Sternal semi-closure using a bioresorbable osteosynthesis device: a new method for delayed sternal closure

Abstract

Purpose

To evaluate the safety and efficacy of our new delayed sternal closure (DSC) method, involving sternal semi-closure using a bioresorbable osteosynthesis device and complete skin closure.

Methods

Between 2013 and 2017, 36 patients underwent DCS at our hospital. The patients were divided into two groups based on the method used for DSC. The later conventional DSC group consisted of 18 patients undergoing late complete sternal closure following fixation of pulmonary and hemodynamic instability, and the new DSC group consisted of 18 patients undergoing early sternal semi-closure a few days after surgery. In the new DSC group, the sternum was fixed with Super Fixsorb MX40, followed by complete skin closure.

Results

Respiratory and hemodynamic conditions, such as systolic blood pressure, cardiac index, tidal volume, and regional oxygen saturation, were significantly more stable in the new DCS group than in the conventional DSC group. The hospital stay was also significantly shorter in the new DSC group. Although there were no serious complications, one patient from the new DCS group suffered deformity of the sternum, which was managed successfully.

Conclusion

The sternal semi-closure method decreases pulmonary and cardiac instability during DSC, making early DSC possible.

http://ift.tt/2FNrvXi

Sternal semi-closure using a bioresorbable osteosynthesis device: a new method for delayed sternal closure

Abstract

Purpose

To evaluate the safety and efficacy of our new delayed sternal closure (DSC) method, involving sternal semi-closure using a bioresorbable osteosynthesis device and complete skin closure.

Methods

Between 2013 and 2017, 36 patients underwent DCS at our hospital. The patients were divided into two groups based on the method used for DSC. The later conventional DSC group consisted of 18 patients undergoing late complete sternal closure following fixation of pulmonary and hemodynamic instability, and the new DSC group consisted of 18 patients undergoing early sternal semi-closure a few days after surgery. In the new DSC group, the sternum was fixed with Super Fixsorb MX40, followed by complete skin closure.

Results

Respiratory and hemodynamic conditions, such as systolic blood pressure, cardiac index, tidal volume, and regional oxygen saturation, were significantly more stable in the new DCS group than in the conventional DSC group. The hospital stay was also significantly shorter in the new DSC group. Although there were no serious complications, one patient from the new DCS group suffered deformity of the sternum, which was managed successfully.

Conclusion

The sternal semi-closure method decreases pulmonary and cardiac instability during DSC, making early DSC possible.

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Upper gastrointestinal malignancies in 2017: current perspectives and future approaches

Future Oncology, Ahead of Print.


http://ift.tt/2phJpKO

Insights into the hepatocellular carcinoma patient journey: results of the first global quality of life survey

Future Oncology, Ahead of Print.


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The role of IDH mutations in acute myeloid leukemia

Future Oncology, Ahead of Print.


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Insights into the hepatocellular carcinoma patient journey: results of the first global quality of life survey

Future Oncology, Ahead of Print.


http://ift.tt/2IqCoA2

The role of IDH mutations in acute myeloid leukemia

Future Oncology, Ahead of Print.


http://ift.tt/2phzjtq

ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40nM; IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2-0.3 µM. In xenografts of both breast and colorectal cancers, the drug has substantial anti-tumor effects. Additionally, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia, and small-cell lung cancer.

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Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcRs) on the surface of adjacent cells. The resulting co-stimulation of OX40 on T cells induced NF-B promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy non-human primates elicited peripheral blood CD4 and CD8 central and effector memory T cell proliferation as well as B cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance anti-tumor immunity in human malignancies.

http://ift.tt/2FOKh0x

A miR-29b Byproduct Sequence Exhibits Potent Tumor Suppressive Activities via Inhibition of NF-{kappa}B Signaling in KRAS Mutant Colon Cancer Cells

We previously demonstrated that miR-29b-3p is a hopeful microRNA (miRNA)-based therapies against colorectal cancer (CRC). In this study, we aimed to clarify a value of miR-29b-1-5p as a next generation treatment, especially for KRAS mutant CRC. RT-PCR assay showed that expression of miR-29b-3p was high and its partner strand, miR-29b-1-5p level was only negligible in clinical CRC samples. Mimic-miR-29b-1-5p significantly inhibited proliferation of KRAS mutant CRC cell lines DLD1 and SW480 and KRAS wild type HT29 cells. Proliferative activity was further examined by either miR-29b-1-5p strand or its opposite complementary sequence because miR-29b-1-5p is a passenger miRNA and may have no physiological function. We found that completely opposite complementary strand to miR-29b-1-5p, but not miR-29b-1-5p possessed a potent anti-tumor effect and named this byproduct miRNA sequence "MIRTX." MIRTX directly targeted the 3'-UTR of CXCR2 and PIK3R1 mRNA and suppressed the NF-B signaling pathway in KRAS mutated CRC cells. in KRAS mutant CRC cells. MIRTX induced apoptosis in DLD1 with down-regulation of anti-apoptotic BCL2, BCL-xL, and MCL1 and up-regulation of cleaved caspase 3 and cleaved PARP. In mouse xenograft models, systemic administration of MIRTX using a super carbonate apatite as a delivery vehicle significantly inhibited tumor growth of DLD1 and HT29 cells without any particular toxicities. In conclusion, these findings indicate that inhibition of NF-B signaling by this novel miRNA-based therapeutic could be a promising treatment against refractory KRAS mutant CRC and KRAS wild CRC.

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ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40nM; IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2-0.3 µM. In xenografts of both breast and colorectal cancers, the drug has substantial anti-tumor effects. Additionally, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia, and small-cell lung cancer.

http://ift.tt/2GwmCTH

Metformin suppresses tumor progression by inactivating stromal fibroblasts in ovarian cancer

Ovarian cancer (OC) is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in OC. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the OC tumor cells. First, we found a significant stromal overexpression of IL6 in patient samples that received cisplatin-based treatment, which was further validated in purified fibroblasts challenged with cisplatin. Stromal fibroblast derived IL6 was proven to mediate OC tumor cell chemoresistance. For the first time we found that the tumor stroma of patients with routine metformin administration exhibited lower IL6 expression. Thus, we presumed that metformin was a potent alleviator of stromal inflammation in OC. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic co-cultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NF-B signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing OC progression through diminishing chemotherapy-induced stromal activation. Therefore, we provide an alternative therapeutic option in targeting stromal inflammation and a potential scheme of combination therapy to improve the chemosensitivity in OC.

http://ift.tt/2Dzuq48

A miR-29b Byproduct Sequence Exhibits Potent Tumor Suppressive Activities via Inhibition of NF-{kappa}B Signaling in KRAS Mutant Colon Cancer Cells

We previously demonstrated that miR-29b-3p is a hopeful microRNA (miRNA)-based therapies against colorectal cancer (CRC). In this study, we aimed to clarify a value of miR-29b-1-5p as a next generation treatment, especially for KRAS mutant CRC. RT-PCR assay showed that expression of miR-29b-3p was high and its partner strand, miR-29b-1-5p level was only negligible in clinical CRC samples. Mimic-miR-29b-1-5p significantly inhibited proliferation of KRAS mutant CRC cell lines DLD1 and SW480 and KRAS wild type HT29 cells. Proliferative activity was further examined by either miR-29b-1-5p strand or its opposite complementary sequence because miR-29b-1-5p is a passenger miRNA and may have no physiological function. We found that completely opposite complementary strand to miR-29b-1-5p, but not miR-29b-1-5p possessed a potent anti-tumor effect and named this byproduct miRNA sequence "MIRTX." MIRTX directly targeted the 3'-UTR of CXCR2 and PIK3R1 mRNA and suppressed the NF-B signaling pathway in KRAS mutated CRC cells. in KRAS mutant CRC cells. MIRTX induced apoptosis in DLD1 with down-regulation of anti-apoptotic BCL2, BCL-xL, and MCL1 and up-regulation of cleaved caspase 3 and cleaved PARP. In mouse xenograft models, systemic administration of MIRTX using a super carbonate apatite as a delivery vehicle significantly inhibited tumor growth of DLD1 and HT29 cells without any particular toxicities. In conclusion, these findings indicate that inhibition of NF-B signaling by this novel miRNA-based therapeutic could be a promising treatment against refractory KRAS mutant CRC and KRAS wild CRC.

http://ift.tt/2GwX60y

Metformin suppresses tumor progression by inactivating stromal fibroblasts in ovarian cancer

Ovarian cancer (OC) is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in OC. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the OC tumor cells. First, we found a significant stromal overexpression of IL6 in patient samples that received cisplatin-based treatment, which was further validated in purified fibroblasts challenged with cisplatin. Stromal fibroblast derived IL6 was proven to mediate OC tumor cell chemoresistance. For the first time we found that the tumor stroma of patients with routine metformin administration exhibited lower IL6 expression. Thus, we presumed that metformin was a potent alleviator of stromal inflammation in OC. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic co-cultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NF-B signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing OC progression through diminishing chemotherapy-induced stromal activation. Therefore, we provide an alternative therapeutic option in targeting stromal inflammation and a potential scheme of combination therapy to improve the chemosensitivity in OC.

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Acquired resistance to a MET antibody in vivo can be overcome by the MET antibody mixture Sym015

Failure of clinical trials due to development of resistance to MET-targeting therapeutic agents is an emerging problem. Mechanisms of acquired resistance to MET tyrosine kinase inhibitors are well described, whereas characterization of mechanisms of resistance toward MET-targeting antibodies is limited. This study investigated mechanisms underlying in vivo resistance to two antibody therapeutics currently in clinical development: an analogue of the MET-targeting antibody emibetuzumab and Sym015, a mixture of two antibodies targeting non-overlapping epitopes of MET. Upon long-term in vivo treatment of a MET-amplified gastric cancer xenograft model (SNU-5), emibetuzumab-resistant, but not Sym015-resistant, tumors emerged. Resistant tumors were isolated and used to establish resistant cell lines. Characterization of both tumors and cell lines using extensive protein and signaling pathway activation mapping along with next-generation sequencing revealed two distinct resistance profiles, one involving PTEN loss and the other involving activation of the PI3Kinase pathway, likely via MYC and ERBB3 copy number gains. PTEN loss left one model unaffected by PI3Kinase/AKT-targeting but sensitive to mTOR-targeting, while the PI3Kinase pathway-activated model was partly sensitive to targeting of multiple PI3Kinase pathway proteins. Importantly, both resistant models were sensitive to treatment with Sym015 in vivo due to antibody-dependent cellular cytotoxicity-mediated tumor growth inhibition, MET degradation, and signaling inhibition. Taken together, our data provide key insights into potential mechanisms of resistance to a single MET-targeting antibody, demonstrate superiority of Sym015 in preventing acquired resistance, and confirm Sym015 anti-tumor activity in tumors resistant to a single MET antibody.

http://ift.tt/2FH0ity

Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcRs) on the surface of adjacent cells. The resulting co-stimulation of OX40 on T cells induced NF-B promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy non-human primates elicited peripheral blood CD4 and CD8 central and effector memory T cell proliferation as well as B cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance anti-tumor immunity in human malignancies.

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Acquired resistance to a MET antibody in vivo can be overcome by the MET antibody mixture Sym015

Failure of clinical trials due to development of resistance to MET-targeting therapeutic agents is an emerging problem. Mechanisms of acquired resistance to MET tyrosine kinase inhibitors are well described, whereas characterization of mechanisms of resistance toward MET-targeting antibodies is limited. This study investigated mechanisms underlying in vivo resistance to two antibody therapeutics currently in clinical development: an analogue of the MET-targeting antibody emibetuzumab and Sym015, a mixture of two antibodies targeting non-overlapping epitopes of MET. Upon long-term in vivo treatment of a MET-amplified gastric cancer xenograft model (SNU-5), emibetuzumab-resistant, but not Sym015-resistant, tumors emerged. Resistant tumors were isolated and used to establish resistant cell lines. Characterization of both tumors and cell lines using extensive protein and signaling pathway activation mapping along with next-generation sequencing revealed two distinct resistance profiles, one involving PTEN loss and the other involving activation of the PI3Kinase pathway, likely via MYC and ERBB3 copy number gains. PTEN loss left one model unaffected by PI3Kinase/AKT-targeting but sensitive to mTOR-targeting, while the PI3Kinase pathway-activated model was partly sensitive to targeting of multiple PI3Kinase pathway proteins. Importantly, both resistant models were sensitive to treatment with Sym015 in vivo due to antibody-dependent cellular cytotoxicity-mediated tumor growth inhibition, MET degradation, and signaling inhibition. Taken together, our data provide key insights into potential mechanisms of resistance to a single MET-targeting antibody, demonstrate superiority of Sym015 in preventing acquired resistance, and confirm Sym015 anti-tumor activity in tumors resistant to a single MET antibody.

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New opportunities for kinase drug repurposing and target discovery

New opportunities for kinase drug repurposing and target discovery

New opportunities for kinase drug repurposing and target discovery, Published online: 16 March 2018; doi:10.1038/s41416-018-0045-6

New opportunities for kinase drug repurposing and target discovery

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The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes, Published online: 16 March 2018; doi:10.1038/s41416-018-0038-5

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

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New opportunities for kinase drug repurposing and target discovery

New opportunities for kinase drug repurposing and target discovery

New opportunities for kinase drug repurposing and target discovery, Published online: 16 March 2018; doi:10.1038/s41416-018-0045-6

New opportunities for kinase drug repurposing and target discovery

http://ift.tt/2DvtQ7q

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes, Published online: 16 March 2018; doi:10.1038/s41416-018-0038-5

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

http://ift.tt/2FWSxPe

The administration of adjuvant chemo(-immuno) therapy in the post ACOSOG-Z0011 Era; a population based study

Publication date: Available online 14 March 2018
Source:European Journal of Surgical Oncology
Author(s): Ingrid G.M. Poodt, Marjolijn L. Rots, Guusje Vugts, Thijs van Dalen, Anne Kuijer, Birgit E.P.J. Vriens, Grard A.P. Nieuwenhuijzen, Robert-Jan Schipper
PurposeThe ACOSOG-Z0011-study has resulted in a trend to a more conservative treatment of the axilla for selected sentinel-node-positive patients. However, axillary nodal involvement has always been an important factor for tumor staging and tailoring adjuvant chemotherapy plans. This study evaluates the impact of omitting completion axillary lymph node dissection(cALND) on the administration of adjuvant chemo(-immuno)therapy in Dutch clinical T1-2N0M0(cT1-2N0M0) sentinel-node-positive breast cancer patients.MethodsData were obtained from the nationwide NABON breast cancer audit. Descriptive analyses were used to demonstrate trends in axillary surgery and adjuvant chemo(-immuno)therapy. Multivariable logistic regression analyses were used to identify factors associated with the prescription of chemo(-immuno)therapy.ResultsIn this cohort of 4331 patients, the omission of a cALND increased from 34% to 92%, and the administration of chemo(-immuno)therapy decreased from 68% to 55%, between 2011 and 2015 (P <0.001). Patients treated with cALND had an OR of 2.2 for receiving adjuvant chemo(-immuno)therapy compared with SLNB only patients. Lower age, a hormone receptor(HR) status other than HR-positive, HER2-negative, increasing tumor grade and stage, and a lymph node status ≥ pN2 were independently associated with a higher probability of chemo(-immuno)therapy (P <0.05).ConclusionsThis study showed that Dutch cT1-2N0M0 sentinel node-positive breast cancer patients treated with cALND had a higher independent probability for receiving adjuvant chemo(-immuno)therapy compared with SLNB only patients, even when corrected for lymph node status and HR-status. Probably, the decisions to administer adjuvant chemo(-immuno)therapy were not only based on guidelines and tumor characteristics, but also on the preferences from physicians and patients.



http://ift.tt/2pi0ncA

Multicystic mesothelioma: operative and long-term outcomes with cytoreductive surgery and hyperthermic intra peritoneal chemotherapy

Publication date: Available online 14 March 2018
Source:European Journal of Surgical Oncology
Author(s): Eran Nizri, Dario Baratti, Marcello Guaglio, Snita Sinukumar, Antonello Cabras, Shigeki Kusamura, Marcello Deraco
BackgroundMulticystic peritoneal mesothelioma (MCPM) is an extremely rare disease with 40-50% rate of recurrence after surgical debulking. Due to the recurrent nature of the disease, the option of cytoreductive surgery combined with hyperthermic peritoneal chemotherapy (HIPEC) was offered for this condition. In the present study we aimed to describe the outcomes of this strategy in a single center cohort.MethodsWe retrospectively reviewed a prospectively collected database of all patients with MCPM that underwent the combined procedure in our center. Clinical presentation, operative procedures and outcomes were reviewed.ResultsBetween August 1997 and October 2017, 19 patients with MCPM underwent 20 cytoreduction and HIPEC procedures in our center. The majority of the patients were females (n=17, 89%), and mean age was 42, as reported in other series. Disease extent, as measured by mean peritoneal carcinomatosis index (PCI) was 15.5±9.9 and total number of procedures performed 6.7±2.6. Major complications occurred in 3 (15%) patients, with no perioperative mortality. After a median of follow-up of 69 months (range 4-220) all patients were alive and 4 patients had recurrence (21%). Patients with high PCI (defined by median PCI) had shorter relapse free survival (RFS) than patient with low PCI (mean RFS= 106.4±6.6 for high PCI vs. 125.6±34.1 for low PCI, p=0.03).ConclusionCytoreduction and HIPEC offer low recurrence rate and prolonged mean RFS for patients with MCPM. The combined procedure can be offered with acceptable morbidity in specialized centers.



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Tissue-Specific Immunoregulation: A Call for Better Understanding of the "Immunostat" in the Context of Cancer [Prospective]

Checkpoint inhibitor therapy has been a breakthrough in cancer research, but only some patients with cancer derive substantial benefit. Although mechanisms underlying sensitivity and resistance to checkpoint inhibitors are being elucidated, the importance of organ-specific regulation of immunity is currently underappreciated. Here, we call for a greater understanding of tissue-specific immunoregulation, namely, "tissue-specific immunostats," to make advances in treatments for cancer. A better understanding of how individual organs at baseline regulate the immune system could enable an improved precision medicine approach to cancer immunotherapy. Cancer Discov; 8(4); 1–8. ©2018 AACR.

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Mutant IDH1 cooperates with ATRX loss to drive the alternative lengthening of telomere (ALT) phenotype in glioma

A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower-grade astrocytomas (LGA) and secondary glioblastoma, we examined an hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb-deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the non-homologous DNA end-joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate re-expression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres, by allowing IDH1-mutant ATRX deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis.

http://ift.tt/2FHpgsE

Folate Receptor Alpha Peptide Vaccine generates immunity in Breast and Ovarian Cancer Patients

Purpose: Folate receptor alpha (FR) is overexpressed in several cancers. Endogenous immunity to the FR has been demonstrated in patients and suggests the feasibility of targeting FR with vaccine or other immune therapies. CD4 helper T cells are central to the development of coordinated immunity and prior work shows their importance in protecting against relapse. Our previous identification of degenerate HLA-class II epitopes from human FR led to the development of a broad coverage epitope pool potentially useful in augmenting antigen-specific immune responses in most patients. Experiment Design: We conducted a Phase I clinical trial testing safety and immunogenicity of this vaccine, enrolling patients with ovarian cancer or breast cancer who completed conventional treatment and who showed no evidence of disease. Patients were initially treated with low dose cyclophosphamide and then vaccinated 6 times, monthly. Immunity and safety were examined during the vaccine period and up to one year later. Results: Vaccination was well tolerated in all patients. Vaccine elicited or augmented immunity in greater than 90% of patients examined. Unlike recall immunity to tetanus toxoid, FR T cell responses developed slowly over the course of vaccination with a median time to maximal immunity at 5 months. Despite slow development of immunity, responsiveness appeared to persist for at least 12 months. Conclusions: The results demonstrate that it is safe to augment immunity to the FR tumor antigen and the developed vaccine is testable for therapeutic activity in the majority of patients whose tumors express FR, regardless of HLA genotype.

http://ift.tt/2FMG9hB

Multivalent binding and biomimetic cell rolling improves the sensitivity and specificity of circulating tumor cell capture

Purpose: We aimed to examine the effects of multivalent binding and biomimetic cell rolling on the sensitivity and specificity of circulating tumor cell (CTC) capture. We also investigated the clinical significance of CTCs and their kinetic profiles in cancer patients undergoing radiotherapy (RT) treatment. Experimental Design: Patients with histologically confirmed primary carcinoma undergoing RT, with or without chemotherapy, were eligible for enrollment. Peripheral blood was collected prospectively at up to 5 time points, including prior to RT, at the first week, mid-point and final week of treatment, as well as 4 to 12 weeks after completion of RT. CTC capture was accomplished using a nanotechnology-based assay (CapioCyte) functionalized with aEpCAM, aHER-2, and aEGFR. Results: CapioCyte was able to detect CTCs in all 24 cancer patients enrolled. Multivalent binding via poly(amidoamine) dendrimers further improved capture sensitivity. We also showed that cell rolling effect can improve CTC capture specificity (% of captured cells that are CK+/CD45-/DAPI+) up to 38%. Among the 18 patients with sequential CTC measurements, the median CTC decreased from 113 CTCs/mL before RT to 32 CTCs/mL at completion of RT (p = 0.001). CTCs declined throughout RT in patients with complete clinical and/or radiographic response, in contrast to an elevation in CTCs at mid or post-RT in the 2 patients with known pathologic residual disease. Conclusions: Our study demonstrated that multivalent binding and cell rolling can improve the sensitivity and specificity of CTC capture compared to multivalent binding alone, allowing reliable monitoring of CTC changes during and after treatment.

http://ift.tt/2GyPV7W

Mutant IDH1 cooperates with ATRX loss to drive the alternative lengthening of telomere (ALT) phenotype in glioma

A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower-grade astrocytomas (LGA) and secondary glioblastoma, we examined an hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb-deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the non-homologous DNA end-joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate re-expression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres, by allowing IDH1-mutant ATRX deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis.

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Folate Receptor Alpha Peptide Vaccine generates immunity in Breast and Ovarian Cancer Patients

Purpose: Folate receptor alpha (FR) is overexpressed in several cancers. Endogenous immunity to the FR has been demonstrated in patients and suggests the feasibility of targeting FR with vaccine or other immune therapies. CD4 helper T cells are central to the development of coordinated immunity and prior work shows their importance in protecting against relapse. Our previous identification of degenerate HLA-class II epitopes from human FR led to the development of a broad coverage epitope pool potentially useful in augmenting antigen-specific immune responses in most patients. Experiment Design: We conducted a Phase I clinical trial testing safety and immunogenicity of this vaccine, enrolling patients with ovarian cancer or breast cancer who completed conventional treatment and who showed no evidence of disease. Patients were initially treated with low dose cyclophosphamide and then vaccinated 6 times, monthly. Immunity and safety were examined during the vaccine period and up to one year later. Results: Vaccination was well tolerated in all patients. Vaccine elicited or augmented immunity in greater than 90% of patients examined. Unlike recall immunity to tetanus toxoid, FR T cell responses developed slowly over the course of vaccination with a median time to maximal immunity at 5 months. Despite slow development of immunity, responsiveness appeared to persist for at least 12 months. Conclusions: The results demonstrate that it is safe to augment immunity to the FR tumor antigen and the developed vaccine is testable for therapeutic activity in the majority of patients whose tumors express FR, regardless of HLA genotype.

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Multivalent binding and biomimetic cell rolling improves the sensitivity and specificity of circulating tumor cell capture

Purpose: We aimed to examine the effects of multivalent binding and biomimetic cell rolling on the sensitivity and specificity of circulating tumor cell (CTC) capture. We also investigated the clinical significance of CTCs and their kinetic profiles in cancer patients undergoing radiotherapy (RT) treatment. Experimental Design: Patients with histologically confirmed primary carcinoma undergoing RT, with or without chemotherapy, were eligible for enrollment. Peripheral blood was collected prospectively at up to 5 time points, including prior to RT, at the first week, mid-point and final week of treatment, as well as 4 to 12 weeks after completion of RT. CTC capture was accomplished using a nanotechnology-based assay (CapioCyte) functionalized with aEpCAM, aHER-2, and aEGFR. Results: CapioCyte was able to detect CTCs in all 24 cancer patients enrolled. Multivalent binding via poly(amidoamine) dendrimers further improved capture sensitivity. We also showed that cell rolling effect can improve CTC capture specificity (% of captured cells that are CK+/CD45-/DAPI+) up to 38%. Among the 18 patients with sequential CTC measurements, the median CTC decreased from 113 CTCs/mL before RT to 32 CTCs/mL at completion of RT (p = 0.001). CTCs declined throughout RT in patients with complete clinical and/or radiographic response, in contrast to an elevation in CTCs at mid or post-RT in the 2 patients with known pathologic residual disease. Conclusions: Our study demonstrated that multivalent binding and cell rolling can improve the sensitivity and specificity of CTC capture compared to multivalent binding alone, allowing reliable monitoring of CTC changes during and after treatment.

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Inhibition of Glycolysis in Prostate Cancer Chemoprevention by Phenethyl Isothiocyanate

We have shown previously that dietary administration of phenethyl isothiocyanate (PEITC), a small molecule from edible cruciferous vegetables, significantly decreases the incidence of poorly-differentiated prostate cancer in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice without any side effects. In this study, we investigated the role of c-Myc-regulated glycolysis in prostate cancer chemoprevention by PEITC. Exposure of LNCaP (androgen-responsive) and 22Rv1 (castration-resistant) human prostate cancer cells to PEITC resulted in suppression of expression as well as transcriptional activity of c-Myc. Prostate cancer cell growth inhibition by PEITC was significantly attenuated by stable overexpression of c-Myc. Analysis of the RNA-Seq data from The Cancer Genome Atlas indicated a significant positive association between Myc expression and gene expression of many glycolysis-related genes including hexokinase II and lactate dehydrogenase A. Expression of these enzyme proteins and lactate levels were decreased upon PEITC treatment in prostate cancer cells, and these effects were significantly attenuated by ectopic expression of c-Myc. A normal prostate stromal cell line (PrSC) was resistant to lactic acid suppression by PEITC treatment. Prostate cancer chemoprevention by PEITC in TRAMP mice was associated with a significant decrease in plasma lactate and pyruvate levels. However, a 1-week intervention with 10 mg PEITC (orally, 4 times/day) was not sufficient to decrease lactate levels in the serum of human subjects. These results indicated that while prostate cancer prevention by PEITC in TRAMP mice was associated with suppression of glycolysis, longer than 1-week intervention might be necessary to observe such an effect in human subjects.

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Specificity Protein Transcription Factors and Cancer: Opportunities for Drug Development

Specificity protein (Sp) transcription factors (TFs) such as Sp1 are critical for early development but their expression decreases with age and there is evidence that transformation of normal cells to cancer cells is associated with upregulation of Sp1, Sp3 and Sp4 which are highly expressed in cancer cells and tumors. Sp1 is a negative prognostic factor for pancreatic, colon, glioma, gastric, breast, prostate, and lung cancer patients. Functional studies also demonstrate that Sp TFs regulate genes responsible for cancer cell growth, survival, migration/invasion, inflammation and drug resistance, and Sp1, Sp3 and Sp4 are also non-oncogene addiction (NOA) genes and important drug targets. The mechanisms of drug-induced downregulation of Sp TFs and pro-oncogenic Sp-regulated genes are complex and include ROS-dependent epigenetic pathways that initially decrease expression of the oncogene cMyc. Many compounds such as curcumin, aspirin and metformin that are active in cancer prevention also exhibit chemotherapeutic activity and these compounds downregulate Sp TFs in cancer cell lines and tumors. The effects of these compounds on downregulation of Sp TFs in normal cells and the contribution of this response to their chemopreventive activity have not yet been determined.

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The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

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New opportunities for kinase drug repurposing and target discovery

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The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

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New opportunities for kinase drug repurposing and target discovery

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Inter-institutional Travel Fellowships—a Need for the Young Surgical Oncologists

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Inter-institutional Travel Fellowships—a Need for the Young Surgical Oncologists

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American Indian Women Cancer Survivor’s Needs and Preferences: Community Support for Cancer Experiences

Abstract

Cancer (the focus of this inquiry) is the leading cause of death among American Indian and Alaska Native women. The purpose of this study was to identify American Indian women cancer survivors' needs and preferences related to community supports for their cancer experience. This qualitative study examined female American Indian cancer survivors' needs and preferences about community support. The sample included 43 American Indian women cancer survivors (the types of cancer survivors included cervical cancer: n = 14; breast cancer: n = 14; and colon and other types: n = 15) residing in the Northern Plains region, in the state of South Dakota. Data were analyzed using qualitative content analysis and were collected between June of 2014 and February of 2015. When asked about their needs and preferences, 82% of participants (n = 35) of female American Indian cancer survivors reported at least one of the following most commonly reported themes: cancer support groups (n = 31, 72%), infrastructure for community support (n = 17, 40%), and cancer education (n = 11, 26%). In addition to the aforementioned themes, 33% of participants (n = 14) indicated the need for an improved healthcare system, with 11% (n = 5) of participants expressly desiring the integration of spirituality and holistic healing options. The majority of American Indian women cancer survivor participants of this study identified a need for more community-based support systems and infrastructures to aid with the cancer survivor experience. Results warrant a community approach to raise awareness, education, and support for American Indian cancer survivors.

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American Indian Women Cancer Survivor’s Needs and Preferences: Community Support for Cancer Experiences

Abstract

Cancer (the focus of this inquiry) is the leading cause of death among American Indian and Alaska Native women. The purpose of this study was to identify American Indian women cancer survivors' needs and preferences related to community supports for their cancer experience. This qualitative study examined female American Indian cancer survivors' needs and preferences about community support. The sample included 43 American Indian women cancer survivors (the types of cancer survivors included cervical cancer: n = 14; breast cancer: n = 14; and colon and other types: n = 15) residing in the Northern Plains region, in the state of South Dakota. Data were analyzed using qualitative content analysis and were collected between June of 2014 and February of 2015. When asked about their needs and preferences, 82% of participants (n = 35) of female American Indian cancer survivors reported at least one of the following most commonly reported themes: cancer support groups (n = 31, 72%), infrastructure for community support (n = 17, 40%), and cancer education (n = 11, 26%). In addition to the aforementioned themes, 33% of participants (n = 14) indicated the need for an improved healthcare system, with 11% (n = 5) of participants expressly desiring the integration of spirituality and holistic healing options. The majority of American Indian women cancer survivor participants of this study identified a need for more community-based support systems and infrastructures to aid with the cancer survivor experience. Results warrant a community approach to raise awareness, education, and support for American Indian cancer survivors.

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American Indian Women Cancer Survivor’s Needs and Preferences: Community Support for Cancer Experiences

Abstract

Cancer (the focus of this inquiry) is the leading cause of death among American Indian and Alaska Native women. The purpose of this study was to identify American Indian women cancer survivors' needs and preferences related to community supports for their cancer experience. This qualitative study examined female American Indian cancer survivors' needs and preferences about community support. The sample included 43 American Indian women cancer survivors (the types of cancer survivors included cervical cancer: n = 14; breast cancer: n = 14; and colon and other types: n = 15) residing in the Northern Plains region, in the state of South Dakota. Data were analyzed using qualitative content analysis and were collected between June of 2014 and February of 2015. When asked about their needs and preferences, 82% of participants (n = 35) of female American Indian cancer survivors reported at least one of the following most commonly reported themes: cancer support groups (n = 31, 72%), infrastructure for community support (n = 17, 40%), and cancer education (n = 11, 26%). In addition to the aforementioned themes, 33% of participants (n = 14) indicated the need for an improved healthcare system, with 11% (n = 5) of participants expressly desiring the integration of spirituality and holistic healing options. The majority of American Indian women cancer survivor participants of this study identified a need for more community-based support systems and infrastructures to aid with the cancer survivor experience. Results warrant a community approach to raise awareness, education, and support for American Indian cancer survivors.

http://ift.tt/2IoYFOB

American Indian Women Cancer Survivor’s Needs and Preferences: Community Support for Cancer Experiences

Abstract

Cancer (the focus of this inquiry) is the leading cause of death among American Indian and Alaska Native women. The purpose of this study was to identify American Indian women cancer survivors' needs and preferences related to community supports for their cancer experience. This qualitative study examined female American Indian cancer survivors' needs and preferences about community support. The sample included 43 American Indian women cancer survivors (the types of cancer survivors included cervical cancer: n = 14; breast cancer: n = 14; and colon and other types: n = 15) residing in the Northern Plains region, in the state of South Dakota. Data were analyzed using qualitative content analysis and were collected between June of 2014 and February of 2015. When asked about their needs and preferences, 82% of participants (n = 35) of female American Indian cancer survivors reported at least one of the following most commonly reported themes: cancer support groups (n = 31, 72%), infrastructure for community support (n = 17, 40%), and cancer education (n = 11, 26%). In addition to the aforementioned themes, 33% of participants (n = 14) indicated the need for an improved healthcare system, with 11% (n = 5) of participants expressly desiring the integration of spirituality and holistic healing options. The majority of American Indian women cancer survivor participants of this study identified a need for more community-based support systems and infrastructures to aid with the cancer survivor experience. Results warrant a community approach to raise awareness, education, and support for American Indian cancer survivors.

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Cabergoline versus bromocriptine for the treatment of giant prolactinomas: A quantitative and systematic review

Abstract

The aim of this study is to compare the efficacy of bromocriptine (BRC) versus cabergoline (CAB) in patients with giant prolactinomas. We searched MEDLINE, EMBASE, CENTRAL and Clinical Trials.gov for studies dated before March 1st, 2016, that used BRC or CAB for the treatment of patients with giant prolactinomas. Specific eligibility criteria were set to identify articles and cases. The selected articles were reviewed, and the data were extracted for analysis. The compared outcomes included tumor shrinkage, tumor response, normalization of prolactin (PRL) level, and visual field defect (VFD) improvement. Gender differences were also considered. Differences between the groups were assessed using Student's t test and the chi-square test. Two hundred and forty-five records were identified, and 10 articles and 104 cases met the inclusion criteria. Based on our analysis, CAB is significantly better than BRC in normalizing PRL levels in patients, especially males, with giant prolactinomas (69.4% versus 31.7%, p = 0.01). However, there was no significant difference between the two drugs in terms of tumor shrinkage, tumor response and VFD improvement (p > 0.05) in male or female patients. CAB exhibits significantly better efficacy than BRC in the normalization of PRL levels in male patients with giant prolactinomas. Regarding tumor reduction and VFD improvement, both drugs are comparably effective for patients of both genders. This quantitative and systematic review provides preliminary evidence in favor of CAB as a medical therapy for treating giant prolactinomas in male patients, especially those with extremely high PRL levels.

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Cabergoline versus bromocriptine for the treatment of giant prolactinomas: A quantitative and systematic review

Abstract

The aim of this study is to compare the efficacy of bromocriptine (BRC) versus cabergoline (CAB) in patients with giant prolactinomas. We searched MEDLINE, EMBASE, CENTRAL and Clinical Trials.gov for studies dated before March 1st, 2016, that used BRC or CAB for the treatment of patients with giant prolactinomas. Specific eligibility criteria were set to identify articles and cases. The selected articles were reviewed, and the data were extracted for analysis. The compared outcomes included tumor shrinkage, tumor response, normalization of prolactin (PRL) level, and visual field defect (VFD) improvement. Gender differences were also considered. Differences between the groups were assessed using Student's t test and the chi-square test. Two hundred and forty-five records were identified, and 10 articles and 104 cases met the inclusion criteria. Based on our analysis, CAB is significantly better than BRC in normalizing PRL levels in patients, especially males, with giant prolactinomas (69.4% versus 31.7%, p = 0.01). However, there was no significant difference between the two drugs in terms of tumor shrinkage, tumor response and VFD improvement (p > 0.05) in male or female patients. CAB exhibits significantly better efficacy than BRC in the normalization of PRL levels in male patients with giant prolactinomas. Regarding tumor reduction and VFD improvement, both drugs are comparably effective for patients of both genders. This quantitative and systematic review provides preliminary evidence in favor of CAB as a medical therapy for treating giant prolactinomas in male patients, especially those with extremely high PRL levels.

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The Imperative of Addressing Cancer Drug Costs and Value

The President's Cancer Panel has released its latest report, Promoting Value, Affordability, and Innovation in Cancer Drug Treatment. The report recommends six actions to maximize the value and affordability of cancer drug treatment.

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The Imperative of Addressing Cancer Drug Costs and Value

The President's Cancer Panel has released its latest report, Promoting Value, Affordability, and Innovation in Cancer Drug Treatment. The report recommends six actions to maximize the value and affordability of cancer drug treatment.

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Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology

Publication date: Available online 15 March 2018
Source:Cell Stem Cell
Author(s): Michael J. Ziller, Juan A. Ortega, Katharina A. Quinlan, David P. Santos, Hongcang Gu, Eric J. Martin, Christina Galonska, Ramona Pop, Susanne Maidl, Alba Di Pardo, Mei Huang, Herbert Y. Meltzer, Andreas Gnirke, C.J. Heckman, Alexander Meissner, Evangelos Kiskinis
The somatic DNA methylation (DNAme) landscape is established early in development but remains highly dynamic within focal regions that overlap with gene regulatory elements. The significance of these dynamic changes, particularly in the central nervous system, remains unresolved. Here, we utilize a powerful human embryonic stem cell differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novo DNAme machinery. We quantitatively dissect the role of DNAme in directing somatic cell fate with high-resolution genome-wide bisulfite-, bulk-, and single-cell-RNA sequencing. We find defects in neuralization and MN differentiation in DNMT3A knockouts (KO) that can be rescued by the targeting of DNAme to key developmental loci using catalytically inactive dCas9. We also find decreased dendritic arborization and altered electrophysiological properties in DNMT3A KO MNs. Our work provides a list of DNMT3A-regulated targets and a mechanistic link between de novo DNAme, cellular differentiation, and human MN function.

Graphical abstract

Teaser

Kiskinis and colleagues demonstrate that DNA methylation dynamics play a central role in the differentiation of human pluripotent stem cells toward highly specialized motor neurons. Through a combination of molecular and functional analysis they identify key transcriptional mediators of these effects and link DNA methylation to neuronal patterning and function.


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Adiposity Results in Metabolic and Inflammation Differences in Premenopausal and Postmenopausal Women Consistent with the Difference in Breast Cancer Risk

Abstract

Obesity is associated with increased risk of breast cancer in postmenopausal but not in premenopausal women. Many factors may be responsible for this difference. The aim of this study was to determine the mechanisms by which the genes related to the AMPK pathway, inflammation, and estrogen actions are affected by adiposity in breast tissue with the objective of identifying differences that may explain the different breast cancer risk in premenopausal and postmenopausal women. Random fine needle aspirates (rFNAs) of breast tissue were collected from 57 premenopausal and 55 postmenopausal women and were classified as normal weight, overweight, or obese. Expression levels of 21 target genes were determined using a TaqMan Low Density Array procedure. Breast tissue estradiol levels were measured by a liquid chromatography-tandem mass spectrometry procedure, and serum estradiol and follicle-stimulating hormone (FSH) were measured by a radioimmunoassay and an enzyme-linked immunosorbent assay, respectively. We found that in postmenopausal women, serum and tissue estradiol levels were increased in those who were overweight, and serum FSH levels were decreased in obese status. Interestingly, RPS6KB1, an AMPK downstream-responsive gene for protein synthesis and cell growth, and estrogen receptor α (encoded by the ESR1 gene) and its target gene GATA3 were significantly decreased in rFNA of premenopausal, obese women. In postmenopausal women, RPS6KB1, ESR1, and GATA3 expression remained unchanged in relation to adiposity. However, prostaglandin-endoperoxide synthase 2 (PTGS2), cyclin D1 (CCND1), and another ESR1 target gene, TFF1, were elevated in rFNA of obese postmenopausal women. Thus, as bodyweight increases, gene expression is indicative of increased proliferation in postmenopausal women but decreased proliferation in premenopausal women. Overall, our data reveal a novel process by which obesity promotes the risk of breast cancer in postmenopausal but not premenopausal women.

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Adiposity Results in Metabolic and Inflammation Differences in Premenopausal and Postmenopausal Women Consistent with the Difference in Breast Cancer Risk

Abstract

Obesity is associated with increased risk of breast cancer in postmenopausal but not in premenopausal women. Many factors may be responsible for this difference. The aim of this study was to determine the mechanisms by which the genes related to the AMPK pathway, inflammation, and estrogen actions are affected by adiposity in breast tissue with the objective of identifying differences that may explain the different breast cancer risk in premenopausal and postmenopausal women. Random fine needle aspirates (rFNAs) of breast tissue were collected from 57 premenopausal and 55 postmenopausal women and were classified as normal weight, overweight, or obese. Expression levels of 21 target genes were determined using a TaqMan Low Density Array procedure. Breast tissue estradiol levels were measured by a liquid chromatography-tandem mass spectrometry procedure, and serum estradiol and follicle-stimulating hormone (FSH) were measured by a radioimmunoassay and an enzyme-linked immunosorbent assay, respectively. We found that in postmenopausal women, serum and tissue estradiol levels were increased in those who were overweight, and serum FSH levels were decreased in obese status. Interestingly, RPS6KB1, an AMPK downstream-responsive gene for protein synthesis and cell growth, and estrogen receptor α (encoded by the ESR1 gene) and its target gene GATA3 were significantly decreased in rFNA of premenopausal, obese women. In postmenopausal women, RPS6KB1, ESR1, and GATA3 expression remained unchanged in relation to adiposity. However, prostaglandin-endoperoxide synthase 2 (PTGS2), cyclin D1 (CCND1), and another ESR1 target gene, TFF1, were elevated in rFNA of obese postmenopausal women. Thus, as bodyweight increases, gene expression is indicative of increased proliferation in postmenopausal women but decreased proliferation in premenopausal women. Overall, our data reveal a novel process by which obesity promotes the risk of breast cancer in postmenopausal but not premenopausal women.

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Protective effects of purple carrot extract ( Daucus carota ) against rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide

Abstract

The aim of this study was to evaluate the chemopreventive potential of purple carrot extract following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide (4NQO). For this purpose, histopathological analysis, proliferative status, antioxidant activity and inflammatory status were investigated in this setting. A total of 20 male rats were distributed into four groups as follows (n = 5 per group): Group 1—free access to water and commercial diet for 12 weeks; Group 2—received 4NQO at 50 ppm dose in drinking water daily and commercial diet for 12 weeks; Group 3—free access to water and received diet supplemented with purple carrot extract (0.1 g/kg) for 12 weeks; and Group 4—received 4NQO at 50 ppm dose in drinking water daily and diet supplemented with purple carrot extract (0.1 g/kg) for 12 weeks. Histopathological analysis revealed that animals treated with purple carrot extract reduced the oral lesions such as dysplasia and squamous cell carcinoma. Animals with oral pre-neoplastic lesions and treated with purple carrot extract decreased ki-67 and 8-OHdG immunoexpression. Moreover, pNFκBp50 and MyD88 protein expressions were decreased after purple carrot treatment associated or not with 4NQO exposure. SOD-Mn mRNA levels increased with treatment with purple carrot extract as well. In conclusion, our results demonstrated that purple carrot extract was able to protect oral lesions induced by 4NQO in Wistar rats as a result of antioxidant activity, anti-inflammatory potential and antiproliferative and antimutagenic actions.

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Protective effects of purple carrot extract ( Daucus carota ) against rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide

Abstract

The aim of this study was to evaluate the chemopreventive potential of purple carrot extract following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide (4NQO). For this purpose, histopathological analysis, proliferative status, antioxidant activity and inflammatory status were investigated in this setting. A total of 20 male rats were distributed into four groups as follows (n = 5 per group): Group 1—free access to water and commercial diet for 12 weeks; Group 2—received 4NQO at 50 ppm dose in drinking water daily and commercial diet for 12 weeks; Group 3—free access to water and received diet supplemented with purple carrot extract (0.1 g/kg) for 12 weeks; and Group 4—received 4NQO at 50 ppm dose in drinking water daily and diet supplemented with purple carrot extract (0.1 g/kg) for 12 weeks. Histopathological analysis revealed that animals treated with purple carrot extract reduced the oral lesions such as dysplasia and squamous cell carcinoma. Animals with oral pre-neoplastic lesions and treated with purple carrot extract decreased ki-67 and 8-OHdG immunoexpression. Moreover, pNFκBp50 and MyD88 protein expressions were decreased after purple carrot treatment associated or not with 4NQO exposure. SOD-Mn mRNA levels increased with treatment with purple carrot extract as well. In conclusion, our results demonstrated that purple carrot extract was able to protect oral lesions induced by 4NQO in Wistar rats as a result of antioxidant activity, anti-inflammatory potential and antiproliferative and antimutagenic actions.

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In silico assessment of the dosimetric quality of a novel, automated radiation treatment planning strategy for linac-based radiosurgery of multiple brain metastases and a comparison with robotic methods

Abstract

Background

To appraise the dosimetric features and the quality of the treatment plan for radiosurgery of multiple brain metastases optimized with a novel automated engine and to compare with plans optimized for robotic-based delivery.

Methods

A set of 15 patients with multiple brain metastases was selected for this in silico study. The technique under investigation is the recently introduced HyperArc. For all patients, three treatment plans were computed and compared: i: a HyperArc; ii: a standard VMAT; iii) a CyberKnife. Dosimetric features were computed for the clinical target volumes as well as for the healthy brain tissue and the organs at risk.

Results

The data showed that the best dose homogeneity was achieved with the VMAT technique. HyperArc allowed to minimize the volume of brain receiving 4Gy (as well as for the mean dose and the volume receiving 12Gy, although not statistically significant). The smallest dose on 1 cm³ volume for all organs at risk is for CK techniques, and the biggest for VMAT (p < 0.05). The Radiation Planning Index coefficient indicates that, there are no significant differences among the techniques investigated, suggesting an equivalence among these.

Conclusion

At treatment planning level, the study demonstrates that the use of HyperArc technique can significantly improve the sparing of the healthy brain while maintaining a full coverage of the target volumes.

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Retrospective dosimetry study of intensity-modulated radiation therapy for nasopharyngeal carcinoma: measurement-guided dose reconstruction and analysis

Abstract

Background

Conventional phantom-based planar dosimetry (2D-PBD) quality assurance (QA) using gamma pass rate (GP (%)) is inadequate to reflect clinically relevant dose error in intensity-modulated radiation therapy (IMRT), owing to a lack of information regarding patient anatomy and volumetric dose distribution. This study aimed to evaluate the dose distribution accuracy of IMRT delivery for nasopharyngeal carcinoma (NPC), which passed the 2D-PBD verification, using a measurement-guided 3D dose reconstruction (3D-MGR) method.

Methods

Radiation treatment plans of 30 NPC cases and their pre-treatment 2D-PBD data were analyzed. 3D dose distribution was reconstructed on patient computed tomography (CT) images using the 3DVH software and compared to the treatment plans. Global and organ-specific dose GP (%), and dose-volume histogram (DVH) deviation of each structure was evaluated. Interdependency between GP (%) and the deviation of the volumetric dose was studied through correlation analysis.

Results

The 3D-MGR achieved global GP (%) similar to conventional 2D-PBD in the same criteria. However, structure-specific GP (%) significantly decreased under stricter criteria, including the planning target volume (PTV). The average deviation of all inspected dose volumes (D_V) and volumetric dose (V_D) parameters ranged from − 2.93% to 1.17%, with the largest negative deviation in V100% of the PTVnx of − 15.66% and positive deviation in D1cc of the spinal cord of 6.66%. There was no significant correlation between global GP (%) of 2D-PBD or 3D-MGR and the deviation of the most volumetric dosimetry parameters (D_V or V_D), when the Pearson's coefficient value of 0.8 was used for correlation evaluation.

Conclusion

Even upon passing the pre-treatment phantom based dosimetric QA, there could still be risk of dose error like under-dose in PTVnx and overdose in critical structures. Measurement-guided 3D volumetric dosimetry QA is recommended as the more clinically efficient verification for the complicated NPC IMRT.

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Cover Image, Volume 117, Number 3, March 1, 2018

The cover image, by Marc G. Stevenson et al., is based on the Research Article Amputations for extremity soft tissue sarcoma in an era of limb salvage treatment: Local control and survival, DOI 10.1002/jso.24881.

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Issue Information - Ed Board

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Issue Information - TOC

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In silico assessment of the dosimetric quality of a novel, automated radiation treatment planning strategy for linac-based radiosurgery of multiple brain metastases and a comparison with robotic methods

Abstract

Background

To appraise the dosimetric features and the quality of the treatment plan for radiosurgery of multiple brain metastases optimized with a novel automated engine and to compare with plans optimized for robotic-based delivery.

Methods

A set of 15 patients with multiple brain metastases was selected for this in silico study. The technique under investigation is the recently introduced HyperArc. For all patients, three treatment plans were computed and compared: i: a HyperArc; ii: a standard VMAT; iii) a CyberKnife. Dosimetric features were computed for the clinical target volumes as well as for the healthy brain tissue and the organs at risk.

Results

The data showed that the best dose homogeneity was achieved with the VMAT technique. HyperArc allowed to minimize the volume of brain receiving 4Gy (as well as for the mean dose and the volume receiving 12Gy, although not statistically significant). The smallest dose on 1 cm³ volume for all organs at risk is for CK techniques, and the biggest for VMAT (p < 0.05). The Radiation Planning Index coefficient indicates that, there are no significant differences among the techniques investigated, suggesting an equivalence among these.

Conclusion

At treatment planning level, the study demonstrates that the use of HyperArc technique can significantly improve the sparing of the healthy brain while maintaining a full coverage of the target volumes.

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Retrospective dosimetry study of intensity-modulated radiation therapy for nasopharyngeal carcinoma: measurement-guided dose reconstruction and analysis

Abstract

Background

Conventional phantom-based planar dosimetry (2D-PBD) quality assurance (QA) using gamma pass rate (GP (%)) is inadequate to reflect clinically relevant dose error in intensity-modulated radiation therapy (IMRT), owing to a lack of information regarding patient anatomy and volumetric dose distribution. This study aimed to evaluate the dose distribution accuracy of IMRT delivery for nasopharyngeal carcinoma (NPC), which passed the 2D-PBD verification, using a measurement-guided 3D dose reconstruction (3D-MGR) method.

Methods

Radiation treatment plans of 30 NPC cases and their pre-treatment 2D-PBD data were analyzed. 3D dose distribution was reconstructed on patient computed tomography (CT) images using the 3DVH software and compared to the treatment plans. Global and organ-specific dose GP (%), and dose-volume histogram (DVH) deviation of each structure was evaluated. Interdependency between GP (%) and the deviation of the volumetric dose was studied through correlation analysis.

Results

The 3D-MGR achieved global GP (%) similar to conventional 2D-PBD in the same criteria. However, structure-specific GP (%) significantly decreased under stricter criteria, including the planning target volume (PTV). The average deviation of all inspected dose volumes (D_V) and volumetric dose (V_D) parameters ranged from − 2.93% to 1.17%, with the largest negative deviation in V100% of the PTVnx of − 15.66% and positive deviation in D1cc of the spinal cord of 6.66%. There was no significant correlation between global GP (%) of 2D-PBD or 3D-MGR and the deviation of the most volumetric dosimetry parameters (D_V or V_D), when the Pearson's coefficient value of 0.8 was used for correlation evaluation.

Conclusion

Even upon passing the pre-treatment phantom based dosimetric QA, there could still be risk of dose error like under-dose in PTVnx and overdose in critical structures. Measurement-guided 3D volumetric dosimetry QA is recommended as the more clinically efficient verification for the complicated NPC IMRT.

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Cover Image, Volume 117, Number 3, March 1, 2018

The cover image, by Marc G. Stevenson et al., is based on the Research Article Amputations for extremity soft tissue sarcoma in an era of limb salvage treatment: Local control and survival, DOI 10.1002/jso.24881.

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Hepatocellular Carcinoma With Portal Venous Invasion

The growing incidence of hepatocellular carcinoma (HCC) is a major global public health challenge. The mortality rate for HCC is very high, and most available treatment options remain palliative. Early-stage HCC can be treated with curative intent with transplantation, resection, or ablation. Level 1 evidence from randomized clinical trials has demonstrated a survival advantage for transarterial chemoembolization (TACE) vs supportive care for intermediate-stage HCC and for systemic therapy with sorafenib, lenvatinib, regorafenib, and cabozantinib for advanced-stage HCC. Recently, immune checkpoint inhibitors have demonstrated impressive antitumor activity with high response rates in advanced HCC, and phase 3 trials are ongoing to assess survival benefits.

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Clinicopathological features and prediction values of HDAC1, HDAC2, HDAC3, and HDAC11 in classical Hodgkin lymphoma

Histone deacetylases (HDACs) are involved in multiple physical and pathological processes in classical Hodgkin lymphoma (cHL). The prognostic value of HDACs in cHL patients has not been discussed. The aim of the current study is to investigate the HDAC1, HDAC2, HDAC3, and HDAC11 expressions, and to evaluate the correlation of HDAC1, HDAC2, HDAC3, and HDAC11 expressions with the survival rate in cHL patients. We retrospectively analyzed clinicopathological data of 28 patients who were diagnosed with cHL between August 2002 and March 2010. Immunohistochemistry was used to detect the expression of HDAC1, HDAC2, HDAC3, and HDAC11 in these patients. The results showed that HDAC1, HDAC3, and HDAC11 were expressed at a higher level in Hodgkin Reed-Sternberg cells, whereas HDAC2 was expressed at a lower level in Hodgkin Reed-Sternberg cells. The expression of HDAC2 had a relationship with pathological type (P=0.012). There was also a correlation between the expression of HDAC11 and the erythrocyte sedimentation rate (P=0.054). Other clinicopathological parameters had no significant correlation with the expression of HDAC1, HDAC2, HDAC3, and HDAC11 in terms of survival (P>0.05). The 10-year total survival rate by Cox multivariate analysis, after taking into account all clinical and pathologic factors, showed that bulky disease retained significance (P=0.028). Higher expression of HDAC1 predicted shorter progression-free survival and overall survival (OS) in cHL patients (P

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Norleual, a hepatocyte growth factor and macrophage stimulating protein dual antagonist, increases pancreatic cancer sensitivity to gemcitabine

Pancreatic cancer is a leading cause of cancer deaths in the USA and is characterized by an exceptionally poor long-term survival rate compared with other major cancers. The hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) growth factor systems are frequently over-activated in pancreatic cancer and significantly contribute to cancer progression, metastasis, and chemotherapeutic resistance. Small molecules homologous to the 'hinge' region of HGF, which participates in its dimerization and activation, had been developed and shown to bind HGF with high affinity, antagonize HGF's actions, and possess anticancer activity. Encouraged by sequence homology between HGF's hinge region and a similar sequence in MSP, our laboratory previously investigated and determined that these same antagonists could also block MSP-dependent cellular responses. Thus, the purpose of this study was to establish that the dual HGF/MSP antagonist Norleual could inhibit the prosurvival activity imparted by both HGF and MSP to pancreatic cancer cells in vitro, and to determine whether this effect translated into an improved chemotherapeutic impact for gemcitabine when delivered in combination in a human pancreatic cancer xenograft model. Our results demonstrate that Norleual does indeed suppress HGF's and MSP's prosurvival effects as well as sensitizing pancreatic cancer cells to gemcitabine in vitro. Most importantly, treatment with Norleual in combination with gemcitabine markedly inhibited in-vivo tumor growth beyond the suppression observed with gemcitabine alone. These results suggest that dual functional HGF/MSP antagonists like Norleual warrant further development and may offer an improved therapeutic outcome for pancreatic cancer patients.

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Investigation of an antitumor drug-delivery system based on anti-HER2 antibody-conjugated BSA nanoparticles

Conjugation of a monoclonal antibody with a nanoparticle often improves its specificity and drug loading in cancer therapy. In this study, we prepared a novel targeting nanodrug-delivery system using 2-methoxy-estradiol (2-ME) based on anti-human epidermal growth factor receptor 2 (HER2) antibody-modified BSA to improve the clinical application and antitumor effect of 2-ME. 2-ME-loaded albumin nanoparticles (2-ME-BSANPs) were prepared using a desolvation method and the anti-HER2 antibodies were conjugated to 2-ME-BSANPs (HER2-2-ME-BSANPs) using the coupling agent, succinimidyl 3-(2-pyridyldithio)propionate. HER2-2-ME-BSANPs were characterized using SDS-polyacrylamide gel electrophoresis, an agglutination test, and an immunofluorescence assay. We found that mouse anti-human anti-HER2 monoclonal antibody was successfully conjugated to the 2-ME-BSANPs. Thereafter, the in-vitro and in-vivo toxicities were evaluated using two cancer cell lines, SK-BR-3 (HER2-overexpressing) and MCF-7 (HER2-underexpressing), using classic pharmacological methods and in-vivo imaging technology. We found that the HER2-2-ME-BSANPs retained the immunospecificity of the anti-HER2 monoclonal antibody, rapidly localized to HER2 receptors, and could be used for targeted cancer therapy.

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Curcumin reverses irinotecan resistance in colon cancer cell by regulation of epithelial–mesenchymal transition

The objective of this study was to investigate the effect and the mechanism by which curcumin reverses irinotecan-induced chemotherapy resistance in colon cancer. Construction of irinotecan-resistant colon cancer model LoVo/CPT-11R cells was performed by increasing drug concentration. The Cell Counting Kit-8 assay was used to detect inhibition of proliferation; cell morphology was observed by an optical microscope. Quantitative RT-PCR and western blotting were performed to detect molecular marker expressions during epithelial–mesenchymal transition (EMT); drug-resistant cells were treated with curcumin at different concentrations and Cell Counting Kit-8 was reperformed to detect cell proliferation after treatments. Drug-resistant cells were then divided into four groups: control group, irinotecan group, curcumin group, and irinotecan+curcumin group; quantitative RT-PCR and western blotting were performed to detect molecular marker expressions during epithelial–mesenchymal transition. Flow cytometry was used to detect cell apoptosis after grouping, and apoptosis-related protein was detected by western blotting. LoVo/CPT-11R cells could survive in culture medium containing irinotecan at 60 μg/ml and the drug-resistance index was 5.69; the drug-resistant cells had a larger volume than normal cells and were poorly connected to each other. E-cadherin expression was downregulated, whereas vimentin and N-cadherin expressions were upregulated. After curcumin treatment, drug-resistant cell proliferation was significantly inhibited; in the curcumin+irinotecan treatment group, E-cadherin expression was upregulated, whereas vimentin and N-cadherin expressions were downregulated. Curcumin could significantly increase cell apoptosis. EMT is involved in the development of irinotecan resistance and curcumin can reverse this drug resistance through reversion of the EMT process.

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Anticancer effect of (S)-crizotinib on osteosarcoma cells by targeting MTH1 and activating reactive oxygen species

MTH1 has become a new rising star in the field of 'cancer phenotypic lethality' and can be targeted in many kinds of tumors. This study aimed to explore the anticancer effect of MTH1-targeted drug (S)-crizotinib on osteosarcoma (OS) cells. We detected MTH1 expression in OS tissues and cells using immunohistochemistry and western blot. The effects of MTH1 on OS cell viability were explored using the siRNA technique and CCK8. The anticancer effects of the MTH1-targeted drug (S)-crizotinib on OS cells were explored by in-vitro assays. The intracellular 8-oxo-dGTP level and oxygen reactive species (ROS) of OS cells were detected by Cy3-conjugated avidin staining and dichlorofluorescein diacetate staining, respectively. The expression of MTH1 was significantly higher in OS tissues and cell lines than that in the corresponding adjacent tissues and osteoblastic cell line. The proliferation of OS cells was significantly inhibited through knockdown of MTH1 by siRNA technology. (S)-Crizotinib could inhibit the proliferation of OS cells with an increase in the apoptosis levels and causing G0/G1 arrest by targeting MTH1 and activating ROS. In addition, (S)-crizotinib could inhibit the migration of OS cells. (S)-Crizotinib could suppress the proliferation and migration, cause G0/G1 arrest, and increase the apoptosis level of OS cells by targeting MTH1 and activating ROS. This study will provide a promising therapeutic target and the theoretical basis for the clinical application of (S)-crizotinib in OS.

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Probable drug–drug interaction between erlotinib and amiodarone causes severe neurotoxicity in a patient with advanced lung cancer

Drug–drug interactions (DDIs) are of great concern in the treatment of cancer, especially when target therapies, such as tyrosine kinase inhibitors, are being used. Here, we report a case of probable DDI between erlotinib and amiodarone leading to severe neurotoxicity. Amiodarone inhibits P-glycoprotein (P-gp), for which erlotinib is a substrate. P-gp is an important drug transporter that is involved in limiting the blood–brain barrier penetration of erlotinib. Clinicians should be aware of emerging data characterizing the effect of the P-gp transport system on drug exposure and its potential for DDI.

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Breast Cancer Differences by Race Due to Screening Disparities—Reply

In Reply Denu suggests that biological differences between breast cancers in black and white patients are largely explained by disparities in access to care, in particular disparity in screening.

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Incorrect Spelling in Byline

In the Original Investigation titled "Baseline Surveillance in Li-Fraumeni Syndrome Using Whole-Body Magnetic Resonance Imaging: A Meta-analysis," published online August 3, 2017, and in the December 2017 print issue, the surname of Lorenzo Mannelli was spelled incorrectly as Manelli. This article has been corrected online.

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Recurrence in Resected Gastroenteropancreatic Neuroendocrine Tumors

This cohort study examines recurrence outcomes in patients with fully resected gastroenteropancreatic neuroendocrine tumors.

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Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma

This randomized clinical trial evaluates the efficacy and safety of transarterial chemoembolization plus external beam radiotherapy compared with sorafenib in patients with hepatocellular carcinoma and macroscopic vascular invasion.

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Breast Cancer Differences by Race Due to Screening Disparities

To the Editor Black breast cancer patients have the highest breast cancer mortality rate, at least partly because black women are more likely to develop triple-negative breast cancer (TNBC). In addition, while outcomes for estrogen receptor/progesterone receptor–positive breast cancer are generally worse for blacks compared with whites, there are no significant differences in outcomes between blacks and whites for TNBC. Two potential reasons for the overall breast cancer survival gap are (1) disparities in access to care and (2) inherent biological differences. To address the latter, Huo and colleagues recently investigated genetic differences between breast cancers in white and black patients using data from The Cancer Genome Atlas (TCGA). They reported a number of biological differences between black and white breast cancers. Interestingly, most tumor genomic differences between races were explained by subtype. Taking all these past and present data into account, I am not convinced that there are inherent genetic differences between blacks and whites that explain the differences in breast cancer outcomes based on race or ancestry and the proportion of breast cancers that are TNBC. Rather, these differences can be largely explained by disparities in access to care.

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Standard vs Dose-Escalated Radiotherapy in Medium-Risk Prostate Cancer

This randomized clinical trial assesses whether dose-escalated radiation therapy vs standard dose improves survival for men with intermediate-risk prostate cancer.

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Using the Cancer Moonshot to Conquer Cancer Disparities

This Viewpoint describes how the Cancer Moonshot Initiative provides an opportunity to address cancer disparities and inequities and ways to ensure that its goals are achieved.

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Clinicopathological features and prediction values of HDAC1, HDAC2, HDAC3, and HDAC11 in classical Hodgkin lymphoma

Histone deacetylases (HDACs) are involved in multiple physical and pathological processes in classical Hodgkin lymphoma (cHL). The prognostic value of HDACs in cHL patients has not been discussed. The aim of the current study is to investigate the HDAC1, HDAC2, HDAC3, and HDAC11 expressions, and to evaluate the correlation of HDAC1, HDAC2, HDAC3, and HDAC11 expressions with the survival rate in cHL patients. We retrospectively analyzed clinicopathological data of 28 patients who were diagnosed with cHL between August 2002 and March 2010. Immunohistochemistry was used to detect the expression of HDAC1, HDAC2, HDAC3, and HDAC11 in these patients. The results showed that HDAC1, HDAC3, and HDAC11 were expressed at a higher level in Hodgkin Reed-Sternberg cells, whereas HDAC2 was expressed at a lower level in Hodgkin Reed-Sternberg cells. The expression of HDAC2 had a relationship with pathological type (P=0.012). There was also a correlation between the expression of HDAC11 and the erythrocyte sedimentation rate (P=0.054). Other clinicopathological parameters had no significant correlation with the expression of HDAC1, HDAC2, HDAC3, and HDAC11 in terms of survival (P>0.05). The 10-year total survival rate by Cox multivariate analysis, after taking into account all clinical and pathologic factors, showed that bulky disease retained significance (P=0.028). Higher expression of HDAC1 predicted shorter progression-free survival and overall survival (OS) in cHL patients (P

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Norleual, a hepatocyte growth factor and macrophage stimulating protein dual antagonist, increases pancreatic cancer sensitivity to gemcitabine

Pancreatic cancer is a leading cause of cancer deaths in the USA and is characterized by an exceptionally poor long-term survival rate compared with other major cancers. The hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) growth factor systems are frequently over-activated in pancreatic cancer and significantly contribute to cancer progression, metastasis, and chemotherapeutic resistance. Small molecules homologous to the 'hinge' region of HGF, which participates in its dimerization and activation, had been developed and shown to bind HGF with high affinity, antagonize HGF's actions, and possess anticancer activity. Encouraged by sequence homology between HGF's hinge region and a similar sequence in MSP, our laboratory previously investigated and determined that these same antagonists could also block MSP-dependent cellular responses. Thus, the purpose of this study was to establish that the dual HGF/MSP antagonist Norleual could inhibit the prosurvival activity imparted by both HGF and MSP to pancreatic cancer cells in vitro, and to determine whether this effect translated into an improved chemotherapeutic impact for gemcitabine when delivered in combination in a human pancreatic cancer xenograft model. Our results demonstrate that Norleual does indeed suppress HGF's and MSP's prosurvival effects as well as sensitizing pancreatic cancer cells to gemcitabine in vitro. Most importantly, treatment with Norleual in combination with gemcitabine markedly inhibited in-vivo tumor growth beyond the suppression observed with gemcitabine alone. These results suggest that dual functional HGF/MSP antagonists like Norleual warrant further development and may offer an improved therapeutic outcome for pancreatic cancer patients.

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Any place left for induction chemotherapy for locally advanced head and neck squamous cell carcinoma?

The issue of induction chemotherapy (ICT) interest in locoregionally advanced squamous cell cancer of the head and neck is a real epic that has been carried out over four phase III studies: PARADIGM, DECIDE, NCT01086826 and lastly the conclusive GORTEC 2007-02. With no significant benefit in overall survival of ICT, followed by concurrent chemoradiation over the standard chemoradiotherapy alone, in three of these studies, and a significant number of treatment-related deaths with the standard regimen docetaxel, cisplatin, and fluorouracil, ICT is no longer a hot topic. However, this strategy might still be useful in the aim of limiting the metastatic extension affecting up to 30% of patients: ICT is systematically associated with a reduced metastatic relapse even though the survival effect is never statistically significant when compared directly with concomitant radiochemotherapy. This review summarizes the major studies with their limits and discusses how the ICT could improve the patients' prognosis in the future.

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Investigation of an antitumor drug-delivery system based on anti-HER2 antibody-conjugated BSA nanoparticles

Conjugation of a monoclonal antibody with a nanoparticle often improves its specificity and drug loading in cancer therapy. In this study, we prepared a novel targeting nanodrug-delivery system using 2-methoxy-estradiol (2-ME) based on anti-human epidermal growth factor receptor 2 (HER2) antibody-modified BSA to improve the clinical application and antitumor effect of 2-ME. 2-ME-loaded albumin nanoparticles (2-ME-BSANPs) were prepared using a desolvation method and the anti-HER2 antibodies were conjugated to 2-ME-BSANPs (HER2-2-ME-BSANPs) using the coupling agent, succinimidyl 3-(2-pyridyldithio)propionate. HER2-2-ME-BSANPs were characterized using SDS-polyacrylamide gel electrophoresis, an agglutination test, and an immunofluorescence assay. We found that mouse anti-human anti-HER2 monoclonal antibody was successfully conjugated to the 2-ME-BSANPs. Thereafter, the in-vitro and in-vivo toxicities were evaluated using two cancer cell lines, SK-BR-3 (HER2-overexpressing) and MCF-7 (HER2-underexpressing), using classic pharmacological methods and in-vivo imaging technology. We found that the HER2-2-ME-BSANPs retained the immunospecificity of the anti-HER2 monoclonal antibody, rapidly localized to HER2 receptors, and could be used for targeted cancer therapy.

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Treatment of pancreatic cancer with intravenous vitamin C: a case report

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and is often discovered at an advanced stage with few therapeutic options. Current conventional regimens for PDA are associated with significant morbidity, decreased quality of life, and a considerable financial burden. As a result, some patients turn to integrative medicine therapies as an alternate option after a diagnosis of PDA. Intravenous pharmacologic ascorbic acid (PAA) is one such treatment. The use of PAA has been passionately debated for many years, but more recent rigorous scientific research has shown that there are significant blood concentration differences when ascorbic acid is given parenterally when compared to oral dosing. This pharmacologic difference appears to be critical for its role in oncology. Here, we report the use of PAA in a patient with poorly differentiated stage IV PDA as an exclusive chemotherapeutic regimen. The patient survived nearly 4 years after diagnosis, with PAA as his sole treatment, and he achieved objective regression of his disease. He died from sepsis and organ failure from a bowel perforation event. This case illustrates the possibility of PAA to effectively control tumor progression and serve as an adjunct to standard of care PDA chemotherapy regimens. Our patient's experience with PAA should be taken into consideration, along with previous research in cell, animal, and clinical experiments to design future treatment trials.

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Comparison of the effect of the antiandrogen apalutamide (ARN-509) versus bicalutamide on the androgen receptor pathway in prostate cancer cell lines

Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide. We compared the activity of ARN versus bicalutamide on prostate cancer cell lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, as well as the levels of the AR downstream proteins prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or hypoxia. The effects on autophagic flux (LC3A, p62, TFEB, LAMP2a, cathepsin D) and cell metabolism-related enzymes (hypoxia-inducible factor 1α/2α, BNIP3, carbonic anhydrase 9, LDHA, PDH, PDH-kinase) were also studied. The 22Rv1 cell line responded to testosterone by increasing the nuclear entry of AR, AR-V7, and phosphorylated AR and by increasing the levels of prostate-specific antigen and TMPRSS2. This effect was strongly abrogated by ARN and to a clearly lower extent by bicalutamide at 10 μmol/l, both in normoxia and in hypoxia. ARN had a stronger antiproliferative effect than bicalutamide, which was prominent in the 22Rv1 hormone-responsive cell line, and completely repressed cell proliferation at a concentration of 100 μmol/l. No effect of testosterone or of antiandrogens on autophagy flux, hypoxia-related proteins, or metabolism enzyme levels was noted. The PC3 and DU145 cell lines showed poor expression of the proteins and were not responsive to testosterone. On the basis of in-vitro studies, evidence has been reported that ARN is more potent than bicalutamide in blocking the AR pathway in normoxia and in hypoxia. This reflects a more robust, dose-dependent, repressive effect on cell proliferation.

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Immunogenicity moderation effect of interleukin-24 on myelogenous leukemia cells

Previous studies have shown that interleukin-24 (IL-24) has tumor-suppressing activity by multiple pathways. However, the immunogenicity moderation effect of IL-24 on malignant cells has not been explored extensively. In this study, we investigated the role of IL-24 in immunogenicity modulation of the myelogenous leukemia cells. Data show that myelogenous leukemia cells express low levels of immunogenicity molecules. Treatment with IL-24 could enhance leukemia cell immunogenicity, predominantly regulate leukemia cells to produce immune-associated cytokines, and improve the cytotoxic sensitivity of these cells to immune effector cells. IL-24 expression could retard transplanted leukemia cell tumor growth in vivo in athymic nude mice. Moreover, IL-24 had marked effects on downregulating the expression of angiogenesis-related proteins vascular endothelial growth factor, cluster of differentiation (CD) 31, CD34, collagen IV and metastasis-related factors CD147, membrane type-1 matrix metalloproteinase (MMP), and MMP-2 and MMP-9 in transplanted tumors. These findings indicated novel functions of this antitumor gene and characterized IL-24 as a promising agent for further clinical trial for hematologic malignancy immunotherapy.

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