No abstract available
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Παρασκευή 12 Μαΐου 2017
Effect of Albumin in Combination With Mannitol on Whole-blood Coagulation In Vitro Assessed by Thromboelastometry.
Background: Albumin and mannitol may interfere with hemostasis, but their coinfluence is unclear. We aimed to determine the effects of albumin alone and in combination with mannitol or Ringer acetate (RAC) on hemostasis in crossover in vitro study. Materials and Methods: From citrated fresh whole blood withdrawn from 10 volunteers, we prepared 2.5, 5, 10, 15, and 20 vol% dilutions of 4% albumin (Alb group). Each sample was thereafter diluted by 15% mannitol (Alb/Man group) or RAC (Alb/RAC group) at a ratio of 9:1. Using thromboelastometry, FibTEM (fibrinogen ROTEM) and ExTEM (extrinsic ROTEM) tests were performed. Results: A 20 vol%, but not 2.5 to 15 vol% dilution of albumin caused a prolonged clot formation time, [alpha]-angle decrease, and maximum clot firmness (MCF) weakening compared with undiluted sample (P
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Combination radiotherapy and cantharidin inhibits lung cancer growth through altering tumor infiltrating lymphocytes
Future Oncology Ahead of Print.
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Combination radiotherapy and cantharidin inhibits lung cancer growth through altering tumor infiltrating lymphocytes
Future Oncology Ahead of Print.
http://ift.tt/2qcXkDr
Combination radiotherapy and cantharidin inhibits lung cancer growth through altering tumor infiltrating lymphocytes
Future Oncology Ahead of Print.
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Continuous Regional Anesthesia and Inpatient Rehabilitation for Pediatric Complex Regional Pain Syndrome.
Background: Evidence supports treatment of pediatric complex regional pain syndromes (CRPS) with physical and occupational therapy and cognitive-behavioral therapy. Some patients have persistent pain and/or limb dysfunction despite these treatments. We performed a retrospective study of pediatric patients with CRPS treated by continuous epidural or peripheral perineural local anesthetic infusions along with inpatient rehabilitation at Boston Children's Hospital. Methods: After approval from the institutional review board, electronic medical records were reviewed for patients treated between September 2003 and September 2014. Primary outcomes were pain and functional scores. Data were collected at the first encounter, at follow-up visits between 4 months before and after admission, and daily while inpatient. Changes over time were assessed using Wilcoxon tests with Dunn corrections. Clinical significance of benefit or harm was assessed by the method of Jacobson and Truax. Response predictors were analyzed using linear mixed models and exploratory logarithmic regression analyses. Results: Pain, function, and disability scores improved during hospitalization and in follow-up over a 4-month period. Seventy percent of patients achieved clinically significant benefit (56% for pain reduction and 40% increased functionality, respectively). Univariate and adjusted predictors of favorable outcome included preadmission resting Numeric Pain Rating Scale score of less than 6 (odds ratio, 5.0; P = 0.0164 and subsequent attendance at the Pediatric Pain Rehabilitation Center at Boston Children's Hospital (odds ratio, 5.0; P = 0.0206). Mean pain scores greater than 3 during the regional anesthesia infusion predicted less favorable outcome. Conclusions: Continuous regional anesthesia may be an option to facilitate intensive rehabilitation for selected pediatric patients with CRPS. Further research should help clarify the role of regional anesthesia in a comprehensive management program. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.
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Continuous Intrathecal Infusion of Cannabinoid Receptor Agonists Attenuates Nerve Ligation-Induced Pain in Rats.
Background and Objectives: Cannabinoid receptors (CB1R/CB2R) are known to play important roles in pain transmission. In this study, we investigated the effects of continuous intrathecal infusion of CB1/2R agonists in the L5/6 spinal nerve ligation pain model. Methods: Under isoflurane anesthesia, rats received nerve ligation and intrathecal catheter connected to an infusion pump. After surgery, saline (1 [mu]L/h), CB1/2R agonist WIN55,212-2, CB1R agonist ACEA, or CB2R agonist AM1241 (1 [mu]mol/h) was given intrathecally for 7 days. The mechanical and thermal sensitivities of rat hindpaw were determined by von Frey hair and radiant heat tests. The expression of CB1/2R and protein levels of CB1/2R, Iba1, glial fibrillary acidic protein, and tumor necrosis factor [alpha] were examined by immunofluorescence study and Western blotting. Results: On postligation day 7, rats that received WIN55,212-2, ACEA or AM1241 had significantly higher mean withdrawal thresholds (6.8, 8.4, and 10.2 g) and latencies (6.3, 7.3, and 9.1 seconds) than did saline-treated rats (1.7 g, 2.2 seconds). Cannabinoid receptors were expressed not only in IB4+ (isolectin B4) and CGRP+ (calcitonin gene-related peptide) dorsal root ganglion neurons, their central terminals, and peripheral axons, but also in neurons, microglia, and astrocytes in spinal cord. Cannabinoid receptor agonists enhanced nerve ligation-induced up-regulation of cannabinoid receptor in spinal cord and dorsal root ganglion. Treatment with WIN55,212-2 or AM1241, but not ACEA, markedly reduced nerve ligation-induced up-regulation of Iba1, glial fibrillary acidic protein, and tumor necrosis factor [alpha] in spinal cord. Conclusions: Continuous intrathecal infusion of CB1/2R agonists elicits antinociception in the pain model. The mechanisms might involve their actions on neurons and glial cells. CB2R, but not CB1R, seems to play an important role in the regulation of nerve injury-induced neuroinflammation. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.
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Retrobulbar Block in Pediatric Vitreoretinal Surgery Eliminates the Need for Intraoperative Fentanyl and Postoperative Analgesia: A Randomized Controlled Study.
Background and Objectives: Pediatric ophthalmologic surgery is traditionally accomplished by general anesthesia with opioids, but respiratory depression remains a major concern. Our study compared the efficacy of retrobulbar block with systemic fentanyl on pain, hemodynamic, and stress response in pediatric vitreoretinal surgery. Methods: A prospective double-blind, randomized controlled study was performed comparing retrobulbar block with intravenously administered fentanyl in 28 children aged 1 to 6 years undergoing vitreoretinal surgery. After general anesthesia was induced, retrobulbar block with 0.5% ropivacaine was accomplished in group RB (general anesthesia plus retrobulbar block) (n = 13), and normal saline was injected into retrobulbar space in group F (general anesthesia alone) (n = 15). Fentanyl 0.5 [mu]g/kg was administered when signs of inadequate anesthesia were observed. Results: Respiratory depression (defined as a persistent respiratory rate
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Diskitis, Osteomyelitis, Spinal Epidural Abscess, Meningitis, and Endocarditis Following Sacroiliac Joint Injection for the Treatment of Low-Back Pain in a Patient on Therapy for Hepatitis C Virus.
Objective: Sacroiliac joint injections are frequently performed procedures in the management of acute and chronic low-back pain, including patients with various immunocompromised states. Infectious complications following these procedures along with other spinal injections are rarely reported, but the true incidence is unknown. The purpose of this report is to highlight the devastating neurologic sequela that can occur, and to discuss potential future management strategies. Case Report: We present a patient who developed diskitis, osteomyelitis, spinal epidural abscess, meningitis, and endocarditis from Staphylococcus aureus, all of which developed shortly after a sacroiliac joint injection. The patient was on treatment for hepatitis C virus, and the resulting immunocompromised state likely contributed to the outcome. Conclusions: Immunocompromised patients should be identified prior to treatment, and the small possibility of devastating complications should be thoughtfully weighed against the potential benefit of the procedure. Conservative management should be maximized initially, and if a procedure is done, strict asepsis must be maintained. Prophylaxis for S. aureus should be considered for immunocompromised patients undergoing interventional spine procedures. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.
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Residual Enoxaparin Activity, Anti-Xa Levels, and Concerns About the American Society of Regional Anesthesia and Pain Medicine Anticoagulation Guidelines.
Currently, the American Society of Regional Anesthesia and Pain Medicine (ASRA) anticoagulation guidelines recommend that before the performance of a neuraxial procedure a minimum of 24 hours should elapse following a treatment dose of enoxaparin (1 mg/kg twice daily or 1.5 mg/kg once daily). The guidelines have since their inception also consistently recommended against the routine use of anti-Xa level monitoring for patients receiving enoxaparin. However, we noted in our clinical practice that anti-Xa levels were frequently still elevated despite patients meeting the time-based recommendation for treatment dose enoxaparin. To further investigate the possibility that residual anticoagulant activity may persist longer than 24 hours after a treatment dose of enoxaparin, we assessed anti-Xa level activity in patients presenting for elective surgery. Despite nearly universal compliance with ASRA's anticoagulation guidelines (1 sample was drawn at 23.25 hours), anti-Xa activity was found to be elevated in 11 of 19 patients. While 10 patients had an anti-Xa level within the peak prophylactic range (0.2-0.5 IU/mL), 1 patient's level was found to still be in the peak therapeutic range (0.5-1.0 IU/mL). These findings suggest that significant anticoagulant activity may persist longer than previously appreciated after the last treatment dose of enoxaparin and that the current time-based ASRA recommendation may not be conservative enough. Further research is needed to delineate the level of anti-Xa activity below which it is likely safe to proceed with a neuraxial procedure, but it may be time to reconsider the utility of anti-Xa level monitoring when it is available. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.
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NKG2D ligand targeted Bispecific T Cell Engagers lead to robust antitumor activity against diverse human tumors
Two new bispecific T cell engaging (BiTE) molecules with specificity for NKG2D ligands were developed and functionally characterized. One, huNKG2D-OKT3, was derived from the extracellular portion of the human NKG2D receptor fused to a CD3 binding single-chain variable fragment (scFv), known as OKT3. NKG2D has multiple ligands, including MICA, which are expressed by a variety of malignant cells. A second molecule, B2-OKT3, was created in the tandem scFv BiTE format that targets MICA on tumor cells and CD3 on human T cells. Both BiTEs specifically activated T cells to kill human tumor cell lines. Cytotoxicity by B2-OKT3 but not huNKG2D-OKT3 is blocked by soluble rMICA. The huNKG2D-OKT3 induced greater T cell cytokine production in comparison to B2-OKT3. No T cell pre-treatment was required for IFN production upon co-culture of B2-OKT3 or huNKG2D-OKT3 with T cells and target cells. The effector memory T cell compartment was the primary source of IFN, and culture of T cells and these BiTEs with plate-bound rMICA showed ligand density dependent production of IFN from both CD4+ and CD8+ T cells. There was two-fold more IFN produced per CD8+ T cell and five-fold greater percentage of CD8+ T cells producing IFN compared to CD4+ T cells. In addition, both BiTEs elicited significant anti-tumor responses against human metastatic melanoma tumor samples using autologous or healthy donor T cells. These data demonstrate the robust anti-tumor activity of these NKG2D ligand binding bispecific proteins and support their further development for clinical use.
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Nanoformulation of Olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation
The use of PARP inhibitors in combination with radiation therapy is a promising strategy to locally enhance DNA-damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation-sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of Olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in -H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral Olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13 week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, this data suggests that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions.
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Niclosamide and bicalutamide combination treatment overcomes enzalutamide and bicalutamide resistant prostate cancer
Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide and enzalutamide resistant CWR22Rv1, enzalutamide resistant C4-2B (C4-2B MDVR) and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide and enzalutamide resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can re-sensitize bicalutamide resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy.
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Identification of the serine biosynthesis pathway as a critical component of BRAF inhibitor resistance of melanoma, pancreatic, and non-small cell lung cancer cells
Metastatic melanoma cells commonly acquire resistance to BRAF V600E inhibitors (BRAFis). In this study, we identified serine biosynthesis as a critical mechanism of resistance. Proteomic assays revealed differential protein expression of serine biosynthetic enzymes PHGDH, PSPH, and PSAT1 following vemurafenib (BRAFi) treatment in sensitive versus acquired resistant melanoma cells. Ablation of PHGDH via siRNA sensitized acquired resistant cells to vemurafenib. Inhibiting the folate cycle, directly downstream of serine synthesis, with methotrexate also displayed similar sensitization. Using the DNA damaging drug gemcitabine, we show that gemcitabine pre-treatment sensitized resistant melanoma cells to BRAFi's vemurafenib and dabrafenib. We extended our findings to BRAF WT tumor cell lines that are intrinsically resistant to vemurafenib and dabrafenib. Pre-treatment of pancreatic cancer and non-small cell lung cancer cell lines with sublethal doses of 50nM and 5nM of gemcitabine respectively, enhanced killing by both vemurafenib and dabrafenib. The novel aspects of this study are the direct identification of serine biosynthesis as a critical mechanism of BRAF V600E inhibitor resistance and the first successful example of using gemcitabine + BRAFi's in combination to kill previously drug resistant cancer cells, creating the translational potential of pre-treatment with gemcitabine prior to BRAFi treatment of tumor cells to reverse resistance within the mutational profile and the WT.
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Resistance to RET-inhibition in RET-rearranged NSCLC is mediated by reactivation of RAS/MAPK signaling.
Oncogenic rearrangements in RET are present in 1-2% of lung adenocarcinoma (LAD) patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent anti-proliferative activity in RET fusion positive LC-2/ad LAD cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose-escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived. PR1 and PR2 cell lines retained expression, but not phosphorylation of the RET fusion and lacked evidence of a resistance mutation in the RET kinase domain. Both resistant lines retained activation of the MAPK pathway. Next-generation RNA sequencing revealed an oncogenic NRAS p.Q61K mutation in the PR1 cell. PR1 cell proliferation was preferentially sensitive to siRNA knockdown of NRAS compared to knockdown of RET, more sensitive to MEK inhibition than the parental line, and NRAS-dependence was maintained in the absence of chronic RET inhibition. Expression of NRAS p.Q61K in RET fusion expressing TPC1 cells conferred resistance to ponatinib. PR2 cells exhibited increased expression of EGFR and AXL. EGFR inhibition decreased cell proliferation and phosphorylation of ERK1/2 and AKT in PR2 cells but not LC-2/ad cells. Although AXL inhibition enhanced PR2 sensitivity to afatinib, it was unable to decrease cell proliferation by itself. Thus, EGFR and AXL cooperatively rescued signaling from RET inhibition in the PR2 cells. Collectively, these findings demonstrate that resistance to ponatinib in RET-rearranged LAD is mediated by bypass signaling mechanisms that result in restored RAS/MAPK activation.
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Discovery of a novel small molecule inhibitor that targets PP2A-{beta}-Catenin signaling and restricts tumor growth and metastasis
Molecular hybridization of different pharmacophores to tackle both tumor growth and metastasis by a single molecular entity can be very effective and unique if the hybrid product shows drug like properties. Here, we report synthesis and discovery of a novel small molecule inhibitor of PP2A-β-catenin signaling that limits both in vivo tumor growth and metastasis. Our molecular hybridization approach resulted in cancer cell selectivity and improved drug like properties of the molecule. Inhibiting PP2A and β-Catenin interaction by selectively engaging PR55α binding site, our most potent small molecule inhibitor diminished the expression of active β-Catenin and its target proteins c-Myc and cyclin D1. Further, it promotes robust E-Cadherin upregulation on the cell surface and increases β-Catenin-E-Cadherin association which may prevent dissemination of metastatic cells. Altogether, we report synthesis and mechanistic insight of a novel drug like molecule to differentially target β-Catenin functionality via interacting with a particular subunit of PP2A.
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Beta-catenin inhibitor BC2059 is efficacious as monotherapy or in combination with proteasome inhibitor bortezomib in multiple myeloma
Currently available treatment options are unlikely to be curative for the majority of multiple myeloma (MM) patients, emphasizing a continuing role for the introduction of investigational agents that can overcome drug resistance. The canonical Wnt/beta-catenin signalling pathway, essential for self-renewal, growth and survival, has been found to be dysregulated in MM, particularly in advanced stages of disease. This provides the rationale for evaluating the novel beta-catenin inhibitor BC2059 as monotherapy and in combination with proteasome inhibitors in vitro and in vivo. Here we show nuclear localisation of beta-catenin in human myeloma cell lines (HMCL), consistent with activation of the canonical Wnt pathway. BC2059 attenuates beta-catenin levels, in both the cytoplasm and the nucleus, reducing the transcriptional activity of the TCF4/LEF complex and the expression of its target gene axin2. Treatment of HMCL with BC2059 inhibits proliferation and induces apoptosis in a dose-dependent manner. This is also observed in HMCL-stromal cell co-cultures, mitigating the protective effect afforded by the stroma. Similarly, BC2059 induces apoptosis in primary MM samples in vitro, causing minimal apoptosis on healthy peripheral blood mononuclear cells (PBMC). Furthermore it synergizes with the proteasome inhibitor bortezomib both in HMCL and primary MM samples. Finally, in xenograft models of human myelomatosis, BC2059 delays tumour growth and prolongs survival with minor on-target side effects. Collectively these results demonstrate the efficacy of targeting the Wnt/ beta-catenin pathway with BC2059 both in vitro and in vivo, at clinically achievable doses. These findings support further clinical evaluation of BC2059 for the treatment of MM.
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NKG2D ligand targeted Bispecific T Cell Engagers lead to robust antitumor activity against diverse human tumors
Two new bispecific T cell engaging (BiTE) molecules with specificity for NKG2D ligands were developed and functionally characterized. One, huNKG2D-OKT3, was derived from the extracellular portion of the human NKG2D receptor fused to a CD3 binding single-chain variable fragment (scFv), known as OKT3. NKG2D has multiple ligands, including MICA, which are expressed by a variety of malignant cells. A second molecule, B2-OKT3, was created in the tandem scFv BiTE format that targets MICA on tumor cells and CD3 on human T cells. Both BiTEs specifically activated T cells to kill human tumor cell lines. Cytotoxicity by B2-OKT3 but not huNKG2D-OKT3 is blocked by soluble rMICA. The huNKG2D-OKT3 induced greater T cell cytokine production in comparison to B2-OKT3. No T cell pre-treatment was required for IFN production upon co-culture of B2-OKT3 or huNKG2D-OKT3 with T cells and target cells. The effector memory T cell compartment was the primary source of IFN, and culture of T cells and these BiTEs with plate-bound rMICA showed ligand density dependent production of IFN from both CD4+ and CD8+ T cells. There was two-fold more IFN produced per CD8+ T cell and five-fold greater percentage of CD8+ T cells producing IFN compared to CD4+ T cells. In addition, both BiTEs elicited significant anti-tumor responses against human metastatic melanoma tumor samples using autologous or healthy donor T cells. These data demonstrate the robust anti-tumor activity of these NKG2D ligand binding bispecific proteins and support their further development for clinical use.
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Nanoformulation of Olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation
The use of PARP inhibitors in combination with radiation therapy is a promising strategy to locally enhance DNA-damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation-sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of Olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in -H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral Olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13 week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, this data suggests that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions.
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Niclosamide and bicalutamide combination treatment overcomes enzalutamide and bicalutamide resistant prostate cancer
Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide and enzalutamide resistant CWR22Rv1, enzalutamide resistant C4-2B (C4-2B MDVR) and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide and enzalutamide resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can re-sensitize bicalutamide resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy.
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Identification of the serine biosynthesis pathway as a critical component of BRAF inhibitor resistance of melanoma, pancreatic, and non-small cell lung cancer cells
Metastatic melanoma cells commonly acquire resistance to BRAF V600E inhibitors (BRAFis). In this study, we identified serine biosynthesis as a critical mechanism of resistance. Proteomic assays revealed differential protein expression of serine biosynthetic enzymes PHGDH, PSPH, and PSAT1 following vemurafenib (BRAFi) treatment in sensitive versus acquired resistant melanoma cells. Ablation of PHGDH via siRNA sensitized acquired resistant cells to vemurafenib. Inhibiting the folate cycle, directly downstream of serine synthesis, with methotrexate also displayed similar sensitization. Using the DNA damaging drug gemcitabine, we show that gemcitabine pre-treatment sensitized resistant melanoma cells to BRAFi's vemurafenib and dabrafenib. We extended our findings to BRAF WT tumor cell lines that are intrinsically resistant to vemurafenib and dabrafenib. Pre-treatment of pancreatic cancer and non-small cell lung cancer cell lines with sublethal doses of 50nM and 5nM of gemcitabine respectively, enhanced killing by both vemurafenib and dabrafenib. The novel aspects of this study are the direct identification of serine biosynthesis as a critical mechanism of BRAF V600E inhibitor resistance and the first successful example of using gemcitabine + BRAFi's in combination to kill previously drug resistant cancer cells, creating the translational potential of pre-treatment with gemcitabine prior to BRAFi treatment of tumor cells to reverse resistance within the mutational profile and the WT.
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Resistance to RET-inhibition in RET-rearranged NSCLC is mediated by reactivation of RAS/MAPK signaling.
Oncogenic rearrangements in RET are present in 1-2% of lung adenocarcinoma (LAD) patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent anti-proliferative activity in RET fusion positive LC-2/ad LAD cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose-escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived. PR1 and PR2 cell lines retained expression, but not phosphorylation of the RET fusion and lacked evidence of a resistance mutation in the RET kinase domain. Both resistant lines retained activation of the MAPK pathway. Next-generation RNA sequencing revealed an oncogenic NRAS p.Q61K mutation in the PR1 cell. PR1 cell proliferation was preferentially sensitive to siRNA knockdown of NRAS compared to knockdown of RET, more sensitive to MEK inhibition than the parental line, and NRAS-dependence was maintained in the absence of chronic RET inhibition. Expression of NRAS p.Q61K in RET fusion expressing TPC1 cells conferred resistance to ponatinib. PR2 cells exhibited increased expression of EGFR and AXL. EGFR inhibition decreased cell proliferation and phosphorylation of ERK1/2 and AKT in PR2 cells but not LC-2/ad cells. Although AXL inhibition enhanced PR2 sensitivity to afatinib, it was unable to decrease cell proliferation by itself. Thus, EGFR and AXL cooperatively rescued signaling from RET inhibition in the PR2 cells. Collectively, these findings demonstrate that resistance to ponatinib in RET-rearranged LAD is mediated by bypass signaling mechanisms that result in restored RAS/MAPK activation.
http://ift.tt/2qcMwoV
Discovery of a novel small molecule inhibitor that targets PP2A-{beta}-Catenin signaling and restricts tumor growth and metastasis
Molecular hybridization of different pharmacophores to tackle both tumor growth and metastasis by a single molecular entity can be very effective and unique if the hybrid product shows drug like properties. Here, we report synthesis and discovery of a novel small molecule inhibitor of PP2A-β-catenin signaling that limits both in vivo tumor growth and metastasis. Our molecular hybridization approach resulted in cancer cell selectivity and improved drug like properties of the molecule. Inhibiting PP2A and β-Catenin interaction by selectively engaging PR55α binding site, our most potent small molecule inhibitor diminished the expression of active β-Catenin and its target proteins c-Myc and cyclin D1. Further, it promotes robust E-Cadherin upregulation on the cell surface and increases β-Catenin-E-Cadherin association which may prevent dissemination of metastatic cells. Altogether, we report synthesis and mechanistic insight of a novel drug like molecule to differentially target β-Catenin functionality via interacting with a particular subunit of PP2A.
http://ift.tt/2pHGCsh
Beta-catenin inhibitor BC2059 is efficacious as monotherapy or in combination with proteasome inhibitor bortezomib in multiple myeloma
Currently available treatment options are unlikely to be curative for the majority of multiple myeloma (MM) patients, emphasizing a continuing role for the introduction of investigational agents that can overcome drug resistance. The canonical Wnt/beta-catenin signalling pathway, essential for self-renewal, growth and survival, has been found to be dysregulated in MM, particularly in advanced stages of disease. This provides the rationale for evaluating the novel beta-catenin inhibitor BC2059 as monotherapy and in combination with proteasome inhibitors in vitro and in vivo. Here we show nuclear localisation of beta-catenin in human myeloma cell lines (HMCL), consistent with activation of the canonical Wnt pathway. BC2059 attenuates beta-catenin levels, in both the cytoplasm and the nucleus, reducing the transcriptional activity of the TCF4/LEF complex and the expression of its target gene axin2. Treatment of HMCL with BC2059 inhibits proliferation and induces apoptosis in a dose-dependent manner. This is also observed in HMCL-stromal cell co-cultures, mitigating the protective effect afforded by the stroma. Similarly, BC2059 induces apoptosis in primary MM samples in vitro, causing minimal apoptosis on healthy peripheral blood mononuclear cells (PBMC). Furthermore it synergizes with the proteasome inhibitor bortezomib both in HMCL and primary MM samples. Finally, in xenograft models of human myelomatosis, BC2059 delays tumour growth and prolongs survival with minor on-target side effects. Collectively these results demonstrate the efficacy of targeting the Wnt/ beta-catenin pathway with BC2059 both in vitro and in vivo, at clinically achievable doses. These findings support further clinical evaluation of BC2059 for the treatment of MM.
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Radiotherapeutic care for brain metastases within the Veterans Health Administration (VHA): Practice patterns and guideline correlation
Abstract
Objective
Brain metastases are common and complex to manage. Our goal was to determine practice patterns and adherence to guidelines among VHA Radiation Oncologists (ROs) regarding management of veterans with brain metastases.
Methods
A survey was e-mailed to all VHA ROs. Information queried included employment status, academic appointment, and years in practice. Number of patients with brain metastases seen per year, steroid usage/dosage, use of prognostic scores, and availability of stereotactic radiosurgery (SRS) and palliative care services was asked. ROs were presented with three scenarios involving patients with brain metastases and asked to choose optimal management.
Results
Sixty-four of 82 ROs responded to the questionnaire. All ROs had palliative care services at their facility. Prognostic scores were routinely calculated by 40.6% of ROs. Thirty-one percent of VA facilities performed SRS, and the remaining facilities referred patients out for this technology.
The responses to management of each of the clinical scenarios follows:
-
(Uncontrolled cancer with hemiplegia, >10 brain metastases, poor Karnofsky Performance Score (KPS), and short life-expectancy (LE)): Sixty-six percent of respondents chose whole-brain radiation (WBRT) and 34% percent chose no intervention/supportive care or steroids only.
-
(Controlled cancer with hemiplegia, 4–6 metastases, KPS 70, and LE >4 months): Ninety-five percent of ROs recommended WBRT.
-
(Newly diagnosed cancer without symptoms, 2 brain lesions, KPS 90, and LE >6 months): Forty-four percent would recommend SRS alone while 35.9% would combine SRS with WBRT.
Conclusion
Veterans with brain metastases treated at VHA radiation oncology centers receive evidence-based care and have access to advanced technologies and palliative care services.
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Radiotherapeutic care for brain metastases within the Veterans Health Administration (VHA): Practice patterns and guideline correlation
Abstract
Objective
Brain metastases are common and complex to manage. Our goal was to determine practice patterns and adherence to guidelines among VHA Radiation Oncologists (ROs) regarding management of veterans with brain metastases.
Methods
A survey was e-mailed to all VHA ROs. Information queried included employment status, academic appointment, and years in practice. Number of patients with brain metastases seen per year, steroid usage/dosage, use of prognostic scores, and availability of stereotactic radiosurgery (SRS) and palliative care services was asked. ROs were presented with three scenarios involving patients with brain metastases and asked to choose optimal management.
Results
Sixty-four of 82 ROs responded to the questionnaire. All ROs had palliative care services at their facility. Prognostic scores were routinely calculated by 40.6% of ROs. Thirty-one percent of VA facilities performed SRS, and the remaining facilities referred patients out for this technology.
The responses to management of each of the clinical scenarios follows:
-
(Uncontrolled cancer with hemiplegia, >10 brain metastases, poor Karnofsky Performance Score (KPS), and short life-expectancy (LE)): Sixty-six percent of respondents chose whole-brain radiation (WBRT) and 34% percent chose no intervention/supportive care or steroids only.
-
(Controlled cancer with hemiplegia, 4–6 metastases, KPS 70, and LE >4 months): Ninety-five percent of ROs recommended WBRT.
-
(Newly diagnosed cancer without symptoms, 2 brain lesions, KPS 90, and LE >6 months): Forty-four percent would recommend SRS alone while 35.9% would combine SRS with WBRT.
Conclusion
Veterans with brain metastases treated at VHA radiation oncology centers receive evidence-based care and have access to advanced technologies and palliative care services.
http://ift.tt/2pHE8Kt
Survival prediction of non-small cell lung cancer patients using radiomics analyses of cone-beam CT images
In this study we investigated the interchangeability of planning CT and cone-beam CT (CBCT) extracted radiomic features. Furthermore, a previously described CT based prognostic radiomic signature for non-small cell lung cancer (NSCLC) patients using CBCT based features was validated.
http://ift.tt/2pHrWJG
PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy
Abstract
Background
Nutrient deprivation, hypoxia, radiotherapy and chemotherapy induce endoplasmic reticulum (ER) stress, which activates the so-called unfolded protein response (UPR). Extensive and acute ER stress directs the UPR towards activation of death-triggering pathways. Cancer cells are selected to resist mild and prolonged ER stress by activating pro-survival UPR. We recently found that drug-resistant tumor cells are simultaneously resistant to ER stress-triggered cell death. It is not known if cancer cells adapted to ER stressing conditions acquire a chemoresistant phenotype.
Methods
To investigate this issue, we generated human cancer cells clones with acquired resistance to ER stress from ER stress-sensitive and chemosensitive cells.
Results
ER stress-resistant cells were cross-resistant to multiple chemotherapeutic drugs: such multidrug resistance (MDR) was due to the overexpression of the plasma-membrane transporter MDR related protein 1 (MRP1). Gene profiling analysis unveiled that cells with acquired resistance to ER stress and chemotherapy share higher expression of the UPR sensor protein kinase RNA-like endoplasmic reticulum kinase (PERK), which mediated the erythroid-derived 2-like 2 (Nrf2)-driven transcription of MRP1. Disrupting PERK/Nrf2 axis reversed at the same time resistance to ER stress and chemotherapy. The inducible silencing of PERK reduced tumor growth and restored chemosensitivity in resistant tumor xenografts.
Conclusions
Our work demonstrates for the first time that the adaptation to ER stress in cancer cells produces a MDR phenotype. The PERK/Nrf2/MRP1 axis is responsible for the resistance to ER stress and chemotherapy, and may represent a good therapeutic target in aggressive and resistant tumors.
http://ift.tt/2r2yjMw
PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy
Abstract
Background
Nutrient deprivation, hypoxia, radiotherapy and chemotherapy induce endoplasmic reticulum (ER) stress, which activates the so-called unfolded protein response (UPR). Extensive and acute ER stress directs the UPR towards activation of death-triggering pathways. Cancer cells are selected to resist mild and prolonged ER stress by activating pro-survival UPR. We recently found that drug-resistant tumor cells are simultaneously resistant to ER stress-triggered cell death. It is not known if cancer cells adapted to ER stressing conditions acquire a chemoresistant phenotype.
Methods
To investigate this issue, we generated human cancer cells clones with acquired resistance to ER stress from ER stress-sensitive and chemosensitive cells.
Results
ER stress-resistant cells were cross-resistant to multiple chemotherapeutic drugs: such multidrug resistance (MDR) was due to the overexpression of the plasma-membrane transporter MDR related protein 1 (MRP1). Gene profiling analysis unveiled that cells with acquired resistance to ER stress and chemotherapy share higher expression of the UPR sensor protein kinase RNA-like endoplasmic reticulum kinase (PERK), which mediated the erythroid-derived 2-like 2 (Nrf2)-driven transcription of MRP1. Disrupting PERK/Nrf2 axis reversed at the same time resistance to ER stress and chemotherapy. The inducible silencing of PERK reduced tumor growth and restored chemosensitivity in resistant tumor xenografts.
Conclusions
Our work demonstrates for the first time that the adaptation to ER stress in cancer cells produces a MDR phenotype. The PERK/Nrf2/MRP1 axis is responsible for the resistance to ER stress and chemotherapy, and may represent a good therapeutic target in aggressive and resistant tumors.
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Circularly permuted TRAIL plus thalidomide and dexamethasone versus thalidomide and dexamethasone for relapsed/refractory multiple myeloma: a phase 2 study
Abstract
Purpose
Circularly permuted TRAIL (CPT) has exhibited promising efficacy as a mono-therapy or in combination with thalidomide for patients with multiple myeloma (MM). In this phase 2 study, the safety and efficacy of CPT in combination with thalidomide and dexamethasone (CPT + TD) was evaluated in patients with pretreated relapsed/refractory MM (RRMM).
Methods
Patients who received at least two previous therapies for MM were randomly assigned at a 2:1 ratio to receive treatment with CPT + TD or thalidomide and dexamethasone (TD). The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), duration of response (DOR) and safety.
Results
Overall, 47 patients were assigned to the CPT + TD group, and 24 patients were recruited to the TD group. The ORR in the CPT + TD group was 38.3 vs. 25.0% in the TD group. The median PFS time was 6.7 months for the CPT + TD group and 3.1 months for the TD group. The median DORs for the CPT + TD and TD groups were 7.1 and 3.2 months, respectively. Most of the adverse effects (AEs) were grade 1 or 2. Serious AEs were reported in 19.7% of the patients. No treatment-related deaths were reported.
Conclusion
CPT plus TD could serve as a new therapeutic strategy for patients with RRMM. A randomized, double-blind, placebo-controlled confirmatory study is currently under way.
http://ift.tt/2qcCxy9
Cellular effect and efficacy of carfilzomib depends on cellular net concentration gradient
Abstract
Purpose
The cellular interrelation between intracellular concentrations of unbound carfilzomib, a second-generation proteasome inhibitor, and subsequent proteasome inhibition and effect on cell viability are unknown and were evaluated for two different exposure regimens: A high dose bolus regime of 500 nM for 1 h followed by 47 h in drug-free media vs. 48-h continuous exposure to 10 nM.
Methods
Eight multiple myeloma cell lines were exposed to either one of the two exposure regimens. We quantified the intracellular unbound carfilzomib fraction up to 48 h with a new ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) method. Intracellular concentrations were compared to simultaneously determined cell viability (AlamarBlue® assay) and proteasomal subunit activity (ProGlo™ assay).
Results
Within the first 10 min, the proportional intracellular enrichment of unbound carfilzomib was higher (313 nM; 62.6%) for the exposure to 500 nM compared to 10 nM (1.93 nM; 19.3%). However, after 1 h, an intracellular/extracellular concentration equilibrium was reached with both settings. At low exposure concentrations, drug removal after 1 h diminished carfilzomib efficacy. Moreover, proteasomal activity recovered when exposed to 10 nM for 48 h. However, when exposure concentration was high (500 nM) proteasome inhibition was complete and sustained even with drug removal after 1 h.
Conclusions
We demonstrated that the carfilzomib concentration gradient determines cellular uptake kinetics. The uptake kinetics in turn affects binding, saturation, and activity of the proteasome. Together, these data underscore the importance of steep concentrations for the in vitro efficacy of carfilzomib.
http://ift.tt/2r9iqQZ
Circularly permuted TRAIL plus thalidomide and dexamethasone versus thalidomide and dexamethasone for relapsed/refractory multiple myeloma: a phase 2 study
Abstract
Purpose
Circularly permuted TRAIL (CPT) has exhibited promising efficacy as a mono-therapy or in combination with thalidomide for patients with multiple myeloma (MM). In this phase 2 study, the safety and efficacy of CPT in combination with thalidomide and dexamethasone (CPT + TD) was evaluated in patients with pretreated relapsed/refractory MM (RRMM).
Methods
Patients who received at least two previous therapies for MM were randomly assigned at a 2:1 ratio to receive treatment with CPT + TD or thalidomide and dexamethasone (TD). The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), duration of response (DOR) and safety.
Results
Overall, 47 patients were assigned to the CPT + TD group, and 24 patients were recruited to the TD group. The ORR in the CPT + TD group was 38.3 vs. 25.0% in the TD group. The median PFS time was 6.7 months for the CPT + TD group and 3.1 months for the TD group. The median DORs for the CPT + TD and TD groups were 7.1 and 3.2 months, respectively. Most of the adverse effects (AEs) were grade 1 or 2. Serious AEs were reported in 19.7% of the patients. No treatment-related deaths were reported.
Conclusion
CPT plus TD could serve as a new therapeutic strategy for patients with RRMM. A randomized, double-blind, placebo-controlled confirmatory study is currently under way.
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Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme
Abstract
Purpose
The role of glioma stem cells (GSCs) in cancer progression is currently debated; however, it is hypothesised that this subpopulation is partially responsible for therapeutic resistance observed in glioblastoma multiforme (GBM). Recent studies have shown that the current treatments not only fail to eliminate the GSC population but even promote GSCs through reprogramming of glioma non-stem cells to stem cells. Since the standard GBM treatment often requires supplementation with adjuvant drugs such as antidepressants, their role in the regulation of the heterogeneous nature of GSCs needs evaluation.
Methods
We examined the effects of imipramine, amitriptyline, fluoxetine, mirtazapine, agomelatine, escitalopram, and temozolomide on the phenotypic signature (CD44, Ki67, Nestin, Sox1, and Sox2 expression) of GSCs isolated from a human T98G cell line. These drugs were examined in several models of hypoxia (1% oxygen, 2.5% oxygen, and a hypoxia-reoxygenation model) as compared to the standard laboratory conditions (20% oxygen).
Results
We report that antidepressant drugs, particularly imipramine and amitriptyline, modulate plasticity, silence the GSC profile, and partially reverse the malignant phenotype of GBM. Moreover, we observed that, in contrast to temozolomide, these tricyclic antidepressants stimulated viability and mitochondrial activity in normal human astrocytes.
Conclusion
The ability of phenotype switching from GSC to non-GSC as stimulated by antidepressants (primarily imipramine and amitriptyline) sheds new light on the heterogeneous nature of GSC, as well as the role of antidepressants in adjuvant GBM therapy.
http://ift.tt/2qaJC4i
Cellular effect and efficacy of carfilzomib depends on cellular net concentration gradient
Abstract
Purpose
The cellular interrelation between intracellular concentrations of unbound carfilzomib, a second-generation proteasome inhibitor, and subsequent proteasome inhibition and effect on cell viability are unknown and were evaluated for two different exposure regimens: A high dose bolus regime of 500 nM for 1 h followed by 47 h in drug-free media vs. 48-h continuous exposure to 10 nM.
Methods
Eight multiple myeloma cell lines were exposed to either one of the two exposure regimens. We quantified the intracellular unbound carfilzomib fraction up to 48 h with a new ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) method. Intracellular concentrations were compared to simultaneously determined cell viability (AlamarBlue® assay) and proteasomal subunit activity (ProGlo™ assay).
Results
Within the first 10 min, the proportional intracellular enrichment of unbound carfilzomib was higher (313 nM; 62.6%) for the exposure to 500 nM compared to 10 nM (1.93 nM; 19.3%). However, after 1 h, an intracellular/extracellular concentration equilibrium was reached with both settings. At low exposure concentrations, drug removal after 1 h diminished carfilzomib efficacy. Moreover, proteasomal activity recovered when exposed to 10 nM for 48 h. However, when exposure concentration was high (500 nM) proteasome inhibition was complete and sustained even with drug removal after 1 h.
Conclusions
We demonstrated that the carfilzomib concentration gradient determines cellular uptake kinetics. The uptake kinetics in turn affects binding, saturation, and activity of the proteasome. Together, these data underscore the importance of steep concentrations for the in vitro efficacy of carfilzomib.
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CYT-Rx20 inhibits ovarian cancer cells in vitro and in vivo through oxidative stress-induced DNA damage and cell apoptosis
Abstract
Purpose
The β-nitrostyrene family has been previously reported to possess anticancer property. However, the biological effects of β-nitrostyrenes on ovarian cancer and the underlying mechanisms involved remain unclear. In the present study, we synthesized a β-nitrostyrene derivative, CYT-Rx20 3′-hydroxy-4′-methoxy-β-methyl-β-nitrostyrene), and investigated its anticancer effects and the putative pathways of action in ovarian cancer.
Methods
The effects of CYT-Rx20 were analyzed using cell viability assay, reactive oxygen species (ROS) generation assay, FACS analysis, annexin V staining, immunostaining, comet assay, immunoblotting, soft agar assay, migration assay, nude mice xenograft study and immunohistochemistry.
Results
CYT-Rx20 induced cytotoxicity in ovarian cancer cells by promoting cell apoptosis via ROS generation and DNA damage. CYT-Rx20-induced cell apoptosis, ROS generation and DNA damage were reversed by thiol antioxidants. In addition, CYT-Rx20 inhibited ovarian cancer cell migration by regulating the expression of epithelial to mesenchymal transition (EMT) markers. In nude mice, CYT-Rx20 inhibited ovarian tumor growth accompanied by increased expression of DNA damage marker γH2AX and decreased expression of EMT marker Vimentin.
Conclusions
CYT-Rx20 inhibits ovarian cancer cells in vitro and in vivo, and has the potential to be further developed into an anti-ovarian cancer drug clinically.
http://ift.tt/2ps6gGz
Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme
Abstract
Purpose
The role of glioma stem cells (GSCs) in cancer progression is currently debated; however, it is hypothesised that this subpopulation is partially responsible for therapeutic resistance observed in glioblastoma multiforme (GBM). Recent studies have shown that the current treatments not only fail to eliminate the GSC population but even promote GSCs through reprogramming of glioma non-stem cells to stem cells. Since the standard GBM treatment often requires supplementation with adjuvant drugs such as antidepressants, their role in the regulation of the heterogeneous nature of GSCs needs evaluation.
Methods
We examined the effects of imipramine, amitriptyline, fluoxetine, mirtazapine, agomelatine, escitalopram, and temozolomide on the phenotypic signature (CD44, Ki67, Nestin, Sox1, and Sox2 expression) of GSCs isolated from a human T98G cell line. These drugs were examined in several models of hypoxia (1% oxygen, 2.5% oxygen, and a hypoxia-reoxygenation model) as compared to the standard laboratory conditions (20% oxygen).
Results
We report that antidepressant drugs, particularly imipramine and amitriptyline, modulate plasticity, silence the GSC profile, and partially reverse the malignant phenotype of GBM. Moreover, we observed that, in contrast to temozolomide, these tricyclic antidepressants stimulated viability and mitochondrial activity in normal human astrocytes.
Conclusion
The ability of phenotype switching from GSC to non-GSC as stimulated by antidepressants (primarily imipramine and amitriptyline) sheds new light on the heterogeneous nature of GSC, as well as the role of antidepressants in adjuvant GBM therapy.
from Cancer via ola Kala on Inoreader http://ift.tt/2qaJC4i
via IFTTT
CYT-Rx20 inhibits ovarian cancer cells in vitro and in vivo through oxidative stress-induced DNA damage and cell apoptosis
Abstract
Purpose
The β-nitrostyrene family has been previously reported to possess anticancer property. However, the biological effects of β-nitrostyrenes on ovarian cancer and the underlying mechanisms involved remain unclear. In the present study, we synthesized a β-nitrostyrene derivative, CYT-Rx20 3′-hydroxy-4′-methoxy-β-methyl-β-nitrostyrene), and investigated its anticancer effects and the putative pathways of action in ovarian cancer.
Methods
The effects of CYT-Rx20 were analyzed using cell viability assay, reactive oxygen species (ROS) generation assay, FACS analysis, annexin V staining, immunostaining, comet assay, immunoblotting, soft agar assay, migration assay, nude mice xenograft study and immunohistochemistry.
Results
CYT-Rx20 induced cytotoxicity in ovarian cancer cells by promoting cell apoptosis via ROS generation and DNA damage. CYT-Rx20-induced cell apoptosis, ROS generation and DNA damage were reversed by thiol antioxidants. In addition, CYT-Rx20 inhibited ovarian cancer cell migration by regulating the expression of epithelial to mesenchymal transition (EMT) markers. In nude mice, CYT-Rx20 inhibited ovarian tumor growth accompanied by increased expression of DNA damage marker γH2AX and decreased expression of EMT marker Vimentin.
Conclusions
CYT-Rx20 inhibits ovarian cancer cells in vitro and in vivo, and has the potential to be further developed into an anti-ovarian cancer drug clinically.
from Cancer via ola Kala on Inoreader http://ift.tt/2ps6gGz
via IFTTT
Paraneoplastic acral vascular syndrome in a patient with metastatic melanoma under immune checkpoint blockade
Abstract
Background
Paraneoplastic acral vascular syndrome (PAVS) is a rare phenomenon which is observed in patients with adenocarcinomas and other malignancies. Various potential pathogenic mechanisms such as tumour invasion of sympathetic nerves, hyperviscosity, hypercoagulability, vasoactive tumour-secreted substances, and immunological mechanisms have been suggested.
Case presentation
We report a 60-year-old Caucasian male attended our hospital with a bulky lymph node mass in the right axilla. Extirpation of a lymph node conglomerate revealed 5 melanoma lymph node metastases. Computed tomography showed a liver metastasis (diameter: 3.8 cm), several retroperitoneal metastases, bilateral metastases in the lung hilus, and prepectoral subcutaneous metastases (Stage IV; pTx, N3, M1c). Lactate dehydrogenase and S100B were slightly elevated. Combination therapy of nivolumab (1 mg/kg BW) and ipilimumab (3 mg/kg BW) was started. Three weeks after the first combination therapy he developed progressive erythema, paraesthesia and pain on the fingertips of both hands. Both cold and warmth was not well tolerated by the patient. Complete work-up excluded associated conditions or factors such as haematological disorders, rheumatologic disorders, hypertension, diabetes or smoking. Treatment was initiated with prostacyclin 20 μg twice daily and oral prednisolone 50 mg in tapering dosage. However, prostacyclin was stopped after the first applications because the pain increased during infusion. The second course of nivolumab and ipilimumab was administered. About 2 weeks later, the patient presented with increased pain and small subungual necrosis. We treated the patient with oral analgetics and intravenous prednisolone 500 mg in tapering dosage. On digital substraction angiography occlusion of all arteries of the fingers was demonstrated. Further rheologic and anti-melanoma treatments were refused by the patient. About 2 months after the second course of nivolumab and ipilimumab combination therapy several fingers showed severe gangrene which finally led to amputations of end phalanges of several fingers. Histopathology did not reveal evidence for vasculitis or other primary vascular pathologies. During the following 2 months the patient experienced dramatic progress of his metastatic disease and finally died at multi-organ failure.
Conclusion
Presence of rapidly progressive digital ischemia in an elderly patient with cancer should always raise clinical suspicion of a paraneoplastic phenomenon when other possible causes have been excluded. In patients treated with immune checkpoint inhibitors such as CTLA-4 and PD-L1 blockers PVAS-like events have not been reported so far. However, it is debatable whether immune checkpoint blockade may play a pathogenetic role in the development of PAVS in patients with malignancies.
http://ift.tt/2qb9MEg
Investigation of DNA repair-related SNPs underlying susceptibility to papillary thyroid carcinoma reveals MGMT as a novel candidate gene in Belarusian children exposed to radiation
Abstract
Background
Genetic factors may influence an individual's sensitivity to ionising radiation and therefore modify his/her risk of developing papillary thyroid carcinoma (PTC). Previously, we reported that common single nucleotide polymorphisms (SNPs) within the DNA damage recognition gene ATM contribute to PTC risk in Belarusian children exposed to fallout from the Chernobyl power plant accident. Here we explored in the same population the contribution of a panel of DNA repair-related SNPs in genes acting downstream of ATM.
Methods
The association of 141 SNPs located in 43 DNA repair genes was examined in 75 PTC cases and 254 controls from the Gomel region in Belarus. All subjects were younger than 15 years at the time of the Chernobyl accident. Conditional logistic regressions accounting for radiation dose were performed with PLINK using the additive allelic inheritance model, and a linkage disequilibrium (LD)-based Bonferroni correction was used for correction for multiple testing.
Results
The intronic SNP rs2296675 in MGMT was associated with an increased PTC risk [per minor allele odds ratio (OR) 2.54 95% CI 1.50, 4.30, P per allele = 0.0006, P corr.= 0.05], and gene-wide association testing highlighted a possible role for ERCC5 (P Gene = 0.01) and PCNA (P Gene = 0.05) in addition to MGMT (P Gene = 0.008).
Conclusions
These findings indicate that several genes acting in distinct DNA repair mechanisms contribute to PTC risk. Further investigation is needed to decipher the functional properties of the methyltransferase encoded by MGMT and to understand how alteration of such functions may lead to the development of the most common type of thyroid cancer.
http://ift.tt/2r9XU2H
The role of BRCA1-IRIS in the development and progression of triple negative breast cancers in Egypt: possible link to disease early lesion
Abstract
Background
Breast cancer is the most globally diagnosed female cancer, with the triple negative breast cancer (TNBC) being the most aggressive subtype of the disease. In this study we aimed at comparing the effect of BRCA1-IRIS overexpression on the clinico-pathological characteristics in breast cancer patients with TNBC or non-TNBC in the largest comprehensive cancer center in Egypt.
Methods
To reach this goal, we conducted an observational study at the National Cancer Institute (NCI), Cairo University (Cairo, Egypt). The data on all diagnosed breast cancer patients, between 2009 and 2012, were reviewed. BRCA1-IRIS expression measured using real time RT/PCR in these patients' tumor samples was correlated to tumor characteristics, such as to clinico-pathological features, therapeutic responses, and survival outcomes.
Results
96 patients were enrolled and of these 45% were TNBC, and 55% were of other subtypes (hereafter, non-TNBC). All patients presented with invasive ductal carcinomas. No significant difference was observed for risk factors, such as age and menopausal status between the TNBC and the non-TNBC groups except after BRCA1-IRIS expression was factored in. The majority of the tumors in both groups were ≤5 cm at surgery (p = 0.013). However, in the TNBC group, ≤5 cm tumors were BRCA1-IRIS-overexpressing, whereas in the non-TNBC group they were BRCA1-IRIS-negative (p = 0.00007). Most of the TNBC patients diagnosed with grade 1 or 2 were BRCA1-IRIS-overexpressing, whereas non-TNBCs were IRIS-negative (p = 0.00035). No statistical significance was measured in patients diagnosed with grade 3 tumors. Statistically significant difference between TNBCs and non-TNBCs and tumor stage with regard to BRCA1-IRIS-overexpression was observed. Presence of axillary lymph node metastases was positively associated with BRCA1-IRIS overexpression in TNBC group, and with BRCA1-IRIS-negative status in the non-TNBC group (p = 0.00009). Relapse after chemotherapy (p < 0.00001), and local recurrence/distant metastasis after surgery (p = 0.0028) were more pronounced in TNBC patients with BRCA1-IRIS-overexpressing tumors compared to non-TNBC patients. Finally, decreased disease-free survival in TNBC/BRCA1-IRIS-overexpressing patients compared to TNBC/BRCA1-IRIS-negative patients, and decreased overall survival in TNBC as well as non-TNBC patients was driven by BRCA1-IRIS overexpression.
Conclusions
TNBC/BRCA1-IRIS-overexpressing tumors are more aggressive than TNBC/BRCA1-IRIS-negative or non-TNBC/BRCA1-IRIS-overexpressing or both negative tumors. Further studies are warranted to define whether BRCA1-IRIS drives the early TNBC lesions growth and dissemination and whether it could be used as a diagnostic biomarker and/or therapeutic target for these lesions at an early stage setting.
http://ift.tt/2qbboh5
A French national breast and thyroid cancer screening programme for survivors of childhood, adolescent and young adult (CAYA) cancers - DeNaCaPST programme
Abstract
Background
Survival of childhood, adolescent and young adult (CAYA) cancers has increased with progress in the management of the treatments and has reached more than 80% at 5 years. Nevertheless, these survivors are at great risk of second cancers and non-malignant co-morbidities in later life. DeNaCaPST is a non-interventional study whose aim is to organize a national screening for thyroid cancer and breast cancer in survivors of CAYA cancers. It will study the compliance with international recommendations, with the aim, regarding a breast screening programme, of offering for every woman living in France, at equal risk, an equal screening.
Method
DeNaCaPST trial is coordinated by the INSERM 1018 unit in cooperation with the LEA (French Childhood Cancer Survivor Study for Leukaemia) study's coordinators, the long term follow up committee and the paediatric radiation committee of the SFCE (French Society of Childhood Cancers).
A total of 35 centres spread across metropolitan France and la Reunion will participate. FCCSS (French Childhood Cancer Survivor Study), LEA and central registry will be interrogated to identify eligible patients. To participate, centers agreed to perform a complete "long-term follow-up consultations" according to good clinical practice and the guidelines of the SFCE (French Society of Children Cancers).
Discussion
As survival has greatly improved in childhood cancers, detection of therapy-related malignancies has become a priority even if new radiation techniques will lead to better protection for organs at risk. International guidelines have been put in place because of the evidence for increased lifetime risk of breast and thyroid cancer. DeNaCaPST is based on these international recommendations but it is important to recognize that they are based on expert consensus opinion and are supported by neither nonrandomized observational studies nor prospective randomized trials in this specific population. Over-diagnosis is a phenomenon inherent in any screening program and therefore such programs must be evaluated.
http://ift.tt/2r9Q5tA
Clinical benefit of adding oxaliplatin to standard neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a meta-analysis
Abstract
Background
Neoadjuvant fluoropirimidine (5FU)-based chemoradiotherapy (CRT) has been considered the standard of care for locally advanced rectal cancer (LARC). Whether addition of oxaliplatin (OXP) will further improve clinical outcomes is still debated. We conducted a meta-analysis to evaluate the role of OXP in this patient population.
Methods
Literature searches were carried out in PubMed, Medline and Scopus databases. End points were overall survival (OS), disease free survival (DFS), local failure (LF) and distant failure (DF). Odd ratio (OR) with 95% confidence interval (CI) was calculated using random effects model.
Results
Four randomized trials were included. Patients treated with OXP-5FU CRT had significantly decreased DF (OR = 0.76; 95% CI, 0.60 to 0.97; p = 0.03) compared to standard CRT. OS, DFS and LF were not significantly different between groups.
Conclusions
OXP significantly decreased DF, but does not improve OS e DFS compared to 5FU CRT. Precise role of OXP in neoadjuvant setting of LARC remains to be determined.
http://ift.tt/2qbgtGq
Paraneoplastic acral vascular syndrome in a patient with metastatic melanoma under immune checkpoint blockade
Abstract
Background
Paraneoplastic acral vascular syndrome (PAVS) is a rare phenomenon which is observed in patients with adenocarcinomas and other malignancies. Various potential pathogenic mechanisms such as tumour invasion of sympathetic nerves, hyperviscosity, hypercoagulability, vasoactive tumour-secreted substances, and immunological mechanisms have been suggested.
Case presentation
We report a 60-year-old Caucasian male attended our hospital with a bulky lymph node mass in the right axilla. Extirpation of a lymph node conglomerate revealed 5 melanoma lymph node metastases. Computed tomography showed a liver metastasis (diameter: 3.8 cm), several retroperitoneal metastases, bilateral metastases in the lung hilus, and prepectoral subcutaneous metastases (Stage IV; pTx, N3, M1c). Lactate dehydrogenase and S100B were slightly elevated. Combination therapy of nivolumab (1 mg/kg BW) and ipilimumab (3 mg/kg BW) was started. Three weeks after the first combination therapy he developed progressive erythema, paraesthesia and pain on the fingertips of both hands. Both cold and warmth was not well tolerated by the patient. Complete work-up excluded associated conditions or factors such as haematological disorders, rheumatologic disorders, hypertension, diabetes or smoking. Treatment was initiated with prostacyclin 20 μg twice daily and oral prednisolone 50 mg in tapering dosage. However, prostacyclin was stopped after the first applications because the pain increased during infusion. The second course of nivolumab and ipilimumab was administered. About 2 weeks later, the patient presented with increased pain and small subungual necrosis. We treated the patient with oral analgetics and intravenous prednisolone 500 mg in tapering dosage. On digital substraction angiography occlusion of all arteries of the fingers was demonstrated. Further rheologic and anti-melanoma treatments were refused by the patient. About 2 months after the second course of nivolumab and ipilimumab combination therapy several fingers showed severe gangrene which finally led to amputations of end phalanges of several fingers. Histopathology did not reveal evidence for vasculitis or other primary vascular pathologies. During the following 2 months the patient experienced dramatic progress of his metastatic disease and finally died at multi-organ failure.
Conclusion
Presence of rapidly progressive digital ischemia in an elderly patient with cancer should always raise clinical suspicion of a paraneoplastic phenomenon when other possible causes have been excluded. In patients treated with immune checkpoint inhibitors such as CTLA-4 and PD-L1 blockers PVAS-like events have not been reported so far. However, it is debatable whether immune checkpoint blockade may play a pathogenetic role in the development of PAVS in patients with malignancies.
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Investigation of DNA repair-related SNPs underlying susceptibility to papillary thyroid carcinoma reveals MGMT as a novel candidate gene in Belarusian children exposed to radiation
Abstract
Background
Genetic factors may influence an individual's sensitivity to ionising radiation and therefore modify his/her risk of developing papillary thyroid carcinoma (PTC). Previously, we reported that common single nucleotide polymorphisms (SNPs) within the DNA damage recognition gene ATM contribute to PTC risk in Belarusian children exposed to fallout from the Chernobyl power plant accident. Here we explored in the same population the contribution of a panel of DNA repair-related SNPs in genes acting downstream of ATM.
Methods
The association of 141 SNPs located in 43 DNA repair genes was examined in 75 PTC cases and 254 controls from the Gomel region in Belarus. All subjects were younger than 15 years at the time of the Chernobyl accident. Conditional logistic regressions accounting for radiation dose were performed with PLINK using the additive allelic inheritance model, and a linkage disequilibrium (LD)-based Bonferroni correction was used for correction for multiple testing.
Results
The intronic SNP rs2296675 in MGMT was associated with an increased PTC risk [per minor allele odds ratio (OR) 2.54 95% CI 1.50, 4.30, P per allele = 0.0006, P corr.= 0.05], and gene-wide association testing highlighted a possible role for ERCC5 (P Gene = 0.01) and PCNA (P Gene = 0.05) in addition to MGMT (P Gene = 0.008).
Conclusions
These findings indicate that several genes acting in distinct DNA repair mechanisms contribute to PTC risk. Further investigation is needed to decipher the functional properties of the methyltransferase encoded by MGMT and to understand how alteration of such functions may lead to the development of the most common type of thyroid cancer.
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The role of BRCA1-IRIS in the development and progression of triple negative breast cancers in Egypt: possible link to disease early lesion
Abstract
Background
Breast cancer is the most globally diagnosed female cancer, with the triple negative breast cancer (TNBC) being the most aggressive subtype of the disease. In this study we aimed at comparing the effect of BRCA1-IRIS overexpression on the clinico-pathological characteristics in breast cancer patients with TNBC or non-TNBC in the largest comprehensive cancer center in Egypt.
Methods
To reach this goal, we conducted an observational study at the National Cancer Institute (NCI), Cairo University (Cairo, Egypt). The data on all diagnosed breast cancer patients, between 2009 and 2012, were reviewed. BRCA1-IRIS expression measured using real time RT/PCR in these patients' tumor samples was correlated to tumor characteristics, such as to clinico-pathological features, therapeutic responses, and survival outcomes.
Results
96 patients were enrolled and of these 45% were TNBC, and 55% were of other subtypes (hereafter, non-TNBC). All patients presented with invasive ductal carcinomas. No significant difference was observed for risk factors, such as age and menopausal status between the TNBC and the non-TNBC groups except after BRCA1-IRIS expression was factored in. The majority of the tumors in both groups were ≤5 cm at surgery (p = 0.013). However, in the TNBC group, ≤5 cm tumors were BRCA1-IRIS-overexpressing, whereas in the non-TNBC group they were BRCA1-IRIS-negative (p = 0.00007). Most of the TNBC patients diagnosed with grade 1 or 2 were BRCA1-IRIS-overexpressing, whereas non-TNBCs were IRIS-negative (p = 0.00035). No statistical significance was measured in patients diagnosed with grade 3 tumors. Statistically significant difference between TNBCs and non-TNBCs and tumor stage with regard to BRCA1-IRIS-overexpression was observed. Presence of axillary lymph node metastases was positively associated with BRCA1-IRIS overexpression in TNBC group, and with BRCA1-IRIS-negative status in the non-TNBC group (p = 0.00009). Relapse after chemotherapy (p < 0.00001), and local recurrence/distant metastasis after surgery (p = 0.0028) were more pronounced in TNBC patients with BRCA1-IRIS-overexpressing tumors compared to non-TNBC patients. Finally, decreased disease-free survival in TNBC/BRCA1-IRIS-overexpressing patients compared to TNBC/BRCA1-IRIS-negative patients, and decreased overall survival in TNBC as well as non-TNBC patients was driven by BRCA1-IRIS overexpression.
Conclusions
TNBC/BRCA1-IRIS-overexpressing tumors are more aggressive than TNBC/BRCA1-IRIS-negative or non-TNBC/BRCA1-IRIS-overexpressing or both negative tumors. Further studies are warranted to define whether BRCA1-IRIS drives the early TNBC lesions growth and dissemination and whether it could be used as a diagnostic biomarker and/or therapeutic target for these lesions at an early stage setting.
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A French national breast and thyroid cancer screening programme for survivors of childhood, adolescent and young adult (CAYA) cancers - DeNaCaPST programme
Abstract
Background
Survival of childhood, adolescent and young adult (CAYA) cancers has increased with progress in the management of the treatments and has reached more than 80% at 5 years. Nevertheless, these survivors are at great risk of second cancers and non-malignant co-morbidities in later life. DeNaCaPST is a non-interventional study whose aim is to organize a national screening for thyroid cancer and breast cancer in survivors of CAYA cancers. It will study the compliance with international recommendations, with the aim, regarding a breast screening programme, of offering for every woman living in France, at equal risk, an equal screening.
Method
DeNaCaPST trial is coordinated by the INSERM 1018 unit in cooperation with the LEA (French Childhood Cancer Survivor Study for Leukaemia) study's coordinators, the long term follow up committee and the paediatric radiation committee of the SFCE (French Society of Childhood Cancers).
A total of 35 centres spread across metropolitan France and la Reunion will participate. FCCSS (French Childhood Cancer Survivor Study), LEA and central registry will be interrogated to identify eligible patients. To participate, centers agreed to perform a complete "long-term follow-up consultations" according to good clinical practice and the guidelines of the SFCE (French Society of Children Cancers).
Discussion
As survival has greatly improved in childhood cancers, detection of therapy-related malignancies has become a priority even if new radiation techniques will lead to better protection for organs at risk. International guidelines have been put in place because of the evidence for increased lifetime risk of breast and thyroid cancer. DeNaCaPST is based on these international recommendations but it is important to recognize that they are based on expert consensus opinion and are supported by neither nonrandomized observational studies nor prospective randomized trials in this specific population. Over-diagnosis is a phenomenon inherent in any screening program and therefore such programs must be evaluated.
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Clinical benefit of adding oxaliplatin to standard neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a meta-analysis
Abstract
Background
Neoadjuvant fluoropirimidine (5FU)-based chemoradiotherapy (CRT) has been considered the standard of care for locally advanced rectal cancer (LARC). Whether addition of oxaliplatin (OXP) will further improve clinical outcomes is still debated. We conducted a meta-analysis to evaluate the role of OXP in this patient population.
Methods
Literature searches were carried out in PubMed, Medline and Scopus databases. End points were overall survival (OS), disease free survival (DFS), local failure (LF) and distant failure (DF). Odd ratio (OR) with 95% confidence interval (CI) was calculated using random effects model.
Results
Four randomized trials were included. Patients treated with OXP-5FU CRT had significantly decreased DF (OR = 0.76; 95% CI, 0.60 to 0.97; p = 0.03) compared to standard CRT. OS, DFS and LF were not significantly different between groups.
Conclusions
OXP significantly decreased DF, but does not improve OS e DFS compared to 5FU CRT. Precise role of OXP in neoadjuvant setting of LARC remains to be determined.
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Negative Psychological Consequences of Breast Cancer among Recently Diagnosed Ethnically Diverse Women
Abstract
Objective
Breast cancer has psychological consequences that impact quality of life (QOL). We examined factors associated with negative psychological consequences of a breast cancer diagnosis, in a diverse sample of 910 recently diagnosed patients (378 African-American, 372 White, and 160 Latina).
Methods
Patients completed an in-person interview as part of the Breast Cancer Care in Chicago study within an average of four months from diagnosis. The Cockburn negative psychological consequences of breast cancer screening scale was revised to focus on a breast cancer diagnosis. Path analysis assessed predictors of psychological consequences and potential mediators between race/ethnicity and psychological consequences.
Results
Compared to White counterparts, bivariate analysis showed African-American (β = 1.4, p < 0.05) and Latina (β = 3.6, p < 0.001) women reported greater psychological consequences. Strongest predictors (P < 0.05 for all) included unmet social support (β = 0.38), and provider trust (β = 0.12), followed by stage at diagnosis (β = 0.10) and perceived neighborhood social disorder (β = 0.09).The strongest mediator between race/ethnicity and psychological consequences was unmet social support.
Conclusions
African-American and Latina women reported greater psychological consequences related to their breast cancer diagnosis; this disparity was mediated by differences in unmet social support. Social support represents a promising point of intervention.
http://ift.tt/2qbaCkc
Negative Psychological Consequences of Breast Cancer among Recently Diagnosed Ethnically Diverse Women
Abstract
Objective
Breast cancer has psychological consequences that impact quality of life (QOL). We examined factors associated with negative psychological consequences of a breast cancer diagnosis, in a diverse sample of 910 recently diagnosed patients (378 African-American, 372 White, and 160 Latina).
Methods
Patients completed an in-person interview as part of the Breast Cancer Care in Chicago study within an average of four months from diagnosis. The Cockburn negative psychological consequences of breast cancer screening scale was revised to focus on a breast cancer diagnosis. Path analysis assessed predictors of psychological consequences and potential mediators between race/ethnicity and psychological consequences.
Results
Compared to White counterparts, bivariate analysis showed African-American (β = 1.4, p < 0.05) and Latina (β = 3.6, p < 0.001) women reported greater psychological consequences. Strongest predictors (P < 0.05 for all) included unmet social support (β = 0.38), and provider trust (β = 0.12), followed by stage at diagnosis (β = 0.10) and perceived neighborhood social disorder (β = 0.09).The strongest mediator between race/ethnicity and psychological consequences was unmet social support.
Conclusions
African-American and Latina women reported greater psychological consequences related to their breast cancer diagnosis; this disparity was mediated by differences in unmet social support. Social support represents a promising point of intervention.
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Effects of definitive and salvage radiotherapy on the distribution of lymphocyte subpopulations in prostate cancer patients
Abstract
Background
Radiotherapy (RT) is an established treatment for patients with primary and recurrent prostate cancer. Herein, the effects of definitive and salvage RT on the composition of lymphocyte subpopulations were investigated in patients with prostate cancer to study potential immune effects.
Patients and methods
A total of 33 prostate cancer patients were treated with definitive (n = 10) or salvage RT (n = 23) after biochemical relapse. The absolute number of lymphocytes and the distribution of lymphocyte subpopulations were analyzed by multiparameter flow cytometry before RT, at the end of RT, and in the follow-up period.
Results
Absolute lymphocyte counts decreased significantly after RT in both patient groups and a significant drop was observed in the percentage of B cells directly after RT from 10.1 ± 1.3 to 6.0 ± 0.7% in patients with definitive RT and from 9.2 ± 0.8 to 5.8 ± 0.7% in patients with salvage RT. In contrast, the percentages of T and natural killer (NK) cells remained unaltered directly after RT in both patient groups. However, 1 year after RT, the percentage of CD3+ T cells was significantly lower in patients with definitive and salvage RT. The percentage of regulatory T cells was slightly upregulated in primary prostate cancer patients after definitive RT, but not after salvage RT.
Conclusion
Definitive and salvage RT exert similar effects on the composition of lymphocyte subpopulations in prostate cancer patients. Total lymphocyte counts are lower in both patient groups compared to healthy controls and further decreased after RT. B cells are more sensitive to definitive and salvage RT than T and NK cells.
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Hyperfractionated accelerated radiation therapy plus cetuximab plus cisplatin chemotherapy in locally advanced inoperable squamous cell carcinoma of the head and neck
Abstract
Background
Cetuximab (CET) is a potent inhibitor of the epidermal growth factor receptor and has been shown to have activity in squamous cell carcinoma of the head and neck (SCCHN). We conducted a single-arm phase II trial of a combination therapy comprising cisplatin (CIS), CET and hyperfractionated accelerated radiotherapy (HART).
Patients and methods
Patients with UICC stage III or IVA/B, M0 SCCHN were enrolled and treated with an initial dose of CET (400 mg/m2) and then with a weekly dosage of 250 mg/m2 during HART. HART was started with a prescribed dosage of 2.0 Gy per day for 3 weeks, followed by 1.4 Gy twice daily to a total dose of 70.6 Gy to the gross tumour volume. CIS (40 mg/m2) was administered weekly (days 1, 8, 15, 22, 29 and 36). The primary objective of the phase II study was to determine the 2‑year progression-free survival (PFS).
Results
Between November 2007 and November 2010, a total of 74 patients were enrolled in the study, of whom 65 were evaluable (83% were men). Median age was 56 years (range 37–69 years). An Oropharyngeal primary tumour was diagnosed in 49%, T4a,b in 65% and N2/3 in 96% of the patients. Of these patients, 85% were smokers or ex-smokers. Complete remission (CR) was observed in 23 patients (35%). The most common toxicity grade was ≥3, including mucositis (58%) and dysphagia (52%). The 2‑ and 5‑year overall survival rates were 64 and 41%, the 2‑ and 5‑year PFS rates were 45 and 32%, and the 2‑ and 5‑year locoregional control rates were 47 and 33%, respectively.
Conclusion
The combination of weekly CIS with HART plus CET is a feasible regimen for these unfavourable smoking-induced cancers. However, the parallel US study (RTOG 0522) showed no advantage of the enhanced triple therapy compared to chemoradiotherapy alone.
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MicroRNA-195 inhibits human gastric cancer by directly targeting basic fibroblast growth factor
Abstract
Purpose
Gastric cancer (GC) is one of the fatal malignancies worldwide with high occurrences but poor outcomes. bFGF has been shown to play significant roles in GC. Yet, whether bFGF affects the development of GC is less studied.
Methods
MicroRNA assays, real-time PCR, and western blot were conducted for expression analysis of miR-195-5p and basic fibroblast growth factor (bFGF). Luciferase activity was measured with mutated bFGF 3′-UTR sequence at the 3′ end of the luciferase gene. Two GC cell lines, SNU-1 and KATO-3 overexpressing miR-195-5p and bFGF were subjected to wound healing assay and transwell invasion assay. Mouse GC xenograft model was established and subjected to tumor size analysis.
Results
Expression levels of miR-195-5p and bFGF showed negative correlation in human GC tissues. MiR-195-5p directly targeted bFGF 3′-UTR as demonstrated by luciferase activity assay. MiR-195-5p, through downregulating bFGF, inhibited the migration and invasion of SNU-1 and KATO-3 cells, as well as tumorigenesis in a xenograft mouse model, which could be restored by re-introduction of bFGF.
Conclusions
MiR-195-5p inhibits tumorigenesis of GC through suppressing bFGF, which supports both miR-195-5p and bFGF as potential therapeutic targets in the treatment of GC.
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MicroRNA-195 inhibits human gastric cancer by directly targeting basic fibroblast growth factor
Abstract
Purpose
Gastric cancer (GC) is one of the fatal malignancies worldwide with high occurrences but poor outcomes. bFGF has been shown to play significant roles in GC. Yet, whether bFGF affects the development of GC is less studied.
Methods
MicroRNA assays, real-time PCR, and western blot were conducted for expression analysis of miR-195-5p and basic fibroblast growth factor (bFGF). Luciferase activity was measured with mutated bFGF 3′-UTR sequence at the 3′ end of the luciferase gene. Two GC cell lines, SNU-1 and KATO-3 overexpressing miR-195-5p and bFGF were subjected to wound healing assay and transwell invasion assay. Mouse GC xenograft model was established and subjected to tumor size analysis.
Results
Expression levels of miR-195-5p and bFGF showed negative correlation in human GC tissues. MiR-195-5p directly targeted bFGF 3′-UTR as demonstrated by luciferase activity assay. MiR-195-5p, through downregulating bFGF, inhibited the migration and invasion of SNU-1 and KATO-3 cells, as well as tumorigenesis in a xenograft mouse model, which could be restored by re-introduction of bFGF.
Conclusions
MiR-195-5p inhibits tumorigenesis of GC through suppressing bFGF, which supports both miR-195-5p and bFGF as potential therapeutic targets in the treatment of GC.
http://ift.tt/2qBzFhG
MicroRNA-195 inhibits human gastric cancer by directly targeting basic fibroblast growth factor
Abstract
Purpose
Gastric cancer (GC) is one of the fatal malignancies worldwide with high occurrences but poor outcomes. bFGF has been shown to play significant roles in GC. Yet, whether bFGF affects the development of GC is less studied.
Methods
MicroRNA assays, real-time PCR, and western blot were conducted for expression analysis of miR-195-5p and basic fibroblast growth factor (bFGF). Luciferase activity was measured with mutated bFGF 3′-UTR sequence at the 3′ end of the luciferase gene. Two GC cell lines, SNU-1 and KATO-3 overexpressing miR-195-5p and bFGF were subjected to wound healing assay and transwell invasion assay. Mouse GC xenograft model was established and subjected to tumor size analysis.
Results
Expression levels of miR-195-5p and bFGF showed negative correlation in human GC tissues. MiR-195-5p directly targeted bFGF 3′-UTR as demonstrated by luciferase activity assay. MiR-195-5p, through downregulating bFGF, inhibited the migration and invasion of SNU-1 and KATO-3 cells, as well as tumorigenesis in a xenograft mouse model, which could be restored by re-introduction of bFGF.
Conclusions
MiR-195-5p inhibits tumorigenesis of GC through suppressing bFGF, which supports both miR-195-5p and bFGF as potential therapeutic targets in the treatment of GC.
http://ift.tt/2qBzFhG
MicroRNA-195 inhibits human gastric cancer by directly targeting basic fibroblast growth factor
Abstract
Purpose
Gastric cancer (GC) is one of the fatal malignancies worldwide with high occurrences but poor outcomes. bFGF has been shown to play significant roles in GC. Yet, whether bFGF affects the development of GC is less studied.
Methods
MicroRNA assays, real-time PCR, and western blot were conducted for expression analysis of miR-195-5p and basic fibroblast growth factor (bFGF). Luciferase activity was measured with mutated bFGF 3′-UTR sequence at the 3′ end of the luciferase gene. Two GC cell lines, SNU-1 and KATO-3 overexpressing miR-195-5p and bFGF were subjected to wound healing assay and transwell invasion assay. Mouse GC xenograft model was established and subjected to tumor size analysis.
Results
Expression levels of miR-195-5p and bFGF showed negative correlation in human GC tissues. MiR-195-5p directly targeted bFGF 3′-UTR as demonstrated by luciferase activity assay. MiR-195-5p, through downregulating bFGF, inhibited the migration and invasion of SNU-1 and KATO-3 cells, as well as tumorigenesis in a xenograft mouse model, which could be restored by re-introduction of bFGF.
Conclusions
MiR-195-5p inhibits tumorigenesis of GC through suppressing bFGF, which supports both miR-195-5p and bFGF as potential therapeutic targets in the treatment of GC.
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Drug development and registration: Challenges and opportunities in ovarian cancer
Many challenges and opportunities present themselves for improving the care and outcome of patients with ovarian cancer. Open, ongoing discussion between regulatory, National Cancer Institute, academic, and pharmaceutical investigators and scientists will lead to benefit and an enhanced understanding of ovarian cancer. See also pages 000-000
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Regulatory considerations on endpoints in ovarian cancer drug development
Ovarian cancer remains a disease entity that is responsible for considerable morbidity and mortality among women worldwide. Modern drug research pipelines and accelerated drug development timelines applied to other disease entities have begun to make an impact on treatment options for patients with advanced ovarian cancer, as exemplified by the recent accelerated approval of 2 agents for this disease as the forerunners of a growing number of registrational trials. Regulatory flexibility for this serious and life-threatening condition spurs the consideration of intermediate endpoints for regulatory trial design, including potential applications in the development of newer therapeutic classes such as targeted therapies and immunotherapies for patients with advanced ovarian cancer. Cancer 2017. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
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Drug development and registration: Challenges and opportunities in ovarian cancer
Many challenges and opportunities present themselves for improving the care and outcome of patients with ovarian cancer. Open, ongoing discussion between regulatory, National Cancer Institute, academic, and pharmaceutical investigators and scientists will lead to benefit and an enhanced understanding of ovarian cancer. See also pages 000-000
http://ift.tt/2qbLZUc
Regulatory considerations on endpoints in ovarian cancer drug development
Ovarian cancer remains a disease entity that is responsible for considerable morbidity and mortality among women worldwide. Modern drug research pipelines and accelerated drug development timelines applied to other disease entities have begun to make an impact on treatment options for patients with advanced ovarian cancer, as exemplified by the recent accelerated approval of 2 agents for this disease as the forerunners of a growing number of registrational trials. Regulatory flexibility for this serious and life-threatening condition spurs the consideration of intermediate endpoints for regulatory trial design, including potential applications in the development of newer therapeutic classes such as targeted therapies and immunotherapies for patients with advanced ovarian cancer. Cancer 2017. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
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Cellular effect and efficacy of carfilzomib depends on cellular net concentration gradient
Abstract
Purpose
The cellular interrelation between intracellular concentrations of unbound carfilzomib, a second-generation proteasome inhibitor, and subsequent proteasome inhibition and effect on cell viability are unknown and were evaluated for two different exposure regimens: A high dose bolus regime of 500 nM for 1 h followed by 47 h in drug-free media vs. 48-h continuous exposure to 10 nM.
Methods
Eight multiple myeloma cell lines were exposed to either one of the two exposure regimens. We quantified the intracellular unbound carfilzomib fraction up to 48 h with a new ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) method. Intracellular concentrations were compared to simultaneously determined cell viability (AlamarBlue® assay) and proteasomal subunit activity (ProGlo™ assay).
Results
Within the first 10 min, the proportional intracellular enrichment of unbound carfilzomib was higher (313 nM; 62.6%) for the exposure to 500 nM compared to 10 nM (1.93 nM; 19.3%). However, after 1 h, an intracellular/extracellular concentration equilibrium was reached with both settings. At low exposure concentrations, drug removal after 1 h diminished carfilzomib efficacy. Moreover, proteasomal activity recovered when exposed to 10 nM for 48 h. However, when exposure concentration was high (500 nM) proteasome inhibition was complete and sustained even with drug removal after 1 h.
Conclusions
We demonstrated that the carfilzomib concentration gradient determines cellular uptake kinetics. The uptake kinetics in turn affects binding, saturation, and activity of the proteasome. Together, these data underscore the importance of steep concentrations for the in vitro efficacy of carfilzomib.
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Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme
Abstract
Purpose
The role of glioma stem cells (GSCs) in cancer progression is currently debated; however, it is hypothesised that this subpopulation is partially responsible for therapeutic resistance observed in glioblastoma multiforme (GBM). Recent studies have shown that the current treatments not only fail to eliminate the GSC population but even promote GSCs through reprogramming of glioma non-stem cells to stem cells. Since the standard GBM treatment often requires supplementation with adjuvant drugs such as antidepressants, their role in the regulation of the heterogeneous nature of GSCs needs evaluation.
Methods
We examined the effects of imipramine, amitriptyline, fluoxetine, mirtazapine, agomelatine, escitalopram, and temozolomide on the phenotypic signature (CD44, Ki67, Nestin, Sox1, and Sox2 expression) of GSCs isolated from a human T98G cell line. These drugs were examined in several models of hypoxia (1% oxygen, 2.5% oxygen, and a hypoxia-reoxygenation model) as compared to the standard laboratory conditions (20% oxygen).
Results
We report that antidepressant drugs, particularly imipramine and amitriptyline, modulate plasticity, silence the GSC profile, and partially reverse the malignant phenotype of GBM. Moreover, we observed that, in contrast to temozolomide, these tricyclic antidepressants stimulated viability and mitochondrial activity in normal human astrocytes.
Conclusion
The ability of phenotype switching from GSC to non-GSC as stimulated by antidepressants (primarily imipramine and amitriptyline) sheds new light on the heterogeneous nature of GSC, as well as the role of antidepressants in adjuvant GBM therapy.
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Prognostic value of ABO blood types in young patients with breast cancer; a nationwide study in Korean Breast Cancer Society
Abstract
The purpose of this study was to investigate the relationship between ABO blood types and breast cancer survival in young Korean patients. This was a retrospective study of 115,474 patients who were surgically treated for primary breast cancer between 1987 and 2011 in Korea. All data were collected by the Korean Breast Cancer Society (KBCS) online breast cancer registry. Each hospital serologically examined the ABO blood types of patients before surgery. There was no significant difference in overall survival (OS) or breast cancer-specific survival (BCSS) among ABO blood types. Type of surgery; T stage; N stage; histologic grade; status of estrogen receptor, progesterone receptor, and HER2; and chemotherapy were significant prognostic factors of OS and BCSS in univariate analysis and multivariate analyses. Compared to women with blood type O, there was a difference in OS and BCSS for blood type A, blood type B, or blood type AB. Compared to blood group non-O, patients with blood group O were more likely to have favorable prognosis when younger than 40 years. Further follow-up studies are necessary to clarify the role of the impact of ABO blood types on prognosis of breast cancer.
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