Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer

OBJECTIVE: We present and analyze long-term outcomes following multimodal therapy for esophageal cancer, in particular the relative impact of histomorphologic tumor regression and nodal status. PATIENTS AND METHODS: A total of 243 patients [(adenocarcinoma (n = 170) and squamous cell carcinoma (n = 73)] treated with neoadjuvant chemoradiotherapy in the period 1990 to 2004 were followed prospectively with a median follow-up of 60 months. Pathologic stage and tumor regression grade (TRG) were documented, the site of first failure was recorded, and Kaplan-Meier survival curves were plotted. RESULTS: Thirty patients (12%) did not undergo surgery due to disease progression or deteriorated performance status. Forty-one patients (19%) had a complete pathologic response (pCR), and there were 31(15%) stage I, 69 (32%) stage II, and 72 (34%) stage III cases. The overall median survival was 18 months, and the 5-year survival was 27%. The 5-year survival of patients achieving a pCR was 50% compared with 37% in non-pCR patients who were node-negative (P = 0.86). Histomorphologic tumor regression was not associated with pre-CRT cTN stage but was significantly (P < 0.05) associated with ypN stage. By multivariate analysis, ypN status (P = 0.002) was more predictive of overall survival than TRG (P = 0.06) or ypT stage (P = 0.39). CONCLUSION: Achieving a node-negative status is the major determinant of outcome following neoadjuvant chemoradiotherapy. Histomorphologic tumor regression is less predictive of outcome than pathologic nodal status (ypN), and the need to include a primary site regression score in a new staging classification is unclear. © 2007 Lippincott Williams & Wilkins, Inc.

Polymorphisms in inflammation pathway genes and endometrial cancer risk

BACKGROUND Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. METHODS To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls. RESULTS Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. CONCLUSIONS These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.

Clinical impacts of mammalian target of rapamycin expression in human colorectal cancers

This study investigated the clinicopathologic roles of mammalian target of rapamycin (mTOR) expression and its relationship to carcinogenesis and tumor progression in a colorectal adenoma-adenocarcinoma model. Two colon cancer cell lines with different pathologic stages (SW480 and SW48) and 1 normal colonic epithelial cell line (FHC) were used, in addition to 119 colorectal adenocarcinomas and 32 adenomas. mTOR expression profiles at messenger RNA (mRNA) and protein levels were investigated in the cells and tissues using real-time quantification polymerase chain reaction and immunohistochemistry. The findings were correlated with the clinicopathologic features of the tumors. The colon cell line from stage III cancer (SW48) showed higher expression of mTOR mRNA than that from stage II cancer (SW480). At the tissue level, mTOR showed higher mRNA and protein expression in colorectal carcinoma than in adenoma. The mRNA and protein expression was correlated with each other in approximately one-third of the carcinomas and adenomas. High levels of mTOR mRNA expression were noted more in carcinoma or adenoma arising from the distal portion of the large intestine (P = .025 and .019, respectively). Within the colorectal cancer population, a high level of expression of mTOR mRNA was related to the presence of lymph node metastases (P = .031), advanced pathologic stage (P = .05), and presence of persistent disease or tumor recurrence (P = .035). To conclude, the study has indicated that mTOR is likely to be involved in the development and progression of colorectal cancer and is linked to cancer initiation, invasiveness, and progression.

Increased sensitivity to tryptophan bioavailability is a positive adaptation by the human strains of Chlamydia pneumoniae

One of the most significant activities induced by interferon-gamma against intracellular pathogens is the induction of IDO (indoleamine 2,3-dioxygenase) expression, which subsequently results in the depletion of tryptophan. We tested the hypothesis that human strains of Chlamydia pneumoniae are more sensitive to tryptophan limitation than animal C. pneumoniae strains. The human strains were significantly more sensitive to IFN-γ than the animal strains in a lung epithelia cell model (BEAS-2B), with exposure to 1 U ml(-1) IFN-γ resulting in complete loss of infectious yield of human strains, compared to the animal strains where reductions in infectious progeny were around 3.5-4.0 log. Strikingly, the IFN-γ induced loss of ability to form infectious progeny production was completely rescued by removal of the IFN-γ and addition of exogenous tryptophan for the human strains, but not the animal strains. In fact, a human heart strain was more capable of entering a non-infectious, viable persistent stage when exposed to IFN-γ and was also more effectively rescued, compared to a human respiratory strain. Exquisite susceptibility to IFN-γ, specifically due to tryptophan availability appears to be a core adaptation of the human C. pneumoniae strains, which may reflect the chronic nature of their infections in this host.

A two-arm cluster randomized control trial to determine the effectiveness of a pressure ulcer prevention bundle for critically ill patients

Purpose This study tested the effectiveness of a pressure ulcer (PU) prevention bundle in reducing the incidence of PUs in critically ill patients in two Saudi intensive care units (ICUs). Design A two-arm cluster randomized experimental control trial. Methods Participants in the intervention group received the PU prevention bundle, while the control group received standard skin care as per the local ICU policies. Data collected included demographic variables (age, diagnosis, comorbidities, admission trajectory, length of stay) and clinical variables (Braden Scale score, severity of organ function score, mechanical ventilation, PU presence, and staging). All patients were followed every two days from admission through to discharge, death, or up to a maximum of 28 days. Data were analyzed with descriptive correlation statistics, Kaplan-Meier survival analysis, and Poisson regression. Findings The total number of participants recruited was 140: 70 control participants (with a total of 728 days of observation) and 70 intervention participants (784 days of observation). PU cumulative incidence was significantly lower in the intervention group (7.14%) compared to the control group (32.86%). Poisson regression revealed the likelihood of PU development was 70% lower in the intervention group. The intervention group had significantly less Stage I (p = 002) and Stage II PU development (p = 026). Conclusions Significant improvements were observed in PU-related outcomes with the implementation of the PU prevention bundle in the ICU; PU incidence, severity, and total number of PUs per patient were reduced. Clinical Relevance Utilizing a bundle approach and standardized nursing language through skin assessment and translation of the knowledge to practice has the potential to impact positively on the quality of care and patient outcome.

A phase field study of morphological instabilities in multilayer thin films

We studied the microstructural evolution of multiple layers of elastically stiff films embedded in an elastically soft matrix using a phase field model. The coherent and planar film/matrix interfaces are rendered unstable by the elastic stresses due to a lattice parameter mismatch between the film and matrix phases, resulting in the break-up of the films into particles. With an increasing volume fraction of the stiff phase, the elastic interactions between neighbouring layers lead to: (i) interlayer correlations from an early stage; (ii) a longer wavelength for the maximally growing wave; and therefore (iii) a delayed break-LIP. Further, they promote a crossover in the mode of instability from a predominantly anti-symmetric (in phase) one to a symmetric (out of phase) one. We have computed a stability diagram for the most probable mode of break-up in terms of elastic modulus Mismatch and Volume fraction. We rationalize our results in terms of the initial driving force for destabilization, and corroborate our conclusions using simulations in elastically anisotropic systems.

Genetic burden associated with varying degrees of disease severity in endometriosis

Endometriosis is primarily characterized by the presence of tissue resembling endometrium outside the uterine cavity and is usually diagnosed by laparoscopy. The most commonly used classification of disease, the revised American Fertility Society (rAFS) system to grade endometriosis into different stages based on disease severity (I to IV), has been questioned as it does not correlate well with underlying symptoms, posing issues in diagnosis and choice of treatment. Using two independent European genome-wide association (GWA) datasets and top-level classification of the endometriosis cases based on rAFS [minimal or mild (Stage A) and moderate-to-severe (Stage B) disease], we previously showed that Stage B endometriosis has greater contribution of common genetic variation to its aetiology than Stage A disease. Herein, we extend our previous analysis to four endometriosis stages [minimal (Stage I), mild (Stage II), moderate (Stage III) and severe (Stage IV) disease] based on the rAFS classification system and compared the genetic burden across stages. Our results indicate that genetic burden increases from minimal to severe endometriosis. For the minimal disease, genetic factors may contribute to a lesser extent than other disease categories. Mild and moderate endometriosis appeared genetically similar, making it difficult to tease them apart. Consistent with our previous reports, moderate and severe endometriosis showed greater genetic burden than minimal or mild disease. Overall, our results provide new insights into the genetic architecture of endometriosis and further investigation in larger samples may help to understand better the aetiology of varying degrees of endometriosis, enabling improved diagnostic and treatment modalities.

Innovative new production systems for low-chill stonefruit in Australia and South-East Asia: a review

Fruit size and quality are major problems in early-season stonefruit cultivars grown in Australia and South-East Asia. In Australia, Thailand and Vietnam, new training and trellising systems are being developed to improve yield and fruit quality. Australian trials found that new training systems, such as the Open Tatura system, are more productive compared with standard vase-trained trees. We established new crop-loading indices for low-chill stonefruit to provide a guide for optimum fruit thinning based on fruit number per canopy surface and butt cross sectional area. Best management practices were developed for low-chill stonefruit cultivation using growth retardants, optimizing leaf nitrogen concentrations and controlling rates and timing of irrigation. Regulated deficit irrigation (RDI) improved fruit sugar concentrations by restricting water application during stage II of fruit growth. New pest and disease control measures are also being developed using a new generation of fruit fly baits. Soft insecticides such as (Spinosad) are used at significantly lower concentrations and have lower mammalian toxicity than the organophosphates currently registered in Australia. In addition, fruit fly exclusion netting effectively eliminated fruit fly and many other insect pests from the orchard with no increase in diseases. This netting system increased sugar concentrations of peach and nectarine by as much as 30%. Economic analyses showed that the break-even point can be reduced from 12 to 6 years Open Tatura trellising and exclusion netting.

Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies

MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNAs' Target Sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)-, and femoral neck (FN)-bone mineral density (BMD). In stage I, 41,102 poly-miRTSs were meta-analyzed in 7 cohorts with a genome-wide significance (GWS) α=0.05/41,102=1.22×10-6. By applying α=5×10-5 (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P-value=7.67×10-6 and 1.58×10-5) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P-value=5.08×10-3) at α=0.10/11=9.09×10-3. PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P-value=7.55×10-6) at α=0.05/2=0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P-value=8.87×10-12). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation. © The Author 2015. Published by Oxford University Press. All rights reserved.

Effect of prestrain on fatigue crack propagation in mild steel containing non-metallic inclusions

The effect of tensile prestrain on fatigue crack propagation behaviour of commercial mild steel with significant amount of stringer inclusions has been studied. In prestrained materials the usual stable stage II crack growth region is preceded by a phase wherein a retardation in crack growth rate occurs. No such behaviour is observed in annealed material. The amount of retardation is found to increase with increase in prestrain. A mechanism for the observed retardation in crack growth rate is also presented.

Interaction of a vortex ring with a single bubble: bubble and vorticity dynamics

The interaction of a single bubble with a single vortex ring in water has been studied experimentally. Measurements of both the bubble dynamics and vorticity dynamics have been done to help understand the two-way coupled problem. The circulation strength of the vortex ring (Gamma) has been systematically varied, while keeping the bubble diameter (D-b) constant, with the bubble volume to vortex core volume ratio (V-R) also kept fixed at about 0.1. The other important parameter in the problem is a Weber number based on the vortex ring strength. (We = 0.87 rho(Gamma/2 pi a)(2)/(sigma/D-b); a = vortex core radius, sigma = surface tension), which is varied over a large range, We = 3-406. The interaction between the bubble and ring for each of the We cases broadly falls into four stages. Stage I is before capture of the bubble by the ring where the bubble is drawn into the low-pressure vortex core, while in stage II the bubble is stretched in the azimuthal direction within the ring and gradually broken up into a number of smaller bubbles. Following this, in stage III the bubble break-up is complete and the resulting smaller bubbles slowly move around the core, and finally in stage IV the bubbles escape. Apart from the effect of the ring on the bubble, the bubble is also shown to significantly affect the vortex ring, especially at low We (We similar to 3). In these low-We cases, the convection speed drops significantly compared to the base case without a bubble, while the core appears to fragment with a resultant large decrease in enstrophy by about 50 %. In the higher-We cases (We > 100), there are some differences in convection speed and enstrophy, but the effects are relatively small. The most dramatic effects of the bubble on the ring are found for thicker core rings at low We (We similar to 3) with the vortex ring almost stopping after interacting with the bubble, and the core fragmenting into two parts. The present idealized experiments exhibit many phenomena also seen in bubbly turbulent flows such as reduction in enstrophy, suppression of structures, enhancement of energy at small scales and reduction in energy at large scales. These similarities suggest that results from the present experiments can be helpful in better understanding interactions of bubbles with eddies in turbulent flows.

A comparative study of failure features in aerospace grade unidirectional and bidirectional woven CFRP composite laminates under four-point bend fatigue loads

Damage mechanisms in unidirectional (UD) and bi-directional (BD) woven carbon fiber reinforced polymer (CFRP) laminates subjected to four point flexure, both in static and fatigue loadings, were studied. The damage progression in composites was monitored by observing the slopes of the load vs. deflection data that represent the stiffness of the given specimen geometry over a number of cycles. It was observed that the unidirectional composites exhibit gradual loss in stiffness whereas the bidirectional woven composites show a relatively quicker loss during stage II of fatigue damage progression. Both, the static and the fatigue failures in unidirectional carbon fiber reinforced polymer composites originates due to generation of cracks on compression face while in bidirectional woven composites the damage ensues from both the compression and the tensile faces. These observations are supported by a detailed fractographic analysis.

Fatigue crack-growth rate in ferrite martensite dual-phase steel

An empirical study is made on the fatigue crack growth rate in ferrite-martensite dual-phase (FMDP) steel. Particular attention is given to the effect of ferrite content in the range of 24.2% to 41.5% where good fatigue resistance was found at 33.8%. Variations in ferrite content did not affect the crack growth rate when plotted against the effective stress intensity factor range  which was assumed to follow a linear relation with the crack tip stress intensity factor range ΔK. A high  corresponds to uniformly distributed small size ferrite and martensite. No other appreciable correlation could be ralated to the microstructure morphology of the FMDP steel. The closure stress intensity factor , however, is affected by the ferrite content with  reaching a maximum value of 0.7. In general, crack growth followed the interphase between the martensite and ferrite.

Dividing the fatigue crack growth process into Stage I and II where the former would be highly sensitive to changes in ΔK and the latter would increase with ΔK depending on the  ratio. The same data when correlated with the strain energy density factor range ΔS showed negligible dependence on mean stress or R ratio for Stage I crack growth. A parameter α involving the ratio of ultimate stress to yield stress, percent reduction of area and R is introduced for Stage II crack growth so that the  data for different R would collapse onto a single curve with a narrow scatter band when plotted against αΔS.

Evolutionary trends of the mitochondrial lineage differentiation in species of genera Martes and Mustela

We compared partial sequences (402 bp) of the mitochondrial cytochrome b gene in 68 individuals of martens (Martes), weasels (Mustela) and their relatives from the Northern Hemisphere to identify the modes of geographic differentiation in each species. We then compared complete sequences (1140 bp) of the gene in 17 species of the family Mustelidae to know the spatial and temporal modes of speciation, constructing linearized trees with transversional substitutions for deeper lineage divergences and with transversions and transitions for younger lineages. Our data suggested that these lineages of Martes and Mustela differentiated in a stepwise fashion with five radiation stages from the generic divergences (stage I) to the intraspecific divergences (stage V), during the last 10 or 20 million years as the fossil evidence suggests. In the lineage of Martes, the first offshoots are of Martes flavigula, M. pennanti, and Gulo gulo (stage II), the second is M. foina (stage III), and the third are M. americana, M. martes, M. melampus, and M. zibellina (stage IV). The divergence of the lineages of Mustela is likely to have taken place concurrently with the radiations of the Martes. These divergence processes are attributable in part to the geographic allocation along the two continents, North America and Eurasia, as well as among peripheral insular domains, such as Taiwan and the Japanese Islands. In addition, the Eurasian continent itself was shown to have been involved in the species diversification in the martens and weasels.

Study on biological characteristics, sexual maturation and reproduction of Liza abu in the water of Khozestan Province

As the most of the fish resources are known and exploited, protecting their generation is of the greatest importance. Aquaculture is one of the efficient procedures in protecting and reviving fish resources and knowing about the reproductive cycle and gonads development has an important role in approaching this aim. Liza abu belongs to the family Mugilidae that according to its resistance to the environmental condition and its fast growth , can be introduced as a fish with economical value. As there is no scientific data on the reproductive biology of this species , study on the reproductive biology and gonad development is considered as the aim of this research . For this purpose , 360 samples of this species were investigated during the period from February 2007 to January 2008 in Khozestan Province . After studing morphological and histological characteristics of gonad specimen , they were prepared through histological method. Samples were prepared through usual histological method and studied under light microscope. According to the results, the maturity stages of male and female Liza abu were separated to six different successive stages. In ovaries , these stages were as follow : In stage І, the oocytes were small , this stage was observed from July to October . In stage ІІ, considerable growth was observed in the oocytes . This stage was observed from October to January . In stage III, due to vitellogenesis, the maximum growth was observed and three layers of theca, granullosa and follicle cells were visible. This stage was observed during January and February . In stage IV, migration of germinal vesicle was observed and due to hydration of the oocytes , their diameter was increased. The ovaries were yellowish and in maximum size and ovules could be easily observed with naked-eye . This stage was observed in February and March . In stage V, spawning occured. This stage was observed in April . In stage VI, ovaries consisted of immature and atretic oocytes and also empty follicles. This stage was observed in May and June. In testes , these stages were as follow : In stage I , the testes were small in size and contained the spermatogonia which were the only cellular components.This stage was observed in August and September . In stage II (maturing virgin ) , the spermatogonia and the primary spermatocytes were visible. This stage was observed in October . In stage III (developing), intensive spermatogenesis was occured and the primary and the secondary spermatocytes were the most visible cells during this stage .This stage was observed from November to January. In stage IV(developed), cells of all stages of spermatogenesis could be seen but the secondary spermatocytes and spermatids were in large number. This stage was observed from January to March. In stage V , the testes were filled with sperms. This stage was observed in March and April .In stage VI, residual spermatozoa and the spermatogonia were visible in the testes. This stage was observed from May to August. According to cyclic changes in GSI, sexual maturation in breeding begins in January and spawning occurs in April. The ova diameter ranged from 30.75 μ in stage I to 472.19 μ in stage IV. In this study , the sex ratio was 1:2.7, and male and female percentage were 27.02% and 72.98% respectively. This means that females predominate males. In this study absolute fecundity was calculated and changing between 30805.44 to 431247.3 was observed and absolute fecundity was calculated 111275.3 in average.