High expression of DJ-1 promotes growth and invasion via the PTEN-AKT pathway and predicts a poor prognosis in colorectal cancer

Abstract

Cancer cell invasion and unlimited proliferation are key factors in patients with colorectal cancer (CRC). Increased protein deglycase DJ-1 in cancer cells is known to promote tumor growth; however, its role in CRC progression is not well defined. In this study, we investigated 100 CRC patients with disease stages I–IV to determine whether DJ-1 could serve as a prognostic biomarker in CRC. These results showed that DJ-1 expression in CRC tissues was higher than that in normal colon tissues and was associated with the (Tumor Node Metastasis) TNM stage. CRC patients with low DJ-1 expression had a longer overall survival than those with high expression, and multivariate and univariate analyses indicated that DJ-1 expression was an independent prognostic factor for overall survival in CRC. Furthermore, DJ-1 overexpression in two colon cancer cell lines, HCT116 and SW480, activated protein kinase AKT and downregulated tumor suppressor PTEN, whereas DJ-1 knockdown upregulated PTEN expression and effectively suppressed CRC cell invasion and proliferation both in vitro and in vivo, revealing a mechanism underlying DJ-1 pro-oncogenic activity in CRC. Treatment of MK2206, the specific AKT inhibitor, significantly decreased DJ-1-mediated cell proliferation and mobility in vitro. Taken together, these results suggest that DJ-1 may be a novel prognostic biomarker and potential therapeutic target in human CRC.

Our data suggest that DJ-1 may be a novel prognostic biomarker and a potential therapeutic target in human CRC.

http://ift.tt/2nX0Q3o

Protein phosphatase 2A (PP2A) inhibitor CIP2A indicates resistance to radiotherapy in rectal cancer

Abstract

Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low-CIP2A-expressing tumors had more frequently moderate or excellent response to long-course (C)RT than patients with high-CIP2A-expressing tumors. They also had higher 36-month disease-specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long-course (C)RT in rectal cancer patients.

Low CIP2A protein expression level associates with a favorable response to long-course chemoradiotherapy in rectal cancer patients. Suppression of CIP2A transcription by siRNA sensitizes colorectal cancer cells to irradiation and decreases their survival in vitro.

http://ift.tt/2o3t6AA

Knowledge about cervical cancer and barriers toward cervical cancer screening among HIV-positive women attending public health centers in Addis Ababa city, Ethiopia

Abstract

Screening rate for cervical cancer among HIV-infected women and among women overall is low in Ethiopia despite the high burden of the disease and HIV infection, which increases cervical cancer risk. In this paper, we assessed knowledge about cervical cancer symptoms, prevention, early detection, and treatment and barriers to screening among HIV-positive women attending community health centers for HIV-infection management in Addis Ababa. A cross-sectional survey of 581 HIV-positive women aged 21–64 years old attending 14 randomly selected community health centers without cervical cancer screening service in Addis Ababa. We used univariate analysis to calculate summary statistics for each variable considered in the analysis, binary logistic regression analysis to measure the degree of association between dependent and independent variables, and multiple regressions for covariate adjusted associations. Statistical significance for all tests was set at P < 0.05. We used thematic analysis to describe the qualitative data. Of the 581 women enrolled in the study with mean age 34.9 ± 7.7 years, 57.8% of participants had heard of cervical cancer and 23.4% were knowledgeable about the symptoms, prevention, early detection, and treatment of the disease. In multivariate analysis, higher educational attainment and employment were significantly associated with good knowledge about cervical cancer. In addition, only 10.8% of the participants ever had screening and 17% ever received recommendation for it. However, 86.2% of them were willing to be screened if free of cost. Knowledge about cervical cancer is poor and cervical cancer screening rate and provider recommendation are low among HIV-positive women attending community health centers for management and follow-up of their disease in Addis Ababa. These findings underscore the need to scale up health education about cervical cancer prevention and early detection among HIV-positive women as well as among primary healthcare providers in the city.

Knowledge about cervical cancer is poor, and cervical cancer screening rate and recommendation are low among HIV-positive women attending community health centers for management and follow-up of their HIV infection in Addis Ababa. These findings underscore the need to scale up health education about cervical cancer prevention and early detection among HIV-positive women as well as among primary healthcare providers in the city.

http://ift.tt/2nYk8pd

High expression of DJ-1 promotes growth and invasion via the PTEN-AKT pathway and predicts a poor prognosis in colorectal cancer

Abstract

Cancer cell invasion and unlimited proliferation are key factors in patients with colorectal cancer (CRC). Increased protein deglycase DJ-1 in cancer cells is known to promote tumor growth; however, its role in CRC progression is not well defined. In this study, we investigated 100 CRC patients with disease stages I–IV to determine whether DJ-1 could serve as a prognostic biomarker in CRC. These results showed that DJ-1 expression in CRC tissues was higher than that in normal colon tissues and was associated with the (Tumor Node Metastasis) TNM stage. CRC patients with low DJ-1 expression had a longer overall survival than those with high expression, and multivariate and univariate analyses indicated that DJ-1 expression was an independent prognostic factor for overall survival in CRC. Furthermore, DJ-1 overexpression in two colon cancer cell lines, HCT116 and SW480, activated protein kinase AKT and downregulated tumor suppressor PTEN, whereas DJ-1 knockdown upregulated PTEN expression and effectively suppressed CRC cell invasion and proliferation both in vitro and in vivo, revealing a mechanism underlying DJ-1 pro-oncogenic activity in CRC. Treatment of MK2206, the specific AKT inhibitor, significantly decreased DJ-1-mediated cell proliferation and mobility in vitro. Taken together, these results suggest that DJ-1 may be a novel prognostic biomarker and potential therapeutic target in human CRC.

Our data suggest that DJ-1 may be a novel prognostic biomarker and a potential therapeutic target in human CRC.

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via IFTTT

Protein phosphatase 2A (PP2A) inhibitor CIP2A indicates resistance to radiotherapy in rectal cancer

Abstract

Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low-CIP2A-expressing tumors had more frequently moderate or excellent response to long-course (C)RT than patients with high-CIP2A-expressing tumors. They also had higher 36-month disease-specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long-course (C)RT in rectal cancer patients.

Low CIP2A protein expression level associates with a favorable response to long-course chemoradiotherapy in rectal cancer patients. Suppression of CIP2A transcription by siRNA sensitizes colorectal cancer cells to irradiation and decreases their survival in vitro.

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Knowledge about cervical cancer and barriers toward cervical cancer screening among HIV-positive women attending public health centers in Addis Ababa city, Ethiopia

Abstract

Screening rate for cervical cancer among HIV-infected women and among women overall is low in Ethiopia despite the high burden of the disease and HIV infection, which increases cervical cancer risk. In this paper, we assessed knowledge about cervical cancer symptoms, prevention, early detection, and treatment and barriers to screening among HIV-positive women attending community health centers for HIV-infection management in Addis Ababa. A cross-sectional survey of 581 HIV-positive women aged 21–64 years old attending 14 randomly selected community health centers without cervical cancer screening service in Addis Ababa. We used univariate analysis to calculate summary statistics for each variable considered in the analysis, binary logistic regression analysis to measure the degree of association between dependent and independent variables, and multiple regressions for covariate adjusted associations. Statistical significance for all tests was set at P < 0.05. We used thematic analysis to describe the qualitative data. Of the 581 women enrolled in the study with mean age 34.9 ± 7.7 years, 57.8% of participants had heard of cervical cancer and 23.4% were knowledgeable about the symptoms, prevention, early detection, and treatment of the disease. In multivariate analysis, higher educational attainment and employment were significantly associated with good knowledge about cervical cancer. In addition, only 10.8% of the participants ever had screening and 17% ever received recommendation for it. However, 86.2% of them were willing to be screened if free of cost. Knowledge about cervical cancer is poor and cervical cancer screening rate and provider recommendation are low among HIV-positive women attending community health centers for management and follow-up of their disease in Addis Ababa. These findings underscore the need to scale up health education about cervical cancer prevention and early detection among HIV-positive women as well as among primary healthcare providers in the city.

Knowledge about cervical cancer is poor, and cervical cancer screening rate and recommendation are low among HIV-positive women attending community health centers for management and follow-up of their HIV infection in Addis Ababa. These findings underscore the need to scale up health education about cervical cancer prevention and early detection among HIV-positive women as well as among primary healthcare providers in the city.

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Characteristic findings of high-grade cervical intraepithelial neoplasia or more on magnifying endoscopy with narrow band imaging

Abstract

Background

Colposcopy, which is a standard modality for diagnosing cervical intraepithelial neoplasia (CIN), can have limited accuracy owing to poor visibility. Flexible magnifying endoscopy with narrow band imaging (ME-NBI) has excellent diagnostic accuracy for early gastrointestinal neoplasms and is expected to be highly useful for CIN diagnosis. This study aimed to determine the characteristic findings and evaluate the diagnostic ability of ME-NBI for lesions ≥ CIN 3.

Methods

A well-designed prospective diagnostic case series conducted at multiple tertiary-care centers. A total of 24 patients who underwent cervical conization with a preoperative diagnosis of high-grade squamous cell intraepithelial lesions (HSILs) or lesions ≥ CIN 3 were enrolled. Prior to conization, still images and video of ME-NBI were captured to investigate the cervical lesions. The images were reviewed based on histological examination of the resected specimens.

Results

The NBI-ME images revealed the following abnormal findings: (1) light white epithelium (l-WE), (2) heavy white epithelium (h-WE), and (3) atypical intra-epithelial papillary capillary loop (IPCL). Pathological examination of the resected specimens confirmed cervical lesions ≥ CIN 3 in 21 patients. The ME-NBI findings were classified into four groups: l-WE, l-WE with atypical IPCL, h-WE, and h-WE with atypical IPCL, at rates of 0, 23.8, 9.5, and 66.7%, respectively. Additionally, all 3 patients with micro-invasive carcinoma showed a strong irregularity of IPCLs.

Conclusion

The lesions ≥ CIN 3 demonstrated characteristic ME-NBI findings of h-WE alone, or l-/h-WE with atypical micro-vessels. This study indicates that ME-NBI may have novel value for CIN diagnosis.

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The clinical features of squamous cell lung carcinoma with sensitive EGFR mutations

Abstract

Background

The process of selecting patients on the basis of epidermal growth factor receptor (EGFR) mutations would likely result in a patient population with greater sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, EGFR mutation status is not routinely examined in patients with squamous cell lung cancer (Sq) because of the low incidence of EGFR mutations and the poor clinical response to EGFR-TKIs.

Methods

We retrospectively reviewed the clinical features of patients at our hospital with Sq who carried EGFR-TKI-sensitive EGFR mutations and assessed their responses to EGFR-TKIs.

Results

EGFR mutation status was tested in 23 of 441 patients with Sq (5.2%) admitted to our hospital during the study period. An EGFR mutation (exon 19 deletion 3, L858R 2) was identified in five of the 23 patients (21.7%), all of whom were female never-smokers. Of these five patients, four (4/9; 44.4%) were in the normal lung group, one (1/12; 8.3%) was in the emphysematous lung group, and none (0/2; 0%) in the fibrotic lung group. Two of these five patients with the EGFR mutation received gefitinib and two received afatinib. Although the two patients who were treated with gefitinib did not respond well to treatment (stable disease, 1 patient; progressive disease, 1 patient), the two patients who were treated with afatinib showed a good response (partial response, 2 patients).

Conclusion

The administration of afatinib to Sq patients after selecting patients using the EGFR mutation test based on their underlying pulmonary disease and smoking status would likely result in a population with a greater sensitivity to afatinib.

from Cancer via ola Kala on Inoreader http://ift.tt/2HeEOB2
via IFTTT

Characteristic findings of high-grade cervical intraepithelial neoplasia or more on magnifying endoscopy with narrow band imaging

Abstract

Background

Colposcopy, which is a standard modality for diagnosing cervical intraepithelial neoplasia (CIN), can have limited accuracy owing to poor visibility. Flexible magnifying endoscopy with narrow band imaging (ME-NBI) has excellent diagnostic accuracy for early gastrointestinal neoplasms and is expected to be highly useful for CIN diagnosis. This study aimed to determine the characteristic findings and evaluate the diagnostic ability of ME-NBI for lesions ≥ CIN 3.

Methods

A well-designed prospective diagnostic case series conducted at multiple tertiary-care centers. A total of 24 patients who underwent cervical conization with a preoperative diagnosis of high-grade squamous cell intraepithelial lesions (HSILs) or lesions ≥ CIN 3 were enrolled. Prior to conization, still images and video of ME-NBI were captured to investigate the cervical lesions. The images were reviewed based on histological examination of the resected specimens.

Results

The NBI-ME images revealed the following abnormal findings: (1) light white epithelium (l-WE), (2) heavy white epithelium (h-WE), and (3) atypical intra-epithelial papillary capillary loop (IPCL). Pathological examination of the resected specimens confirmed cervical lesions ≥ CIN 3 in 21 patients. The ME-NBI findings were classified into four groups: l-WE, l-WE with atypical IPCL, h-WE, and h-WE with atypical IPCL, at rates of 0, 23.8, 9.5, and 66.7%, respectively. Additionally, all 3 patients with micro-invasive carcinoma showed a strong irregularity of IPCLs.

Conclusion

The lesions ≥ CIN 3 demonstrated characteristic ME-NBI findings of h-WE alone, or l-/h-WE with atypical micro-vessels. This study indicates that ME-NBI may have novel value for CIN diagnosis.

http://ift.tt/2GdVJTf

The clinical features of squamous cell lung carcinoma with sensitive EGFR mutations

Abstract

Background

The process of selecting patients on the basis of epidermal growth factor receptor (EGFR) mutations would likely result in a patient population with greater sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, EGFR mutation status is not routinely examined in patients with squamous cell lung cancer (Sq) because of the low incidence of EGFR mutations and the poor clinical response to EGFR-TKIs.

Methods

We retrospectively reviewed the clinical features of patients at our hospital with Sq who carried EGFR-TKI-sensitive EGFR mutations and assessed their responses to EGFR-TKIs.

Results

EGFR mutation status was tested in 23 of 441 patients with Sq (5.2%) admitted to our hospital during the study period. An EGFR mutation (exon 19 deletion 3, L858R 2) was identified in five of the 23 patients (21.7%), all of whom were female never-smokers. Of these five patients, four (4/9; 44.4%) were in the normal lung group, one (1/12; 8.3%) was in the emphysematous lung group, and none (0/2; 0%) in the fibrotic lung group. Two of these five patients with the EGFR mutation received gefitinib and two received afatinib. Although the two patients who were treated with gefitinib did not respond well to treatment (stable disease, 1 patient; progressive disease, 1 patient), the two patients who were treated with afatinib showed a good response (partial response, 2 patients).

Conclusion

The administration of afatinib to Sq patients after selecting patients using the EGFR mutation test based on their underlying pulmonary disease and smoking status would likely result in a population with a greater sensitivity to afatinib.

http://ift.tt/2HeEOB2

Beasley’s 1981 paper: The power of a well-designed cohort study to drive liver cancer research and prevention

Publication date: Available online 13 February 2018
Source:Cancer Epidemiology
Author(s): Jill Koshiol, Zhiwei Liu, Thomas R. O'Brien, Allan Hildesheim
The 1981 Lancet paper by Beasley et al., "Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan" is a seminal publication that clearly demonstrated that chronic infection with hepatitis B virus (HBV), as measured by seropositivity for the hepatitis B surface antigen (HBsAg), preceded the development of hepatocellular carcinoma (HCC). In doing so, this study paved the way for liver cancer prevention efforts through the implementation of hepatitis B vaccination programs. In this commentary, we will describe the discovery of HBV, which led to the study by Beasley et al.; summarize the major findings of the Beasley paper and its implications; discuss the importance of well-designed cohort studies for prevention activities; and consider the ramifications of the Beasley study and the work that has followed since.



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Beasley’s 1981 paper: The power of a well-designed cohort study to drive liver cancer research and prevention

Publication date: Available online 13 February 2018
Source:Cancer Epidemiology
Author(s): Jill Koshiol, Zhiwei Liu, Thomas R. O'Brien, Allan Hildesheim
The 1981 Lancet paper by Beasley et al., "Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan" is a seminal publication that clearly demonstrated that chronic infection with hepatitis B virus (HBV), as measured by seropositivity for the hepatitis B surface antigen (HBsAg), preceded the development of hepatocellular carcinoma (HCC). In doing so, this study paved the way for liver cancer prevention efforts through the implementation of hepatitis B vaccination programs. In this commentary, we will describe the discovery of HBV, which led to the study by Beasley et al.; summarize the major findings of the Beasley paper and its implications; discuss the importance of well-designed cohort studies for prevention activities; and consider the ramifications of the Beasley study and the work that has followed since.



http://ift.tt/2BWrbqZ

The Experience of Adolescents and Young Adults Treated for Cancer in an Adult Setting: A Review of the Literature

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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The Experience of Adolescents and Young Adults Treated for Cancer in an Adult Setting: A Review of the Literature

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2Hd3I49

Computed tomography densitometric study of anti-angiogenic effect of regorafenib in colorectal cancer liver metastasis

Future Oncology, Ahead of Print.


http://ift.tt/2styvqe

Computed tomography densitometric study of anti-angiogenic effect of regorafenib in colorectal cancer liver metastasis

Future Oncology, Ahead of Print.


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The acceptability and feasibility of lay-health led interventions for the prevention and early detection of cancer

Abstract

Background

US-based evidence suggests that lay-health worker (LHW) interventions can increase awareness around cancer risk-related lifestyles, symptom recognition and screening programme uptake. The suitability of LHW interventions in the UK and the potential barriers and facilitators for implementation is currently unknown. This study explored the acceptability and feasibility of developing LHW interventions for cancer prevention, screening and early diagnosis.

Methods

Purposive sampling recruited five separate lay groups: a) completed cancer treatment; b) friends/family of cancer patients; c) cancer hospital volunteers; d) cancer charity volunteers; and e) members of the public. Audio-recorded focus groups and semi-structured interviews were transcribed for thematic analysis using framework matrices.

Results

Forty-one people (66% female, aged 23-84 years) participated. Three main themes are reported: i) scope of LHW roles, with a clear remit embedded within communities or primary care practices, ii) defining LHW tasks, with a focus on supporting people overcome barriers including lack of cancer symptom knowledge and non-attendance at screening and iii) clear boundaries, with LHW training and on-going support from healthcare staff seen as key for intervention success. All groups were uncomfortable about having lifestyle-related risk conversations and potentially inflicting guilt. The post-treatment group expressed less concern about the possible emotional impact of discussing cancer symptoms, compared to the other groups.

Conclusions

LHW interventions to promote early diagnosis or screening were generally considered acceptable in a UK context. LHW interventions focussing on reducing cancer risk may be less feasible.

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Relationships between family resilience and posttraumatic growth in breast cancer survivors and caregiver burden

Abstract

Objective

To examine the relationships between family resilience and posttraumatic growth (PTG) of breast cancer survivors and caregiver burden among principal caregivers in China.

Methods

Participants in this cross-sectional study comprised 108 women aged 26–74 years (M = 49, SD = 9) with early-stage breast cancer and 108 principal caregivers. Participants were recruited from a comprehensive cancer center of a public hospital in Shandong Province, China. The principal caregivers completed the Shortened Chinese Version of the Family Resilience Assessment Scale (FRAS-C) and the Chinese Version of the Zarit Caregiver Burden Interview (CZBI); patients completed the Short Form of the Posttraumatic Growth Inventory (PTGI-SF) and questions designed to obtain sociodemographic information. Hierarchical regression analysis was conducted to assess the adjusted association between family resilience and PTG and caregiver burden, while controlling for sociodemographics.

Results

Families showed a slightly elevated level of family resilience since the cancer experience and patients showed a moderate degree of PTG. Principal caregivers reported moderate burden. FRAS-C total score was positively related to PTGI-SF total score (β = .28, P < .01) and was negatively related to CZBI total score (β = -.28, P < .01).

Conclusions

Family resilience impacts PTG of breast cancer survivors and caregiver burden. Our findings indicated the necessity of interventions to facilitate family resilience, promote PTG among breast cancer survivors, and decrease family members' caregiver burden.

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Psychosocial functioning and risk factors among siblings of children with cancer: An updated systematic review

Abstract

Objectives

Siblings' psychosocial adjustment to childhood cancer is poorly understood. This systematic review summarizes findings and limitations of the sibling literature since 2008, provides clinical recommendations, and offers future research directions.

Method

MEDLINE/Pubmed, CINAHL, and PsycINFO were searched for articles related to siblings, psychosocial functioning, and pediatric cancer. After systematic screening, studies meeting inclusion criteria were rated for scientific merit, and findings were extracted and synthesized. In total, 102 studies were included (63 quantitative, 35 qualitative, four mixed-methods).

Results

Methodological limitations are common. Mean levels of anxiety, depression, and general adjustment are similar across siblings and comparisons, but symptoms of cancer-related posttraumatic stress are prevalent. School-aged siblings display poorer academic functioning and more absenteeism but similar peer relationships than peers. Quality of life findings are mixed. Adult siblings engage in higher levels of risky health behaviors and may have poorer health outcomes than comparisons. Risk factors for poor sibling adjustment include lower social support, poorer family functioning, lower income, non-White race, and shorter time since diagnosis, but findings are inconsistent. Qualitative themes include siblings' maturity, compassion, and autonomy, but also strong negative emotions, uncertainty, family disruptions, limited parental support, school problems, altered friendships, and unmet needs.

Conclusion

Despite methodological limitations, research indicates a strong need for sibling support. Clinical recommendations include identifying at-risk siblings and developing interventions to facilitate family communication and increase siblings' social support, cancer-related knowledge, and treatment involvement. Future longitudinal studies focusing on mechanisms and moderators of siblings' adjustment would inform timing and targets of psychosocial care.

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via IFTTT

The acceptability and feasibility of lay-health led interventions for the prevention and early detection of cancer

Abstract

Background

US-based evidence suggests that lay-health worker (LHW) interventions can increase awareness around cancer risk-related lifestyles, symptom recognition and screening programme uptake. The suitability of LHW interventions in the UK and the potential barriers and facilitators for implementation is currently unknown. This study explored the acceptability and feasibility of developing LHW interventions for cancer prevention, screening and early diagnosis.

Methods

Purposive sampling recruited five separate lay groups: a) completed cancer treatment; b) friends/family of cancer patients; c) cancer hospital volunteers; d) cancer charity volunteers; and e) members of the public. Audio-recorded focus groups and semi-structured interviews were transcribed for thematic analysis using framework matrices.

Results

Forty-one people (66% female, aged 23-84 years) participated. Three main themes are reported: i) scope of LHW roles, with a clear remit embedded within communities or primary care practices, ii) defining LHW tasks, with a focus on supporting people overcome barriers including lack of cancer symptom knowledge and non-attendance at screening and iii) clear boundaries, with LHW training and on-going support from healthcare staff seen as key for intervention success. All groups were uncomfortable about having lifestyle-related risk conversations and potentially inflicting guilt. The post-treatment group expressed less concern about the possible emotional impact of discussing cancer symptoms, compared to the other groups.

Conclusions

LHW interventions to promote early diagnosis or screening were generally considered acceptable in a UK context. LHW interventions focussing on reducing cancer risk may be less feasible.

http://ift.tt/2Ep3gSw

Relationships between family resilience and posttraumatic growth in breast cancer survivors and caregiver burden

Abstract

Objective

To examine the relationships between family resilience and posttraumatic growth (PTG) of breast cancer survivors and caregiver burden among principal caregivers in China.

Methods

Participants in this cross-sectional study comprised 108 women aged 26–74 years (M = 49, SD = 9) with early-stage breast cancer and 108 principal caregivers. Participants were recruited from a comprehensive cancer center of a public hospital in Shandong Province, China. The principal caregivers completed the Shortened Chinese Version of the Family Resilience Assessment Scale (FRAS-C) and the Chinese Version of the Zarit Caregiver Burden Interview (CZBI); patients completed the Short Form of the Posttraumatic Growth Inventory (PTGI-SF) and questions designed to obtain sociodemographic information. Hierarchical regression analysis was conducted to assess the adjusted association between family resilience and PTG and caregiver burden, while controlling for sociodemographics.

Results

Families showed a slightly elevated level of family resilience since the cancer experience and patients showed a moderate degree of PTG. Principal caregivers reported moderate burden. FRAS-C total score was positively related to PTGI-SF total score (β = .28, P < .01) and was negatively related to CZBI total score (β = -.28, P < .01).

Conclusions

Family resilience impacts PTG of breast cancer survivors and caregiver burden. Our findings indicated the necessity of interventions to facilitate family resilience, promote PTG among breast cancer survivors, and decrease family members' caregiver burden.

http://ift.tt/2CiyJ38

Psychosocial functioning and risk factors among siblings of children with cancer: An updated systematic review

Abstract

Objectives

Siblings' psychosocial adjustment to childhood cancer is poorly understood. This systematic review summarizes findings and limitations of the sibling literature since 2008, provides clinical recommendations, and offers future research directions.

Method

MEDLINE/Pubmed, CINAHL, and PsycINFO were searched for articles related to siblings, psychosocial functioning, and pediatric cancer. After systematic screening, studies meeting inclusion criteria were rated for scientific merit, and findings were extracted and synthesized. In total, 102 studies were included (63 quantitative, 35 qualitative, four mixed-methods).

Results

Methodological limitations are common. Mean levels of anxiety, depression, and general adjustment are similar across siblings and comparisons, but symptoms of cancer-related posttraumatic stress are prevalent. School-aged siblings display poorer academic functioning and more absenteeism but similar peer relationships than peers. Quality of life findings are mixed. Adult siblings engage in higher levels of risky health behaviors and may have poorer health outcomes than comparisons. Risk factors for poor sibling adjustment include lower social support, poorer family functioning, lower income, non-White race, and shorter time since diagnosis, but findings are inconsistent. Qualitative themes include siblings' maturity, compassion, and autonomy, but also strong negative emotions, uncertainty, family disruptions, limited parental support, school problems, altered friendships, and unmet needs.

Conclusion

Despite methodological limitations, research indicates a strong need for sibling support. Clinical recommendations include identifying at-risk siblings and developing interventions to facilitate family communication and increase siblings' social support, cancer-related knowledge, and treatment involvement. Future longitudinal studies focusing on mechanisms and moderators of siblings' adjustment would inform timing and targets of psychosocial care.

http://ift.tt/2Ep31H6

A DNA-interacting payload designed to eliminate cross-linking improves the therapeutic index of antibody-drug conjugates (ADCs)

Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared to those of the cross-linker. Thus, the improved in vivo tolerability and anti-tumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.

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A correlative analysis of PD-L1, PD-1, PD-L2, EGFR, HER2, and HER3 expression in oropharyngeal squamous cell carcinoma

We explored potential associations of the PD-1/PD-L1/PD-L2 pathway with clinical characteristics, outcome, and expression of EGFR, HER2, HER3 in oropharyngeal squamous cell carcinoma (OPSCC) using an institutional database. Protein expression was assessed by immunohistochemistry on tissue microarray sections (EGFR, HER2, HER3) or whole tissue sections (PD-1/PD-L1/PD-L2). Expression of EGFR, HER2, HER3, PD-L1, and PD-L2 was quantified on tumor cells. Maximum density of PD-1 positive lymphocytes was measured on a scale of 0-4 within the tumor mass and peritumoral stroma. Associations between biomarkers and patient outcomes were tested using descriptive and inferential statistics, logistic regression, and Cox proportional hazards models. We analyzed tissue samples from 97 OPSCC cases: median age 59 years, p16+ (71%), male (83.5%), never smokers (18%), stage 3-4 disease (77%). 25% of cases were PD-L1 positive. The proportion of PD-L1+ tumors was higher in p16+ (29%) than p16- OPSCC (11%, p=0.047). There was no correlation between PD-L1, PD-L2, PD-1, EGFR, HER2, or HER3 expression. Positive PD-L1 status correlated with advanced nodal disease on multivariate analysis (OR 5.53 (CI 1.06-28.77), p=0.042). Negative PD-L2 expression was associated with worse survival (HR 3.99 (1.37-11.58), p=0.011) in p16- OPSCC. Lower density of PD-1+ lymphocytes in peritumoral stroma was associated with significantly increased risk of death on multivariate analysis (HR=3.17 (CI 1.03-9.78), p=0.045) after controlling for prognostic factors such as stage and p16 status. PD-L1 expression on tumor cells correlates with p16 status and advanced nodal status in OPSCC. PD-1+ lymphocytes in peritumoral stroma serve as an independent prognostic factor for overall survival.

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In vitro and in vivo activity of IMGN853, an Antibody-Drug Conjugate targeting Folate Receptor Alpha linked to DM4, in biologically aggressive endometrial cancers

Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FR) expression in these biologically aggressive (Type II) endometrial cancers,and evaluate FR as a targetable receptor for IMGN853 (Mirvetuximab soravtansine). The expression of FR was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FR. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/patient derived xenograft (PDX) models. Semi-quantitative IHC analysis indicated that 41% of the USC patients overexpress FR. Further, overexpression of FR (ie, 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared to control in 2+ expressing uterine tumor cell lines. In contrast,tumor cell lines with low FR showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FR = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FR, IMGN853 treatment showed complete resolution of tumors (p< 0.001). Treatment with IMGN853 in USC PDX model (BIO(K)1), expressing 2+ FR, induced 2-fold increase in median survival (p< 0.001). IMGN853 shows impressive anti-tumor activity in biologically aggressive FR 2+ uterine cancers. This preclinical data suggests that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FR may benefit from this treatment

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MicroRNA-203 inhibits long noncoding RNA HOTAIR and regulates tumorigenesis through epithelial-to-mesenchymal transition pathway in renal cell carcinoma

This study aims to investigate the role of miR-203-HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly under-expressed whereas HOTAIR was overexpressed in RCC cell-lines and clinical specimens compared to normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathological characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration and invasion with an induction of apoptosis and cell cycle arrest. Whereas, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203-HOTAIR interaction resulted in the inhibition of epithelial to mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers) and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal-marker), KLF4 and nanog (stemness-markers) was also observed. This is the first report demonstrating miR-203 mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis.

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MI130004, a novel antibody-drug conjugate combining trastuzumab with a molecule of marine origin, shows outstanding in vivo activity against HER2 expressing tumors

In the search for novel payloads to design new antibody-drug conjugates (ADCs), marine compounds represent an interesting opportunity given their unique chemical features. PM050489 is a marine compound that binds β-tubulin at a new site and disrupts the microtubule network hence leading to mitotic aberrations and cell death. PM050489 has been conjugated to trastuzumab via Cys residues through a non-cleavable linker and the resulting ADC, named MI130004, has been studied. Analysis of MI130004 delivered data consistent with the presence of two molecules of PM050489 per antibody molecule, likely bound to both sides of the intermolecular disulfide bond connecting the antibody light and heavy chains. The antitumor activity of MI130004 was analyzed in vitro and in vivo in different cell lines of diverse tumor origin (breast, ovary, and gastric cancer) expressing different levels of HER2. MI130004 showed very high in vitro potency and good selectivity for tumor cells that overexpressed HER2. At the cellular level, MI130004 impaired tubulin polymerization, causing disorganization and disintegration of the microtubule network which ultimately led to mitotic failure, mirroring the effect of its payload. Treatment with MI130004 in mice carrying histologically diverse tumors expressing HER2 induced a long-lasting antitumor effect with statistically significant inhibition of tumor growth coupled with increases in median survival time compared to vehicle or trastuzumab. These results strongly suggest that MI130004 is endowed with remarkable anticancer activity and confirm the extraordinary potential of marine compounds for the design of new ADCs.

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PIM kinases are a potential prognostic biomarker and therapeutic target in neuroblastoma

The majority of high-risk neuroblastoma patients are refractory to, or relapse on current treatment regimens, resulting in 5-year survival rates of less than 50%. This emphasizes the urgent need to identify novel therapeutic targets. Here, we report that high PIM kinase expression is correlated with poor overall survival. Treatment of neuroblastoma cell lines with the pan-PIM inhibitors AZD1208 or PIM-447 suppressed proliferation through inhibition of mTOR signaling. In a panel of neuroblastoma cell lines, we observed a marked binary response to PIM inhibition, suggesting that specific genetic lesions control responses to PIM inhibition. Using a genome-wide CRISPR-Cas9 genetic screen, we identified NF1 loss as the major resistance mechanism to PIM kinase inhibitors. Treatment with AZD1208 impaired the growth of NF1 wild type xenografts, while NF1 knock out cells were insensitive. Thus, our data indicate that PIM inhibition may be a novel targeted therapy in NF1 wild type neuroblastoma.

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A Spatio-temporal Model of Macrophage-mediated Drug Resistance in Glioma Immunotherapy

The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment in driving the development of acquired drug resistance remain elusive, which significantly impedes effective clinical cancer treatment. Recent experimental studies have revealed a macrophage-mediated drug resistance mechanism in which the tumor microenvironment undergoes adaptation in response to macrophage-targeted colony-stimulating factor-1 receptor (CSF1R) inhibition therapy in gliomas. In this study, we developed a spatio-temporal model to quantitatively describe the interplay between glioma cells and CSF1R inhibitor-targeted macrophages through CSF1 and IGF1 pathways. Our model was used to investigate the evolutionary kinetics of the tumor regrowth and the associated dynamic adaptation of the tumor microenvironment in response to the CSF1R inhibitor treatment. The simulation result obtained using this model was in agreement with the experimental data. The sensitivity analysis revealed the key parameters involved in the model, and their potential impacts on the model behavior were examined. Moreover, we demonstrated that the drug resistance is dose-dependent. In addition, we quantitatively evaluated the effects of combined CSFR inhibition and IGF1 receptor (IGF1R) inhibition with the goal of designing more effective therapies for gliomas. Our study provides quantitative and mechanistic insights into the microenvironmental adaptation mechanisms that operate during macrophage-targeted immunotherapy and has implications for drug dose optimization and the design of more effective combination therapies.

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NEO212 Inhibits Migration and Invasion of Glioma Stem Cells

Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10 fold more cytotoxic to glioma stem cells (GSCs) than TMZ, and is active against TMZ-resistant tumor cells. In this study, we show that NEO212 decreases migration and invasion of primary cultures of patient-derived GSCs, in both mesenchymal USC02 and proneural USC04 populations. The mechanism by which NEO212 reduces migration and invasion appears to be independent of its DNA alkylating effects, which cause cytotoxicity during the first hours of treatment, and is associated with a decrease in the FAK/Src signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases the production of matrix metalloproteinases MMP2 and MMP9, crucial for GSC invasion. Gene expression analysis of epithelial and mesenchymal markers suggests that NEO212 increases the expression of epithelial-like characteristics, suggesting a reversion of the epithelial-to-mesenchymal transition (EMT) process. Furthermore, in an in vivo orthotopic glioma model, NEO212 decreases tumor progression by reducing invasion of GSCs, thereby increasing survival time of mice. These studies indicate that NEO212, in addition to cytotoxicity, can effectively reduce migration and invasion in GSCs, thus exhibiting significant clinical value in the reduction of invasion and malignant glioma progression.

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Small molecule-mediated activation of RAS elicits biphasic modulation of phospho ERK levels that are regulated through negative feedback on SOS1

Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacological modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS mutant isoforms. We show that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant or after pretreatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of a S1178A SOS1 mutant. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated RAS-GTP levels over time in response to compound, as compared to the biphasic changes in RAS-GTP exhibited in cells expressing wild-type SOS1. These results suggest that small molecule targeting of SOS1 can elicit a biphasic modulation of RAS-GTP and phospho ERK levels through negative feedback on SOS1 that regulates the interaction between SOS1 and GRB2.

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A correlative analysis of PD-L1, PD-1, PD-L2, EGFR, HER2, and HER3 expression in oropharyngeal squamous cell carcinoma

We explored potential associations of the PD-1/PD-L1/PD-L2 pathway with clinical characteristics, outcome, and expression of EGFR, HER2, HER3 in oropharyngeal squamous cell carcinoma (OPSCC) using an institutional database. Protein expression was assessed by immunohistochemistry on tissue microarray sections (EGFR, HER2, HER3) or whole tissue sections (PD-1/PD-L1/PD-L2). Expression of EGFR, HER2, HER3, PD-L1, and PD-L2 was quantified on tumor cells. Maximum density of PD-1 positive lymphocytes was measured on a scale of 0-4 within the tumor mass and peritumoral stroma. Associations between biomarkers and patient outcomes were tested using descriptive and inferential statistics, logistic regression, and Cox proportional hazards models. We analyzed tissue samples from 97 OPSCC cases: median age 59 years, p16+ (71%), male (83.5%), never smokers (18%), stage 3-4 disease (77%). 25% of cases were PD-L1 positive. The proportion of PD-L1+ tumors was higher in p16+ (29%) than p16- OPSCC (11%, p=0.047). There was no correlation between PD-L1, PD-L2, PD-1, EGFR, HER2, or HER3 expression. Positive PD-L1 status correlated with advanced nodal disease on multivariate analysis (OR 5.53 (CI 1.06-28.77), p=0.042). Negative PD-L2 expression was associated with worse survival (HR 3.99 (1.37-11.58), p=0.011) in p16- OPSCC. Lower density of PD-1+ lymphocytes in peritumoral stroma was associated with significantly increased risk of death on multivariate analysis (HR=3.17 (CI 1.03-9.78), p=0.045) after controlling for prognostic factors such as stage and p16 status. PD-L1 expression on tumor cells correlates with p16 status and advanced nodal status in OPSCC. PD-1+ lymphocytes in peritumoral stroma serve as an independent prognostic factor for overall survival.

http://ift.tt/2CiUFet

In vitro and in vivo activity of IMGN853, an Antibody-Drug Conjugate targeting Folate Receptor Alpha linked to DM4, in biologically aggressive endometrial cancers

Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FR) expression in these biologically aggressive (Type II) endometrial cancers,and evaluate FR as a targetable receptor for IMGN853 (Mirvetuximab soravtansine). The expression of FR was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FR. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/patient derived xenograft (PDX) models. Semi-quantitative IHC analysis indicated that 41% of the USC patients overexpress FR. Further, overexpression of FR (ie, 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared to control in 2+ expressing uterine tumor cell lines. In contrast,tumor cell lines with low FR showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FR = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FR, IMGN853 treatment showed complete resolution of tumors (p< 0.001). Treatment with IMGN853 in USC PDX model (BIO(K)1), expressing 2+ FR, induced 2-fold increase in median survival (p< 0.001). IMGN853 shows impressive anti-tumor activity in biologically aggressive FR 2+ uterine cancers. This preclinical data suggests that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FR may benefit from this treatment

http://ift.tt/2Erkuim

A DNA-interacting payload designed to eliminate cross-linking improves the therapeutic index of antibody-drug conjugates (ADCs)

Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared to those of the cross-linker. Thus, the improved in vivo tolerability and anti-tumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.

http://ift.tt/2CgPhs1

MicroRNA-203 inhibits long noncoding RNA HOTAIR and regulates tumorigenesis through epithelial-to-mesenchymal transition pathway in renal cell carcinoma

This study aims to investigate the role of miR-203-HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly under-expressed whereas HOTAIR was overexpressed in RCC cell-lines and clinical specimens compared to normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathological characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration and invasion with an induction of apoptosis and cell cycle arrest. Whereas, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203-HOTAIR interaction resulted in the inhibition of epithelial to mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers) and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal-marker), KLF4 and nanog (stemness-markers) was also observed. This is the first report demonstrating miR-203 mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis.

http://ift.tt/2En2jKu

MI130004, a novel antibody-drug conjugate combining trastuzumab with a molecule of marine origin, shows outstanding in vivo activity against HER2 expressing tumors

In the search for novel payloads to design new antibody-drug conjugates (ADCs), marine compounds represent an interesting opportunity given their unique chemical features. PM050489 is a marine compound that binds β-tubulin at a new site and disrupts the microtubule network hence leading to mitotic aberrations and cell death. PM050489 has been conjugated to trastuzumab via Cys residues through a non-cleavable linker and the resulting ADC, named MI130004, has been studied. Analysis of MI130004 delivered data consistent with the presence of two molecules of PM050489 per antibody molecule, likely bound to both sides of the intermolecular disulfide bond connecting the antibody light and heavy chains. The antitumor activity of MI130004 was analyzed in vitro and in vivo in different cell lines of diverse tumor origin (breast, ovary, and gastric cancer) expressing different levels of HER2. MI130004 showed very high in vitro potency and good selectivity for tumor cells that overexpressed HER2. At the cellular level, MI130004 impaired tubulin polymerization, causing disorganization and disintegration of the microtubule network which ultimately led to mitotic failure, mirroring the effect of its payload. Treatment with MI130004 in mice carrying histologically diverse tumors expressing HER2 induced a long-lasting antitumor effect with statistically significant inhibition of tumor growth coupled with increases in median survival time compared to vehicle or trastuzumab. These results strongly suggest that MI130004 is endowed with remarkable anticancer activity and confirm the extraordinary potential of marine compounds for the design of new ADCs.

http://ift.tt/2CkHHN6

PIM kinases are a potential prognostic biomarker and therapeutic target in neuroblastoma

The majority of high-risk neuroblastoma patients are refractory to, or relapse on current treatment regimens, resulting in 5-year survival rates of less than 50%. This emphasizes the urgent need to identify novel therapeutic targets. Here, we report that high PIM kinase expression is correlated with poor overall survival. Treatment of neuroblastoma cell lines with the pan-PIM inhibitors AZD1208 or PIM-447 suppressed proliferation through inhibition of mTOR signaling. In a panel of neuroblastoma cell lines, we observed a marked binary response to PIM inhibition, suggesting that specific genetic lesions control responses to PIM inhibition. Using a genome-wide CRISPR-Cas9 genetic screen, we identified NF1 loss as the major resistance mechanism to PIM kinase inhibitors. Treatment with AZD1208 impaired the growth of NF1 wild type xenografts, while NF1 knock out cells were insensitive. Thus, our data indicate that PIM inhibition may be a novel targeted therapy in NF1 wild type neuroblastoma.

http://ift.tt/2EqxXqB

A Spatio-temporal Model of Macrophage-mediated Drug Resistance in Glioma Immunotherapy

The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment in driving the development of acquired drug resistance remain elusive, which significantly impedes effective clinical cancer treatment. Recent experimental studies have revealed a macrophage-mediated drug resistance mechanism in which the tumor microenvironment undergoes adaptation in response to macrophage-targeted colony-stimulating factor-1 receptor (CSF1R) inhibition therapy in gliomas. In this study, we developed a spatio-temporal model to quantitatively describe the interplay between glioma cells and CSF1R inhibitor-targeted macrophages through CSF1 and IGF1 pathways. Our model was used to investigate the evolutionary kinetics of the tumor regrowth and the associated dynamic adaptation of the tumor microenvironment in response to the CSF1R inhibitor treatment. The simulation result obtained using this model was in agreement with the experimental data. The sensitivity analysis revealed the key parameters involved in the model, and their potential impacts on the model behavior were examined. Moreover, we demonstrated that the drug resistance is dose-dependent. In addition, we quantitatively evaluated the effects of combined CSFR inhibition and IGF1 receptor (IGF1R) inhibition with the goal of designing more effective therapies for gliomas. Our study provides quantitative and mechanistic insights into the microenvironmental adaptation mechanisms that operate during macrophage-targeted immunotherapy and has implications for drug dose optimization and the design of more effective combination therapies.

http://ift.tt/2ChiL9p

NEO212 Inhibits Migration and Invasion of Glioma Stem Cells

Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10 fold more cytotoxic to glioma stem cells (GSCs) than TMZ, and is active against TMZ-resistant tumor cells. In this study, we show that NEO212 decreases migration and invasion of primary cultures of patient-derived GSCs, in both mesenchymal USC02 and proneural USC04 populations. The mechanism by which NEO212 reduces migration and invasion appears to be independent of its DNA alkylating effects, which cause cytotoxicity during the first hours of treatment, and is associated with a decrease in the FAK/Src signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases the production of matrix metalloproteinases MMP2 and MMP9, crucial for GSC invasion. Gene expression analysis of epithelial and mesenchymal markers suggests that NEO212 increases the expression of epithelial-like characteristics, suggesting a reversion of the epithelial-to-mesenchymal transition (EMT) process. Furthermore, in an in vivo orthotopic glioma model, NEO212 decreases tumor progression by reducing invasion of GSCs, thereby increasing survival time of mice. These studies indicate that NEO212, in addition to cytotoxicity, can effectively reduce migration and invasion in GSCs, thus exhibiting significant clinical value in the reduction of invasion and malignant glioma progression.

http://ift.tt/2EqxAfP

Small molecule-mediated activation of RAS elicits biphasic modulation of phospho ERK levels that are regulated through negative feedback on SOS1

Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacological modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS mutant isoforms. We show that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant or after pretreatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of a S1178A SOS1 mutant. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated RAS-GTP levels over time in response to compound, as compared to the biphasic changes in RAS-GTP exhibited in cells expressing wild-type SOS1. These results suggest that small molecule targeting of SOS1 can elicit a biphasic modulation of RAS-GTP and phospho ERK levels through negative feedback on SOS1 that regulates the interaction between SOS1 and GRB2.

http://ift.tt/2CiTQCi

The Balance Players of the Adaptive Immune System

Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)–restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer. Vaccination against genetically stable cells with regular HLA expression is an attractive way to directly target immunosuppressive cells in addition to attracting proinflammatory cells into the tumor microenvironment. Importantly, vaccination toward IDO or PD-L1 to potentiate such T cells have proven safe, with minimal toxicity in the clinical phase I trials conducted thus far.Significance: Autoreactive effector T cells that specifically recognize regulatory cells might be useful to harness for cancer immunotherapy to target the immune-suppressive tumor microenvironment. Cancer Res; 1–4. ©2018 AACR.

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SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin-Rho GTPase-Hippo Pathways

Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signalling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.

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A DDX31/mutant-p53/EGFR axis promotes multistep progression of muscle invasive bladder cancer

The p53 and EGFR pathways are frequently altered in bladder cancers, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31 bound mutp53/SP1 and enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin (p-NCL) in advanced MIBC, leading to EGFR-Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31-NCL interaction resulted in downregulation of EGFR-Akt signaling, eliciting an in vivo anti-tumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31-NCL formation may lead to potential treatment strategies for advanced MIBC.

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The FACT inhibitor CBL0137 synergizes with cisplatin in small cell lung cancer by increasing NOTCH1 expression and targeting tumor-initiating cells

Traditional treatments of small cell lung cancer (SCLC) with cisplatin, a standard of care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TIC in SCLC in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TIC. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically. In response to CBL0137 alone, TIC were more sensitive than non-TIC, in part because CBL0137 increased expression of the tumor suppressor NOTCH1 by abrogating the binding of negative regulator SP3 to the NOTCH1 promoter, and in part because treatment decreased the high expression of stem cell transcription factors. The combination of cisplatin and CBL0137 greatly reduced the growth of a patient-derived xenograft in mice and also the growth of a syngeneic mouse SCLC tumor. Thus, CBL0137 can be a highly effective drug against SCLC, especially in combination with cisplatin.

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The Balance Players of the Adaptive Immune System

Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)–restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer. Vaccination against genetically stable cells with regular HLA expression is an attractive way to directly target immunosuppressive cells in addition to attracting proinflammatory cells into the tumor microenvironment. Importantly, vaccination toward IDO or PD-L1 to potentiate such T cells have proven safe, with minimal toxicity in the clinical phase I trials conducted thus far.Significance: Autoreactive effector T cells that specifically recognize regulatory cells might be useful to harness for cancer immunotherapy to target the immune-suppressive tumor microenvironment. Cancer Res; 1–4. ©2018 AACR.

http://ift.tt/2Bu0oBr

SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin-Rho GTPase-Hippo Pathways

Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signalling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.

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A DDX31/mutant-p53/EGFR axis promotes multistep progression of muscle invasive bladder cancer

The p53 and EGFR pathways are frequently altered in bladder cancers, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31 bound mutp53/SP1 and enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin (p-NCL) in advanced MIBC, leading to EGFR-Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31-NCL interaction resulted in downregulation of EGFR-Akt signaling, eliciting an in vivo anti-tumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31-NCL formation may lead to potential treatment strategies for advanced MIBC.

http://ift.tt/2BuHcDC

The FACT inhibitor CBL0137 synergizes with cisplatin in small cell lung cancer by increasing NOTCH1 expression and targeting tumor-initiating cells

Traditional treatments of small cell lung cancer (SCLC) with cisplatin, a standard of care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TIC in SCLC in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TIC. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically. In response to CBL0137 alone, TIC were more sensitive than non-TIC, in part because CBL0137 increased expression of the tumor suppressor NOTCH1 by abrogating the binding of negative regulator SP3 to the NOTCH1 promoter, and in part because treatment decreased the high expression of stem cell transcription factors. The combination of cisplatin and CBL0137 greatly reduced the growth of a patient-derived xenograft in mice and also the growth of a syngeneic mouse SCLC tumor. Thus, CBL0137 can be a highly effective drug against SCLC, especially in combination with cisplatin.

http://ift.tt/2BVUTMD

Avoiding the Trap of Misdiagnosis: Valuable Teaching Points Derived from a Case of Longstanding Popliteal Artery Entrapment Syndrome

Popliteal artery entrapment syndrome (PAES), a condition predominantly affecting young individuals, is a rare clinical entity that can result in significant morbidity. The presence of lower limb pain and claudication in young, physically active individuals should prompt consideration for PAES. Early diagnosis and management is crucial to prevent long-term complications; however, diagnosis is fraught with challenges due to the rarity of the disease and its similar clinical presentation with more common conditions. We present a case of a young female with PAES who was misdiagnosed and underwent a tarsal tunnel release for suspected tarsal tunnel syndrome and subsequent fasciotomies for presumed chronic exertional compartment syndrome (CECS) without any relief. We outline the insidious undiagnosed course of her condition over a period of 12 years, discuss teaching points of how to recognize key differences of PAES and associated conditions, and provide recommendations for how to make the right diagnosis.

http://ift.tt/2BZmGvT

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel, Published online: 13 February 2018; doi:10.1038/bjc.2017.486

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel

http://ift.tt/2Gd2ODE

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology, Published online: 13 February 2018; doi:10.1038/bjc.2017.485

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

http://ift.tt/2GbpiES

IKKα is required in the intestinal epithelial cells for tumour stemness

IKKα is required in the intestinal epithelial cells for tumour stemness

IKK<i>α</i> is required in the intestinal epithelial cells for tumour stemness, Published online: 13 February 2018; doi:10.1038/bjc.2017.459

IKKα is required in the intestinal epithelial cells for tumour stemness

http://ift.tt/2Ha02QN

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection, Published online: 13 February 2018; doi:10.1038/bjc.2017.473

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

http://ift.tt/2G9owIE

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424, Published online: 13 February 2018; doi:10.1038/bjc.2017.484

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

http://ift.tt/2GamEz8

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

Regulation of ITGA3 by the dual-stranded <i>microRNA</i>-199 family as a potential prognostic marker in bladder cancer, Published online: 13 February 2018; doi:10.1038/bjc.2017.439

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

http://ift.tt/2HeAB0v

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma, Published online: 13 February 2018; doi:10.1038/bjc.2017.495

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

http://ift.tt/2H9ZYk1

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma, Published online: 13 February 2018; doi:10.1038/bjc.2018.3

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

http://ift.tt/2H9ZQkx

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel, Published online: 13 February 2018; doi:10.1038/bjc.2017.486

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel

from Cancer via ola Kala on Inoreader http://ift.tt/2Gd2ODE
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Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology, Published online: 13 February 2018; doi:10.1038/bjc.2017.485

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

from Cancer via ola Kala on Inoreader http://ift.tt/2GbpiES
via IFTTT

IKKα is required in the intestinal epithelial cells for tumour stemness

IKKα is required in the intestinal epithelial cells for tumour stemness

IKK<i>α</i> is required in the intestinal epithelial cells for tumour stemness, Published online: 13 February 2018; doi:10.1038/bjc.2017.459

IKKα is required in the intestinal epithelial cells for tumour stemness

from Cancer via ola Kala on Inoreader http://ift.tt/2Ha02QN
via IFTTT

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection, Published online: 13 February 2018; doi:10.1038/bjc.2017.473

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

from Cancer via ola Kala on Inoreader http://ift.tt/2G9owIE
via IFTTT

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424, Published online: 13 February 2018; doi:10.1038/bjc.2017.484

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

from Cancer via ola Kala on Inoreader http://ift.tt/2GamEz8
via IFTTT

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

Regulation of ITGA3 by the dual-stranded <i>microRNA</i>-199 family as a potential prognostic marker in bladder cancer, Published online: 13 February 2018; doi:10.1038/bjc.2017.439

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

from Cancer via ola Kala on Inoreader http://ift.tt/2HeAB0v
via IFTTT

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma, Published online: 13 February 2018; doi:10.1038/bjc.2017.495

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

from Cancer via ola Kala on Inoreader http://ift.tt/2H9ZYk1
via IFTTT

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma, Published online: 13 February 2018; doi:10.1038/bjc.2018.3

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

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Quantification of scatter radiation from radiographic procedures in a neonatal intensive care unit

Abstract

Background

In a neonatal intensive care unit (NICU), preterm infants are often exposed to a large number of radiographic examinations, which could cause adjacent neonates, family caregivers and staff members to be exposed to a dose amount due to scatter radiation.

Objective

To provide information on scatter radiation exposure levels in a NICU, to compare these values with the effective dose limits established by the European Union and to evaluate the effectiveness of radiation protection devices in this setting.

Materials and methods

Radiation exposure levels due to scatter radiation were estimated by passive detectors (thermoluminescent dosimeters) and direct dosimetric measurements (with a dose rate meter); in the latter case, an angular map of the scatter dose distribution was achieved.

Results

The dose due to scatter radiation to staff in our setting is approximately 160 μSv/year, which is markedly lower than the effective dose limit for workers established by the European Union (20 mSv/year). The doses range between 0.012 and 0.095 μSv/radiograph. Considering a mean hospitalization period of 3 months and our NICU workload, the corresponding scatter radiation dose to an adjacent patient and/or his/her caregiver is at most 40 μSv.

Conclusion

For distances greater than 1 m from the irradiation field, both scatter dose absorbed by a staff member during a year and that by an adjacent patient and/or his/her caregiver during hospitalization is less than 1 mSv, which is the exposure limit for public members in a year.

http://ift.tt/2EGJvFA

Quantification of scatter radiation from radiographic procedures in a neonatal intensive care unit

Abstract

Background

In a neonatal intensive care unit (NICU), preterm infants are often exposed to a large number of radiographic examinations, which could cause adjacent neonates, family caregivers and staff members to be exposed to a dose amount due to scatter radiation.

Objective

To provide information on scatter radiation exposure levels in a NICU, to compare these values with the effective dose limits established by the European Union and to evaluate the effectiveness of radiation protection devices in this setting.

Materials and methods

Radiation exposure levels due to scatter radiation were estimated by passive detectors (thermoluminescent dosimeters) and direct dosimetric measurements (with a dose rate meter); in the latter case, an angular map of the scatter dose distribution was achieved.

Results

The dose due to scatter radiation to staff in our setting is approximately 160 μSv/year, which is markedly lower than the effective dose limit for workers established by the European Union (20 mSv/year). The doses range between 0.012 and 0.095 μSv/radiograph. Considering a mean hospitalization period of 3 months and our NICU workload, the corresponding scatter radiation dose to an adjacent patient and/or his/her caregiver is at most 40 μSv.

Conclusion

For distances greater than 1 m from the irradiation field, both scatter dose absorbed by a staff member during a year and that by an adjacent patient and/or his/her caregiver during hospitalization is less than 1 mSv, which is the exposure limit for public members in a year.

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Dual-Stained Cervical Cytology and Histology with Claudin-1 and Ki67

Abstract

Several biomarkers are in use to improve the sensitivity and specificity of cervical cancer screening. Previously, increased expression of tight junction protein claudin-1 (CLDN1) was detected in premalignant and malignant cervical lesions and applied for cytology screening. To improve the specificity, a double immunoreaction with CLDN1/Ki67 was developed in the recent study. Parallel p16/Ki67 (CINtec® PLUS) and CLDN1/Ki67 dual-stained cytology and histology were performed and compared. p16/Ki67 immunoreaction showed positivity in 317 out of 1596 smears with negativity in 1072 and unacceptable reactions in 207 samples. CLDN1/Ki67 dual staining was positive in 200 of 1358 samples, negative in 962, whereas 196 smears could not be evaluated due to technical reasons. Considering the high-grade squamous intraepithelial lesion cytology as gold standard, sensitivity of CLDN1/Ki67 reaction was 76%, specificity was 85.67%, while for p16/Ki67 sensitivity was 74% and specificity was 81.38%. Comparison of CLDN1/Ki67 and p16/Ki67 dual stainings showed the results of the two tests not to be significantly different. Analysing histological slides from 63 cases, the results of the two tests agreed perfectly. As conclusion the sensitivity and specificity proved to be similar using p16/Ki67 and CLDN1/Ki67 double immunoreactions both on LBC samples and on histological slides.

http://ift.tt/2BtmpQP

The Great Esophageal Escape: A Case of Extreme Esophageal Interfraction Motion during Neoadjuvant Chemoradiation Therapy

Publication date: Available online 13 February 2018
Source:Practical Radiation Oncology
Author(s): Stephen R. Grant, Chelsea M. Page, Irma Diaz, Stephen Bush, Tomasz Bista, Lehendrick M. Turner, Gary V. Walker




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Assessing the utility of the Spinal Instability in Neoplasia (SINS) score to predict fracture after conventional radiation therapy (RT) for spinal metastases

Publication date: Available online 13 February 2018
Source:Practical Radiation Oncology
Author(s): Diana D. Shi, Lauren M. Hertan, Tai Chung Lam, Sonia Skamene, John H. Chi, Michael Groff, Charles H. Cho, Marco L. Ferrone, Mitchel Harris, Yu-Hui Chen, Tracy Anne Balboni
PurposeAssessing the stability of spinal metastases is critical for making treatment decisions. The SINS score was developed by the Spine Oncology Study Group to categorize tumor-related lesions. However, data describing its utility in predicting fractures in patients with spinal metastases is limited. The purpose of this study is to assess the validity of the SINS score in predicting new or worsening fracture after radiation therapy (RT) to spine metastases.Materials/MethodsThis is a retrospective analysis of patients treated with conventional RT alone (median total dose: 30 Gy, range: 8 – 47 Gy; median number of fractions: 10 , range: 1 – 25) for spinal metastasis at XXXX from 2006 to 2013. A SINS score was calculated for each lesion (range: 0-18). The primary endpoint was time from RT start to radiographically documented new or worsening fracture or last disease assessment.ResultsA total of 203 patients and 250 lesions were included in analysis. The percentages of lesions with SINS scores of 0-6, 7-12, and 13-18 were 38.8%, 54.8%, and 6.4%, respectively. Of 250 lesions, 20.4% developed new or worsening fractures; 14.4% for SINS 0-6, 21.2% for SINS 7-12, and 50.0% for SINS 13-18. Multivariate analysis adjusted for gender, age, ECOG, histology, and total dose, indicated that compared to stable lesions (SINS: 0-6), potentially unstable lesions (SINS 7-12) demonstrated a greater likelihood of new or worsening fracture that was not statistically significant ([HR] 1.66; 95% CI 0.85, 3.22; p = 0.14), and unstable lesions (SINS 13-18) were significantly more likely to develop to new or worsening fracture ([HR] 4.37, 95% CI 1.80, 10.61; p = 0.001)ConclusionsIn this study of patients undergoing RT for spinal metastases, 20.4% developed new or worsening vertebral fractures. The SINS score is demonstrated to be a useful tool to assess fracture risk after RT.



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The Great Esophageal Escape: A Case of Extreme Esophageal Interfraction Motion during Neoadjuvant Chemoradiation Therapy

Publication date: Available online 13 February 2018
Source:Practical Radiation Oncology
Author(s): Stephen R. Grant, Chelsea M. Page, Irma Diaz, Stephen Bush, Tomasz Bista, Lehendrick M. Turner, Gary V. Walker




http://ift.tt/2EEvI21

Assessing the utility of the Spinal Instability in Neoplasia (SINS) score to predict fracture after conventional radiation therapy (RT) for spinal metastases

Publication date: Available online 13 February 2018
Source:Practical Radiation Oncology
Author(s): Diana D. Shi, Lauren M. Hertan, Tai Chung Lam, Sonia Skamene, John H. Chi, Michael Groff, Charles H. Cho, Marco L. Ferrone, Mitchel Harris, Yu-Hui Chen, Tracy Anne Balboni
PurposeAssessing the stability of spinal metastases is critical for making treatment decisions. The SINS score was developed by the Spine Oncology Study Group to categorize tumor-related lesions. However, data describing its utility in predicting fractures in patients with spinal metastases is limited. The purpose of this study is to assess the validity of the SINS score in predicting new or worsening fracture after radiation therapy (RT) to spine metastases.Materials/MethodsThis is a retrospective analysis of patients treated with conventional RT alone (median total dose: 30 Gy, range: 8 – 47 Gy; median number of fractions: 10 , range: 1 – 25) for spinal metastasis at XXXX from 2006 to 2013. A SINS score was calculated for each lesion (range: 0-18). The primary endpoint was time from RT start to radiographically documented new or worsening fracture or last disease assessment.ResultsA total of 203 patients and 250 lesions were included in analysis. The percentages of lesions with SINS scores of 0-6, 7-12, and 13-18 were 38.8%, 54.8%, and 6.4%, respectively. Of 250 lesions, 20.4% developed new or worsening fractures; 14.4% for SINS 0-6, 21.2% for SINS 7-12, and 50.0% for SINS 13-18. Multivariate analysis adjusted for gender, age, ECOG, histology, and total dose, indicated that compared to stable lesions (SINS: 0-6), potentially unstable lesions (SINS 7-12) demonstrated a greater likelihood of new or worsening fracture that was not statistically significant ([HR] 1.66; 95% CI 0.85, 3.22; p = 0.14), and unstable lesions (SINS 13-18) were significantly more likely to develop to new or worsening fracture ([HR] 4.37, 95% CI 1.80, 10.61; p = 0.001)ConclusionsIn this study of patients undergoing RT for spinal metastases, 20.4% developed new or worsening vertebral fractures. The SINS score is demonstrated to be a useful tool to assess fracture risk after RT.



http://ift.tt/2sw6KgJ