Black–White differences in stage-specific colorectal cancer survival rates, suggesting disparities in the management of cancer.^8–10In this article, we assessed whether differences in stage-specific colorectal cancer survival rates reflected racial differences over 4 decades. In doing so, we adjusted for differences in incidence and screening, focusing instead on the management of tumors once they are found. Racial disparities are likely a product of a broad set of social, biological, and environmental factors. By observing changes in stage-specific mortality over time, rather than statically at a cross-sectional moment, we may develop a better understanding of how these factors have contributed to increased racial disparities.     

Association of <Emphasis Type="Italic">IL-10</Emphasis> Gene Polymorphism (−819C &gt; T, −592C &gt; A and −1082G &gt; A) with Preterm Birth

Objective

To analyze the association of IL-10 gene and its polymorphisms with preterm birth (PTB).

Methods

Five hundred and fifty nine women with term birth and 559 with preterm birth were recruited from Lucknow, India. Genetic association analysis was conducted between cases and controls. Subjects recruited as cases were women (aged between 18–40 y) with singleton delivery before 37 wk of gestation and controls were with delivery after or on 37 wk. The genotyping was performed for rs1800871, rs1800872 and rs1800896 for assessing the allelic distribution, haplotypic association and linkage disequilibrium analysis. IL-10mRNA levels were evaluated by real time quantitative polymerase chain reaction (PCR) method.

Results

The risk of PTB was found significant in women carrying IL-10 (?1082) GA genotype [OR=1.72(1.7–2.5), p=0.006]. The haplotypic analysis of studied polymorphisms for rs1800871, rs1800872 and rs1800896 depicted the association of ATA (p=0.02) and ATC (p=0.01) haplotypes with PTB. The IL-10 mRNA levels were significantly lower in cases (p=0.05).

Conclusions

IL-10 marks a protective impact in the inflammatory pathway of PTB.

     

Assessment of Mineral Intake by Kidney Stone Patients of Kangra District, Himachal Pradesh with Respect to their Gender, Age and Income

Objectives

To assess the family history of stones and association of mineral intake with gender, age and income of kidney stone patients.

Methods

A total of 130 kidney stone patients were selected randomly from Kangra district of Himachal Pradesh and family history of stones and mineral intake was assessed.

Results

Out of selected patients, majority (80.77 %) were first time stone sufferers. There was significant (at 1 % level) association between family history of kidney stone patients with respect to gender of patients. Further study revealed that the intake of sodium, calcium, magnesium and phosphorous was higher than recommended dietary allowances (RDA). Among male patients, the intake of sodium, calcium and magnesium was higher for age group III (above 45 y) and intake of potassium and phosphorous was higher for age group I. In female kidney stone patients, intake of sodium, calcium and phosphorous was high for age group II, intake of potassium was high in case of age group I and intake of magnesium was high for age group III. Regression studies revealed that there was significantly higher intake of calcium and phosphorous by male kidney stone patients than female kidney stone patients. With the increase in age, the intake of calcium and phosphorous decreased.

Conclusions

Assessment of mineral intake is necessary to enable the health care providers, to give advice and suggestions to the patients to carry out preventive measures in reducing the risk of prevalence of kidney stones in this area and further advice to the suffering patients to prevent the recurrence of stone formation.     

Enhancing sorafenib-mediated sensitization to gemcitabine in experimental pancreatic cancer through EMAP II

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies and tends to be relatively resistant to conventional therapies. Activated Ras oncogene mutations are found in up to 90% of PDAC, leading to activation of the Ras/Raf/MEK/ERK signaling pathway. Sorafenib is a multikinase inhibitor of the Ras/Raf/MEK/ERK pathway and of tumor angiogenesis. Endothelial monocyte activating polypeptide II (EMAP) enhances gemcitabine effects in PDAC. Antitumor activity of sorafenib was evaluated in combination with gemcitabine (Gem) and the antiangiogenic agent EMAP in experimental PDAC.

Methods

Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. Animal survival studies were performed in murine PDAC xenografts.

Results

Sorafenib decreased phospho-MEK, phospho-ERK1/2, phospho-p70S6K and phospho-4EBP-1 expression in PDAC cells. Sorafenib inhibited in vitro proliferation of all four PDAC cell lines tested. Additive effects on cell proliferation inhibition were observed in the gemcitabine-sorafenib combination in PDAC cells, and in combinations of sorafenib or EMAP with gemcitabine in endothelial (HUVEC) and fibroblast (WI-38) cells. Sorafenib, alone or in combination with gemcitabine and EMAP, induced apoptosis in HUVECs and WI-38 cells as observed via increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. Compared to controls (median survival: 22 days), animal survival increased after Gem therapy (29 days) but not in sorafenib (23 days) or EMAP therapy alone (25 days). Further increases in survival occurred in combination therapy groups Gem+sorafenib (30 days, p=0.004), Gem+EMAP (33 days, p=0.002), and Gem+sorafenib+EMAP (36 days, p=0.004), but not after the sorafenib+EMAP combination (24 days).

Conclusions

These findings demonstrate that the addition of a polymechanistic antiangiogenic agent such as EMAP can enhance the combination treatment effects of sorafenib and cytotoxic PDAC therapy.