Type 2C protein phosphatases (PP2Cs) are vitally involved in abscisic acid (ABA) signaling. Here, we show that a synthetic growth inhibitor called pyrabactin functions as a selective ABA agonist. ...Pyrabactin acts through PYRABACTIN RESISTANCE 1 (PYR1), the founding member of a family of START proteins called PYR/PYLs, which are necessary for both pyrabactin and ABA signaling in vivo. We show that ABA binds to PYR1, which in turn binds to and inhibits PP2Cs. We conclude that PYR/PYLs are ABA receptors functioning at the apex of a negative regulatory pathway that controls ABA signaling by inhibiting PP2Cs. Our results illustrate the power of the chemical genetic approach for sidestepping genetic redundancy.
Purpose miRNAs are small, nonprotein coding RNAs that are differentially expressed in many malignancies. We previously identified 80 miRNAs that are dysregulated in clear cell renal cell carcinoma. ...In this study we validated over expression of the miR-17-92 cluster in clear cell renal cell carcinoma and tested the effect of 2 members of this cluster (miR-17-5p and miR-20a) on tumor proliferation. We also elucidated the role of miRNA in clear cell renal cell carcinoma pathogenesis with bioinformatics. Materials and Methods miRNA expression was validated by quantitative reverse transcriptase-polymerase chain reaction. The cell proliferation effect of miR-17-5p and miR-20a was tested in a renal adenocarcinoma cell line model. Multiple in silico analyses were done of dysregulated miRNAs. Results We validated miR-71-92 cluster over expression in clear cell renal cell carcinoma by quantitative reverse transcriptase-polymerase chain reaction. Transfection of miR-20a inhibitor significantly decreased cell proliferation in a dose dependent manner. Transfection of miR-17-5p, which is not endogenously expressed in the ACHN cell line, led to increased cell proliferation compared to control values. This effect was suppressed by miR-17-5p inhibitor. Bioinformatics analysis identified 10 clusters of miRNAs dysregulated in clear cell renal cell carcinoma that followed the same expression patterns. We also identified matching patterns between reported chromosomal aberration in clear cell renal cell carcinoma and miRNA dysregulation for 37.5% of the miRNAs. Target prediction analysis was done using multiple algorithms. Many key molecules in clear cell renal cell carcinoma pathogenesis, including HIFs, mTOR, VEGF and VHL, were potential targets for dysregulated miRNAs. Conclusions A significant number of dysregulated proteins in clear cell renal cell carcinoma are potential miRNA targets. Also, many clear cell renal cell carcinoma dysregulated miRNAs are phylogenetically conserved.
We seek to identify the differentially expressed miRNAs in the clear cell subtype (ccRCC) of kidney cancer.
We performed a miRNA microarray analysis to compare the miRNA expression levels between ...ccRCC tissues and their normal counterpart. The top dysregulated miRNAs were validated by quantitative RT-PCR analysis. Bioinformatics analysis was also performed.
A total of 33 dysregulated miRNAs were identified in ccRCC, including 21 upregulated miRNAs and many of these miRNAs have been reported to be dysregulated in other malignancies and have a potential role in cancer pathogenesis. The miRNAs showed a significant correlation with reported chromosomal aberration sites. We also utilized target prediction algorithms to identify gene targets. Preliminary analyses showed these targets can be directly involved in RCC pathogenesis.
We identified miRNAs that are dysregulated in ccRCC and bioinformatics analysis suggests that these miRNAs may be involved in cancer pathogenesis and have the potential to be biomarkers.
Renal cell carcinoma (RCC) is the most common neoplasm in the adult kidney. Unfortunately, there are currently no biomarkers for the diagnosis of RCC. In addition to early detection, biomarkers have ...a potential use for prognosis, for monitoring recurrence after treatment, and as predictive markers for treatment efficiency. In this study, we identified proteins that are dysregulated in RCC, utilizing a quantitative mass spectrometry analysis. We compared the protein expression of kidney cancer tissues to their normal counterparts from the same patient using LC−MS/MS. iTRAQ labeling permitted simultaneous quantitative analysis of four samples (cancer, normal, and two controls) by separately tagging the peptides in these samples with four cleavable mass-tags (114, 115, 116, and 117 Da). The samples were then pooled, and the tagged peptides resolved first by strong cation exchange chromatography and then by nanobore reverse phase chromatography coupled online to nanoelectrospray MS/MS. We identified a total of 937 proteins in two runs. There was a statistically significant positive correlation of the proteins identified in both runs (r p = 0.695, p < 0.001). Using a cutoff value of 0.67 fold for underexpression and 1.5 fold for overexpression, we identified 168 underexpressed proteins and 156 proteins that were overexpressed in RCC compared to normal tissues. These dysregulated proteins in RCC were statistically significantly different from those of transitional cell carcinoma and end-stage glomerulonephritis. We performed an in silico validation of our results using different tools and databases including Serial Analysis of Gene Expression (SAGE), UniGene EST ProfileViewer, Cancer Genome Anatomy Project, and Gene Ontology consortium analysis.
microRNAs (miRNAs) are non-coding RNAs that target specific mRNAs. They have been shown to control many biological processes including cancer pathogenesis. Kallikreins (KLKs) are a family of serine ...proteases that are attracting interest as cancer biomarkers. The mechanism of regulation of kallikrein expression is largely unknown. We investigated the potential roles of miRNAs in regulating KLK expression. Using a bioinformatics approach, we identified 96 strong KLK/miRNA interactions. KLK10 is the most frequently targeted kallikrein, followed by KLK5 and KLK13. KLK1, KLK3, KLK8 and KLK12 do not have strongly predicted miRNA/KLK interactions. Ten miRNAs are predicted to target more than one KLK. KLK2, KLK4, KLK5 and KLK10 have multiple miRNA-targeting sites on their transcript. Chromosomes 19 and 14 harbor significantly more KLK-targeting miRNAs. Many KLK-targeting miRNAs have been shown to be dysregulated in malignancy. We experimentally verified our bioinformatics data for the let-7f miRNA in a cell line model. let-7f transfection led to a significant decrease in secreted KLK6 and KLK10 protein levels. Co-transfection of let-7f and anti-let-7f inhibitor was able to partially rescue these protein levels. We conclude that miRNAs play a role in the regulation of KLK expression. Further studies are needed to investigate whether this regulation is altered in cancer.
Kallikrein-related peptidases (KLKs) have been shown to be differentially expressed in various malignancies and shown to be useful tumor markers. Previous immunohistochemistry (IHC) analysis ...demonstrated that KLKs 5, 6, 10, and 11 have a potential prognostic significance in renal cell carcinoma (RCC). To further explore the significance of KLKs, we examined KLKs 1, 6, 7, and 15 in different subtypes of renal tumors. KLK1 has stronger expression in high grade compared to low grade clear cell RCC. However, KLK6 and KLK7 show strong expression in low grade in contrast to high grade clear cell RCC. Furthermore, the expression of KLK7 can distinguish between oncocytoma and chromophobe RCC. Oncocytoma showed diffuse, strong granular cytoplasmic staining, but chromophobe RCC showed focal weak homogeneous cytoplasmic stain. The pattern of staining of different KLKs can also be helpful in differentiating some of the subtypes of renal tumors. Our results show the potential ability of KLKs to serve as diagnostic markers and expand previous data about the prognostic significance of KLKs in kidney cancer. In addition, our study is the first to show the ability of KLK staining to distinguish various types of kidney cancers when morphology is similar.
We recently identified a group of proteins which are dysregulated in renal cell carcinoma (RCC). In this study, we performed bioinformatics and pathway analysis of these proteins. Proteins were ...mapped to gene ontology biological processes. The upregulated proteins tend to cluster in processes, such as cancer initiation and progression. In addition, we identified a number of pathways that are significantly enriched in RCC. Some of these are ‘common’ pathways which are dysregulated in many cancers, but we also identified a number of pathways which were not previously linked to RCC. In addition to their potential prognostic values, many of these pathways have a potential as therapeutic targets for RCC. To verify our findings, we compared our proteins to a pool of datasets from published reports. Although there were only a minimal number of common proteins, there was a significant overlap between the identified pathways in the two groups. Moreover, out of 16 individually discovered genes identified by a literature search, 10 were found to be related to our dysregulated pathways. We also verified the upregulation of the mammalian target of rapamycin signaling pathway in RCC by immunohistochemistry. Finally, we highlight the potential clinical applications of pathway analysis in kidney cancer.
Purpose
The study adopted a randomized controlled trial to compare the effect of culturally compatible psychosocial interventions on multiple aspects of quality of life (QoL) for family caregivers of ...lung cancer patients.
Methods
157 Chinese informal caregivers of lung cancer patients were recruited together with the family members for whom they were providing care, and randomly assigned to either integrative body-mind-spirit intervention (I-BMS) or cognitive behavioral therapy (CBT). Patient-caregiver dyads attended the same arm of intervention in separate groups for 8 weeks. Assessments of generic QoL, anxiety, depression, perceived stress, insomnia, and caregiving burden were measured before intervention (
T
0
), within 1-week (
T
1
), 8-week (
T
2
), and 16-week (
T
3
) post-intervention.
Results
Adopting the intention-to-treat analysis, family caregivers in receipt of both I-BMS and CBT exhibited a statistically significant improvement in generic QoL immediately following intervention and at follow-up assessments, with moderate effect size. Improvement of insomnia was found at
T
1
for both modes, which deteriorated at follow-up; both modes reduced anxiety and perceived stress at follow-up. No intervention effect was observed in depression and domains of caregiving burden. There was no significant interaction effect between intervention type and time. No main or interaction effect between sample background variables and intervention type was found to predict symptomatic changes at
T
1
and
T
3
.
Conclusions
Culturally attuned I-BMS and CBT exhibited equivalent effectiveness in improving psychological distress and generic QoL for family caregivers of lung cancer patients. To improve the evaluation of outcomes, future study could benefit from incorporating a usual care control.
Purposes/objectives: This paper reports the comparative efficacies of integrative body-mind-spirit intervention (I-BMS) and cognitive behavioral therapy (CBT) in patient-caregiver parallel groups for ...Chinese patients with lung cancer.
Design: Randomized controlled trial (RCT).
Methods: One hundred and fifty-seven patient-caregiver dyads with no marked functional impairment were randomized into one of the two interventions with eight weekly patient-caregiver parallel groups. Assessments were conducted at baseline, within one, eight- and sixteen-weeks post-intervention. Effects of treatment group across time were analyzed by multilevel modeling.
Findings: CBT led to greater reduction in emotional vulnerability than I-BMS. I-BMS resulted in greater increase in overall QoL and spiritual self-care, and more reduction in depression than CBT. Patients in both interventions experienced improvement in physical, emotional and spiritual, except social, domains of QoL.
Conclusion: I-BMS was more efficacious for diverse domains of QoL, and CBT was more effective for emotional well-being, despite the relatively small between-group effect sizes.
Implications for psychosocial providers/policy: (1) With the expanding repertoire of psychosocial interventions for families facing lung cancer, it has become imperative to investigate the comparative efficacies of empirically supported and culturally adapted interventions. (2) Our findings show that I-BMS was more effective for diverse domains of QoL, while CBT was more efficacious with emotional well-being, although both interventions led to significant improvements in physical, emotional and spiritual domains of patient QoL. (3) Patient-caregiver parallel groups have been shown to be effective for enhancing QoL of Chinese lung cancer patients. (4) Care professionals are encouraged to dispense interventions based on the idiosyncratic needs and preferences of the patients to maximize the treatment effects.
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