Purpose

EGFR genotyping is now standard in the management of advanced lung adenocarcinoma, as this biomarker predicts marked benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 19 insertions are a poorly described family of EGFR mutations, and their association with EGFR TKI-sensitivity in lung adenocarcinoma is uncertain.

Experimental Design

Patients with lung cancers harboring EGFR exon 19 insertions were studied. The predicted effects of the insertions on the structure of the EGFR protein were examined, and EGFR exon 19 insertions were introduced into Ba/F3 cells to assess oncogenicity and in vitro sensitivity to EGFR TKIs. In patients receiving TKI, response magnitude was assessed with serial computed tomography (CT) measurement.

Results

Twelve tumors harboring EGFR exon 19 insertions were identified; patients were predominately female (92%) and never-smokers (75%). The 11 specimens available for full sequencing all demonstrated an 18 bp insertion that resulted in the substitution of a Pro for Leu at residue 747. The mutant EGFR transformed the Ba/F3 cells, which were then sensitive to EGFR TKI. Six patients with measurable disease received TKI and 5 had a response on serial CT.

Conclusions

EGFR exon 19 insertions are a newly appreciated family of EGFR TKI-sensitizing mutations, and patients with tumors harboring these mutations should be treated with EGFR-TKI. While these mutations may be missed through the use of some mutation-specific assays, the addition of PCR product size analysis to multi-gene assays allows sensitive detection of both exon 19 insertion and deletion mutations.

The analysis of protein-protein-interactions is a key focus of proteomics efforts. The yeast two-hybrid system has been the most commonly used method in genome-wide searches for protein interaction partners. However, the throughput of the current yeast two-hybrid array approach is hampered by the involvement of the time-consuming LacZ assay and/or the incompatibility of liquid handling automation due to the requirement for selection of colonies/diploids on agar plates. To facilitate large-scale yeast two-hybrid assays, we report a novel array approach by coupling a GFP reporter based yeast two-hybrid system with high throughput flow cytometry that enables the processing of a 96 well plate in as little as 3 minutes. In this approach, the yEGFP reporter has been established in both AH109 (MATa) and Y187 (MATα) reporter cells. It not only allows the generation of two copies of GFP reporter genes in diploid cells, but also allows the convenient determination of self-activators generated from both bait and prey constructs by flow cytometry. We demonstrate a Y2H array assay procedure that is carried out completely in liquid media in 96-well plates by mating bait and prey cells in liquid YPD media, selecting the diploids containing positive interaction pairs in selective media and analyzing the GFP reporter directly by flow cytometry. We have evaluated this flow cytometry based array procedure by showing that the interaction of the positive control pair P53/T is able to be reproducibly detected at 72 hrs post-mating compared to the negative control pairs. We conclude that our flow cytometry based yeast two-hybrid approach is robust, convenient, quantitative, and is amenable to large-scale analysis using liquid-handling automation.

Background

Pathologic studies play an important role in evaluating patients with Alport syndrome besides genotyping. Difficulties still exist in diagnosing Alport syndrome (AS), and misdiagnosis is a not-so-rare event, even in adult patient evaluated with renal biopsy.

Methods

We used nested case–control study to investigate 52 patients previously misdiagnosed and 52 patients initially diagnosed in the China Alport Syndrome Treatments and Outcomes Registry e-system.

Results

We found mesangial proliferative glomerulonephritis (MsPGN, 26.9%) and focal and segmental glomerulosclerosis (FSGS, 19.2%) were the most common misdiagnosis. FSGS was the most frequent misdiagnosis in female X-linked AS (fXLAS) patients (34.8%), and MsPGN in male X-linked AS (mXLAS) patients (41.2%). Previous misdiagnosed mXLAS patients (13/17, 76.5%) and autosomal recessive AS (ARAS) patients (8/12, 66.7%) were corrected after a second renal biopsy. While misdiagnosed fXLAS patients (18/23, 78.3%) were corrected after a family member diagnosed (34.8%) or after rechecking electronic microscopy and/or collagen-IV alpha-chains immunofluresence study (COL-IF) (43.5%) during follow-up. With COL-IF as an additional criterion for AS diagnosis, we found that patients with less than 3 criteria reached have increased risk of misdiagnosis (3.29-fold for all misdiagnosed AS patients and 3.90-fold for fXLAS patients).

Conclusion

We emphasize timely and careful study of electronic microscopy and COL-IF in pathologic evaluation of AS patients. With renal and/or skin COL-IF as additional criterion, 3 diagnosis criteria reached are the cutoff for diagnosing AS pathologically.

Background

Malaria causes over one million deaths annually, posing an enormous health and economic burden in endemic regions. The completion of genome sequencing of the causative agents, a group of parasites in the genus Plasmodium, revealed potential drug and vaccine candidates. However, genomics-driven target discovery has been significantly hampered by our limited knowledge of the cellular networks associated with parasite development and pathogenesis. In this paper, we propose an approach based on aligning neighborhood PPI subnetworks across species to identify network components in the malaria parasite P. falciparum.

Results

Instead of only relying on sequence similarities to detect functional orthologs, our approach measures the conservation between the neighborhood subnetworks in protein-protein interaction (PPI) networks in two species, P. falciparum and E. coli. 1,082 P. falciparum proteins were predicted as functional orthologs of known transcriptional regulators in the E. coli network, including general transcriptional regulators, parasite-specific transcriptional regulators in the ApiAP2 protein family, and other potential regulatory proteins. They are implicated in a variety of cellular processes involving chromatin remodeling, genome integrity, secretion, invasion, protein processing, and metabolism.

Conclusions

In this proof-of-concept study, we demonstrate that a subnetwork alignment approach can reveal previously uncharacterized members of the subnetworks, which opens new opportunities to identify potential therapeutic targets and provide new insights into parasite biology, pathogenesis and virulence. This approach can be extended to other systems, especially those with poor genome annotation and a paucity of knowledge about cellular networks.

Ascites syndrome is still a problem for chicken industry in various parts of the world. Despite the intensive investigations of this syndrome for many years, its pathogenesis remains unclear. The objective of this study was to analyze the difference in hepatic proteomics between ascites and healthy broilers by two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Changes of biochemical parameters of liver and blood were also determined. The results indicated that red blood cell counts (RBC), hematocrit (HCT) and haemoglobin (HGB) of ascites broilers were significantly greater than healthy broilers. Hepatic malondialdehyde (MDA) level of ascites broilers was significantly increased, and the activity of total superoxide dismutase (T-SOD) was significantly decreased. Hepatic lactic acid (LD) level of ascitic broilers were significantly lower than healthy ones. Serum glucose and cholesterol level of ascites broilers were significantly increased, and serum globulin level was significantly decreased in ascites broilers. There was no significant difference in triglyceride (TG) and blood urea nitrogen (BUN) level. The activity of liver hexokinase (HK) and succinodehydrogenase (SDH) in ascites broilers was significantly decreased, and there was no significant difference in the activity of liver pyruvate kinase (PK) and Na+-K+-ATPase. The hepatic proteomics analysis showed that 18 proteins expression difference were identified between ascites and healthy broilers. These proteins were mainly involved in: 1) cytoskeleton; 2) glucose, lipids and amino acid metabolism; 3) cell secretion; 4) cell apoptosis; 5) signal transduction; 6) immune and inflammatory response; and 7) cellular redox homeostasis. Mitochondrial isoform phosphoenolpyruvate carboxykinase (M-PEPCK) mainly participates in gluconeogenesis of chicken liver. In conclusion, liver oxidative damage was significantly aggravated, but antioxidant capacity was decreased in cold-induced ascites broilers. Serum glucose level was significantly increased, with liver M-PEPCK expression higher in ascites broilers, which implied that some potential regulatory reagents may reduce ascites susceptibility and mortality under cold temperature by increasing liver gluconeogenesis level.

Background

The Oxford classification of IgA nephropathy (IgAN) provides a useful tool for prediction of renal prognosis. However, the application of this classification in children with IgAN needs validation in different patient populations.

Methods

A total of 218 children with IgAN from 7 renal centers in China were enrolled. The inclusion criteria was similar to the original Oxford study.

Results

There were 98 patients (45%) with mesangial proliferation (M1), 51 patients (23%) with endocapillary proliferation (E1), 136 patients (62%) with segmental sclerosis/adhesion lesion (S1), 13 patients (6%) with moderate tubulointerstitial fibrosis (T1 26-50% of cortex scarred), and only 2 patients (1%) with severe tubulointerstitial fibrosis (T2, >50% of cortex scarred). During a median follow-up duration of 56 months, 24 children (12.4%) developed ESRD or 50% decline in renal function. In univariate COX analysis, we found that tubular atrophy/interstitial fibrosis (HR 4.3, 95%CI 1.8-10.5, P < 0.001) and segmental glomerulosclerosis (HR 9.2 1.2-68.6, P = 0.03) were significant predictors of renal outcome. However, mesangial hypercellularity, endocapillary proliferation, crescents, and necrosis were not associated with renal prognosis. In the multivariate COX regression model, none of these pathologic lesions were shown to be independent risk factors of unfavorable renal outcome except for tubular atrophy/interstitial fibrosis (HR 2.9, 95%CI 1.0-7.9 P = 0.04).

Conclusions

We confirmed tubular atrophy/interstitial fibrosis was the only feature independently associated with renal outcomes in Chinese children with IgAN.

AIM: To investigate whether activated carbon nanoparticles suspension (ACNS) or methylene blue (MB) can increase the detected number of lymph nodes in colorectal cancer.

METHODS: Sixty-seven of 72 colorectal cancer patients treated at our hospital fulfilled the inclusion criteria of the study which was conducted from December 2010 to February 2012. Seven patients refused to participate. Eventually, 60 patients were included, and randomly assigned to three groups (20 in each group): ACNS group (group A), MB group (group B) and non-stained conventional surgical group (group C). In group A, patients received subserosal injection of 1 mL ACNS in a 4-quadrant region around the mass. In group B, the main artery of specimen was identified and isolated after the specimen was removed, and 2 mL MB was slowly injected into the isolated, stretched and fixed vessel. In group C, no ACNS and MB were injected. All the mesentery lymph nodes were isolated and removed systematically by visually inspecting and palpating the adipose tissue.

RESULTS: No difference was observed among the three groups in age, gender, tumor location, tumor diameter, T-stage, degree of differentiation, postoperative complications and peritoneal drainage retention time. The total number of detected lymph nodes was 535, 476 and 223 in the three groups, respectively. The mean number of detected lymph nodes per patient was significantly higher in group A than in group C (26.8 ± 8.4 vs 12.2 ± 3.2, P < 0.001). Similarly, there were significantly more lymph nodes detected in group B than in group C (23.8 ± 6.9 vs 12.2 ± 3.2, P < 0.001). However, there was no significant difference between group A and group B. There were 50, 46 and 32 metastatic lymph nodes dissected in 13 patients of group A, 10 patients of group B and 11 patients of group C, without significant differences among the three groups. Eleven of the 60 patients had insufficient number of detected lymph nodes (< 12). Only one patient with T4a rectal cancer had 10 lymph nodes detected in group B, the other 10 patients were all from group C. Based on the different diameter categories, the number of detected lymph nodes in groups A and B was significantly higher than in group C. However, there was no statistically significant difference between group A and group B. The metastatic lymph nodes were not significant different among the three groups. Similarly, tumor location, T stage and tumor differentiation did not affect the staining results. Body mass index was a minor influencing factor in the two different staining methods. The stained lymph nodes can easily be identified from the mesenteric adipose tissues, and the staining time for lymph nodes was not significantly different compared with unstained group. None of the patients in groups A and B had drug-related complications.

CONCLUSION: Both activated carbon nanoparticles suspension in vivo and methylene blue in vitro can be used as tracers to increase the detected number of lymph nodes in colorectal cancer.

It is of great interest to identify new neurons in the adult human brain, but the persistence of neurogenesis in the subventricular zone (SVZ) and the existence of the rostral migratory stream (RMS)-like pathway in the adult human forebrain remain highly controversial. In the present study, we have described the general configuration of the RMS in adult monkey, fetal human and adult human brains. We provide evidence that neuroblasts exist continuously in the anterior ventral SVZ and RMS of the adult human brain. The neuroblasts appear singly or in pairs without forming chains; they exhibit migratory morphologies and co-express the immature neuronal markers doublecortin, polysialylated neural cell adhesion molecule and βIII-tubulin. Few of these neuroblasts appear to be actively proliferating in the anterior ventral SVZ but none in the RMS, indicating that neuroblasts distributed along the RMS are most likely derived from the ventral SVZ. Interestingly, no neuroblasts are found in the adult human olfactory bulb. Taken together, our data suggest that the SVZ maintains the ability to produce neuroblasts in the adult human brain.

Background

The extracellular matrix (ECM) provides a supportive microenvironment for cells, which is suitable as a tissue engineering scaffold. Mechanical stimulus plays a significant role in the fate of osteoblast, suggesting that it regulates ECM formation. Therefore, we investigated the influence of mechanical stimulus on ECM formation and bioactivity.

Methods

Mouse osteoblastic MC3T3-E1 cells were cultured in cell culture dishes and stimulated with mechanical tensile strain. After removing the cells, the ECMs coated on dishes were prepared. The ECM protein and calcium were assayed and MC3T3-E1 cells were re-seeded on the ECM-coated dishes to assess osteoinductive potential of the ECM.

Results

The cyclic tensile strain increased collagen, bone morphogenetic protein 2 (BMP-2), BMP-4, and calcium levels in the ECM. Compared with the ECM produced by unstrained osteoblasts, those of mechanically stimulated osteoblasts promoted alkaline phosphatase activity, elevated BMP-2 and osteopontin levels and mRNA levels of runt-related transcriptional factor 2 (Runx2) and osteocalcin (OCN), and increased secreted calcium of the re-seeded MC3T3-E1 cells.

Conclusion

Mechanical strain promoted ECM production of osteoblasts in vitro, increased BMP-2/4 levels, and improved osteoinductive potential of the ECM. This study provided a novel method to enhance bioactivity of bone ECM in vitro via mechanical strain to osteoblasts.

PALB2/FANCN is mutated in breast and pancreatic cancers and Fanconi anemia (FA). It controls the intranuclear localization, stability, and DNA repair function of BRCA2 and links BRCA1 and BRCA2 in DNA homologous recombination repair and breast cancer suppression. Here, we show that PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and represses the master antioxidant transcription factor NRF2. PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF2 for KEAP1 binding. PALB2 promotes NRF2 accumulation and function in the nucleus and lowers the cellular reactive oxygen species (ROS) level. In addition, PALB2 also regulates the rate of NRF2 export from the nucleus following induction. Our findings identify PALB2 as a regulator of cellular redox homeostasis and provide a new link between oxidative stress and the development of cancer and FA.

Background

Cardiac shock wave therapy (CSWT) improves cardiac function in patients with severe coronary artery disease (CAD). We aimed to evaluate the clinical outcomes of a new CSWT treatment regimen.

Methods

The 55 patients with severe CAD were randomly divided into 3 treatment groups. The control group (n = 14) received only medical therapy. In group A ( n = 20), CSWT was performed 3 times within 3 months. In group B ( n = 21), patients underwent 3 CSWT sessions/week, and 9 treatment sessions were completed within 1 month. Primary outcome measurement was 6-minute walk test (6MWT). Other measurements were also evaluated.

Results

The 6MWT, CCS grading of angina, dosage of nitroglycerin, NYHA classification, and SAQ scores were improved in group A and B compared to control group.

Conclusions

A CSWT protocol with 1 month treatment duration showed similar therapeutic efficacy compared to a protocol of 3 months duration.

Clinical trial registry

We have registered on ClinicalTrials.gov, the protocol ID is CSWT IN CHINA.

Effective immobilization and transportation are vital to the life-saving acute medical care needed when treating critically injured people. However, the most common types of stretchers used today are wrought with problems that can lead to further medical complications, difficulty in employment and rescue, and ineffective transitions to hospital treatment. Here we report a novel first aid stretcher called the “emergency carpet”, which solves these problems with a unique design for spine injured patients. Polyurethane composite material, obtained by a novel process of manually mixing isocyanate and additives, can be poured into a specially designed fabric bag and allowed to harden to form a rigid human-shaped stretcher. The effectiveness of the emergency carpet was examined in the pre-hospital management of victims with spinal fractures. Additionally, it was tested on flat ground and complex terrain as well as in the sea and air. We demonstrated that the emergency carpet can be assembled and solidified on the scene in 5 minutes, providing effective immobilization to the entire injured body. With the protection of the emergency carpet, none of the 20 patients, who were finally confirmed to have spinal column fracture or dislocation, had any neurological deterioration during transportation. Furthermore, the carpet can be handled and transported by multiple means under differing conditions, without compromising immobilization. Finally, the emergency carpet allows the critically injured patient to receive multiple examinations such as X-ray, CT, and MRI without being removed from the carpet. Our results demonstrate that the emergency carpet has ideal capabilities for immobilization, extrication, and transportation of the spine injured patients. Compared with other stretchers, it allows for better mobility, effective immobilization, remarkable conformity to the body, and various means for transportation. The emergency carpet is promising for its intrinsic advantages in the pre-hospital management of accident victims.

Background

Spontaneous spinal epidural hematoma (SSEH) is an uncommon clinical entity. It produces a severe neurological deficit and prompt decompression is usually the first choice of treatment. Brown-Séquard syndrome is commonly seen in the setting of spinal trauma or an extramedullary spinal neoplasm, but rarely caused by SSEH.

Methods

Case report and literature review.

Findings

A previously healthy man presented with Brown-Séquard syndrome below T5–T6 cord segment secondary to spontaneous epidural hematoma. He opted for conservative treatment, which was followed by rapid resolution.

Conclusions

Although Brown-Séquard syndrome as a presenting feature of SSEH is rare, it does exist in exceptional case, which should be taken into consideration for differential diagnosis. Prompt surgical decompression is an absolute surgical indication widely accepted for patient with progressive neurological deficit. However, SSEH presenting with incomplete neurological insult such as Brown-Séquard syndrome might have a benign course. Successful non-operative management of this problem does not make it a standard of care, and surgical decompression remains the standard treatment for SSEH.

AIM: To study the expression of eukaryotic translation initiation factor 4E (eIF4E), which is closely correlated with malignant tumors, and its relationship to prognosis in hepatocellular carcinoma.

METHODS: Western blotting was performed to quantify the elF4E protein expression in the normal human liver cell line L02 and the hepatoma cell lines Hep3B, HepG2, and Huh7. Forty-six hepatocellular carcinoma samples with complete clinical data were obtained from Changzheng Hospital during the period of December 2008 to July 2009. The expression of eIF4E in the tumor samples and their adjacent tissues were detected by immunohistochemistry. The relationship between the test results and hepatocellular carcinoma (HCC) prognosis was statistically analysed by using a COX proportional hazard model.

RESULTS: Western blotting analysis showed that there were distinct eIF4E protein bands in all three of the hepatoma cell lines. In particular, the HepG2 cell line had the highest level of eIF4E protein expression. The L02 cell group had a low eIF4E expression. Immunohistochemical assay showed that there were 32 cases in which the tumour tissue expression was higher than their adjacent tissues, accounting for 69.57%. There were also 14 cases in which the tumour tissue expression was lower or no significant difference was found, accounting for 30.43%. COX proportional hazards model analysis showed that HCC prognosis was related to the depth of invasion, the overexpression of eIF4E and p53, possibly as independent HCC prognostic predictors.

CONCLUSION: In summary, eIF4E expression is associated with liver cancer, and patients with high eIF4E expression levels have a higher risk of recurrence.

Background

Clinical significance of microscopic peritoneal carcinomatosis remained unclear. The aim of this study was to evaluate the prognostic value of microscopic peritoneal carcinomatosis in gastric cancer.

Methods

From 1996 to 2007, 4426 patients underwent gastrectomy for gastric cancer at Fudan University Shanghai Cancer Center. The clinical and pathological data were reviewed to identify patients with microscopic peritoneal carcinomatosis (group 1). The clinicopathological features and prognosis were examined. Additionally, 242 stage-matched gastric cancer patients without microscopic peritoneal carcinomatosis (group 2) and 118 with macroscopic peritoneal carcinomatosis (group 3) were selected as control groups.

Results

Microscopic peritoneal carcinomatosis was found in 121 patients. There were 85 males and 36 females (2.36:1). There was a higher incidence rate of large size tumor (≥5 cm) (P = 0.045), Borrmann IV (P = 0.000), and serosal invasion (P = 0.000) in gastric cancer with microscopic peritoneal carcinomatosis compared with the control group. The 5-year survival rate of gastric cancer with microscopic peritoneal carcinomatosis was 24%, significantly poorer than that of the stage-matched control group but better than that of patients with macroscopic peritoneal carcinomatosis. The independent prognostic factors identified included pathological stage and operative curability.

Conclusions

The presence of microscopic peritoneal carcinomatosis was associated with worse prognosis for gastric cancer, but curative surgery showed potential to improve prognosis.

In the title mol­ecule, C13H19NO4, except for two C atoms of the tert-butyl group, the non-H atoms are almost coplanar (r.m.s. deviation = 0.2542 Å). In the crystal, mol­ecules are linked into centrosymmetric dimers by two inter­molecular N—H⋯O hydrogen bonds, forming an R 2 2(10) ring motif.

Human papillomavirus type 16 plays a critical role in the neoplastic transformation of cervical cancers. Molecular variants of HPV16 existing in different ethnic groups have shown substantial phenotypic differences in pathogenicity, immunogenicity and tumorigenicity. In this study, we sequenced the entire HPV16 genome of 76 isolates originated from Anyang, central China. Phylogenetic analysis of these sequences identified two major variants of HPV16 in the Anyang area, namely the European prototype (E(p)) and the European Asian type (E(As)). These two variants show a high degree of divergence between groups, and the E(p) comprised higher genetic diversity than the E(As). Analysis with two measurements of genetic diversity indicated that viral population size was relatively stable in this area in the past. Codon based likelihood models revealed strong statistical support for adaptive evolution acting on the E6 gene. Bayesian analysis identified several important amino acid positions that may be driving adaptive selection in the HPV 16 population, including R10G, D25E, L83V, and E113D in the E6 gene. We hypothesize that the positive selection at these codons might be a contributing factor responsible for the phenotypic differences in carcinogenesis and immunogenicity among cervical cancers in China based on the potential roles of these molecular variants reported in other studies.

Background

The clinical importance of preoperative tumor markers remain elusive in gastric cancer. The aim of this study was to evaluate the prognostic value of AFP, CEA, CA19-9, and CA50 in T4a stage gastric cancer.

Methods

Two hundred and seventy-three T4a gastric cancer patients who underwent curative D2 gastrectomy between 1996 and 2005 were evaluated. The correlation between tumor markers and clinicopathologic characteristics and prognostic value of preoperative tumor markers were investigated.

Results

Correlation analysis showed that AFP was associated with Borrmann type (P = 0.010); CEA with sex (P = 0.029), tumors site (P = 0.014), and N stage (P = 0.001); CA19-9 with age (P = 0.047), tumor site (P = 0.011), lymphovascular invasion (P = 0.004), and N stage (P = 0.000); CA50 with age (P = 0.017), tumor site (P = 0.004), tumor size (P = 0.014), and N stage (P = 0.000). Multivariate analysis showed that the positivity of preoperative CEA, CA19-9, and CA50 were major independent poor prognostic factors of patients with T4a stage gastric cancer.

Conclusions

Preoperative serum tumor marker might be a candidate for the staging system in addition to conventional factors.

Objective

The objective of this study was to explore the time distribution patterns of the onset of chest pain in subjects with acute ST-elevation myocardial infarction in a Chinese population.

Methods

A total of 1467 patients with acute ST-elevation myocardial infarction were enrolled from 2003 to 2010. The hourly, daily, monthly, seasonal and day-of-week fluctuations in the prevalence of acute ST-elevation myocardial infarction were analyzed.

Results

A peak was found between the morning hours of 07:31 and 08:30. A second peak was observed between 14:31 and 15:30, and a third peak was found between 23:31 and 00:30 (p<0.001). The monthly maximum was recorded in November and the minimum was in April (p<0.001). The number of daily cases was greatest in autumn and lowest in the spring (p = 0.001). Day-of-the-week variations of ST-elevation acute myocardial infarction were not found, except in patients more than 75-years-old.

Conclusions

Periodic variations in the frequency of ST-elevation acute myocardial infarction in Chinese patients showed significant differences with regard to diurnal, monthly and seasonal patterns. The exact mechanisms underlying these circadian variations require further study.

Background

Accurate prognostication of locally advanced nasopharyngeal carcinoma (NPC) will benefit patients for tailored therapy. Here, we addressed this issue by developing a mathematical algorithm based on support vector machine (SVM) through integrating the expression levels of multi-biomarkers.

Methodology/Principal Findings

Ninety-seven locally advanced NPC patients in a randomized controlled trial (RCT), consisting of 48 cases serving as training set and 49 cases as testing set of SVM models, with 5-year follow-up were studied. We designed SVM models by selecting the variables from 38 tissue molecular biomarkers, which represent 6 tumorigenesis signaling pathways, and 3 EBV-related serological biomarkers. We designed 3 SVM models to refine prognosis of NPC with 5-year follow-up. The SVM1 displayed highly predictive sensitivity (sensitivity, specificity were 88.0% and 81.9%, respectively) by integrating the expression of 7 molecular biomarkers. The SVM2 model showed highly predictive specificity (sensitivity, specificity were 84.0% and 94.5%, respectively) by grouping the expression level of 12 molecular biomarkers and 3 EBV-related serological biomarkers. The SVM3 model, constructed by combination SVM1 with SVM2, displayed a high predictive capacity (sensitivity, specificity were 88.0% and 90.3%, respectively). We found that 3 SVM models had strong power in classification of prognosis. Moreover, Cox multivariate regression analysis confirmed these 3 SVM models were all the significant independent prognostic model for overall survival in testing set and overall patients.

Conclusions/Significance

Our SVM prognostic models designed in the RCT displayed strong power in refining patient prognosis for locally advanced NPC, potentially directing future target therapy against the related signaling pathways.

The complete mol­ecule of the title compound, C12H14Cl2N2O2, is generated by a crystallographic twofold axis with two C atoms of the central benzene ring lying on the axis. In the crystal, N—H⋯O hydrogen bonds link the mol­ecules into chains parallel to the c axis.

Malaria continues to be one of the most devastating global health problems due to the high morbidity and mortality it causes in endemic regions. The search for new antimalarial targets is of high priority because of the increasing prevalence of drug resistance in malaria parasites. Malarial proteases constitute a class of promising therapeutic targets as they play important roles in the parasite life cycle and it is possible to design and screen for specific protease inhibitors. In this mini-review, we provide a phylogenomic overview of malarial proteases. An evolutionary perspective on the origin and divergence of these proteases will provide insights into the adaptive mechanisms of parasite growth, development, infection, and pathogenesis.B

Background

Human papillomavirus (HPV) has been observed repeatedly in esophageal squamous cell carcinoma (ESCC) tissues. However, the causal relationship between HPV infection and the onset of ESCC remains unknown. A large cohort study focusing on this topic is being carried out in rural Anyang, China.

Methodology/Principal Findings

The Anyang Esophageal Cancer Cohort Study (AECCS) is a population-based prospective endoscopic cohort study designed to investigate the association of HPV infection and ESCC. This paper provides information regarding the design and implementation of this study. In particular we describe the recruitment strategies and quality control procedures which have been put into place, and the custom designed computer-aided survey system (CASS) used for this project. This system integrates barcode technology and unique identification numbers, and has been developed to facilitate real-time data management throughout the workflow using a wireless local area network. A total of 8,112 (75.3%) of invited subjects participated in the baseline endoscopic examination; of those invited two years later to take part in the first cycle of follow-up, 91.9% have complied.

Conclusions/Significance

The AECCS study has high potential for evaluating the causal relationship between HPV infection and the occurrence of ESCC. The experience in setting up the AECCS may be beneficial for others planning to initiate similar epidemiological studies in developing countries.

Background

The aim of this study was to determine the health expenses incurred by families with children with autism spectrum disorder (ASD) and those expenses' relation to total household income and expenditures.

Methods

In this cross-sectional study, health care expenditure data were collected through face-to-face interviews. Expenses included annual costs for clinic visits, medication, behavioral therapy, transportation, and accommodations. Health care costs as a percentage of total household income and expenditures were also determined. The participants included 290 families with ASD children who were treated at the Children Development and Behavior Research Center, Harbin Medical University, China.

Results

Families with ASD children from urban and rural areas had higher per-capita household expenditures by 60.8% and 74.7%, respectively, compared with provincial statistics for 2007. Behavioral therapy accounted for the largest proportion of health expenses (54.3%) for ASD children. In 19.9% of urban and 38.2% of rural families, health care costs exceeded the total annual household income. Most families (89.3% of urban families; 88.1% of rural families) in that province reported higher health care expenditures than the provincial household average.

Conclusion

For families with ASD children, the economic burden of health care is substantially higher than the provincial average.