Synthesis,antimalarial activity and cytotoxicity of 4-aminoquinoline–triazine conjugates

A series of 4-aminoquinoline–triazine conjugates with different substitution pattern have been synthesized and evaluated for their in vitro antimalarial activity against chloroquine-sensitive and resistant strains of Plasmodium falciparum. Compounds 16, 19, 28 and 35 exhibited promising antimalarial activity against both strains of P. falciparum. Cytotoxicity of these compounds was tested against three cell lines. Several compounds did not show any cytotoxicity up to a high concentration (48 μM), others exhibited mild toxicities but selective index for antimalarial activity was high for most of these conjugates.     

Effect of Nutrition and Physical Factors on Mycelial Growth and Production of Pigments and Nonchromatic UV-absorbing Compounds of Alternaria eichhorniae

Alternaria eichhorniae is a host-specific biocontrol agent for managing waterhyacinth ( Eichhornia crassipes ) in Egypt. An important diagnostic characteristic of this fungus is the production of crimson-red phytotoxic pigments in the medium under certain conditions. A virulent isolate, A. eichhorniae 5 (Ae5), was studied to determine the optimum conditions for its growth and production of pigments and nonchromatic UV-absorbing metabolites (UVACs). The maximum production of pigments was obtained when cultures were grown on potato dextrose agar (PDA) with 20% dextrose, an initial pH of 4.5 at 25–30°C under continuous darkness or diurnal light, and without wrapping the culture plates. The maximum yields of the nonchromatic, 229- and 286-nm-absorbing compounds were obtained on PDA with 20–50% of dextrose at 20–30°C under continuous darkness. Culture plates, unwrapped or wrapped with only one layer of Parafilm at pH from 3.8 to 6.2 were favourable in this respect. There was a strong inverse relationship between linear mycelial growth and pigmentation as a function of light. Furthermore, the reduction in aeration, presumably proportional to the number of layers of Parafilm wrappings, led to lower levels of the red pigment(s) and the nonpigmented UVACs, to reduced mycelial growth, and a suppression of sporulation. Different culture-filtrate fractions of Ae5 were tested for phytotoxicity. At the concentrations of 0.5 and 1% w/v of the partially purified culture filtrate fractions, all except the butanol 1 fraction, had no toxic effect on waterhyacinth leaf-segments. Butanol fractions at 10% (w/v) concentration were significantly more damaging than aqueous fractions (10% w/v) and the area of necrosis increased with time.     

A sustainable sensitive spectrofluorimetric approach for the determination of the multipotent protein lactoferrin in different pharmaceuticals and infant milk formula: Compliance with greenness metrics

The current study presents the first spectrofluorimetric approach for the estimation of lactoferrin, depending on the measurement of its native fluorescence at 337 nm after excitation at 230 nm, without the need for any hazardous chemicals or reagents. It was found that the fluorescence intensity versus concentration calibration plot was linear over the concentration range of 0.1–10.0 μg/mL with quantitation and detection limits of 0.082 and 0.027 μg/mL, respectively. The method was accordingly validated according to the ICH recommendations. The developed method was applied for the estimation of lactoferrin in different dosage forms, including capsules and sachets with high percent recoveries (97.84–102.53) and low %RSD values (<1.95). Lactoferrin is one of the key nutrients in milk powder and a significant nutritional fortifier. In order to assess the quality of milk powder, it is essential to rapidly and accurately quantify the lactoferrin content of the product. Therefore, the presented study was successfully applied for the selective estimation of lactoferrin in milk powder with acceptable percent recoveries (96.45–104.92) and %RSD values (≤3.607). Finally, the green profile of the method was estimated using two assessment tools: Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE), which demonstrated its excellent greenness.     

Survival Analysis of Patients with Interval Cancer Undergoing Gastric Cancer Screening by Endoscopy

AimsInterval cancer is a key factor that influences the effectiveness of a cancer screening program. To evaluate the impact of interval cancer on the effectiveness of endoscopic screening, the survival rates of patients with interval cancer were analyzed.MethodsWe performed gastric cancer-specific and all-causes survival analyses of patients with screen-detected cancer and patients with interval cancer in the endoscopic screening group and radiographic screening group using the Kaplan-Meier method. Since the screening interval was 1 year, interval cancer was defined as gastric cancer detected within 1 year after a negative result. A Cox proportional hazards model was used to investigate the risk factors associated with gastric cancer-specific and all-causes death.ResultsA total of 1,493 gastric cancer patients (endoscopic screening group: n = 347; radiographic screening group: n = 166; outpatient group: n = 980) were identified from the Tottori Cancer Registry from 2001 to 2008. The gastric cancer-specific survival rates were higher in the endoscopic screening group than in the radiographic screening group and the outpatients group. In the endoscopic screening group, the gastric cancer-specific survival rate of the patients with screen-detected cancer and the patients with interval cancer were nearly equal (P = 0.869). In the radiographic screening group, the gastric cancer-specific survival rate of the patients with screen-detected cancer was higher than that of the patients with interval cancer (P = 0.009). For gastric cancer-specific death, the hazard ratio of interval cancer in the endoscopic screening group was 0.216 for gastric cancer death (95%CI: 0.054-0.868) compared with the outpatient group.ConclusionThe survival rate and the risk of gastric cancer death among the patients with screen-detected cancer and patients with interval cancer were not significantly different in the annual endoscopic screening. These results suggest the potential of endoscopic screening in reducing mortality from gastric cancer.     

Occurrence and distribution of tomato seed-borne mycoflora in Saudi Arabia and its correlation with the climatic variables

One hundred samples of tomato seeds were collected in 2011 and 2012 from tomato-cultivated fields in Saudi Arabia and screened for their seed-borne mycoflora. A total of 30 genera and 57 species of fungi were recovered from the collected seed samples using agar plate and deep-freezing blotter methods. The two methods differed as regards the frequency of recovered seed-borne fungi. Seven fungi among those recovered from tomato seeds, which are known as plant pathogens, were tested for their pathogenicity and transmission on tomato seedlings. The recovery rate of these pathogens gradually decreased from root up to the upper stem, and did not reach to the stem apex. The distribution of tomato seed-borne fungi was also investigated throughout Saudi Arabia. In this concern, Al-Madena governorate recorded the highest incidence of fungal flora associated with tomato seeds. The impact of meteorological variables on the distribution of tomato seed-borne mycoflora was explored using the ordination technique (canonical correspondence analysis). Among all climatic factors, relative humidity was the most influential variable in this regard. Our findings may provide a valuable contribution to our understanding of future global disease change and may be used also to predict disease occurrence and fungal transfer to new uninfected areas.     

Mutationmapper: A Tool to Aid the Mapping of Protein Mutation Data

There has been a rapid increase in the amount of mutational data due to, amongst other things, an increase in single nucleotide polymorphism (SNP) data and the use of site-directed mutagenesis as a tool to help dissect out functional properties of proteins. Many manually curated databases have been developed to index point mutations but they are not sustainable with the ever-increasing volume of scientific literature. There have been considerable efforts in the automatic extraction of mutation specific information from raw text involving use of various text-mining approaches. However, one of the key problems is to link these mutations with its associated protein and to present this data in such a way that researchers can immediately contextualize it within a structurally related family of proteins. To aid this process, we have developed an application called MutationMapper. Point mutations are extracted from abstracts and are validated against protein sequences in Uniprot as far as possible. Our methodology differs in a fundamental way from the usual text-mining approach. Rather than start with abstracts, we start with protein sequences, which facilitates greatly the process of validating a potential point mutation identified in an abstract. The results are displayed as mutations mapped on to the protein sequence or a multiple sequence alignment. The latter enables one to readily pick up mutations performed at equivalent positions in related proteins. We demonstrate the use of MutationMapper against several examples including a single sequence and multiple sequence alignments. The application is available as a web-service at http://mutationmapper.bioch.ox.ac.uk.     

A Community-Based,Case-Control Study Evaluating Mortality Reduction from Gastric Cancer by Endoscopic Screening in Japan

Aims

Although the incidence of gastric cancer has decreased in the last 3 decades, it remains the second leading cause of cancer death worldwide. In Asian countries, the burden of gastric cancer has remained, and cancer screening is normally expected to reduce gastric cancer death. We conducted a community-based, case-control study to evaluate the reduction of mortality from gastric cancer by endoscopic screening.

Methods

Case subjects were defined as individuals who had died of gastric cancer between 2003 and 2006 in 4 cities in Tottori Prefecture, and between 2006 and 2010 in Niigata City, Japan. Up to 6 control subjects were matched by sex, birth year (±3 years), and the residence of each corresponding case subject from the population lists in the study areas. Control subjects were required to be disease-free at the time when the corresponding case subjects were diagnosed as having gastric cancer. The odds ratios (ORs) were calculated for those who had participated in endoscopic or radiographic screening before the reference date when the case subjects were diagnosed as having gastric cancer, compared with subjects who had never participated in any screening. Conditional logistic-regression models for matched sets were used to estimate the ORs and 95% confidence intervals (CIs).

Results

The case subjects consisted of 288 men and 122 women for case subjects, with 2,292 matched control subjects. Compared with those who had never been screened before the date of diagnosis of gastric cancer in the case subjects, the ORs within 36 months from the date of diagnosis were 0.695 (95% CI: 0.489–0.986) for endoscopic screening and 0.865 (95% CI : 0.631–1.185) for radiographic screening.

Conclusions

The results suggest a 30% reduction in gastric cancer mortality by endoscopic screening compared with no screening within 36 months before the date of diagnosis of gastric cancer.     

Synthesis,antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin

A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed potent cytotoxicity towards these cell lines with IC₅₀ values below 1 μM, which is better than doxorubicin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant (W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening. This level of activity warrants further investigation of the compounds for development as anticancer and antimalarial agents.     

Synthesis and antifungal activities of miltefosine analogs

Miltefosine is an alkylphosphocholine that shows broad-spectrum in vitro antifungal activities and limited in vivo efficacy in mouse models of cryptococcosis. To further explore the potential of this class of compounds for the treatment of systemic mycoses, nine analogs (3a?3i) were synthesized by modifying the choline structural moiety and the alkyl chain length of miltefosine. In vitro testing of these compounds against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans revealed that N-benzyl-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3a), N,N-dimethyl-N-(4-nitrobenzyl)-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3d), and N-(4-methoxybenzyl)-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3e) exhibited minimum inhibitory concentrations (MIC) of 2.5–5.0 μg/mL against all tested pathogens, when compared to miltefosine with MICs of 2.5–3.3 μg/mL. Compound 3a showed low in vitro cytotoxicity against three mammalian cell lines similar to miltefosine. In vivo testing of 3a and miltefosine against C. albicans in a mouse model of systemic infection did not demonstrate efficacy. The results of this study indicate that further investigation will be required to determine the potential usefulness of the alkylphosphocholines in the treatment of invasive fungal infections.