Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma.
Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT).
The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have > 5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT.
This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy.
Lymphocyte-Predominant Hodgkin Lymphoma
Available methods for differentiating human embryonic (ES) and induced pluripotent stem (iPS) cells into neurons are often cumbersome, slow and variable. Alternatively, human fibroblasts can be directly converted into induced neuronal (iN) cells. However, with present techniques conversion is inefficient, synapse formation is limited, and only small amounts of neurons can be generated. Here, we show that human ES and iPS cells can be converted into functional iN cells with nearly 100% yield and purity in less than two weeks by forced expression of a single transcription factor. The resulting ES-iN or iPS-iN cells exhibit quantitatively reproducible properties independent of the cell line of origin, form mature pre- and postsynaptic specializations, and integrate into existing synaptic networks when transplanted into mouse brain. As illustrated by selected examples, our approach enables large-scale studies of human neurons for questions such as analyses of human diseases, examination of human-specific genes, and drug screening.
Asian Americans have disproportionately high prevalence of chronic hepatitis B virus infection in the United States and yet have low hepatitis B screening and vaccination rates. We developed three photonovels specifically designed for Chinese, Korean, and Vietnamese Americans and evaluated their cultural relevance and effectiveness in increasing self-efficacy and intention to have a hepatitis B screening. Photonovels' storylines were drawn from focus group themes, and lay people from each community played actors/actresses in community settings. Photonovels were pilot tested, revised, and distributed in a hepatitis B intervention. A two-page process evaluation questionnaire was mailed to 441 participants after one month. Descriptive analysis and multiple logistic regressions were conducted to assess the overall evaluation of the photonovel and to assess factors associated with self-efficacy and intention to have hepatitis B screening. Eighty-four percent of participants responded to the process evaluation. The majority of participants either strongly agreed or agreed that the cancer information in the photonovel was helpful, the story was written by someone who knows the community, and the information was easy to understand. Overall, more than 80% of them thought this photonovel was a good teaching tool. Favorable evaluation of the photonovel was associated with both having intention and self-efficacy to have a hepatitis B screening in the next 5 months. When stratified by level of education and income, the associations were stronger among the lower income and education groups. Culturally appropriate photonovels are useful tools to promote hepatitis B screening among Asian Americans, especially among those of lower socioeconomic status.
Asian Americans; community-based participatory research; educational material; hepatitis B; photonovel; screening
As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches.
Structure-based drug design; protein modeling; focused library design; pharmacophore; flexible docking; high-throughput virtual screening; de novo design; protein-protein interaction; polypharmacology
The objective of this study is to examine the association between acculturation and BMI among Asian Americans using multiple measures of acculturation. Data of 847 Chinese, Korean and Vietnamese recruited for a health education program in Maryland during 2009 to 2010 were used. Acculturation was measured by the short version of Suinn-Lew Asian Self-Identity Acculturation Scale (SL-ASIA) and its individual components. Height and weight were measured by trained staff. Multiple linear regressions were used to estimate the association between acculturation and BMI. After adjusting for age, gender, education, income, marital status, and ethnicity, SL-ASIA (β = 0.71, SE = 0.28), having education in the US (β = 0.56, SE = 0.28), younger age of arrival (0–5 years: β = 3.32, SE = 0.76, 6–10 years: β = 1.55, SE = 0.78), self identified as Americans (β = 1.51, SE = 0.77) and equal preference of Asian/American food in restaurants (β = 0.92, SE = 0.28) were significantly associated with increased BMI. The association between acculturation and BMI was stronger among men than women, strongest among Chinese and weakest among Vietnamese. Acculturation was moderately associated with increased BMI among Asian Americans and this association varied by measures of acculturation. The association of acculturation and BMI was moderated by sex and ethnicity groups.
BMI; Obesity; Acculturation; Asian Americans
Chronic inactivation of a neural network is known to induce homeostatic upregulation of synaptic strength, a form of synaptic plasticity that differs from Hebbian-type synaptic plasticity in that it is not input-specific, but involves all synapses of an individual neuron. However, it is unclear how homeostatic and Hebbian synaptic plasticity interact in the same neuron. Here we show that long-term potentiation (LTP) at Schaffer collateral-CA1 synapses is greatly enhanced in cultured mouse hippocampal slices after chronic (60 hour) network-activity blockade with tetrodotoxin (TTX). This increase in LTP is not due to an altered synaptic NMDA receptor composition or presynaptic function. Instead, we found that silencing neural network activity not only increases the abundance of both AMPA and NMDA receptors at existing synapses as previously described, but also promotes the presence of new glutamatergic synapses that contain only NMDA receptors – a class of synapses that are functionally silent due to the absence of AMPA receptors. Induction of LTP in TTX-treated neurons leads to insertion of AMPA receptors into the silent synapses, therefore “switching on” these silent synapses, which produces the observed enhancement of LTP magnitude. Our findings suggest that homeostatic synaptic plasticity manifests not only in the adjustment of the strength of existing synapses, but also in the modulation of new synapse formation/maintenance. Moreover, presence of new but functionally silent synapses enables more robust LTP to occur through rapid conversion of silent synapses to active synapses, resulting in a stronger input-specific modulation of synapses following prolonged network silencing.
homeostatic plasticity; AMPA receptor; synaptic scaling; silent synapse; LTP
The West Liao River valley in Northeast China is an ecologically diverse region, populated in prehistory by human populations with a wide range of cultures and modes of subsistence. To help understand the human evolutionary history of this region, we performed Y chromosome analyses on ancient human remains from archaeological sites ranging in age from 6500 to 2700 BP.
47 of the 70 individuals provided reproducible results. They were assigned into five different Y sub-haplogroups using diagnostic single nucleotide polymorphisms, namely N1 (xN1a, N1c), N1c, C/C3e, O3a (O3a3) and O3a3c. We also used 17 Y short tandem repeat loci in the non-recombining portion of the Y chromosome. There appears to be significant genetic differences between populations of the West Liao River valley and adjacent cultural complexes in the prehistoric period, and these prehistoric populations were shown to carry similar haplotypes as present-day Northeast Asians, but at markedly different frequencies.
Our results suggest that the prehistoric cultural transitions were associated with immigration from the Yellow River valley and the northern steppe into the West Liao River valley. They reveal the temporal continuity of Y chromosome lineages in populations of the West Liao River valley over 5000 years, with a concurrent increase in lineage diversity caused by an influx of immigrants from other populations.
The serine/threonine kinase Akt has proven to be a significant signaling target, involved in various biological functions. Because of its cardinal role in numerous cellular responses, Akt has been implicated in many human diseases, particularly cancer. It has been established that Akt is a viable and feasible target for anticancer therapeutics. Analysis of all Akt kinases reveals conserved homology for an N-terminal regulatory domain, which contains a pleckstrin-homology (PH) domain for cellular translocation, a kinase domain with serine/threonine specificity, and a C-terminal extension domain. These well defined regions have been targeted, and various approaches, including in silico methods, have been implemented to develop Akt inhibitors. In spite of unique techniques and a prolific body of knowledge surrounding Akt, no targeted Akt therapeutics have reached the market yet. Here we will highlight successes and challenges to date on the development of anticancer agents modulating the Akt pathway in recent patents as well as discuss the methods employed for this task. Special attention will be given to patents with focus on those discoveries using computer-aided drug design approaches.
Akt; anticancer therapeutics; computer-aided drug design; drug discovery and development; pleckstrin-homology (PH) domain; serine/threonine kinase
In 1995, the Children's Cancer Group (CCG) opened a trial for patients with Hodgkin's lymphoma evaluating whether low-dose involved-field radiation therapy (IFRT) improved event-free survival (EFS) for patients achieving a complete response after chemotherapy. We present the long-term study outcome using final data through March 2007.
Patients and Methods
Between January 1995 and December 1998, 826 eligible patients were enrolled onto CCG 5942. Four hundred ninety-eight patients achieving an initial complete response to chemotherapy were randomly assigned to receive IFRT or no further therapy. EFS and overall survival (OS) were assessed from the date of study entry or random assignment, as appropriate.
Ten-year EFS and OS rates for the entire cohort were 83.5% and 92.5%, respectively. In an as-treated analysis for randomly assigned patients, the 10-year EFS and OS rates were 91.2% and 97.1%, respectively, for IFRT and 82.9% and 95.9%, respectively, for no further therapy. For EFS and OS comparisons, P = .004 and P = .50, respectively. Bulk disease, “B” symptoms, and nodular sclerosis histology were risk factors for inferior EFS.
With a median follow-up of 7.7 years, IFRT produced a statistically significant improvement in EFS but no improvement in OS. For individual patients, the relative risks of relapse versus late effects of IFRT must be considered. Patient and disease characteristics and early response assessment will aid in deciding which patients are most likely to benefit from IFRT.
Breast cancer incidence and the number of breast cancer survivors have been rapidly increasing among Chinese and Korean women in the United States. However, few data are available regarding quality of life in Asian American breast cancer survivors. This qualitative study aims to describe Asian American women’s perceptions of quality of life and their breast cancer experiences. In-depth interviews with four Chinese and five Korean American breast cancer survivors and three oncologists were conducted in Chinese, Korean, or English. Interviews were recorded and transcripts were translated into English. Qualitative analyses were performed by two independent coders and then discussed and agreed upon by the research team. The respondents reported that the breast cancer experience had affected various domains of quality of life, but women reported having limited resources with which to cope effectively. Depression, anxiety, and stress were commonly reported, but women rarely discussed these issues with family and friends or sought professional help. As immigrants, women’s loneliness and a lack of social support and culturally relevant resources seemed to be major barriers to maintaining good quality of life. Women also expressed interest in learning more about alternative therapies and relaxation skills. These findings can be used to help inform the development of a culturally appropriate intervention for Asian American breast cancer survivors. Future programs may provide information in women’s native languages to teach skills to cope with stress and anxiety, increase women’s self-efficacy within the context of their cultural background, and enhance social support among women from the same ethnic group.
breast cancer; quality of life; survivorship; Asian American; Chinese American; Korean American
Apolipoprotein (apo) O is a novel apolipoprotein that is present predominantly in high density lipoprotein (HDL). However, overexpression of apoO does not impact on plasma HDL levels or functionality in human apoA-I transgenic mice. Thus, the physiological function of apoO is not yet known. In the present study, we investigated relationships between plasma apoO levels and high-sensitive C-reactive protein (hs-CRP) levels, as well as other lipid parameters in healthy subjects (n = 111) and patients with established acute coronary syndrome (ACS) (n = 50). ApoO was measured by the sandwich dot-blot technique with recombinant apoO as a protein standard. Mean apoO level in healthy subjects was 2.21 ± 0.83 µg/ml whereas it was 4.94 ± 1.59 µg/ml in ACS patients. There were significant differences in plasma level of apoO between two groups (P < 0.001). In univariate analysis, apoO correlated significantly with lg(hsCRP) (r = 0.48, P < 0.001) in ACS patients. Notably, no significant correlation between apoO and other lipid parameters was observed. Logistic regression analysis showed that plasma apoO level was an independent predictor of ACS (OR = 5.61, 95% CI 2.16–14.60, P < 0.001). In conclusion, apoO increased in ACS patients, and may be regarded as an independent inflammatory predictor of ACS patients.
apolipoproteins; atherosclerosis; high density lipoprotein; inflammation; lipoproteins
Chronic inflammation is thought to be the leading cause of colorectal cancer, and interleukin-10 (IL10) has been identified as a potent immunomodulatory cytokine that regulates inflammatory responses in the gastrointestinal tract. Although several single nucleotide polymorphisms (SNPs) in IL10 have been associated with the risk of colorectal cancer, their prognostic significance has not been determined. Two hundred and eighty-two colorectal cancer patients were genotyped for two candidate cancer-associated SNPs in IL10. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis and Cox regression model. The minor homozygote GG genotype of IL10 rs3021094 was significantly associated with a 3.30-fold higher risk of death compared with the TT+TG genotypes (P=0.011). The patients with IL10 rs3021094 GG genotype also had a poorer overall survival in Kaplan-Meier analysis (log-rank P=0.007) and in multivariate Cox regression model (P=0.044) adjusting for age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, and perineural invasion. In conclusion, our results suggest that IL10 rs3021094 might be a valuable prognostic biomarker for colorectal cancer patients.
Colorectal Neoplasms; Inflammation; Interleukin-10; Polymorphism; Survival
A new method, named “re-growth etching”, which introduces a unique etchant “AuI”, has been developed to fabricate large-sized porous gold nanostructures. The size of nanostructures and the number of pores can be regulated by the molar ratio of Ag and Au in the precursor. We have evaluated their performance by a model reaction of the reduction of 4-nitrophenol. The catalytic property of porous Au from Ag67.6Au32.4 (Sample 3) is higher than those of other obtained products, which are mainly attributed to its hollows-interior, porous-exterior, and the large amount of Au. The method for the large-sized porous metal nanostructures has been established for the first time and shows the potential of this route to expand the scope of fabricating porous metal nanostructures.
The control of RNA splicing is often modulated by exonic motifs near splice sites. Chief among these are exonic splice enhancers (ESEs). Well-described ESEs in mammals are purine rich and cause predictable skews in codon and amino acid usage toward exonic ends. Looking across species, those with relatively abundant intronic sequence are those with the more profound end of exon skews, indicative of exonization of splice site recognition. To date, the only intron-rich species that have been analyzed are mammals, precluding any conclusions about the likely ancestral condition. Here, we examine the patterns of codon and amino acid usage in the vicinity of exon–intron junctions in the brown alga Ectocarpus siliculosus, a species with abundant large introns, known SR proteins, and classical splice sites. We find that amino acids and codons preferred/avoided at both 3′ and 5′ ends in Ectocarpus, of which there are many, tend, on average, to also be preferred/avoided at the same exon ends in humans. Moreover, the preferences observed at the 5′ ends of exons are largely the same as those at the 3′ ends, a symmetry trend only previously observed in animals. We predict putative hexameric ESEs in Ectocarpus and show that these are purine rich and that there are many more of these identified as functional ESEs in humans than expected by chance. These results are consistent with deep phylogenetic conservation of SR protein binding motifs. Assuming codons preferred near boundaries are “splice optimal” codons, in Ectocarpus, unlike Drosophila, splice optimal and translationally optimal codons are not mutually exclusive. The exclusivity of translationally optimal and splice optimal codon sets is thus not universal.
ESE; Ectocarpus; splicing; translational selection
Recent studies have proposed a new prognostic factor (metastatic lymph node ratio, or MLNR) for patients with esophageal cancer (EC). However, to the best of our knowledge, there have been no studies conducted to date regarding MLNR in elderly patients. The aim of this study was to determine the prognostic value of MLNR staging compared with the 2010 American Joint Committee on Cancer (AJCC) N staging in elderly patients with EC.
From January 2001 to December 2009, a retrospective analysis of 132 consecutive patients older than 70 years of age with esophageal squamous cell carcinoma (ESCC) was conducted. Prognostic factors for disease-specific survival were analyzed. Receiver operating characteristic curves were also plotted to verify the accuracy of MLNR staging and N staging for survival prediction.
The disease-specific survival rates of N0, N1, N2 and N3 patients according to the AJCC Cancer Staging Manual Seventh Edition N staging were 65.5%, 42.9%, 22.2% and 0, respectively (N0 vs N1, P = 0.017; N1 vsN2, = 0.050; N2 vs N3, P < 0.001). The disease-specific survival rates of MLNR0, MLNR1, MLNR2 and MLNR3 patients were 65.5%, 45.0%, 21.1% and 0, respectively (MLNR0 vsMLNR1, P = 0.026; MLNR1 vs MLNR2, P = 0.033; MLNR2 vs MLNR3, P = 0.015). The areas under the curve were 0.731 for the 2010 AJCC N staging and 0.737 for the MLNR staging.
MLNR is an independent predictor of survival in elderly patients with ESCC. MLNR staging predicts survival after EC similarly to the 2010 AJCC N classifications and should be considered an alternative to current N staging.
Esophageal cancer; Lymph node ratio; Overall survival; TNM classification
Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors.
Patients and Methods
One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques.
A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m2: reference; 1 to 100 mg/m2: odds ratio [OR], 1.65; 101 to 150 mg/m2: OR, 3.85; 151 to 200 mg/m2: OR, 3.69; 201 to 250 mg/m2: OR, 7.23; 251 to 300 mg/m2: OR, 23.47; > 300 mg/m2: OR, 27.59; Ptrend < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m2) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m2) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status.
This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m2. Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.
Interactions between breast cancer patients and their oncologists are important as effective patient-physician communication can facilitate the delivery of quality cancer care. However, little is known about patient-physician communication processes among Asian American breast cancer patients, who may have unique communication needs and challenges. Thus, we interviewed Asian American patients and several oncologists to explore patient-physician communication processes in breast cancer care.
We conducted in-depth interviews with nine Chinese- or Korean American breast cancer patients and three Asian American oncologists who routinely provided care for Asian American patients in the Washington DC metropolitan area in 2010. We conducted patient interviews in Chinese or Korean and then translated into English. We conducted physicians’ interviews in English. We performed qualitative analyses to identify themes.
For women with limited English proficiency, language was the greatest barrier to understanding information and making treatment-related decisions. Both patients and oncologists believed that interpretation provided by patients’ family members may not be accurate, and patients may neglect to ask questions because of their worry of burdening others. We observed cultural differences regarding expectations of the doctor’s role and views of cancer recovery. As expressed by the patients and observed by oncologists, Asian American women are less likely to be assertive and are mostly reliant on physicians to make treatment decisions. However, many patients expressed a desire to be actively involved in the decision-making process.
Findings provide preliminary insight into patient-physician communication and identify several aspects of patient-physician communication that need to be improved for Asian American breast cancer patients. Proper patient education with linguistically and culturally appropriate information and tools may help improve communication and decision-making processes for Asian American women with breast cancer.
Asian American; breast cancer; patient-physician communication; language barrier; cultural difference; treatment decision making
The purpose of the present study was to estimate the prevalence of depression in Chinese university students, and to identify the socio-demographic factors associated with depression in this population. A multi-stage stratified sampling procedure was used to select university students (N = 5245) in Harbin (Heilongjiang Province, Northeastern China), who were aged 16–35 years. The Beck Depression Inventory (BDI) was used to determine depressive symptoms of the participants. BDI scores of 14 or higher were categorized as depressive for logistic regression analysis. Depression was diagnosed by the Structured Clinical Interview (SCID) for the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV). 11.7% of the participants had a BDI score 14 or higher. Major Depressive Disorder was seen in 4.0% of Chinese university students. There were no statistical differences in the incidence of depression when gender, ethnicity, and university classification were analyzed. Multivariate analysis showed that age, study year, satisfaction with major, family income situation, parental relationship and mother's education were significantly associated with depression. Moderate depression is prevalent in Chinese university students. The students who were older, dissatisfied with their major, had a lower family income, poor parental relationships, and a lower level of mother's education were susceptible to depression.
The lymphatic system plays a key role in tissue fluid homeostasis and lymphatic dysfunction due to genetic defects or lymphatic vessel obstruction can cause lymphedema, disfiguring tissue swellings often associated with fibrosis and recurrent infections without available cures to date. In this study, retinoic acids (RAs) were determined to be a potent therapeutic agent that is immediately applicable to reduce secondary lymphedema.
Methods and Results
We report that RAs promote proliferation, migration and tube formation of cultured lymphatic endothelial cells (LECs) by activating FGF-receptor signaling. Moreover, RAs control the expression of cell-cycle checkpoint regulators such as p27Kip1, p57Kip2 and the aurora kinases through both an Akt-mediated non-genomic action and a transcription-dependent genomic action that is mediated by Prox1, a master regulator of lymphatic development. Moreover, 9-cisRA was found to activate in vivo lymphangiogenesis in animals based on mouse trachea, matrigel plug and cornea pocket assays. Finally, we demonstrate that 9-cisRA can provide a strong therapeutic efficacy in ameliorating the experimental mouse tail lymphedema by enhancing lymphatic vessel regeneration.
These in vitro and animal studies demonstrate that 9-cisRA potently activates lymphangiogenesis and promotes lymphatic regeneration in an experimental lymphedema model, presenting it as a promising novel therapeutic agent to treat human lymphedema patients.
lymphangiogenesis; lymphedema; retinoic acids; lymphatic regeneration; therapy
We report here the complete genome sequence of the porcine epidemic diarrhea virus strain CH/ZMDZY/11 isolated from central China. Our data, together with sequence data of porcine epidemic diarrhea virus (PEDV) isolates from other parts in China, will help to understand better the epidemiology and genetic diversity of PEDV field isolates in China.
Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non–small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting.
We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan–Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided.
Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor–dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers.
Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.
Compelling evidence has implicated the Wnt signaling pathway in the pathogenesis of colorectal cancer. We assessed the use of tag single nucleotide polymorphisms (tSNPs) in adenomatous polyposis coli (APC)/β-catenin (CTNNB1) genes to predict outcomes in patients with colorectal cancer. We selected and genotyped 10 tSNP to predict common variants across entire APC and CTNNB1 genes in 282 colorectal cancer patients. The associations of these tSNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. The 5-year overall survival rate was 68.3%. Survival tree analysis identified a higher-order genetic interaction profile consisting of the APC rs565453, CTNNB1 2293303, and APC rs1816769 that was significantly associated with overall survival. The 5-year survival overall rates were 89.2%, 66.1%, and 58.8% for the low-, medium-, and high-risk genetic profiles, respectively (log-rank P = 0.001). After adjusting for possible confounders, including age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, perineural invasion, and lymph node involvement, the genetic interaction profile remained significant. None of the studied SNPs were individually associated with distant metastasis-free survival and overall survival. Our results suggest that the genetic interaction profile among Wnt pathway SNPs might potentially increase the prognostic value in outcome prediction for colorectal cancer.
Background: Colorectal cancer metastasis is a multistep process involving degradation of extracellular matrix components by proteolytic enzymes. Among them, matrix metalloproteinases (MMPs) are the principal degrading enzymes and their expressions/activities are also correlated with survival. Much research has showed the associations between genetic polymorphisms in MMPs and risk of colorectal cancer; however, their prognostic significance has not been well determined.
Methods: We selected and genotyped 4 cancer-associated single nucleotide polymorphisms (SNPs) in a cohort of 282 colorectal cancer patients. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis.
Results: The relative risks of developing distant metastasis after curative surgery were higher in individuals with minor homozygote AA genotype than in those with GG/GA genotypes at MMP2 rs243866 (P = 0.012). Survival tree analysis also identified a higher-order genetic interaction profile consisting of MMP2 rs243866 and MMP2 rs2285053 that was significantly associated with distant metastasis-free survival (Ptrend = 0.016). After adjusting for possible confounders, the genetic interaction profile remained significant (Ptrend = 0.050).
Conclusions: These results suggest that genetic variations in the MMP2 might be potential predictors of distant metastasis-free survival after curative surgery.
colorectal cancer; matrix metalloproteinases; single nucleotide polymorphism; metastasis; survival.
Ectopic lymphoid tissue, also known as tertiary lymphoid organs (TLO) develop adaptively within sites of chronic tissue inflammation, thereby allowing the host to efficiently crossprime specific immune effector cells within sites of disease. Recent evidence suggests that the presence of TLO in the tumor microenvironment (TME) predicts better overall survival. We will discuss the relevance of extranodal T cell priming within the TME as a means to effectively promote anti-tumor immunity and the strategic use of dendritic cell (DC)-based therapies to reinforce this clinically preferred process in the cancer-bearing host.
dendritic cells; extranodal; cross-priming; therapy; cancer