Psychometric properties of the Spanish SABA Reliance Questionnaire (SRQ) among patients with asthma.

Background: Patient beliefs about their asthma and its treatment may contribute to overreliance on short-acting ß2-agonist (SABA) therapy, leading to increased risk for potentially life-threatening exacerbations. The SABA Reliance Questionnaire (SRQ) is a validated tool for evaluating patients beliefs about SABAs that may lead to overreliance and overuse. Objective: Our aim was to evaluate the psychometric properties of the Spanish version of the SRQ. Methods: This was an observational, cross-sectional, single-country questionnaire validation study in adults with asthma. Reliability (ordinal α) and validity (convergent and discriminant) of SRQ were evaluated. Concurrent validity was assessed with the Beliefs about Medication Questionnaire, the Treatment Satisfaction Questionnaire for Medication, and a visual analog scale item to assess patients' perceptions of the importance of their reliever inhaler. Discriminant validity was assessed through differences in mean SRQ sum score between patients with high adherence to inhaled corticosteroids and those with low adherence, as measured by the Medication Adherence Report Scale-9 and the Test of Adherence to Inhalers. Results: The Spanish-SRQ exhibited good psychometric properties among 131 patients with asthma. Internal consistency was confirmed with an ordinal α of 0.85. All 5 items were useful for measuring patients' beliefs about SABAs that may lead them to be overreliant on SABAs. Concurrent validity with the Beliefs about Medication Questionnaire, Treatment Satisfaction Questionnaire for Medication, and a visual analog scale item assessing patients' perceptions of the importance of their reliever inhaler was demonstrated. Conclusion: The Spanish version of the SRQ is a valid tool for evaluating potential overreliance on SABAs in Spanish-speaking patients to enable early intervention and support.

KCNH2 encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression.

KCNH2 encodes hERG1, the voltage-gated potassium channel that conducts the rapid delayed rectifier potassium current (IKr) in human cardiac tissue. hERG1 is one of the first channels expressed during early cardiac development, and its dysfunction is associated with intrauterine fetal death, sudden infant death syndrome, cardiac arrhythmia, and sudden cardiac death. Here, we identified a hERG1 polypeptide (hERG1NP) that is targeted to the nuclei of immature cardiac cells, including human stem cell-derived cardiomyocytes (hiPSC-CMs) and neonatal rat cardiomyocytes. The nuclear hERG1NP immunofluorescent signal is diminished in matured hiPSC-CMs and absent from adult rat cardiomyocytes. Antibodies targeting distinct hERG1 channel epitopes demonstrated that the hERG1NP signal maps to the hERG1 distal C-terminal domain. KCNH2 deletion using CRISPR simultaneously abolished IKr and the hERG1NP signal in hiPSC-CMs. We then identified a putative nuclear localization sequence (NLS) within the distal hERG1 C-terminus, 883-RQRKRKLSFR-892. Interestingly, the distal C-terminal domain was targeted almost exclusively to the nuclei when overexpressed HEK293 cells. Conversely, deleting the NLS from the distal peptide abolished nuclear targeting. Similarly, blocking α or ß1 karyopherin activity diminished nuclear targeting. Finally, overexpressing the putative hERG1NP peptide in the nuclei of HEK cells significantly reduced hERG1a current density, compared to cells expressing the NLS-deficient hERG1NP or GFP. These data identify a developmentally regulated polypeptide encoded by KCNH2, hERG1NP, whose presence in the nucleus indirectly modulates hERG1 current magnitude and kinetics.

The ERG1 K+ Channel and Its Role in Neuronal Health and Disease.

The ERG1 potassium channel, encoded by KCNH2, has long been associated with cardiac electrical excitability. Yet, a growing body of work suggests that ERG1 mediates physiology throughout the human body, including the brain. ERG1 is a regulator of neuronal excitability, ERG1 variants are associated with neuronal diseases (e.g., epilepsy and schizophrenia), and ERG1 serves as a potential therapeutic target for neuronal pathophysiology. This review summarizes the current state-of-the-field regarding the ERG1 channel structure and function, ERG1's relationship to the mammalian brain and highlights key questions that have yet to be answered.

Group-based Exercise Therapy Improves Psychosocial Health and Physical Fitness in Breast Cancer Patients in Hawai'i.

Cancer diagnosis and treatment often negatively impact quality of life, worsening prognosis, and long-term survival in cancer patients. Rehabilitation is effective at reversing cancer-related effects, but these services are not standardized. An implementation study was conducted to determine the usability and efficacy of group-based exercise therapy delivered from an outpatient therapy clinic. Thirty breast cancer patients (mean age ± standard deviation [SD],= 55 ± 10 years) completed 36 90-minute group-based exercise sessions in small groups. Team-based exercises were used to foster peer interaction and social support. Usability was evaluated with participant feedback, adherence, and occurrence of adverse events. Effectiveness was measured with the Revised Piper Fatigue, the City of Hope Quality of Life (QOL), and the Beck Depression Inventories. Paired t-tests and 2-way ANOVAs were used to detect significance (P<.05); Cohen's d was used to measure effect size. Twenty-five patients completed the program; they reported that they liked the program design. One anticipated, moderate adverse event occurred. The intervention improved fatigue and QOL, where significant main effects of time were detected [Fatigue: (F(1,76)=29.78, P <.001); QOL: (F(1,80)=24.42, P<.0001)]. Improvements in the fatigue inventory's behavioral/security and sensory dimensions (Cohen's d=-0.43 and È¡0.68, respectively) and the physical dimension of the QOL inventory were detected (Cohen's d=0.92). There were no significant changes in depression (P=.0735). Seven patients continued to participate in exercise classes for 2.5-years post-intervention, demonstrating achievability of program maintenance. Providing group-based exercise therapy services at an outpatient clinic is an effective and practical approach to improve cancer patients' QOL.

Understanding Attitudes and Roles of Oncology Advanced Practitioners in the Setting of Cancer Clinical Trials: A Pilot Study.

PURPOSE: Oncology advanced practitioners (APs), including nurse practitioners, physician assistants, clinical nurse specialists, and pharmacists, are skilled health-care providers who contribute significantly to quality cancer care. However, little is known about how APs function within the clinical trials arena. With low rates of clinical trial enrollment among the adult oncology patient population, APs could play an important role in improving clinical trial enrollment. METHODS: A descriptive cross-sectional study was conducted based on a 57-item survey of oncology APs' attitudes, beliefs, and roles in relation to cancer clinical trials. RESULTS: To assess validity and internal consistency of the survey, a pilot data collection was completed on 14 respondents from Hawaii. The survey's internal consistency across the subscales was moderate to very high, with Cronbach's alpha ranging between 0.55 and 0.86. The majority of oncology APs were interested in being more involved in the clinical trials process, and many are registered as investigators through the National Cancer Institute (NCI). However, few respondents reported being involved in recruitment, consenting, protocol development, or being actively involved with a research base. CONCLUSIONS: This survey was found to be a valid tool to measure APs' attitudes and roles in regards to clinical trials. This survey is just the beginning of data collection in regards to clinical trials among this group of health-care professionals. RECOMMENDATIONS: To gain further insight into oncology APs and their roles in clinical trials, it is recommended that this survey be implemented on a national level as a first step in moving this issue forward.

Nitric oxide-targeted therapy inhibits stemness and increases the efficacy of tamoxifen in estrogen receptor-positive breast cancer cells.

Cancer stem cells (CSCs) are involved in the resistance of estrogen (ER)-positive breast tumors against endocrine therapy. On the other hand, nitric oxide (NO) plays a relevant role in CSC biology, although there are no studies addressing how this important signaling molecule may contribute to resistance to antihormonal therapy in ER+ breast cancer. Therefore, we explored whether targeting NO in ER+ breast cancer cells impacts CSC subpopulation and sensitivity to hormonal therapy with tamoxifen. NO was targeted in ER+ breast cancer cells by specific NO depletion and NOS2 silencing and mammosphere formation capacity, stem cell markers and tamoxifen sensitivity were analyzed. An orthotopic breast tumor model in mice was also performed to analyze the efficacy of NO-targeted therapy plus tamoxifen. Kaplan-Meier curves were made to analyze the association of NOS2 gene expression with survival of ER+ breast cancer patients treated with tamoxifen. Our results show that targeting NO inhibited mamosphere formation, CSC markers expression and increased the antitumoral efficacy of tamoxifen in ER+ breast cancer cells, whereas tamoxifen-resistant cells displayed higher expression levels of NOS2 and Notch-1 compared with parental cells. Notably, NO-targeted therapy plus tamoxifen was more effective than either treatment alone in an orthotopic breast tumor model in immunodeficient mice. Furthermore, low NOS2 expression was significantly associated with a higher metastasis-free survival in ER+ breast cancer patients treated with tamoxifen. In conclusion, our data support that NO-targeted therapy in ER+ breast cancer may contribute to increase the efficacy of antihormonal therapy avoiding the development of resistance to these treatments.

SWATH-based proteomics reveals processes associated with immune evasion and metastasis in poor prognosis colorectal tumours.

Newly emerged proteomic methodologies, particularly data-independent acquisition (DIA) analysis-related approaches, would improve current gene expression-based classifications of colorectal cancer (CRC). Therefore, this study was aimed to identify protein expression signatures using SWATH-MS DIA and targeted data extraction, to aid in the classification of molecular subtypes of CRC and advance in the diagnosis and development of new drugs. For this purpose, 40 human CRC samples and 7 samples of healthy tissue were subjected to proteomic and bioinformatic analysis. The proteomic analysis identified three different molecular CRC subtypes: P1, P2 and P3. Significantly, P3 subtype showed high agreement with the mesenchymal/stem-like subtype defined by gene expression signatures and characterized by poor prognosis and survival. The P3 subtype was characterized by decreased expression of ribosomal proteins, the spliceosome, and histone deacetylase 2, as well as increased expression of osteopontin, SERPINA 1 and SERPINA 3, and proteins involved in wound healing, acute inflammation and complement pathway. This was also confirmed by immunodetection and gene expression analyses. Our results show that these tumours are characterized by altered expression of proteins involved in biological processes associated with immune evasion and metastasis, suggesting new therapeutic options in the treatment of this aggressive type of CRC.

Parental Antibiotic Use in Urban and Peri-Urban Health Care Centers in Lima: A Cross-Sectional Study of Knowledge, Attitudes, and Practices.

In pediatric patients, the antibiotic use is affected by parental beliefs and practices; especially in countries where it is possible to acquire them without prescription. This study aims to describe the knowledge, attitudes, and practices on antibiotic use among parents of children from urban and peri-urban health care centers in Lima. A cross-sectional study was performed at 1 urban and 2 peri-urban health care centers selected in Lima, Perú. Parents of children below the age of 3 years answered a knowledge-attitudes-practices-validated questionnaire about antibiotic use and were categorized as high, moderate, and low knowledge regarding antibiotics. We analyzed potential determinants for low knowledge and having medicated their children with unprescribed antibiotics using bivariate and multivariate analyses. A total of 224 parents were enrolled, and 8% were categorized as low knowledge. Half of the parents could not recognize that antibiotics cannot cure viral infections, 59.4% disagreed with "antibiotics speed up recovery from a cold," and 53.2% stored antibiotics at home. Remarkably 23.5% of parents reported having medicated their children with antibiotics without prescription, which was associated with belonging to the peri-urban health care center, use of antibiotics by their children in the last 12 months, and having purchased antibiotics without physicians' prescription. An alarming overuse of antibiotics without prescription was described among children below the age of 3 years. Educational interventions, addressing parental attitudes and practices, and health policies should be developed to limit inappropriate antibiotic use especially in peri-urban communities.

Evaluation of Dwell Time for Peripheral Intravenous Catheters Started in the Field for Geriatric Blunt Trauma Patients.

Replacement time for peripheral intravenous (PIV) catheters started in the field is unclear. The purpose of this study was to compare field-start PIV catheter dwell time of 2 days or less versus field-start PIV catheter dwell time of more than 2 days for the development of indicators of infection for geriatric blunt trauma patients. A retrospective case series was conducted at the state-designated trauma referral center. Activated trauma team patients with blunt injury were included if 65 years or older and if admitted from the field for 7 days or more with a PIV catheter placed prehospital. Presence of fever, abnormal white blood cell (WBC) count, and a positive Quick Sequential Organ Failure Assessment (qSOFA) score as recommended by the Surviving Sepsis Campaign were used to describe potential infection and were analyzed in relation to PIV catheter dwell time with statistical significance set at p < .05. Forty-two patients (28%) had PIV catheter dwell time of 2 days or less, and 108 (72%) had PIV catheter dwell time of more than 2 days. At dwell time of more than 2 days, a statistically significant smaller percentage of patients demonstrated positive qSOFA score (p = .005) and fever (p = .003) and approached statistical significance for abnormal WBC count (p = .05). Dwell time of more than 2 days for field-start PIV catheters did not lead to an increase in fevers, abnormal WBC count, or positive qSOFA scores. These data support consideration of longer dwell time for PIV catheters initiated in the field for geriatric blunt trauma patients. Further studies are needed.

A role for endothelial nitric oxide synthase in intestinal stem cell proliferation and mesenchymal colorectal cancer.

BACKGROUND: Nitric oxide (NO) has been highlighted as an important agent in cancer-related events. Although the inducible nitric oxide synthase (iNOS) isoform has received most attention, recent studies in the literature indicate that the endothelial isoenzyme (eNOS) can also modulate different tumor processes including resistance, angiogenesis, invasion, and metastasis. However, the role of eNOS in cancer stem cell (CSC) biology and mesenchymal tumors is unknown. RESULTS: Here, we show that eNOS was significantly upregulated in VilCre ERT2 Apc fl/+ and VilCre ERT2 Apc fl/fl mouse intestinal tissue, with intense immunostaining in hyperproliferative crypts. Similarly, the more invasive VilCre ERT2 Apc fl/+ Pten fl/+ mouse model showed an overexpression of eNOS in intestinal tumors whereas this isoform was not expressed in normal tissue. However, none of the three models showed iNOS expression. Notably, when 40 human colorectal tumors were classified into different clinically relevant molecular subtypes, high eNOS expression was found in the poor relapse-free and overall survival mesenchymal subtype, whereas iNOS was absent. Furthermore, Apc fl/fl organoids overexpressed eNOS compared with wild-type organoids and NO depletion with the scavenger carboxy-PTIO (c-PTIO) decreased the proliferation and the expression of stem-cell markers, such as Lgr5, Troy, Vav3, and Slc14a1, in these intestinal organoids. Moreover, specific NO depletion also decreased the expression of CSC-related proteins in human colorectal cancer cells such as ß-catenin and Bmi1, impairing the CSC phenotype. To rule out the contribution of iNOS in this effect, we established an iNOS-knockdown colorectal cancer cell line. NO-depleted cells showed a decreased capacity to form tumors and c-PTIO treatment in vivo showed an antitumoral effect in a xenograft mouse model. CONCLUSION: Our data support that eNOS upregulation occurs after Apc loss, emerging as an unexpected potential new target in poor-prognosis mesenchymal colorectal tumors, where NO scavenging could represent an interesting therapeutic alternative to targeting the CSC subpopulation.

The addition of celecoxib improves the antitumor effect of cetuximab in colorectal cancer: role of EGFR-RAS-FOXM1-ß- catenin signaling axis.

Here we showed that the addition of the COX-2 inhibitor celecoxib improved the antitumor efficacy in colorectal cancer (CRC) of the monoclonal anti-EGFR antibody cetuximab. The addition of celecoxib augmented the efficacy of cetuximab to inhibit cell proliferation and to induce apoptosis in CRC cells. Moreover, the combination of celecoxib and cetuximab was more effective than either treatment alone in reducing the tumor volume in a mouse xenograft model. The combined treatment enhanced the inhibition of EGFR signaling and altered the subcellular distribution of ß-catenin. Moreover, knockdown of FOXM1 showed that this transcription factor participates in this enhanced antitumoral response. Besides, the combined treatment decreased ß-catenin/FOXM1 interaction and reduced the cancer stem cell subpopulation in CRC cells, as indicated their diminished capacity to form colonospheres. Notably, the inmunodetection of FOXM1 in the nuclei of tumor cells in human colorectal adenocarcinomas was significantly associated with response of patients to cetuximab. In summary, our study shows that the addition of celecoxib enhances the antitumor efficacy of cetuximab in CRC due to impairment of EGFR-RAS-FOXM1-ß-catenin signaling axis. Results also support that FOXM1 could be a predictive marker of response of mCRC patients to cetuximab therapy.

High-sensitivity Cardiac Troponin Elevation after Electroconvulsive Therapy: A Prospective, Observational Cohort Study.

BACKGROUND: While electroconvulsive therapy is widely regarded as a lifesaving and safe procedure, evidence regarding its effects on myocardial cell injury is sparse. The objective of this investigation was to determine the incidence and magnitude of new cardiac troponin elevation after electroconvulsive therapy using a novel high-sensitivity cardiac troponin I assay. METHODS: This was a prospective cohort study in adult patients undergoing electroconvulsive therapy in a single academic center (up to three electroconvulsive therapy treatments per patient). The primary outcome was new high-sensitivity cardiac troponin I elevation after electroconvulsive therapy, defined as an increase of high-sensitivity cardiac troponin I greater than 100% after electroconvulsive therapy compared to baseline with at least one value above the limit of quantification (10 ng/l). Twelve-lead electrocardiogram and high-sensitivity cardiac troponin I values were obtained before and 15 to 30 min after electroconvulsive therapy; in a subset of patients, an additional 2-h high-sensitivity cardiac troponin I value was obtained. RESULTS: The final study population was 100 patients and a total of 245 electroconvulsive therapy treatment sessions. Eight patients (8 of 100; 8%) experienced new high-sensitivity cardiac troponin I elevation after electroconvulsive therapy with a cumulative incidence of 3.7% (9 of 245 treatments; one patient had two high-sensitivity cardiac troponin I elevations), two of whom had a non-ST-elevation myocardial infarction (incidence 2 of 245; 0.8%). Median high-sensitivity cardiac troponin I concentrations did not increase significantly after electroconvulsive therapy. Tachycardia and/or elevated systolic blood pressure developed after approximately two thirds of electroconvulsive therapy treatments. CONCLUSIONS: Electroconvulsive therapy appears safe from a cardiac standpoint in a large majority of patients. A small subset of patients with preexisting cardiovascular risk factors, however, may develop new cardiac troponin elevation after electroconvulsive therapy, the clinical relevance of which is unclear in the absence of signs of myocardial ischemia.

Altered S-nitrosothiol homeostasis provides a survival advantage to breast cancer cells in HER2 tumors and reduces their sensitivity to trastuzumab.

The monoclonal antibody trastuzumab against HER2/neu, which is overexpressed in 15-20% of breast cancers, has clinical efficacy but many patients do not respond to initial treatment or develop resistance during treatment. Nitric oxide (NO) regulates cell signaling by targeting specific cysteine residues in proteins, forming S-nitrosothiols (SNO) in a process known as S-nitrosylation. We previously reported that molecular characteristics in breast cancer may dictate the tumor response to impaired SNO homeostasis. In the present study, we explored the role of SNO homeostasis in HER2 breast tumors. The antiproliferative action of trastuzumab in HER2-overexpressing BT-474 and SKBR-3 cells was suppressed when S-nitrosoglutathione reductase (GSNOR/ADH5) activity, which plays a key role in SNO homeostasis, was specifically inhibited with the pyrrole derivative compound N6022. Moreover, GSNOR inhibition restored the activation of survival signaling pathways involved in the resistance to anti-HER2 therapies (AKT, Src and c-Abl kinases and TrkA/NRTK1, TrkB/NRTK2, EphA1 and EphA3 receptors) and reduced the apoptotic effect of trastuzumab. Accordingly, GSNOR inhibition augmented the S-nitrosylation of apoptosis-related proteins, including Apaf-1, pSer73/63 c-Jun, calcineurin subunit α and HSF1. In agreement with in vitro data, immunohistochemical analyses of 51 breast tumors showed that HER2 expression was associated with lower expression of GSNOR protein. Moreover, gene expression analysis confirmed that high ADH5/GSNOR gene expression was associated with high patient survival rates in HER2 tumors. In conclusion, our data provide evidence of molecular mechanisms contributing to the progression of HER2+ breast cancers and could facilitate the development of therapeutic options to counteract resistance to anti-HER2 therapies.

Genetic variants in the renin-angiotensin system predict response to bevacizumab in cancer patients.

BACKGROUND: Currently, there are no predictive biomarkers for anti-angiogenic strategies in cancer, but response to anti-angiogenic drugs is associated with development of hypertension secondary to treatment. Therefore, this study explored the clinical relevance of genetic polymorphisms in some components of the renin-angiotensin system (RAS). MATERIAL AND METHODS: Genomic DNA was isolated from peripheral blood from 95 metastatic breast or colorectal cancer patients treated with bevacizumab, and AGTR1-A1166C (rs5186), AGT-M235T (rs699) SNPs and ACE I/D (rs4646994) polymorphisms were genotyped using RT-PCR. Circulating vascular endothelial grow factor and angiotensin converting enzyme (ACE) levels were analysed using ELISA kits. The antitumoral activity of bevacizumab was assayed in mice orthotopically xenografted with AGTR1-overexpressing breast cancer cells. RESULTS: The ACE IN/IN genotype was associated with a higher rate of disease progression compared to DEL/IN and DEL/DEL genotypes (36% vs. 11·1% P < 0·05). Similarly, AGTR1-1166A/A genotype was also associated with a higher rate of disease progression compared to AGTR1-1166A/C and AGTR1-1166C/C genotypes (24·4% vs. 2·7% P < 0·01). ACE IN/IN genotype was also found to be associated with shorter time to treatment failure compared to ACE IN/DEL and ACE DEL/DEL genotypes (14 weeks vs. 41·71, P = 0·033), whereas circulating ACE levels were found to be associated with a better response to bevacizumab treatment. Besides, in vivo experiments showed a significantly higher antitumoral activity of bevacizumab in tumours derived from AGTR1-overexpressing breast cancer cells. CONCLUSIONS: A higher activity of ACE-angiotensin-II-AGTR1 axis is associated with a better response to bevacizumab, supporting that the RAS can be an important source of potential predictive markers of response to anti-angiogenic drugs.

Simultaneous inhibition of EGFR/VEGFR and cyclooxygenase-2 targets stemness-related pathways in colorectal cancer cells.

Despite the demonstrated benefits of anti-EGFR/VEGF targeted therapies in metastatic colorectal cancer (mCRC), many patients initially respond, but then show evidence of disease progression. New therapeutic strategies are needed to make the action of available drugs more efficient. Our study aimed to explore whether simultaneous targeting of EGFR/VEGF and cyclooxygenase-2 (COX-2) may aid the treatment and management of mCRC patients. The dual tyrosine kinase inhibitor AEE788 and celecoxib were used to inhibit EGFR/VEGFR and COX-2, respectively, in colorectal cancer cells. COX-2 inhibition with celecoxib augmented the antitumoral and antiangiogenic efficacy of AEE788, as indicated by the inhibition of cell proliferation, induction of apoptosis and G1 cell cycle arrest, down-regulation of VEGF production by cancer cells and reduction of cell migration. These effects were related with a blockade in the EGFR/VEGFR signaling axis. Notably, the combined AEE788/celecoxib treatment prevented ß-catenin nuclear accumulation in tumor cells. This effect was associated with a significant downregulation of FOXM1 protein levels and an impairment in the interaction of this transcription factor with ß-catenin, which is required for its nuclear localization. Furthermore, the combined treatment also reduced the expression of the stem cell markers Oct 3/4, Nanog, Sox-2 and Snail in cancer cells, and contributed to the diminution of the CSC subpopulation, as indicated by colonosphere formation assays. In conclusion, the combined treatment of AEE788 and celecoxib not only demonstrated enhanced anti-tumoral efficacy in colorectal cancer cells, but also reduced colon CSCs subpopulation by targeting stemness-related pathways. Therefore, the simultaneous targeting of EGFR/VEGF and COX-2 may aid in blocking mCRC progression and improve the efficacy of existing therapies in colorectal cancer.

Libre albedrío y ciencias penales / Free will and criminal sciences

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Reversal of PCNA ubiquitylation by Ubp10 in Saccharomyces cerevisiae.

Regulation of PCNA ubiquitylation plays a key role in the tolerance to DNA damage in eukaryotes. Although the evolutionary conserved mechanism of PCNA ubiquitylation is well understood, the deubiquitylation of ubPCNA remains poorly characterized. Here, we show that the histone H2B(K123) ubiquitin protease Ubp10 also deubiquitylates ubPCNA in Saccharomyces cerevisiae. Our results sustain that Ubp10-dependent deubiquitylation of the sliding clamp PCNA normally takes place during S phase, likely in response to the simple presence of ubPCNA. In agreement with this, we show that Ubp10 forms a complex with PCNA in vivo. Interestingly, we also show that deletion of UBP10 alters in different ways the interaction of PCNA with DNA polymerase ζ-associated protein Rev1 and with accessory subunit Rev7. While deletion of UBP10 enhances PCNA-Rev1 interaction, it decreases significantly Rev7 binding to the sliding clamp. Finally, we report that Ubp10 counteracts Rad18 E3-ubiquitin ligase activity on PCNA at lysine 164 in such a manner that deregulation of Ubp10 expression causes tolerance impairment and MMS hypersensitivity.

Enhancing life after cancer in diverse communities.

BACKGROUND: Although large numbers of cancer survivors exist in every community, including minority communities, there is a significant gap in knowledge about best practices for these patients. METHODS: The Community Networks Program, funded by the National Cancer Institute Center to Reduce Cancer Health Disparities, has developed and tested unique services for these communities. These programs have used community-based participatory research techniques under a framework of diffusion of innovation and communications theory. RESULTS: This article describes some specifically tailored interventions that may be useful to a wide range of providers working with the underserved. CONCLUSIONS: Enhancing life after cancer can be achieved in underserved communities by supplementing local resources.