DNA damage response inhibitors: mechanisms and potential applications in cancer therapy

Publication date: Available online 19 September 2017
Source:Cancer Treatment Reviews
Author(s): Laura Carrassa, Giovanna Damia
Over the last decade the unravelling of the molecular mechanisms of the DNA damage response pathways and of the genomic landscape of human tumors have paved the road to new therapeutic approaches in oncology. It is now clear that tumors harbour defects in different DNA damage response steps, mainly signalling and repair, rendering them more dependent on the remaining pathways. We here focus on the proteins ATM, ATR, CHK1 and WEE1, reviewing their roles in the DNA damage response and as targets in cancer therapy. In the last decade specific inhibitors of these proteins have been designed, and their potential antineoplastic activity has been explored both in monotherapy strategies against tumors with specific defects (synthetic lethality approach) and in combination with radiotherapy or chemotherapeutic or molecular targeted agents. The preclinical and clinical evidence of antitumor activity of these inhibitors emanating from these research efforts will be critically reviewed. Lastly, the potential therapeutic feasibility of combining together such inhibitors with the aim to target particular subsets of tumors will be also discussed. .



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The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis

The tumor acidic microenvironment, a common biochemical event in solid tumors, offers evolutional advantage for tumors cells and even enhances their aggressive phenotype. However, little is known about the mol...

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Beyond classic dermoscopic patterns of dermatofibromas: a prospective research study

The usual stereotypical dermoscopic pattern associated with dermatofibromas is a pigment network and central white patch. However, this pattern may be difficult to diagnose in some variant cases. We aimed to d...

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Roles for Innate Immunity in Combination Immunotherapies

Immunity to infectious agents involves a coordinated response of innate and adaptive immune cells working in concert, with many feed-forward and regulatory interactions between both arms of the immune system. In contrast, many therapeutic strategies to augment immunity against tumors have focused predominantly on stimulation of adaptive immunity. However, a growing appreciation of the potential contributions of innate immune effectors to antitumor immunity, especially in the context of combination immunotherapy, is leading to novel strategies to elicit a more integrated immune response against cancer. Here we review antitumor activities of innate immune cells, mechanisms of their synergy with adaptive immune responses against tumors, and discuss recent studies highlighting the potential of combination therapies recruiting both innate and adaptive immune effectors to eradicate established tumors. Cancer Res; 77(19); 1–7. ©2017 AACR.

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New Advances and Challenges of Targeting Cancer Stem Cells

The second International Cancer Stem Cell Conference in Cleveland, Ohio, on September 20–23, 2016, convened 330 attendees from academic, industrial, and clinical organizations. It featured a debate on the concepts and challenges of the cancer stem cells (CSC) as well as CSC-centered scientific sessions on clinical trials, genetics and epigenetics, tumor microenvironment, immune suppression, metastasis, therapeutic resistance, and emerging novel concepts. The conference hosted 35 renowned speakers, 100 posters, 20 short talks, and a preconference workshop. The reported advances of CSC research and therapies fostered new collaborations across national and international borders, and inspired the next generation's young scientists. Cancer Res; 77(19); 1–6. ©2017 AACR.

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Roles for Innate Immunity in Combination Immunotherapies

Immunity to infectious agents involves a coordinated response of innate and adaptive immune cells working in concert, with many feed-forward and regulatory interactions between both arms of the immune system. In contrast, many therapeutic strategies to augment immunity against tumors have focused predominantly on stimulation of adaptive immunity. However, a growing appreciation of the potential contributions of innate immune effectors to antitumor immunity, especially in the context of combination immunotherapy, is leading to novel strategies to elicit a more integrated immune response against cancer. Here we review antitumor activities of innate immune cells, mechanisms of their synergy with adaptive immune responses against tumors, and discuss recent studies highlighting the potential of combination therapies recruiting both innate and adaptive immune effectors to eradicate established tumors. Cancer Res; 77(19); 1–7. ©2017 AACR.

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New Advances and Challenges of Targeting Cancer Stem Cells

The second International Cancer Stem Cell Conference in Cleveland, Ohio, on September 20–23, 2016, convened 330 attendees from academic, industrial, and clinical organizations. It featured a debate on the concepts and challenges of the cancer stem cells (CSC) as well as CSC-centered scientific sessions on clinical trials, genetics and epigenetics, tumor microenvironment, immune suppression, metastasis, therapeutic resistance, and emerging novel concepts. The conference hosted 35 renowned speakers, 100 posters, 20 short talks, and a preconference workshop. The reported advances of CSC research and therapies fostered new collaborations across national and international borders, and inspired the next generation's young scientists. Cancer Res; 77(19); 1–6. ©2017 AACR.

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HIGH BCR-ABL/GUSIS LEVELS AT DIAGNOSIS OF CHRONIC PHASE CML ARE ASSOCIATED WITH UNFAVORABLE RESPONSES TO STANDARD-DOSE IMATINIB

Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate Imatinib responses. Experimental Design: We correlated BCR-ABL/GUSIS and BCR-ABL/ABLIS transcripts at diagnosis with the outcome - defined by the 2013 European LeukemiaNet recommendations - of 272 newly diagnosed CML patients receiving Imatinib 400 mg/daily. Applying Receiver Operating Characteristic curves we defined BCR-ABL/GUSIS and BCR-ABL/ABLIS levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS) and overall survival (OS). Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as "warnings", 22.4% failed Imatinib and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), 7 (2.5%) attributable to disease progression. We found that higher BCR-ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (p<0.001), FFS (p<0.001) and EFS (p<0.001). Elevated BCR-ABL/GUSIS levels were also associated with lower rates of TFS (p=0.029) but not with OS (p=0.132). Similarly, high BCR-ABL/ABL levels at diagnosis were associated with inferior rates of OR (p=0.03), FFS (p=0.001) and EFS (p=0.005), but not with TFS (p=0.167) or OS (p=0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates. Conclusions: Our data suggest that high BCR-ABL transcripts at diagnosis measured employing GUS as a reference gene identify CML patients unlikely to benefit from standard dose Imatinib.

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ImmunoPET of malignant and normal B cells with 89Zr- and 124I-labeled obinutuzumab antibody fragments reveals differential CD20 internalization in vivo

Purpose: The B-cell antigen CD20 provides a target for antibody-based positron emission tomography (immunoPET). We engineered antibody fragments targeting human CD20 and studied their potential as immunoPET tracers in transgenic mice (huCD20TM) and in a murine lymphoma model expressing human CD20. Experimental Design: Anti-CD20 cys-diabody (cDb) and cys-minibody (cMb) based on rituximab (Rx) and obinutuzumab (GA101) were radioiodinated and used for immunoPET imaging of a murine lymphoma model. Pairwise comparison of obinutuzumab-based antibody fragments labeled with residualizing (89Zr) versus non-residualizing (124I) radionuclides by region of interest (ROI) analysis of serial PET images was conducted both in the murine lymphoma model and in huCD20TM to asses antigen modulation in vivo. Results: 124I-GAcDb and 124I-GAcMb produced high-contrast immunoPET images of B-cell lymphoma and outperformed the respective rituximab-based tracers. ImmunoPET imaging of huCD20TM showed specific uptake in lymphoid tissues. The use of the radiometal 89Zr as alternative label for GAcDb and GAcMb yielded greater target-specific uptake and retention compared with 124I-labeled tracers. Pairwise comparison of 89Zr- and 124I-labeled GAcDb and GAcMb allowed assessment of in vivo internalization of CD20/antibody complexes and revealed that CD20 internalization differs between malignant and endogenous B cells. Conclusions: These obinutuzumab-based PET tracers have the ability to noninvasively and quantitatively monitor CD20-expression and have revealed insights into CD20 internalization upon antibody binding in vivo. Because they are based on a humanized mAb they have the potential for direct clinical translation and could improve patient selection for targeted therapy, dosimetry prior to radioimmunotherapy (RIT), and prediction of response to therapy.

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The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-derived IL-6

Purpose: Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAM in colorectal cancer (CRC) are contradictory. We therefore investigated the functions, mechanisms and clinical significance of TAMs in CRC. Experimental Design: We measured the macrophage infiltration (CD68), P-gp and Bcl2 expression in CRC tissues using Immunohistochemistry staining. Co-culture of TAMs and CRC cells both in vitro and in vivo models was used to evaluate the effects of TAMs on CRC chemoresistance. Cytokine Antibody Arrays, enzyme linked immunosorbent assay, neutralizing antibody and luciferase reporter assay were performed to uncover the underlying mechanism. Results: TAM infiltration was associated with chemoresistance in CRC patients. CRC-conditioned macrophages increased CRC chemoresistance and reduced drug-induced apoptosis by secreting IL-6, which could be blocked by a neutralizing anti-IL-6 antibody. Macrophage-derived IL-6 activated the IL-6R/STAT3 pathway in CRC cells, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-204-5p. Rescue experiment confirmed that miR-204-5p is a functional target mediating the TAM-induced CRC chemoresistance. miR-155-5p, a key microRNA regulating C/EBPβ, was frequently downregulated in TAM, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL-6 in TAM, and TAM-secreted IL-6 then induced chemoresistance by activating the IL-6R/STAT3/miR-204-5p pathway in CRC cells. Conclusions: Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL-6 signaling in TAM could induce chemoresistance in CRC cells by regulating the IL-6R/STAT3/miR-204-5p axis, revealing a new crosstalk between immune cells and tumor cells in CRC microenvironment.

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BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer.

Purpose: Bladder cancer (BC) is a current clinical and social problem. At diagnosis, most patients present non-muscle invasive tumors, characterized by a high recurrence rate, which could progress to muscle invasive disease and metastasis. Bone morphogenetic protein (BMP)-dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in BC is still unclear. Experimental Design: Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed in vitro by experiments with BC cell lines and peripheral blood monocyte-derived macrophages. Results: We observed BMP4 expression is associated and favored type-2 macrophage differentiation. In vitro experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from BC cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL-10. Using a series of human BC patient samples we also observed increased expression of BMP4 in advanced and undifferentiated tumors in close correlation with epithelial-mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced BMPR2 expression. Conclusions: These findings suggest that BMP4 secretion by BC cells provides the M2 signal necessary for a pro-tumoral immune environment. In addition, the repression of BMPR2 by miR-21 makes the tumor cells refractory to the pro-differentiating actions mediated by BMP ligands, favoring tumor growth.

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Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients using an IVIVE-PBPK Modeling Approach

Purpose: AZD1775, a first-in-class, small molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radio-sensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across human blood-brain barrier (BBB). Experimental Design: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 glioblastoma patients. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a 4-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process. Results: AZD1775 exhibited good tumor penetration in glioblastoma patients, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII-ABCB1 or MDCKII-ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue. Conclusions: In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors.

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Therapeutic drug monitoring of carboplatin in high-dose protocol (TI-CE) for advanced germ cell tumors: pharmacokinetic results of a phase 2 multicenter study

PURPOSE: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling inter-patient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative. EXPERIMENTAL DESIGN: Eighty nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction. RESULTS: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentile, respectively). The new covariate equation [CL (mL/min) = 130.7 x (Scr/83)–0.826 x (BW/76)+0.907 x (Age/36)–0.223 with Scr in μM, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared to other equations. CONCLUSION: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young males patients could be used if TDM cannot be implemented.

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Characterization of the Immune Microenvironment in Hepatocellular Carcinoma (HCC)

Purpose: Hepatocellular carcinoma (HCC) often arises in the setting of chronic liver inflammation and may be responsive to novel immunotherapies. Experimental Design: To characterize the immune microenvironment in HCC, immunohistochemical (IHC) staining was performed for CD8 positive T lymphocytes, PD-1 positive and LAG-3 positive lymphocytes, CD163 positive macrophages, and PD-L1 expression in tumor and liver background from 29 cases of resected HCC. Results: Expression of CD8 was reduced in tumor and expression of CD163 was reduced at the tumor interface. Positive clusters of PD-L1 expression were identified in 24/29 cases (83%) and positive expression of LAG-3 on tumor infiltrating lymphocytes was identified in 19/29 cases (65%). The expression of both PD-L1 and LAG-3 was increased in tumor relative to liver background. No association between viral status or other clinicopathologic features and expression of any of the IHC markers investigated was noted. Conclusions: LAG-3 and PD-L1, two inhibitory molecules implicated in CD8 T-cell tolerance, are increased in most HCC tumors, providing a basis for investigating combinatorial checkpoint blockade with a LAG-3 and PD-L1 inhibitor in HCC.

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HIGH BCR-ABL/GUSIS LEVELS AT DIAGNOSIS OF CHRONIC PHASE CML ARE ASSOCIATED WITH UNFAVORABLE RESPONSES TO STANDARD-DOSE IMATINIB

Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate Imatinib responses. Experimental Design: We correlated BCR-ABL/GUSIS and BCR-ABL/ABLIS transcripts at diagnosis with the outcome - defined by the 2013 European LeukemiaNet recommendations - of 272 newly diagnosed CML patients receiving Imatinib 400 mg/daily. Applying Receiver Operating Characteristic curves we defined BCR-ABL/GUSIS and BCR-ABL/ABLIS levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS) and overall survival (OS). Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as "warnings", 22.4% failed Imatinib and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), 7 (2.5%) attributable to disease progression. We found that higher BCR-ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (p<0.001), FFS (p<0.001) and EFS (p<0.001). Elevated BCR-ABL/GUSIS levels were also associated with lower rates of TFS (p=0.029) but not with OS (p=0.132). Similarly, high BCR-ABL/ABL levels at diagnosis were associated with inferior rates of OR (p=0.03), FFS (p=0.001) and EFS (p=0.005), but not with TFS (p=0.167) or OS (p=0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates. Conclusions: Our data suggest that high BCR-ABL transcripts at diagnosis measured employing GUS as a reference gene identify CML patients unlikely to benefit from standard dose Imatinib.

http://ift.tt/2ypjy7B

ImmunoPET of malignant and normal B cells with 89Zr- and 124I-labeled obinutuzumab antibody fragments reveals differential CD20 internalization in vivo

Purpose: The B-cell antigen CD20 provides a target for antibody-based positron emission tomography (immunoPET). We engineered antibody fragments targeting human CD20 and studied their potential as immunoPET tracers in transgenic mice (huCD20TM) and in a murine lymphoma model expressing human CD20. Experimental Design: Anti-CD20 cys-diabody (cDb) and cys-minibody (cMb) based on rituximab (Rx) and obinutuzumab (GA101) were radioiodinated and used for immunoPET imaging of a murine lymphoma model. Pairwise comparison of obinutuzumab-based antibody fragments labeled with residualizing (89Zr) versus non-residualizing (124I) radionuclides by region of interest (ROI) analysis of serial PET images was conducted both in the murine lymphoma model and in huCD20TM to asses antigen modulation in vivo. Results: 124I-GAcDb and 124I-GAcMb produced high-contrast immunoPET images of B-cell lymphoma and outperformed the respective rituximab-based tracers. ImmunoPET imaging of huCD20TM showed specific uptake in lymphoid tissues. The use of the radiometal 89Zr as alternative label for GAcDb and GAcMb yielded greater target-specific uptake and retention compared with 124I-labeled tracers. Pairwise comparison of 89Zr- and 124I-labeled GAcDb and GAcMb allowed assessment of in vivo internalization of CD20/antibody complexes and revealed that CD20 internalization differs between malignant and endogenous B cells. Conclusions: These obinutuzumab-based PET tracers have the ability to noninvasively and quantitatively monitor CD20-expression and have revealed insights into CD20 internalization upon antibody binding in vivo. Because they are based on a humanized mAb they have the potential for direct clinical translation and could improve patient selection for targeted therapy, dosimetry prior to radioimmunotherapy (RIT), and prediction of response to therapy.

http://ift.tt/2xPhzvU

The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-derived IL-6

Purpose: Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAM in colorectal cancer (CRC) are contradictory. We therefore investigated the functions, mechanisms and clinical significance of TAMs in CRC. Experimental Design: We measured the macrophage infiltration (CD68), P-gp and Bcl2 expression in CRC tissues using Immunohistochemistry staining. Co-culture of TAMs and CRC cells both in vitro and in vivo models was used to evaluate the effects of TAMs on CRC chemoresistance. Cytokine Antibody Arrays, enzyme linked immunosorbent assay, neutralizing antibody and luciferase reporter assay were performed to uncover the underlying mechanism. Results: TAM infiltration was associated with chemoresistance in CRC patients. CRC-conditioned macrophages increased CRC chemoresistance and reduced drug-induced apoptosis by secreting IL-6, which could be blocked by a neutralizing anti-IL-6 antibody. Macrophage-derived IL-6 activated the IL-6R/STAT3 pathway in CRC cells, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-204-5p. Rescue experiment confirmed that miR-204-5p is a functional target mediating the TAM-induced CRC chemoresistance. miR-155-5p, a key microRNA regulating C/EBPβ, was frequently downregulated in TAM, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL-6 in TAM, and TAM-secreted IL-6 then induced chemoresistance by activating the IL-6R/STAT3/miR-204-5p pathway in CRC cells. Conclusions: Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL-6 signaling in TAM could induce chemoresistance in CRC cells by regulating the IL-6R/STAT3/miR-204-5p axis, revealing a new crosstalk between immune cells and tumor cells in CRC microenvironment.

http://ift.tt/2yoe9xx

BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer.

Purpose: Bladder cancer (BC) is a current clinical and social problem. At diagnosis, most patients present non-muscle invasive tumors, characterized by a high recurrence rate, which could progress to muscle invasive disease and metastasis. Bone morphogenetic protein (BMP)-dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in BC is still unclear. Experimental Design: Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed in vitro by experiments with BC cell lines and peripheral blood monocyte-derived macrophages. Results: We observed BMP4 expression is associated and favored type-2 macrophage differentiation. In vitro experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from BC cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL-10. Using a series of human BC patient samples we also observed increased expression of BMP4 in advanced and undifferentiated tumors in close correlation with epithelial-mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced BMPR2 expression. Conclusions: These findings suggest that BMP4 secretion by BC cells provides the M2 signal necessary for a pro-tumoral immune environment. In addition, the repression of BMPR2 by miR-21 makes the tumor cells refractory to the pro-differentiating actions mediated by BMP ligands, favoring tumor growth.

http://ift.tt/2xPV0Hw

Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients using an IVIVE-PBPK Modeling Approach

Purpose: AZD1775, a first-in-class, small molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radio-sensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across human blood-brain barrier (BBB). Experimental Design: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 glioblastoma patients. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a 4-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process. Results: AZD1775 exhibited good tumor penetration in glioblastoma patients, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII-ABCB1 or MDCKII-ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue. Conclusions: In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors.

http://ift.tt/2yoe3Gb

Therapeutic drug monitoring of carboplatin in high-dose protocol (TI-CE) for advanced germ cell tumors: pharmacokinetic results of a phase 2 multicenter study

PURPOSE: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling inter-patient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative. EXPERIMENTAL DESIGN: Eighty nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction. RESULTS: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentile, respectively). The new covariate equation [CL (mL/min) = 130.7 x (Scr/83)–0.826 x (BW/76)+0.907 x (Age/36)–0.223 with Scr in μM, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared to other equations. CONCLUSION: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young males patients could be used if TDM cannot be implemented.

http://ift.tt/2xQc9B9

Characterization of the Immune Microenvironment in Hepatocellular Carcinoma (HCC)

Purpose: Hepatocellular carcinoma (HCC) often arises in the setting of chronic liver inflammation and may be responsive to novel immunotherapies. Experimental Design: To characterize the immune microenvironment in HCC, immunohistochemical (IHC) staining was performed for CD8 positive T lymphocytes, PD-1 positive and LAG-3 positive lymphocytes, CD163 positive macrophages, and PD-L1 expression in tumor and liver background from 29 cases of resected HCC. Results: Expression of CD8 was reduced in tumor and expression of CD163 was reduced at the tumor interface. Positive clusters of PD-L1 expression were identified in 24/29 cases (83%) and positive expression of LAG-3 on tumor infiltrating lymphocytes was identified in 19/29 cases (65%). The expression of both PD-L1 and LAG-3 was increased in tumor relative to liver background. No association between viral status or other clinicopathologic features and expression of any of the IHC markers investigated was noted. Conclusions: LAG-3 and PD-L1, two inhibitory molecules implicated in CD8 T-cell tolerance, are increased in most HCC tumors, providing a basis for investigating combinatorial checkpoint blockade with a LAG-3 and PD-L1 inhibitor in HCC.

http://ift.tt/2yodWKL

What is the optimal number of library plans in ART for locally advanced cervical cancer?

Library-of-plans ART is used to manage daily anatomy changes in locally advanced cervical cancer. In our institute, the library contains 2 VMAT plans for patients with large cervix-uterus motion. Increasing this number could be beneficial for tissue sparing, but is burdensome while the dosimetric gain is yet unclear. This study's aim is to determine the optimal number of plans at an individual patient level.

http://ift.tt/2fibscf

Prostate cancer post-prostatectomy radiotherapy: CT vs MRI for vesico-urethral anastomosis target delineation

Vesico-urethral anastomosis (VUA) is critical to the clinical target volume (CTV) in post-prostatectomy radiotherapy (PPRT), as it is the commonest site of recurrence. Typically, this is performed on a CT alone but guidelines recommend MRI.

http://ift.tt/2xvfZ1E

Heart dose associated with overall survival in locally advanced NSCLC patients treated with hypofractionated chemoradiotherapy

Association of heart dose and overall survival was investigated in a cohort including 469 locally-advanced NSCLC patients receiving daily low-dose hypofractionated chemo-radiotherapy. Significant associations were found over a range of dose parameters. Multivariate analysis showed significant associations of heart_V2Gy:HR=1.007%−1 (95% CI:1.002–1.013; p=0.006), age:HR=1.026year−1 (1.011–1.042; p=0.001) and GTV volume:HR=1.001cc−1 (1.000–1.002; p=0.006) with overall survival.

http://ift.tt/2fif9P5

Meeting abstracts from the 65th British Thyroid Association Annual Meeting

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A retrospective review of the multidisciplinary management of medullary thyroid cancer: eligibility for systemic therapy

Abstract

Background

Medullary thyroid carcinoma (MTC) accounts for 1-2% of all thyroid cancers. The clinical course of metastatic disease can be indolent. Our aim was to characterize the natural history of disease to evaluate the true proportion of patients who would be eligible for the currently available systemic therapies.

Methods

The British Columbia Cancer Agency (BCCA) provides cancer care to a population of 4.6 million. A retrospective chart review was conducted of all patients with MTC referred to the BCCA from 1991 to 2013. Clinical characteristics, pathology, treatment and outcome data were collected. Relapse free survival and overall survival was determined for patients based on staging at the time of diagnosis.

Results

Of the 98 patients referred to the BCCA during the study period, inherited mutations were found in 6% though 60% did not undergo genetic testing. Based on clinical SEER staging at diagnosis 50% had localized disease, 38% regional, and 12% had distant metastasis. 77% had complete surgical resection of which 25% received adjuvant radiation therapy. Five year relapse free survival (RFS) for localized and regional disease was 75% and 66%, respectively (p = 0.006). Initial treatment of 23 patients with locally unresectable and metastatic disease predominantly involved multiple modalities. Of the 37 patients with relapsed or metastatic MTC only 7 (19%) patients received one or more course of chemotherapy for metastatic disease: 1 temsirolimus, 2 adriamycin, 3 sunitinib, 3 sorafenib, and 3 vandetanib. Five year OS based on clinical SEER stage: localized 93%, regional 72% and distant 33% (p < 0.001).

Conclusion

Localized and regional MTC treatment patterns reflect multidisciplinary management based on disease characteristics. Patients with distant disease had poor outcomes with 28% of patients dying from disease. In our cohort the minority of patients ultimately received systemic therapy due to timing and lack of TKI availability.

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Meeting abstracts from the 65th British Thyroid Association Annual Meeting

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A retrospective review of the multidisciplinary management of medullary thyroid cancer: eligibility for systemic therapy

Abstract

Background

Medullary thyroid carcinoma (MTC) accounts for 1-2% of all thyroid cancers. The clinical course of metastatic disease can be indolent. Our aim was to characterize the natural history of disease to evaluate the true proportion of patients who would be eligible for the currently available systemic therapies.

Methods

The British Columbia Cancer Agency (BCCA) provides cancer care to a population of 4.6 million. A retrospective chart review was conducted of all patients with MTC referred to the BCCA from 1991 to 2013. Clinical characteristics, pathology, treatment and outcome data were collected. Relapse free survival and overall survival was determined for patients based on staging at the time of diagnosis.

Results

Of the 98 patients referred to the BCCA during the study period, inherited mutations were found in 6% though 60% did not undergo genetic testing. Based on clinical SEER staging at diagnosis 50% had localized disease, 38% regional, and 12% had distant metastasis. 77% had complete surgical resection of which 25% received adjuvant radiation therapy. Five year relapse free survival (RFS) for localized and regional disease was 75% and 66%, respectively (p = 0.006). Initial treatment of 23 patients with locally unresectable and metastatic disease predominantly involved multiple modalities. Of the 37 patients with relapsed or metastatic MTC only 7 (19%) patients received one or more course of chemotherapy for metastatic disease: 1 temsirolimus, 2 adriamycin, 3 sunitinib, 3 sorafenib, and 3 vandetanib. Five year OS based on clinical SEER stage: localized 93%, regional 72% and distant 33% (p < 0.001).

Conclusion

Localized and regional MTC treatment patterns reflect multidisciplinary management based on disease characteristics. Patients with distant disease had poor outcomes with 28% of patients dying from disease. In our cohort the minority of patients ultimately received systemic therapy due to timing and lack of TKI availability.

http://ift.tt/2wEMGFM

Combination immunotherapy strategies in advanced Non-Small Cell Lung Cancer (NSCLC): Does biological rationale meet clinical needs?

Publication date: Available online 19 September 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Ilaria Attili, Antonio Passaro, Alberto Pavan, PierFranco Conte, Filippo De Marinis, Laura Bonanno
Immune checkpoint inhibitors (ICIs) have emerged as one of the main new therapeutic options for advanced non-small cell lung cancer (NSCLC) patients. Even though they demonstrated superiority towards standard chemotherapy in different disease settings, the response rates do not exceed 45% in highly molecularly selected patients. This is related to known limitations of the available biomarkers, as well to the complex and dynamic nature of tumor microenvironment. The study of the different strategies adopted by tumor cells to escape the immune system lays the basis of the new combination strategies. This review focuses on analyzing the biological rationale and early clinical data available concerning therapeutic strategies combining ICIs together, ICIs with different regimens and schedules of standard chemotherapy, ICIs with tyrosine kinase inhibitors, ICIs with antiangiogenic agents and ICs with radiotherapy.



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Critical Risk-Benefit Assessment of the Novel Anti-Cancer Aurora A Kinase Inhibitor Alisertib (MLN8237): A Comprehensive Review of the Clinical Data

Publication date: Available online 18 September 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Yaman Tayyar, Luqman Jubair, Sora Fallaha, Nigel McMillan
BackgroundMany current anticancer chemotherapeutics suffer from significant side effects, which have led to the exploration of more targeted therapies. This resulted in the exploration of inhibitors of Aurora A kinase as a potential anti-cancer treatment. Alisertib (MLN8237) has proven to be a potent Aurora A kinase inhibitor that had the highest safety profile among its therapeutic family. Phase I/II/III clinical trials with Alisertib have been carried out and reported promising efficacy, yet serious side effects. This article attempts to assess the clinical effect of Alisertib administration in various cancer phenotypes while describing the reported side effects.MethodsAlisertib clinical data were systematically retrieved from Medline, CINAHL, PubMed, and Cochrane Central Register of Controlled Trials and analyzed for quality, relevance, and originality in three stages prior to inclusion.ResultsOverall, seven studies met inclusion criteria and enrolled a total of 630 patients. The reported "potential" clinical effect of Alisertib in various tumours is promising as it improved time to disease progression, progression-free survival, and the duration of disease stability. The achieved improvement therefore rationalizes its further investigation as a novel anticancer therapy. However, the administration of the drug was associated with serious haematological disturbances in a relatively high percentage of patients.ConclusionThe evidence of the anti-tumour effect of Alisertib administration is compelling in various types of malignancies. The reported side effects were serious but manageable in many cases. Topical or more targeted routes of administration are suggested when possible to overcome off-target events with systematic administration of the drug.



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Combination immunotherapy strategies in advanced Non-Small Cell Lung Cancer (NSCLC): Does biological rationale meet clinical needs?

Publication date: Available online 19 September 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Ilaria Attili, Antonio Passaro, Alberto Pavan, PierFranco Conte, Filippo De Marinis, Laura Bonanno
Immune checkpoint inhibitors (ICIs) have emerged as one of the main new therapeutic options for advanced non-small cell lung cancer (NSCLC) patients. Even though they demonstrated superiority towards standard chemotherapy in different disease settings, the response rates do not exceed 45% in highly molecularly selected patients. This is related to known limitations of the available biomarkers, as well to the complex and dynamic nature of tumor microenvironment. The study of the different strategies adopted by tumor cells to escape the immune system lays the basis of the new combination strategies. This review focuses on analyzing the biological rationale and early clinical data available concerning therapeutic strategies combining ICIs together, ICIs with different regimens and schedules of standard chemotherapy, ICIs with tyrosine kinase inhibitors, ICIs with antiangiogenic agents and ICs with radiotherapy.



http://ift.tt/2f95AOD

Critical Risk-Benefit Assessment of the Novel Anti-Cancer Aurora A Kinase Inhibitor Alisertib (MLN8237): A Comprehensive Review of the Clinical Data

Publication date: Available online 18 September 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Yaman Tayyar, Luqman Jubair, Sora Fallaha, Nigel McMillan
BackgroundMany current anticancer chemotherapeutics suffer from significant side effects, which have led to the exploration of more targeted therapies. This resulted in the exploration of inhibitors of Aurora A kinase as a potential anti-cancer treatment. Alisertib (MLN8237) has proven to be a potent Aurora A kinase inhibitor that had the highest safety profile among its therapeutic family. Phase I/II/III clinical trials with Alisertib have been carried out and reported promising efficacy, yet serious side effects. This article attempts to assess the clinical effect of Alisertib administration in various cancer phenotypes while describing the reported side effects.MethodsAlisertib clinical data were systematically retrieved from Medline, CINAHL, PubMed, and Cochrane Central Register of Controlled Trials and analyzed for quality, relevance, and originality in three stages prior to inclusion.ResultsOverall, seven studies met inclusion criteria and enrolled a total of 630 patients. The reported "potential" clinical effect of Alisertib in various tumours is promising as it improved time to disease progression, progression-free survival, and the duration of disease stability. The achieved improvement therefore rationalizes its further investigation as a novel anticancer therapy. However, the administration of the drug was associated with serious haematological disturbances in a relatively high percentage of patients.ConclusionThe evidence of the anti-tumour effect of Alisertib administration is compelling in various types of malignancies. The reported side effects were serious but manageable in many cases. Topical or more targeted routes of administration are suggested when possible to overcome off-target events with systematic administration of the drug.



http://ift.tt/2w5GPcN

Optimal MRI sequences for 68 Ga-PSMA-11 PET/MRI in evaluation of biochemically recurrent prostate cancer

Abstract

Background

PET/MRI can be used for the detection of disease in biochemical recurrence (BCR) patients imaged with ⁶⁸Ga-PSMA-11 PET. This study was designed to determine the optimal MRI sequences to localize positive findings on ⁶⁸Ga-PSMA-11 PET of patients with BCR after definitive therapy. Fifty-five consecutive prostate cancer patients with BCR imaged with ⁶⁸Ga-PSMA-11 3.0T PET/MRI were retrospectively analyzed. Mean PSA was 7.9 ± 12.9 ng/ml, and mean PSA doubling time was 7.1 ± 6.6 months. Detection rates of anatomic correlates for prostate-specific membrane antigen (PSMA)-positive foci were evaluated on small field of view (FOV) T2, T1 post-contrast, and diffusion-weighted images. For prostate bed recurrences, the detection rate of dynamic contrast-enhanced (DCE) imaging for PSMA-positive foci was evaluated. Finally, the detection sensitivity for PSMA-avid foci on 3- and 8-min PET acquisitions was compared.

Results

PSMA-positive foci were detected in 89.1% (49/55) of patients evaluated. Small FOV T2 performed best for lymph nodes and detected correlates for all PSMA-avid lymph nodes. DCE imaging performed the best for suspected prostate bed recurrence, detecting correlates for 87.5% (14/16) of PSMA-positive prostate bed foci. The 8-min PET acquisition performed better than the 3-min acquisition for lymph nodes smaller than 1 cm, detecting 100% (57/57) of lymph nodes less than 1 cm, compared to 78.9% (45/57) for the 3-min acquisition.

Conclusion

PSMA PET/MRI performed well for the detection of sites of suspected recurrent disease in patients with BCR. Of the MRI sequences obtained for localization, small FOV T2 images detected the greatest proportion of PSMA-positive abdominopelvic lymph nodes and DCE imaging detected the greatest proportion of PSMA-positive prostate bed foci. The 8-min PET acquisition was superior to the 3 min acquisition for detection of small lymph nodes.

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Issue Information

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Optimal MRI sequences for 68 Ga-PSMA-11 PET/MRI in evaluation of biochemically recurrent prostate cancer

Abstract

Background

PET/MRI can be used for the detection of disease in biochemical recurrence (BCR) patients imaged with ⁶⁸Ga-PSMA-11 PET. This study was designed to determine the optimal MRI sequences to localize positive findings on ⁶⁸Ga-PSMA-11 PET of patients with BCR after definitive therapy. Fifty-five consecutive prostate cancer patients with BCR imaged with ⁶⁸Ga-PSMA-11 3.0T PET/MRI were retrospectively analyzed. Mean PSA was 7.9 ± 12.9 ng/ml, and mean PSA doubling time was 7.1 ± 6.6 months. Detection rates of anatomic correlates for prostate-specific membrane antigen (PSMA)-positive foci were evaluated on small field of view (FOV) T2, T1 post-contrast, and diffusion-weighted images. For prostate bed recurrences, the detection rate of dynamic contrast-enhanced (DCE) imaging for PSMA-positive foci was evaluated. Finally, the detection sensitivity for PSMA-avid foci on 3- and 8-min PET acquisitions was compared.

Results

PSMA-positive foci were detected in 89.1% (49/55) of patients evaluated. Small FOV T2 performed best for lymph nodes and detected correlates for all PSMA-avid lymph nodes. DCE imaging performed the best for suspected prostate bed recurrence, detecting correlates for 87.5% (14/16) of PSMA-positive prostate bed foci. The 8-min PET acquisition performed better than the 3-min acquisition for lymph nodes smaller than 1 cm, detecting 100% (57/57) of lymph nodes less than 1 cm, compared to 78.9% (45/57) for the 3-min acquisition.

Conclusion

PSMA PET/MRI performed well for the detection of sites of suspected recurrent disease in patients with BCR. Of the MRI sequences obtained for localization, small FOV T2 images detected the greatest proportion of PSMA-positive abdominopelvic lymph nodes and DCE imaging detected the greatest proportion of PSMA-positive prostate bed foci. The 8-min PET acquisition was superior to the 3 min acquisition for detection of small lymph nodes.

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Issue Information

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Analysis of microRNA (miRNA) expression profiles reveals 11 key biomarkers associated with non-small cell lung cancer

Abstract

Background

Non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancer cases which cause most of cancer-related deaths globally. However, the results vary largely in different studies due to different platforms and sample sizes. Here, we aim to identify the key miRNAs in the carcinogenesis of NSCLC that might be potential biomarkers for this cancer.

Methods

Meta-analysis was performed on miRNA profile using seven datasets of NSCLC studies. Furthermore, we predicted and investigated the functions of genes regulated by key miRNAs.

Results

Eleven key miRNAs were identified, including 2 significantly upregulated ones (hsa-miR-21-5p and hsa-miR-233-3p) and 9 downregulated ones (hsa-miR-126-3p, hsa-miR-133a-3p, hsa-miR-140-5p, hsa-miR-143-5p, hsa-miR-145-5p, hsa-miR-30a-5p, hsa-miR-30d-3p, hsa-miR-328-3pn, and hsa-miR-451). The functional enrichment analysis revealed that both up- and downregulated miRNAs were proportionally associated with regulation of transcription from RNA polymerase II promoter. According to transcription factor analysis, there were 65 (43.9%) transcription factors influenced by both up- and downregulated miRNAs.

Conclusions

In this study, 11 meta-signature miRNAs, as well as their target genes and transcription factors, were found to play significant role in carcinogenesis of NSCLC. These target genes identified in our study may be profitable to diagnosis and prognostic prediction of NSCLC as biomarkers.

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Analysis of microRNA (miRNA) expression profiles reveals 11 key biomarkers associated with non-small cell lung cancer

Abstract

Background

Non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancer cases which cause most of cancer-related deaths globally. However, the results vary largely in different studies due to different platforms and sample sizes. Here, we aim to identify the key miRNAs in the carcinogenesis of NSCLC that might be potential biomarkers for this cancer.

Methods

Meta-analysis was performed on miRNA profile using seven datasets of NSCLC studies. Furthermore, we predicted and investigated the functions of genes regulated by key miRNAs.

Results

Eleven key miRNAs were identified, including 2 significantly upregulated ones (hsa-miR-21-5p and hsa-miR-233-3p) and 9 downregulated ones (hsa-miR-126-3p, hsa-miR-133a-3p, hsa-miR-140-5p, hsa-miR-143-5p, hsa-miR-145-5p, hsa-miR-30a-5p, hsa-miR-30d-3p, hsa-miR-328-3pn, and hsa-miR-451). The functional enrichment analysis revealed that both up- and downregulated miRNAs were proportionally associated with regulation of transcription from RNA polymerase II promoter. According to transcription factor analysis, there were 65 (43.9%) transcription factors influenced by both up- and downregulated miRNAs.

Conclusions

In this study, 11 meta-signature miRNAs, as well as their target genes and transcription factors, were found to play significant role in carcinogenesis of NSCLC. These target genes identified in our study may be profitable to diagnosis and prognostic prediction of NSCLC as biomarkers.

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The roles of ubiquitin modifying enzymes in neoplastic disease

Publication date: Available online 18 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Nishi Kumari, Patrick William Jaynes, Azad Saei, Prasanna Vasudevan Iyengar, John Lalith Charles Richard, Pieter Johan Adam Eichhorn
The initial experiments performed by Rose, Hershko, and Ciechanover describing the identification of a specific degradation signal in short-lived proteins paved the way to the discovery of the ubiquitin mediated regulation of numerous physiological functions required for cellular homeostasis. Since their discovery of ubiquitin and ubiquitin function over 30years ago it has become wholly apparent that ubiquitin and their respective ubiquitin modifying enzymes are key players in tumorigenesis. The human genome encodes approximately 600 putative E3 ligases and 80 deubiquitinating enzymes and in the majority of cases these enzymes exhibit specificity in sustaining either pro-tumorigenic or tumour repressive responses. In this review, we highlight the known oncogenic and tumour suppressive effects of ubiquitin modifying enzymes in cancer relevant pathways with specific focus on PI3K, MAPK, TGFβ, WNT, and YAP pathways. Moreover, we discuss the capacity of targeting DUBs as a novel anticancer therapeutic strategy.



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Randomized controlled trial of increasing physical activity on objectively measured and self-reported cognitive functioning among breast cancer survivors: The memory & motion study

BACKGROUND

Increasing physical activity can improve cognition in healthy and cognitively impaired adults; however, the benefits for cancer survivors are unknown. The current study examined a 12-week physical activity intervention, compared with a control condition, on objective and self-reported cognition among breast cancer survivors.

METHODS

Sedentary breast cancer survivors were randomized to an exercise arm (n = 43) or a control arm (n = 44). At baseline and at 12 weeks, objective cognition was measured with the National Institutes of Health Cognitive Toolbox, and self-reported cognition using the Patient-Reported Outcomes Measurement Information System scales. Linear mixed-effects regression models tested intervention effects for changes in cognition scores.

RESULTS

On average, participants (n = 87) were aged 57 years (standard deviation, 10.4 years) and were 2.5 years (standard deviation, 1.3 years) post surgery. Scores on the Oral Symbol Digit subscale (a measure of processing speed) evidenced differential improvement in the exercise arm versus the control arm (b = 2.01; P < .05). The between-group differences in improvement on self-reported cognition were not statistically significant but were suggestive of potential group differences. Time since surgery moderated the correlation, and participants who were ≤2 years post surgery had a significantly greater improvement in Oral Symbol Digit score (exercise vs control (b = 4.00; P < .01), but no significant improvement was observed in patients who were >2 years postsurgery (b = −1.19; P = .40). A significant dose response was observed with greater increased physical activity associated with objective and self-reported cognition in the exercise arm.

CONCLUSIONS

The exercise intervention significantly improved processing speed, but only among those who had been diagnosed with breast cancer within the past 2 years. Slowed processing speed can have substantial implications for independent functioning, supporting the potential importance of early implementation of an exercise intervention among patients with breast cancer. Cancer 2017. © 2017 American Cancer Society.

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Randomized controlled trial of increasing physical activity on objectively measured and self-reported cognitive functioning among breast cancer survivors: The memory & motion study

BACKGROUND

Increasing physical activity can improve cognition in healthy and cognitively impaired adults; however, the benefits for cancer survivors are unknown. The current study examined a 12-week physical activity intervention, compared with a control condition, on objective and self-reported cognition among breast cancer survivors.

METHODS

Sedentary breast cancer survivors were randomized to an exercise arm (n = 43) or a control arm (n = 44). At baseline and at 12 weeks, objective cognition was measured with the National Institutes of Health Cognitive Toolbox, and self-reported cognition using the Patient-Reported Outcomes Measurement Information System scales. Linear mixed-effects regression models tested intervention effects for changes in cognition scores.

RESULTS

On average, participants (n = 87) were aged 57 years (standard deviation, 10.4 years) and were 2.5 years (standard deviation, 1.3 years) post surgery. Scores on the Oral Symbol Digit subscale (a measure of processing speed) evidenced differential improvement in the exercise arm versus the control arm (b = 2.01; P < .05). The between-group differences in improvement on self-reported cognition were not statistically significant but were suggestive of potential group differences. Time since surgery moderated the correlation, and participants who were ≤2 years post surgery had a significantly greater improvement in Oral Symbol Digit score (exercise vs control (b = 4.00; P < .01), but no significant improvement was observed in patients who were >2 years postsurgery (b = −1.19; P = .40). A significant dose response was observed with greater increased physical activity associated with objective and self-reported cognition in the exercise arm.

CONCLUSIONS

The exercise intervention significantly improved processing speed, but only among those who had been diagnosed with breast cancer within the past 2 years. Slowed processing speed can have substantial implications for independent functioning, supporting the potential importance of early implementation of an exercise intervention among patients with breast cancer. Cancer 2017. © 2017 American Cancer Society.

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O-GlcNAc-Dependent Regulation of Progesterone Receptor Function in Breast Cancer

Abstract

Emerging clinical trial data implicate progestins in the development of breast cancer. While the role for the progesterone receptor (PR) in this process remains controversial, it is clear that PR, a steroid-activated nuclear receptor, alters the transcriptional landscape of breast cancer. PR interacts with many different types of proteins, including transcriptional co-activators and co-repressors, transcription factors, nuclear receptors, and proteins that post-translationally modify PR (i.e., kinases and phosphatases). Herein, we identify a novel interaction between PR and O-GlcNAc transferase (OGT), the enzyme that catalyzes the addition of a single N-acetylglucosamine sugar, referred to as O-GlcNAc, to acceptor serines and threonines in target proteins. This interaction between PR and OGT leads to the post-translational modification of PR by O-GlcNAc. Moreover, we show that O-GlcNAcylated PR is more transcriptionally active on PR-target genes, despite the observation that PR messenger RNA and protein levels are decreased when O-GlcNAc levels are high. O-GlcNAcylation in breast cancer is clinically relevant, as we show that O-GlcNAc levels are higher in breast cancer as compared to matched normal tissues, and PR-positive breast cancers have higher levels of OGT. These data predict that under conditions where O-GlcNAc levels are high (breast cancer), PR, through an interaction with the modifying enzyme OGT, will exhibit increased O-GlcNAcylation and potentiated transcriptional activity. Therapeutic strategies aimed at altering cellular O-GlcNAc levels may have profound effects on PR transcriptional activity in breast cancer.

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Mucinous adenocarcinoma on perianal fistula. A rising entity?

Abstract

Introduction

Mucinous adenocarcinoma on perianal fistula is a rare entity; it could be underdiagnosed because it behaves often as a regular perianal fistula.

Materials and methods

We have recently treated four cases in our unit. We present them and review the literature, emphasizing on clinical characteristic and therapeutic options. The four patients were male with a mean age of 64. Three of them were classified as locally advances cases and therefore treated with neoadjuvant therapy.

Results

All of them underwent laparoscopic abdominoperineal escisión. Surgical specimens are described and clinical characteristic specified. Review of the literature shows that this disease has a very high potential risk of local recurrence and we must be aggressive with the resection. Sometimes plastic surgery is needed to reconstruct the perianal wound.

Conclusions

Mucinous adenocarcinoma associated with anal fistula is a rare disease. Neoadjuvant chemoradiotherapy followed by an adequate abdominoperineal excision may result in favourable outcomes.

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O-GlcNAc-Dependent Regulation of Progesterone Receptor Function in Breast Cancer

Abstract

Emerging clinical trial data implicate progestins in the development of breast cancer. While the role for the progesterone receptor (PR) in this process remains controversial, it is clear that PR, a steroid-activated nuclear receptor, alters the transcriptional landscape of breast cancer. PR interacts with many different types of proteins, including transcriptional co-activators and co-repressors, transcription factors, nuclear receptors, and proteins that post-translationally modify PR (i.e., kinases and phosphatases). Herein, we identify a novel interaction between PR and O-GlcNAc transferase (OGT), the enzyme that catalyzes the addition of a single N-acetylglucosamine sugar, referred to as O-GlcNAc, to acceptor serines and threonines in target proteins. This interaction between PR and OGT leads to the post-translational modification of PR by O-GlcNAc. Moreover, we show that O-GlcNAcylated PR is more transcriptionally active on PR-target genes, despite the observation that PR messenger RNA and protein levels are decreased when O-GlcNAc levels are high. O-GlcNAcylation in breast cancer is clinically relevant, as we show that O-GlcNAc levels are higher in breast cancer as compared to matched normal tissues, and PR-positive breast cancers have higher levels of OGT. These data predict that under conditions where O-GlcNAc levels are high (breast cancer), PR, through an interaction with the modifying enzyme OGT, will exhibit increased O-GlcNAcylation and potentiated transcriptional activity. Therapeutic strategies aimed at altering cellular O-GlcNAc levels may have profound effects on PR transcriptional activity in breast cancer.

http://ift.tt/2xk6QIE

Mucinous adenocarcinoma on perianal fistula. A rising entity?

Abstract

Introduction

Mucinous adenocarcinoma on perianal fistula is a rare entity; it could be underdiagnosed because it behaves often as a regular perianal fistula.

Materials and methods

We have recently treated four cases in our unit. We present them and review the literature, emphasizing on clinical characteristic and therapeutic options. The four patients were male with a mean age of 64. Three of them were classified as locally advances cases and therefore treated with neoadjuvant therapy.

Results

All of them underwent laparoscopic abdominoperineal escisión. Surgical specimens are described and clinical characteristic specified. Review of the literature shows that this disease has a very high potential risk of local recurrence and we must be aggressive with the resection. Sometimes plastic surgery is needed to reconstruct the perianal wound.

Conclusions

Mucinous adenocarcinoma associated with anal fistula is a rare disease. Neoadjuvant chemoradiotherapy followed by an adequate abdominoperineal excision may result in favourable outcomes.

http://ift.tt/2xusnPp

Salvage rates and prognostic factors after relapse in children and adolescents with malignant peripheral nerve sheath tumors

Abstract

Background

Malignant peripheral nerve sheath tumor (MPNST) is one of the most common nonrhabdomyosarcoma soft tissue sarcomas encountered in pediatric age, and it is generally characterized by poor outcome, particularly for relapsing patients.

Materials and methods

This study considered 73 patients <21 years of age with relapsing MPNST observed among 120 patients enrolled in Italian pediatric protocols from 1979 to 2004. With the aim of possibly establishing a risk-adapted stratification, patients' outcome was examined using univariate and multivariate analysis based on clinical features at onset, first-line treatments, clinical findings at the time of first relapse, and second-line treatments.

Results

The time to relapse ranged from 1 to 204 months after first diagnosis (median 7 months). The first relapse event was mainly local. At the time of our analysis, nine patients were alive in remission. The median overall survival after first relapse was 11 months, and the survival rates were 39.2% at 1 year and 15.8% at 5 years. The factors revealing the greatest impact on prognosis were as follows: initial tumor invasiveness, time of relapse, and achievement of a secondary complete remission (which was related to the feasibility of radical surgery).

Conclusions

Our study confirmed the unsatisfactory prognosis for pediatric patients with relapsing MPNST and pointed to a risk-adapted stratification model for the purposes of deciding second-line treatments. For the time being, an aggressive surgical approach seems to be the only effective salvage treatment and should be recommended. New therapeutic approaches are under evaluation with a view to improving current outcomes.

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Therapeutic plasma exchange for a case of refractory opsoclonus myoclonus ataxia syndrome

Abstract

Opsoclonus myoclonus ataxia syndrome (OMAS) can be refractory to standard therapies and devastating. Alternative treatments are imperative. A 14-month-old male diagnosed with neuroblastoma and paraneoplastic OMAS achieved complete cancer remission with chemotherapy. The OMAS, however, persisted over the subsequent 4 years despite numerous immune-modulatory and immunosuppressive therapies. The patient ultimately achieved complete remission following therapeutic plasma exchange (TPE) combined with rituximab and intravenous immunoglobulin. After three asymptomatic years, he relapsed. Upon reintroducing TPE and rituximab plus oral prednisolone, the patient rapidly achieved a second complete remission. This case offers proof-of-principle for the potential efficacy of TPE for neuroblastoma-associated OMAS.

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Medical marijuana in pediatric oncology: A review of the evidence and implications for practice

Abstract

Medical marijuana (MM) has become increasingly legal at the state level and accessible to children with serious illness. Pediatric patients with cancer may be particularly receptive to MM, given purported benefits in managing cancer-related symptoms. In this review, we examine the evidence for MM as a supportive care agent in pediatric oncology. We describe the current legal status of MM, mechanism of action, common formulations, and potential benefits versus risks for pediatric oncology patients. We offer suggestions for how providers might approach MM requests. Throughout, we comment on avenues for future investigation on this growing trend in supportive care.

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Salvage rates and prognostic factors after relapse in children and adolescents with malignant peripheral nerve sheath tumors

Abstract

Background

Malignant peripheral nerve sheath tumor (MPNST) is one of the most common nonrhabdomyosarcoma soft tissue sarcomas encountered in pediatric age, and it is generally characterized by poor outcome, particularly for relapsing patients.

Materials and methods

This study considered 73 patients <21 years of age with relapsing MPNST observed among 120 patients enrolled in Italian pediatric protocols from 1979 to 2004. With the aim of possibly establishing a risk-adapted stratification, patients' outcome was examined using univariate and multivariate analysis based on clinical features at onset, first-line treatments, clinical findings at the time of first relapse, and second-line treatments.

Results

The time to relapse ranged from 1 to 204 months after first diagnosis (median 7 months). The first relapse event was mainly local. At the time of our analysis, nine patients were alive in remission. The median overall survival after first relapse was 11 months, and the survival rates were 39.2% at 1 year and 15.8% at 5 years. The factors revealing the greatest impact on prognosis were as follows: initial tumor invasiveness, time of relapse, and achievement of a secondary complete remission (which was related to the feasibility of radical surgery).

Conclusions

Our study confirmed the unsatisfactory prognosis for pediatric patients with relapsing MPNST and pointed to a risk-adapted stratification model for the purposes of deciding second-line treatments. For the time being, an aggressive surgical approach seems to be the only effective salvage treatment and should be recommended. New therapeutic approaches are under evaluation with a view to improving current outcomes.

http://ift.tt/2f8DIdC

Therapeutic plasma exchange for a case of refractory opsoclonus myoclonus ataxia syndrome

Abstract

Opsoclonus myoclonus ataxia syndrome (OMAS) can be refractory to standard therapies and devastating. Alternative treatments are imperative. A 14-month-old male diagnosed with neuroblastoma and paraneoplastic OMAS achieved complete cancer remission with chemotherapy. The OMAS, however, persisted over the subsequent 4 years despite numerous immune-modulatory and immunosuppressive therapies. The patient ultimately achieved complete remission following therapeutic plasma exchange (TPE) combined with rituximab and intravenous immunoglobulin. After three asymptomatic years, he relapsed. Upon reintroducing TPE and rituximab plus oral prednisolone, the patient rapidly achieved a second complete remission. This case offers proof-of-principle for the potential efficacy of TPE for neuroblastoma-associated OMAS.

http://ift.tt/2w5JXWo

Medical marijuana in pediatric oncology: A review of the evidence and implications for practice

Abstract

Medical marijuana (MM) has become increasingly legal at the state level and accessible to children with serious illness. Pediatric patients with cancer may be particularly receptive to MM, given purported benefits in managing cancer-related symptoms. In this review, we examine the evidence for MM as a supportive care agent in pediatric oncology. We describe the current legal status of MM, mechanism of action, common formulations, and potential benefits versus risks for pediatric oncology patients. We offer suggestions for how providers might approach MM requests. Throughout, we comment on avenues for future investigation on this growing trend in supportive care.

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Long-Term Nerve Damage Possible after Chemotherapy for Breast Cancer

Many women who receive taxane-based chemotherapy to treat breast cancer experience long-term nerve damage, or peripheral neuropathy, data from a large clinical trial show.

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Long-Term Nerve Damage Possible after Chemotherapy for Breast Cancer

Many women who receive taxane-based chemotherapy to treat breast cancer experience long-term nerve damage, or peripheral neuropathy, data from a large clinical trial show.

http://ift.tt/2jGRmJZ

Serum HOTAIR and GAS5 levels as predictors of survival in patients with glioblastoma

Abstract

Background: Circulating long non-coding RNAs (lncRNAs) are a new class of cancer biomarkers. However, their significance in predicting outcomes in glioblastoma patients is unclear.

Methods: We measured the levels of six known oncogenic lncRNAs -- CRNDE, GAS5, H19, HOTAIR, MALAT1 and TUG1 in serum samples from 106 patients with primary glioblastoma and analyzed their association with outcomes.

Results: High levels of HOTAIR were associated with increased likelihood of death (adjusted hazard ratio [HR] = 2.04; 95% confidence interval [CI] = 1.08−9.76), recurrence, and progression (adjusted HR = 1.82; 95% CI = 1.04−6.17). High levels of GAS5 were associated with decreased likelihood of death (adjusted HR = 0.44; 95% CI = 0.18−0.99), recurrence, and progression (adjusted HR = 0.46; 95% CI = 0.16−0.98).

Conclusion: HOTAIR and GAS5 levels could serve as reciprocal prognostic predictors of survival and disease progression in patients with glioblastoma. This article is protected by copyright. All rights reserved

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Early genetic aberrations in patients with sporadic colorectal cancer

Abstract

Chromosome instability (CIN) is widely observed in both sporadic and hereditary colorectal cancer (CRC). Defects in APC and WNT signaling are primarily associated with CIN in hereditary CRC, but the genetic causes for CIN in sporadic CRC remain elusive. Using high-density SNP array and exome data from The Cancer Genome Atlas, we characterized loss of heterozygosity (LOH) and copy number variation (CNV) in the peripheral blood, normal colon and corresponding tumor tissue in 15 CRC patients with proficient mismatch repair (MMR) and 24 CRC patients with deficient MMR. We found a high frequency of 18q LOH in tumors and arm-specific enrichment of genetic aberrations on 18q in the normal colon (primarily copy neutral LOH) and blood (primarily copy gain). These aberrations were specific to the sporadic, pMMR CRC. Though in tumor samples genetic aberrations were observed for genes commonly mutated in hereditary CRC (e.g. APC, CTNNB1, SMAD4, BRAF), none of them showed LOH or CNV in the normal colon or blood. DCC located on 18q21.1 topped the list of genes with genetic aberrations in the tumor. In an independent cohort of 13 patients subjected to Whole Genome Sequencing, we found LOH and CNV on 18q in adenomatous polyp and tumor tissues. Our data suggests that patients with sporadic CRC may have genetic aberrations preferentially enriched on 18q in their blood, normal colon epithelium and non-malignant polyp lesions that may prove useful as a clinical marker for sporadic CRC detection and risk assessment. This article is protected by copyright. All rights reserved

http://ift.tt/2ybDBFE

TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer

Abstract

TNFAIP8 is associated with prognosis of several human malignancies. However, the molecular mechanism of TNFAIP8 in lung cancer remains unknown. In our study, we found TNFAIP8 could enhance TEAD luciferase activity and inhibits the activity of Hippo pathway. TNFAIP8 also increased cyclin D1, CDK6 and decreased p27 in lung cancer cells. In addition, TNFAIP8 increased total YAP protein and promoted nuclear localization of YAP. More importantly, YAP depletion blocked the role of TNFAIP8 on cell cycle-related proteins and TEAD luciferase activity, revealing that TNFAIP8 regulates Hippo pathway in a YAP-dependend manner. Further experiments identified that TNFAIP8 depletion enhanced LATS1 phosphorylation and TNFAIP8 overexpression decreased phosphorylated LAST1 level. LATS1 siRNA treatment reversed the effects of TNFAIP8 plasmid or siRNA on YAP and cell cycle proteins. Besides, immunofluorescence and co-immunoprecipitation demonstrated the interaction between TNFAIP8 and LATS1 in H460 and H1299 cells, suggesting that TNFAIP8 regulates Hippo signaling through its interaction with LATS1. Colony formation assays and transwell assays showed that YAP or LATS1 depletion reversed the positive effect of TNFAIP8 on cell proliferation and invasion. TNFAIP8 depletion could increase MMP-7 and TNFAIP8 overexpression could decrease MMP-7 at both protein and mRNA levels, without significant changes of E-cadherin, N-cadherin and Vimentin. Collectively, the present study provides a novel finding that TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer. TNFAIP8 may serve as a candidate biomarker for poor prognosis and a target for new therapies. This article is protected by copyright. All rights reserved

http://ift.tt/2xerKHw

Serum HOTAIR and GAS5 levels as predictors of survival in patients with glioblastoma

Abstract

Background: Circulating long non-coding RNAs (lncRNAs) are a new class of cancer biomarkers. However, their significance in predicting outcomes in glioblastoma patients is unclear.

Methods: We measured the levels of six known oncogenic lncRNAs -- CRNDE, GAS5, H19, HOTAIR, MALAT1 and TUG1 in serum samples from 106 patients with primary glioblastoma and analyzed their association with outcomes.

Results: High levels of HOTAIR were associated with increased likelihood of death (adjusted hazard ratio [HR] = 2.04; 95% confidence interval [CI] = 1.08−9.76), recurrence, and progression (adjusted HR = 1.82; 95% CI = 1.04−6.17). High levels of GAS5 were associated with decreased likelihood of death (adjusted HR = 0.44; 95% CI = 0.18−0.99), recurrence, and progression (adjusted HR = 0.46; 95% CI = 0.16−0.98).

Conclusion: HOTAIR and GAS5 levels could serve as reciprocal prognostic predictors of survival and disease progression in patients with glioblastoma. This article is protected by copyright. All rights reserved

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Early genetic aberrations in patients with sporadic colorectal cancer

Abstract

Chromosome instability (CIN) is widely observed in both sporadic and hereditary colorectal cancer (CRC). Defects in APC and WNT signaling are primarily associated with CIN in hereditary CRC, but the genetic causes for CIN in sporadic CRC remain elusive. Using high-density SNP array and exome data from The Cancer Genome Atlas, we characterized loss of heterozygosity (LOH) and copy number variation (CNV) in the peripheral blood, normal colon and corresponding tumor tissue in 15 CRC patients with proficient mismatch repair (MMR) and 24 CRC patients with deficient MMR. We found a high frequency of 18q LOH in tumors and arm-specific enrichment of genetic aberrations on 18q in the normal colon (primarily copy neutral LOH) and blood (primarily copy gain). These aberrations were specific to the sporadic, pMMR CRC. Though in tumor samples genetic aberrations were observed for genes commonly mutated in hereditary CRC (e.g. APC, CTNNB1, SMAD4, BRAF), none of them showed LOH or CNV in the normal colon or blood. DCC located on 18q21.1 topped the list of genes with genetic aberrations in the tumor. In an independent cohort of 13 patients subjected to Whole Genome Sequencing, we found LOH and CNV on 18q in adenomatous polyp and tumor tissues. Our data suggests that patients with sporadic CRC may have genetic aberrations preferentially enriched on 18q in their blood, normal colon epithelium and non-malignant polyp lesions that may prove useful as a clinical marker for sporadic CRC detection and risk assessment. This article is protected by copyright. All rights reserved

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TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer

Abstract

TNFAIP8 is associated with prognosis of several human malignancies. However, the molecular mechanism of TNFAIP8 in lung cancer remains unknown. In our study, we found TNFAIP8 could enhance TEAD luciferase activity and inhibits the activity of Hippo pathway. TNFAIP8 also increased cyclin D1, CDK6 and decreased p27 in lung cancer cells. In addition, TNFAIP8 increased total YAP protein and promoted nuclear localization of YAP. More importantly, YAP depletion blocked the role of TNFAIP8 on cell cycle-related proteins and TEAD luciferase activity, revealing that TNFAIP8 regulates Hippo pathway in a YAP-dependend manner. Further experiments identified that TNFAIP8 depletion enhanced LATS1 phosphorylation and TNFAIP8 overexpression decreased phosphorylated LAST1 level. LATS1 siRNA treatment reversed the effects of TNFAIP8 plasmid or siRNA on YAP and cell cycle proteins. Besides, immunofluorescence and co-immunoprecipitation demonstrated the interaction between TNFAIP8 and LATS1 in H460 and H1299 cells, suggesting that TNFAIP8 regulates Hippo signaling through its interaction with LATS1. Colony formation assays and transwell assays showed that YAP or LATS1 depletion reversed the positive effect of TNFAIP8 on cell proliferation and invasion. TNFAIP8 depletion could increase MMP-7 and TNFAIP8 overexpression could decrease MMP-7 at both protein and mRNA levels, without significant changes of E-cadherin, N-cadherin and Vimentin. Collectively, the present study provides a novel finding that TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer. TNFAIP8 may serve as a candidate biomarker for poor prognosis and a target for new therapies. This article is protected by copyright. All rights reserved

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Radiation therapy versus surgery for patients with cervical squamous cell carcinoma who have undergone neoadjuvant chemotherapy revisited

Abstract

Background

The therapeutic significance of neoadjuvant chemotherapy (NAC) followed by radiation therapy (RT) was negated during the early 1990s. Here, we compared post-NAC RT to surgery for chemo-sensitive cervical squamous cell carcinoma (SCC).

Methods

This study included 79 consecutive patients with cervical SCC who were treated by NAC followed by surgery (n = 49) or by definitive RT (n = 30). We compared characteristics and survival outcomes between the surgery and RT groups by their responses to NAC.

Results

Of the 79 patients, 70 (89%) had stage II–IV disease and 41 (52%) had radiological pelvic lymph node enlargement. The 5-year disease-specific survival (DSS) rate of the entire cohort was 66.4% (median follow-up 54 months). Fifty-five patients (70%) achieved sufficient (complete or partial) responses to NAC. Among patients with insufficient NAC responses, the 5-year DSS rate of the surgery group (55.6%) was significantly higher than the RT group (20.0%; P = 0.044). However, among patients with sufficient responses to NAC, 5-year DSS rates did not significantly differ between the surgery and RT groups (82.3 vs 78.6%; P = 0.79) even though the RT group had many more unfavorable prognostic factors and received fewer subsequent treatments than the surgery group.

Conclusions

Post-NAC survival outcomes among patients with chemo-sensitive cervical SCC who then underwent RT were not inferior to those treated with surgery, and NAC did not detract from the efficacy of subsequent RT. Among selected patients who respond favorably to NAC, RT could be a less invasive substitute for surgery without compromising treatment outcomes.

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Radiation therapy versus surgery for patients with cervical squamous cell carcinoma who have undergone neoadjuvant chemotherapy revisited

Abstract

Background

The therapeutic significance of neoadjuvant chemotherapy (NAC) followed by radiation therapy (RT) was negated during the early 1990s. Here, we compared post-NAC RT to surgery for chemo-sensitive cervical squamous cell carcinoma (SCC).

Methods

This study included 79 consecutive patients with cervical SCC who were treated by NAC followed by surgery (n = 49) or by definitive RT (n = 30). We compared characteristics and survival outcomes between the surgery and RT groups by their responses to NAC.

Results

Of the 79 patients, 70 (89%) had stage II–IV disease and 41 (52%) had radiological pelvic lymph node enlargement. The 5-year disease-specific survival (DSS) rate of the entire cohort was 66.4% (median follow-up 54 months). Fifty-five patients (70%) achieved sufficient (complete or partial) responses to NAC. Among patients with insufficient NAC responses, the 5-year DSS rate of the surgery group (55.6%) was significantly higher than the RT group (20.0%; P = 0.044). However, among patients with sufficient responses to NAC, 5-year DSS rates did not significantly differ between the surgery and RT groups (82.3 vs 78.6%; P = 0.79) even though the RT group had many more unfavorable prognostic factors and received fewer subsequent treatments than the surgery group.

Conclusions

Post-NAC survival outcomes among patients with chemo-sensitive cervical SCC who then underwent RT were not inferior to those treated with surgery, and NAC did not detract from the efficacy of subsequent RT. Among selected patients who respond favorably to NAC, RT could be a less invasive substitute for surgery without compromising treatment outcomes.

http://ift.tt/2fwKzho

The growing rift between epidemiologists and their data

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Mother’s education and offspring asthma risk in 10 European cohort studies

Abstract

Highly prevalent and typically beginning in childhood, asthma is a burdensome disease, yet the risk factors for this condition are not clarified. To enhance understanding, this study assessed the cohort-specific and pooled risk of maternal education on asthma in children aged 3–8 across 10 European countries. Data on 47,099 children were obtained from prospective birth cohort studies across 10 European countries. We calculated cohort-specific prevalence difference in asthma outcomes using the relative index of inequality (RII) and slope index of inequality (SII). Results from all countries were pooled using random-effects meta-analysis procedures to obtain mean RII and SII scores at the European level. Final models were adjusted for child sex, smoking during pregnancy, parity, mother's age and ethnicity. The higher the score the greater the magnitude of relative (RII, reference 1) and absolute (SII, reference 0) inequity. The pooled RII estimate for asthma risk across all cohorts was 1.46 (95% CI 1.26, 1.71) and the pooled SII estimate was 1.90 (95% CI 0.26, 3.54). Of the countries examined, France, the United Kingdom and the Netherlands had the highest prevalence's of childhood asthma and the largest inequity in asthma risk. Smaller inverse associations were noted for all other countries except Italy, which presented contradictory scores, but with small effect sizes. Tests for heterogeneity yielded significant results for SII scores. Overall, offspring of mothers with a low level of education had an increased relative and absolute risk of asthma compared to offspring of high-educated mothers.

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Dependence of micronuclei assay on the depth of absorbed dose

Publication date: November–December 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 6
Author(s): Seyed Mohammad Mahdi Abtahi, Seyed Mahmoud Reza Aghamiri, Masoumeh Yadolahi, Aziz Mahmoudzadeh
AimThe purpose of the present study is to investigate the dependence of micronuclei response on the depth of absorbed dose.BackgroundOne of the most common cytogenetic methods used for radiation dosimetry is micronuclei (MN). Being less complex and faster than other methods are two remarkable advantages of the MN method which make it suitable for monitoring of population. In biological dosimetry based on the micronuclei method, the investigation into the dependence of response on the depth in which dose is absorbed is significant, though has received less attention so far.Materials and methodsBlood samples were poured in separate vials to be irradiated at different depths using a linear accelerator system.ResultsAccording to the results, MN, as a function of the absorbed dose, had the best fitness with the linear–quadratic model at all depths. Furthermore, the results showed the dependence of MN response on the depth of absorbed dose. For doses up to 2Gy, the maximum difference from the reference depth of 1.5cm was related to the depth of 10cm; however, by increasing the absorbed dose, the response associated with the depth of 20cm showed the maximum deviation from the reference depth.ConclusionsConsequently, it is necessary to apply a correction factor to the biological dosimetry. The correction factor is dependent on the depth and the absorbed dose.



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Current Methods to Define Metabolic Tumor Volume in Positron Emission Tomography: Which One is Better?

Abstract

Numerous methods to segment tumors using ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET) have been introduced. Metabolic tumor volume (MTV) refers to the metabolically active volume of the tumor segmented using FDG PET, and has been shown to be useful in predicting patient outcome and in assessing treatment response. Also, tumor segmentation using FDG PET has useful applications in radiotherapy treatment planning. Despite extensive research on MTV showing promising results, MTV is not used in standard clinical practice yet, mainly because there is no consensus on the optimal method to segment tumors in FDG PET images. In this review, we discuss currently available methods to measure MTV using FDG PET, and assess the advantages and disadvantages of the methods.

http://ift.tt/2xeKvKN

Current Methods to Define Metabolic Tumor Volume in Positron Emission Tomography: Which One is Better?

Abstract

Numerous methods to segment tumors using ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET) have been introduced. Metabolic tumor volume (MTV) refers to the metabolically active volume of the tumor segmented using FDG PET, and has been shown to be useful in predicting patient outcome and in assessing treatment response. Also, tumor segmentation using FDG PET has useful applications in radiotherapy treatment planning. Despite extensive research on MTV showing promising results, MTV is not used in standard clinical practice yet, mainly because there is no consensus on the optimal method to segment tumors in FDG PET images. In this review, we discuss currently available methods to measure MTV using FDG PET, and assess the advantages and disadvantages of the methods.

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The growing rift between epidemiologists and their data

from Cancer via ola Kala on Inoreader http://ift.tt/2fgFP2E
via IFTTT

Mother’s education and offspring asthma risk in 10 European cohort studies

Abstract

Highly prevalent and typically beginning in childhood, asthma is a burdensome disease, yet the risk factors for this condition are not clarified. To enhance understanding, this study assessed the cohort-specific and pooled risk of maternal education on asthma in children aged 3–8 across 10 European countries. Data on 47,099 children were obtained from prospective birth cohort studies across 10 European countries. We calculated cohort-specific prevalence difference in asthma outcomes using the relative index of inequality (RII) and slope index of inequality (SII). Results from all countries were pooled using random-effects meta-analysis procedures to obtain mean RII and SII scores at the European level. Final models were adjusted for child sex, smoking during pregnancy, parity, mother's age and ethnicity. The higher the score the greater the magnitude of relative (RII, reference 1) and absolute (SII, reference 0) inequity. The pooled RII estimate for asthma risk across all cohorts was 1.46 (95% CI 1.26, 1.71) and the pooled SII estimate was 1.90 (95% CI 0.26, 3.54). Of the countries examined, France, the United Kingdom and the Netherlands had the highest prevalence's of childhood asthma and the largest inequity in asthma risk. Smaller inverse associations were noted for all other countries except Italy, which presented contradictory scores, but with small effect sizes. Tests for heterogeneity yielded significant results for SII scores. Overall, offspring of mothers with a low level of education had an increased relative and absolute risk of asthma compared to offspring of high-educated mothers.

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via IFTTT

The growing rift between epidemiologists and their data

http://ift.tt/2fgFP2E

Mother’s education and offspring asthma risk in 10 European cohort studies

Abstract

Highly prevalent and typically beginning in childhood, asthma is a burdensome disease, yet the risk factors for this condition are not clarified. To enhance understanding, this study assessed the cohort-specific and pooled risk of maternal education on asthma in children aged 3–8 across 10 European countries. Data on 47,099 children were obtained from prospective birth cohort studies across 10 European countries. We calculated cohort-specific prevalence difference in asthma outcomes using the relative index of inequality (RII) and slope index of inequality (SII). Results from all countries were pooled using random-effects meta-analysis procedures to obtain mean RII and SII scores at the European level. Final models were adjusted for child sex, smoking during pregnancy, parity, mother's age and ethnicity. The higher the score the greater the magnitude of relative (RII, reference 1) and absolute (SII, reference 0) inequity. The pooled RII estimate for asthma risk across all cohorts was 1.46 (95% CI 1.26, 1.71) and the pooled SII estimate was 1.90 (95% CI 0.26, 3.54). Of the countries examined, France, the United Kingdom and the Netherlands had the highest prevalence's of childhood asthma and the largest inequity in asthma risk. Smaller inverse associations were noted for all other countries except Italy, which presented contradictory scores, but with small effect sizes. Tests for heterogeneity yielded significant results for SII scores. Overall, offspring of mothers with a low level of education had an increased relative and absolute risk of asthma compared to offspring of high-educated mothers.

http://ift.tt/2xujjKc

Spiral Fracture in Young Infant Causing a Diagnostic Dilemma: Nutritional Rickets versus Child Abuse

Fractures are uncommon in young, nonambulatory infants. The differential diagnosis includes nonaccidental injury (NAI) and metabolic bone disease, including rickets. While rickets typically present after six months of age, multiple cases have been reported in younger infants. We report a case of an 11-week-old male infant who presented with a spiral fracture of the humerus and no radiologic evidence of rickets. A detailed psychosocial assessment failed to reveal any risk factors for NAI. The patient had elevated alkaline phosphatase and PTH with low 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D levels. Additionally, the mother was noncompliant with prenatal vitamins, exclusively breastfeeding without vitamin D supplementation, and had markedly low vitamin D levels 15 weeks postpartum. The biochemical data and history were consistent with rickets. Given the diagnostic dilemma, the working diagnosis was rickets and the patient was started on ergocalciferol with subsequent normalization of his laboratory values and healing of the fracture. These findings are consistent with nutritional rickets largely due to maternal-fetal hypovitaminosis D. This case highlights that in young infants rickets should be considered even in the absence of positive radiologic findings. Additionally, it illustrates the importance of maintaining adequate vitamin D supplementation during pregnancy and early infancy.

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Somatic health effects of Chernobyl: 30 years on

Abstract

2016 marked the 30th anniversary of the Chernobyl Nuclear Power Plant accident. We and others wrote reviews for the 25th anniversary. Since then, additional papers have appeared and it seems timely to highlight lessons learned. To present, not a systematic review, but a commentary drawing attention to notable findings. We include not only recent reports and updates on previous results, but key findings from prior Chernobyl studies. The dose-dependent increase in Papillary Thyroid Cancer (PTC) following childhood I-131 exposure in Ukraine and Belarus has now been shown to persist for decades. Studies of post-Chernobyl PTCs have produced novel information on chromosomal rearrangements and gene fusions, critical to understanding molecular mechanisms. Studies of clean-up workers/liquidators suggest dose-related increases of thyroid cancer and hematological malignancies in adults. They also report increases in cardiovascular and cerebrovascular disease. If confirmed, these would have significant public health and radiation protection implications. The lens opacities following low to moderate doses found earlier are also a concern, particularly among interventional radiologists who may receive substantial lens doses. Finally, there is some, inconsistent, evidence for genetic effects among offspring of exposed persons. Further efforts, including improved dosimetry, collection of information on other risk factors, and continued follow-up/monitoring of established cohorts, could contribute importantly to further understand effects of low doses and dose-rates of radiation, particularly in young people, and ensure that appropriate public health and radiation protection systems are in place. This will require multinational collaborations and long-term funding.

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Somatic health effects of Chernobyl: 30 years on

Abstract

2016 marked the 30th anniversary of the Chernobyl Nuclear Power Plant accident. We and others wrote reviews for the 25th anniversary. Since then, additional papers have appeared and it seems timely to highlight lessons learned. To present, not a systematic review, but a commentary drawing attention to notable findings. We include not only recent reports and updates on previous results, but key findings from prior Chernobyl studies. The dose-dependent increase in Papillary Thyroid Cancer (PTC) following childhood I-131 exposure in Ukraine and Belarus has now been shown to persist for decades. Studies of post-Chernobyl PTCs have produced novel information on chromosomal rearrangements and gene fusions, critical to understanding molecular mechanisms. Studies of clean-up workers/liquidators suggest dose-related increases of thyroid cancer and hematological malignancies in adults. They also report increases in cardiovascular and cerebrovascular disease. If confirmed, these would have significant public health and radiation protection implications. The lens opacities following low to moderate doses found earlier are also a concern, particularly among interventional radiologists who may receive substantial lens doses. Finally, there is some, inconsistent, evidence for genetic effects among offspring of exposed persons. Further efforts, including improved dosimetry, collection of information on other risk factors, and continued follow-up/monitoring of established cohorts, could contribute importantly to further understand effects of low doses and dose-rates of radiation, particularly in young people, and ensure that appropriate public health and radiation protection systems are in place. This will require multinational collaborations and long-term funding.

from Cancer via ola Kala on Inoreader http://ift.tt/2f7msoS
via IFTTT

Somatic health effects of Chernobyl: 30 years on

Abstract

2016 marked the 30th anniversary of the Chernobyl Nuclear Power Plant accident. We and others wrote reviews for the 25th anniversary. Since then, additional papers have appeared and it seems timely to highlight lessons learned. To present, not a systematic review, but a commentary drawing attention to notable findings. We include not only recent reports and updates on previous results, but key findings from prior Chernobyl studies. The dose-dependent increase in Papillary Thyroid Cancer (PTC) following childhood I-131 exposure in Ukraine and Belarus has now been shown to persist for decades. Studies of post-Chernobyl PTCs have produced novel information on chromosomal rearrangements and gene fusions, critical to understanding molecular mechanisms. Studies of clean-up workers/liquidators suggest dose-related increases of thyroid cancer and hematological malignancies in adults. They also report increases in cardiovascular and cerebrovascular disease. If confirmed, these would have significant public health and radiation protection implications. The lens opacities following low to moderate doses found earlier are also a concern, particularly among interventional radiologists who may receive substantial lens doses. Finally, there is some, inconsistent, evidence for genetic effects among offspring of exposed persons. Further efforts, including improved dosimetry, collection of information on other risk factors, and continued follow-up/monitoring of established cohorts, could contribute importantly to further understand effects of low doses and dose-rates of radiation, particularly in young people, and ensure that appropriate public health and radiation protection systems are in place. This will require multinational collaborations and long-term funding.

http://ift.tt/2f7msoS