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Nathan Goodyear

Interleukin‐2 enhances the natural killer cell response to Herceptin‐coated H... - 1 views

  • administration of low‐dose IL‐2 results in expansion of a CD3– / CD56+ NK cell population in patients with advanced cancer
  • approximately 20 % will overexpress theHer2 / neu proto‐oncogene
  • In breast cancer, Her2 / neu overexpression is associated with a worse histologicalgrade, decreased relapse‐free and overall survival periods, and altered sensitivity to chemotherapeutic regimens
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  • NK cells are large granular lymphocytes that comprise approximately 10 % of circulating lymphocytes
  • all human NK cells express the CD56 antigen
  • treatment with various concentrations of IL‐2 in vivo may induce distinct functions within the NK cell compartment and, therefore, may have profound effects on NK cell‐mediated cytotoxicity
  • CD56bright
  • CD56dim
  • We show here that ADCC conducted by NK cells in vitro is enhanced by IL‐2 activation and is critically dependent on interactions between FcγRIII on NK cells and Herceptin‐coated tumor targets
  • administration of low‐dose IL‐2 to patients results in the marked expansion of a CD56+ population of immune effectors with the ability to lyse antibody‐coated cancer targets
  • NK cells represented only 7 % of lymphocytes prior to therapy but comprised over 50 % of the population after 10 weeks of low‐dose IL‐2
  • These data suggest that the enhanced ADCC seen following the expansion of NK cells with low‐dose IL‐2 is likely due to an increase in the overall number of NK cells
  • co‐administration of IL‐2 with rhu4D5 mAb will enhance activation of NK cell effector functions
  • Stimulation of NK cells with IL‐2 resulted in a significant increase in the lysis of rhu4D5‐coated targets
  • We have shown that costimulation with IL‐2 plus rhu4D5 results in significant production of IFN‐γ by NK cells with concomitant up‐regulation of cell‐surface activation and adhesion molecules
  • It has been previously demonstrated that continuous low‐dose IL‐2 can expand a CD56+ lymphocyte population, and we have now shown that this cell population is a potent mediator of ADCC against rhu4D5 mAb‐coated Her2 / neu+ targets
  • These results suggest that administration of low‐dose IL‐2 can be used to expand NK cell numbers, while higher doses may be used to enhance their cytolytic capacity in the setting of mAb therapy
  • we have demonstrated that NK cell lysis of Her2 / neu+ breast cancer cell lines in the presence of rhu4D5 mAb is markedly enhanced following stimulation with IL‐2
  • we have presented evidence that administration of low‐dose IL‐2 in vivo results in the expansion of a potent NK cell effector population
  • Our experiments suggest that NK cells costimulated with IL‐2 and immobilized IgG can secrete potent immunomodulatory cytokines which may serve to potentiate the anti‐tumor immune response.
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    low dose IL-2 found to expand NK levels in conjuction in with herceptin in HER-2 positive breast cancer cell lines.
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Nathan Goodyear

Evolving landscape of human epidermal growth factor receptor 2-positive breast cancer t... - 0 views

  • 15%–20%
  • key mediator of cell growth, differentiation, and survival
  • of higher histological grade and are more likely to invade axillary lymph nodes
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  • shortened survival and an increased risk of disease recurrence and metastasis
  • Currently, four HER2-directed agents are approved for the treatment of patients with HER2+ breast cancer: trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1)
  • biosimilars
  • trastuzumab may provide greater benefit when administered concurrently with chemotherapy rather than after, and this has become the standard approach
  • concurrent use of anthracyclines (ie, doxorubicin or epirubicin) and trastuzumab is not recommended because of an increased risk for cardiac toxicity
    • Nathan Goodyear
       
      avoid herceptin in conjuction with antracyclines i.e. doxorubicin
  • Sequential doxorubicin plus cyclophosphamide followed by concomitant paclitaxel or docetaxel and trastuzumab is recommended for most patients
    • Nathan Goodyear
       
      top recommended regimen combination
  • Guidelines also recommend trastuzumab in combination with paclitaxel, docetaxel and carboplatin, or docetaxel and cyclophosphamide, particularly for patients with increased risk for cardiac toxicity or those with small (≤1 cm), node-negative HER2+ tumors
    • Nathan Goodyear
       
      good alternative in patients with increased risk of cardiac toxicity.
  • guidelines recommend up to 1 year of adjuvant trastuzumab
  • Neoadjuvant chemotherapy with trastuzumab is associated with higher rates of pathologic complete response (pCR) than chemotherapy alone or in combination with lapatinib
  • the combination of trastuzumab, lapatinib, and chemotherapy is not recommended because it failed to demonstrate noninferiority versus trastuzumab and chemotherapy in the adjuvant setting
  • recommend the combination of trastuzumab, pertuzumab, and chemotherapy as neoadjuvant treatment for patients with locally advanced HER2+ breast cancer and for some patients (node-positive or tumor ≥2 cm) with early-stage disease
  • neoadjuvant chemotherapy in combination with pertuzumab and trastuzumab reduced the risk of progression or death by 31% and recurrence or death by 40% versus trastuzumab alone
  • Concurrent chemotherapy and HER2-directed therapy improves survival outcomes over chemotherapy alon
  • dual inhibition of HER2 with trastuzumab and pertuzumab in combination with paclitaxel reduced the risk of death or progression by approximately 40% compared with concurrent trastuzumab and paclitaxel
  • the combination of trastuzumab, pertuzumab, and taxane chemotherapy is the preferred first-line regimen
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    HER-2 + breast cancer = appx 15-20% of all breast cancers and is a marker of worse prognosis and an indication for targeted immunotherapy blockade.
Nathan Goodyear

Cyclooxygenase-2 Induces EP1- and HER-2/Neu-Dependent Vascular Endothelial Growth Facto... - 0 views

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    COX-2 is overexpressed in a variety of human cancers i.e. colorectal, prostate, lung adenocarcinoma.  This study hightlights the increased tumor metastatic potential via upregulation of VEGF-C via EP1 and HER-2 dependent pathways.  This upregulation was correlated with survival and mets.
Nathan Goodyear

High expression of ACE2 in HER2 subtype of breast cancer is a marker of poor prognosis - 0 views

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    Decrease survival in breast cancer with HER-2+. Makes since when one understands HER-2
Nathan Goodyear

Anticancer mechanisms of cannabinoids - 0 views

  • modulating key cell signalling pathways involved in the control of cancer cell proliferation and survival
  • cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals
  • Cannabis sativa L. (marijuana)
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  • of the approximately 108 cannabinoids produced by C. sativa, Δ9-tetrahydrocannabinol (thc) is the most relevant because of its high potency and abundance in plant preparations
  • Tetrahydrocannabinol exerts a wide variety of biologic effects by mimicking endogenous substances—the endocannabinoids anandamide3 and 2-arachidonoylglycerol4,5—that engage specific cell-surface cannabinoid receptors
  • the cb2 receptor was initially described to be present in the immune system6, but was more recently shown to also be expressed in cells from other origins
  • transient receptor potential cation channel subfamily V, member 1
  • orphan G protein–coupled receptor 55
  • Most of the effects produced by cannabinoids in the nervous system and in non-neural tissues rely on cb1 receptor activation
  • two major cannabinoid-specific receptors—cb1 and cb2
  • cardiovascular tone, energy metabolism, immunity, and reproduction
  • cannabinoids are well known to exert palliative effects in cancer patients
  • best-established use is the inhibition of chemotherapy-induced nausea and vomiting
  • thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer
  • cannabinoid receptors and their endogenous ligands are both generally upregulated in tumour tissue compared with non-tumour tissue
  • cb2 promotes her2 (human epidermal growth factor receptor 2) pro-oncogenic signalling in breast cancer
  • pharmacologic activation of cannabinoid receptors decreases tumour growth
  • endocannabinoid signalling can also have a tumour-suppressive role
  • pharmacologic stimulation of cb receptors is, in most cases, antitumourigenic. Nonetheless, a few reports have proposed a tumour-promoting effect of cannabinoids
  • most prevalent effect is the induction of cancer cell death by apoptosis and the inhibition of cancer cell proliferation
  • impair tumour angiogenesis and block invasion and metastasis
  • thc and other cannabinoids induce the apoptotic death of glioma cells by cb1- and cb2-dependent stimulation
  • Autophagy is primarily a cytoprotective mechanism, although its activation can also lead to cell death
  • autophagy is important for cannabinoid antineoplastic activity
  • autophagy is upstream of apoptosis in the mechanism of cannabinoid-induced cell death
  • the effect of cannabinoids in hormone- dependent tumours might rely, at least in part, on the ability to interfere with the activation of growth factor receptors
  • glioma cells), pharmacologic blockade of either cb1 or cb2 prevents cannabinoid-induced cell death with similar efficacy
  • other types of cancer cells (pancreatic48, breast24, or hepatic43 carcinoma cells, for example), antagonists of cb2 but not of cb1 inhibit cannabinoid antitumour actions
  • thc promotes cancer cell death in a cb1- or cb2-dependent manner (or both) at lower concentrations
  • cannabidiol (cbd), a phytocannabinoid with a low affinity for cannabinoid receptors15, and other marijuana-derived cannabinoids57 have also been proposed to promote the apoptotic death of cancer cells acting independently of the cb1 and cb2 receptors
  • In cancer cells, cannabinoids block the activation of the vascular endothelial growth factor (vegf) pathway, an inducer of angiogenesi
  • In vascular endothelial cells, cannabinoid receptor activation inhibits proliferation and migration, and induces apoptosis
  • cb1 or cb2 receptor agonists (or both) reduce the formation of distant tumour masses in animal models of both induced and spontaneous metastasis, and inhibit adhesion, migration, and invasiveness of glioma64, breast65,66, lung67,68, and cervical68 cancer cells in culture
  • the ceramide/p8–regulated pathway plays a general role in the antitumour activity of cannabinoids targeting cb1 and cb2
  • cbd, by acting independently of the cb1 and cb2 receptors, produces a remarkable anti-tumour effect—including reduction of invasiveness and metastasis
  • cannabinoids can also enhance immune system–mediated tumour surveillance in some contexts
  • ability of thc to reduce inflammation75,76, an effect that might prevent certain types of cancer
  • recent observations suggest that the combined administration of cannabinoids with other anticancer drugs acts synergistically to reduce tumour growth
  • combined administration of gemcitabine (the benchmark agent for the treatment of pancreatic cancer) and various cannabinoid agonists synergistically reduced the viability of pancreatic cancer cells
  • Other reports indicated that anandamide and HU-210 might also enhance the anticancer activity of paclitaxel89 and 5-fluorouracil90 respectively
  • Combined administration of thc and cbd enhances the anticancer activity of thc and reduces the dose of thc needed to induce its tumour growth-inhibiting activity
  • Preclinical animal models have yielded data indicating that systemic (oral or intraperitoneal) administration of cannabinoids effectively decreases tumour growth
  • Combinations of cannabinoids with classical chemotherapeutic drugs such as the alkylating agent temozolomide (the benchmark agent for the management of glioblastoma80,84) have been shown to produce a strong anticancer action in animal models
  • pharmacologic inhibition of egfr, erk83, or akt enhances the cell-death-promoting action of thc in glioma cultures (unpublished observations by the authors), which suggests that targeting egfr and the akt and erk pathways could enhance the antitumour effect of cannabinoids
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    Good review of the anticancer effects of cananbinoids.
Nathan Goodyear

Androgen receptor positive triple negative breast cancer: Clinicopathologic, prognostic... - 0 views

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    Androgen receptor status helps to determine prognosis in breast cancer. High risk is AR-/HER-2+ and low risk is AR+/HER-2-
Nathan Goodyear

18FDG-PET/CT for predicting the outcome in ER+/HER2- breast cancer patients: comparison... - 0 views

  • our study confirms that baseline PET parameters measured before neoadjuvant treatment have prognostic values in ER+/HER2- locally advanced breast cancer patients
  • It has been suggested that high baseline 18F-fluorodeoxyglucose (18FDG) uptake assessed by high standardized uptake value (SUV) could be associated with poor prognostic factors such as the high histological grade [2] as well as worse survival
  • several teams observed that the change in SUV values early during neoadjuvant treatment could be a good indicator of pathological response and potentially outcome
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  • others studies suggested that baseline 18FDG uptake, which would avoid performing a second examination, could also be of interest to predict patient outcome, especially in ER+/HER2- BC
  • ER+/HER2- BC has less intense 18FDG uptake than some other phenotypes such as TN carcinoma
  • Patients with high baseline 18FDG tumor uptake are at higher risk of early recurrence
  • The 3-year EFS was 78.4% in patients with baseline tumor SUVmax > 8.3 (vs. 94.0% in those with SUVmax ≤ 8.3)
  • event-free survival (EFS)
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    Study finds benefit of PET scan in prognosis in ER+/HER2- breast cancers.
Nathan Goodyear

The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer... - 0 views

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    Curcumin downregulates HER-2 oncoprotein in breast cancer in vitro and in vivo.  IN this study, the combination of taxol and curcumin was comparable to that of taxol and perceptin.
Nathan Goodyear

The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer... - 0 views

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    Curcumin found to decrease HER-2, EGFR and effectively decrease the PI3k/Akt and MAPK signaling pathways.
Nathan Goodyear

Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer. - Pu... - 0 views

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    CB2 overexpression found to upregulate HER2 expression in breast cancer.  This has prognostic and therapeutic value.
Nathan Goodyear

Ki-67 is a prognostic parameter in breast cancer patients: results of a large populatio... - 0 views

  • A wide range of techniques is available to assess tumor cell proliferation such as calculating mitotic figures in stained tissue segments, flow cytometric analysis to determine the proportion of cells being in the S phase of the cell cycle, examination of thymidine-labeling index, proliferating cell nuclear antigen (PCNA), or cyclins E and D
  • Ki-67 is a nuclear protein being associated with cellular proliferation and was originally identified by Gerdes et al.
  • Ki-67 nuclear antigen is expressed in certain phases of the cell cycle namely S, G1, G2, and M phases, but is nonexisting in G0
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  • Ki-67 is also expressed at low levels (<3 % of cells) in ER-negative cells, but not in ER-positive cells
  • A meta-analysis involving 12,155 patients demonstrated that the Ki-67 positivity confers a higher risk of recurrence and a worse survival rate in patients with early breast cancer.
  • high levels of Ki-67 are associated with worse prognoses
  • Ki-67 was associated with worse survival rates
  • associated with proliferation
  • higher tumor stages and higher nodal status were associated with higher Ki-67 quartiles indicating that the more aggressive the tumor is the higher is the percentage of cells positively stained for Ki-67
  • Previous studies were able to demonstrate that a prognostic model, the IHC 4 score, using ER, PR, HER2, and Ki-67 provides similar prognostic information to that in the 21-gene Genomic Health recurrence score
  • ER status has been largely identified as being inversely correlated with Ki-67, with the higher rates of ER positivity shown in the lowest proliferating tumors
  • high levels of Ki-67 are associated with HER2/-neu positivity according to former studies
  • higher values of Ki-67-labeling index were associated with adverse prognostic factors
  • Ki-67-labeling index was associated with larger tumors, higher tumor grade, peritumoral vascular invasion, and HER-2 positivity
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     Increased disease free survival and overall survival in people with breast cancer with ki-67 <15%
Nathan Goodyear

Role of maximum standardized uptake value in fluorodeoxyglucose positron emission tomog... - 0 views

  • 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is an effective and popular technique for evaluating patients before and after breast cancer surgery.
  • Quantitative FDG-PET/CT imaging is becoming prevalent in cancer treatment as it measures glucose metabolism that reflects the growth potential and metabolic activity of malignant tumors
  • The FDG-PET/CT findings of primary lesions in colorectal and lung cancers correlate with metastasis and prognosis because FDG reflects tumor viability
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  • The technique is valuable for predicting the prognosis of patients with recurrent breast cancer and for determining and predicting the outcomes of neoadjuvant chemotherapy
  • FDG-PET/CT is useful not only for evaluating metastasis but also for predicting the prognosis of recurrent breast cancer and measuring treatment effects
  • reports remain limited to small-scale clinical trials of about 100 patients.
  • MaxSUV, which is the most popular FDG-PET/CT value, can vary up to 30&nbsp;% because of differences among PET/CT devices and among the operators who create the images
  • the degree of malignancy would increase with an increase in maxSUV when ER or HER-2 signaling is involved.
  • Factors that determine the rate of cancer progression include T-factor (tumor diameter) and N-factor (presence or absence/number of lymph node metastasis)
  • The prognostic factors applied in breast cancer can be broadly divided into those that determine staging and those that determine biological tumor characteristics
  • Prognosis was previously predicted based on T, N, and M staging, which indicates the degree of progression. However, prognosis is now predicted and treatment regimes are presently selected by also considering ER and HER-2 levels, which determine the nature of the tumor
  • maxSUV presently serves as an indicator of metabolic activity during cancer therapy. For instance, the maxSUV of primary lung and hematological cancer lesions correlates with metastasis and prognosis, whereas maxSUV also seems useful for predicting the prognosis of recurrent breast cancer and in determining and predicting the outcome of neoadjuvant chemotherapy
  • The maxSUV cut-off calculated from ROC curves for recurrence was 3.0
  • Factors that determine the nature of tumors also include ER, HER-2, Ki-67 labeling index, and nuclear grade
  • both ER status and maxSUV as independent prognostic factors
  • maxSUV has a closer correlation with prognosis
  • maxSUV, clinical T-factor and ER were significant prognostic factors
  • Our results showed that maxSUV has the potential to be a novel prognostic factor and that it can be used to determine future therapies
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    Retrospective, multi-facility finds maxSUV can be used in prognosis in cancer.  Others have shown benefit in recurrence risk.  MaxSUV was found to be an independent factor.
Nathan Goodyear

Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeu... - 0 views

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    Good overall review of the HER2 oncogene
Nathan Goodyear

Fat-free mass index and fat mass index percentiles in Caucasians aged 1898 y - 0 views

  • BMI is the sum of FFMI+FMI
  • FMI were significantly higher in elderly subjects as compared to younger ones
  • During menopause and aging39,40 changes in FFM and FM are not adequately picked up by changes in BMI
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  • One advantage of FMI, as compared to the BMI concept, is that it amplifies the relative effect of aging on body fat
  • We believe that the definition of obesity based on relative body fat (ie percentage) remains of great value for the definition of obesity. However, in a situation in which a patient is losing weight without substantially changing his/her relative body fat (as is the case with crash diets), the calculation of FMI will quantitatively reveal the amount of body fat store lost.
  • high sensitivity of FMI (respectively FFMI) to a slight change of body fat stores
  • Sarcopenic obesity has been defined as a low FFM associated with a high body fat
  • relative FFM lower than 73% (ie a relative body fat greater than 27%) in men and a FFM lower than 62% (ie a body fat greater than 38%) in women.
  • FMIs greater than 8.2 kg/m2 in men and 11.8 kg/m2 in women would define the 'overfat' status (rather than the overweight range) in terms of fat mass
  • In young women, FMI averaged 5.5 kg/m2 (range 5th-95th percentile: 3.5-8.7 kg/m2) ie 38% higher than in males
  • the average FMI for young men was 4.0 kg/m2
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    good review of FMI, FFMI, and BMI.
Nathan Goodyear

Rare Occurrence of 3 "H": Hypercalcemia, Hemolytic Anemia and Hodgkin's Lymphoma - 0 views

  • administered zoledronic acid (4&nbsp;mg). Prednisolone (1&nbsp;mg/kg/day) was started and simultaneously, she was administered first cycle of ABVD (Adriamycin: 25&nbsp;mg/m2, Bleomycin: 10&nbsp;U/m2, Vinblastine: 6&nbsp;mg/m2 and Dacarbazine: 375&nbsp;mg/m2), which led to normalisation of serum calcium levels over 4&nbsp;days and improvement in her hemoglobin levels
  • Etiology of anemia in Hodgkin’s lymphoma is multifactorial. Anemia of chronic disease, decreased red cell survival, infiltration of bone marrow by tumor and marrow suppression by chemotherapy/radiotherapy are the common mechanisms
  • Our case had only a transient response to steroids and chemotherapy. Therefore, she was treated with Rituximab which brought hemolysis under control
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  • Mechanism of hypercalcemia in HL has long been suggested to involve extra-renal activation of 1α-hydroxylase leading to production of 1, 25(OD)2 Vitamin D3 or Calcitriol, an active metabolite of Vitamin D, which leads to increased re-absorption of calcium and phosphate from intestine, increased osteoclast activation and bone resorption as well as increased phosphate re-absorption in renal tubules
  • Hypercalcemia of malignancy involves three mechanisms: 1. Humoral hypercalcemia mediated by PTHrP—seen in solid tumors like breast cancer and adult T cell leukemia/lymphoma (ATLL), 2. Direct osteoclast mediated bone resorption due to bony metastasis—seen in solid tumors and multiple myeloma, 3. Calcitriol mediated hypercalcemia—seen in Hodgkin’s and non-Hodgkin’s lymphoma as well as granulomatous disorders like tuberculosis, sarcoidosis, leprosy and disseminated Candidiasis
  • Hypercalcemia in HL is rare and its incidence has been reported as 0.9, 1.6 and 5.4&nbsp;% in different series
  • The source of 1α-hydroxylase in HL has been postulated as monocytes and macrophages infiltrating the tumor akin to tuberculosis or sarcoidosis and is stimulated by IFN-γ secreted by T-lymphocytes
  • Like sarcoidosis, patients with HL exhibit increased sensitivity to Vitamin D supplements and sunlight, which have been found to precipitate hypercalcemia in these patients
  • Classical biochemical profile in Calcitriol mediated hypercalcemia include: an elevated calcium, normal/slightly elevated phosphate, normal 25(OH) Vitamin D, suppressed PTHrP and PTH, elevated Calcitriol and a normal/increased tubular reabsorption of phosphate
  • not been associated with a poorer prognosis and tends to subside after treatment of the underlying disease
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    great read on hypercalcemia in hodgkin's lymphoma.
Nathan Goodyear

Trastuzumab and Interleukin-2 in HER2-positive Metastatic Breast Cancer | Clinical Canc... - 0 views

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    Herceptin and IL-2 increase NK cell expansion when used in conjunction.  The IL-2 was the low dose protocol for 7 weeks.
Nathan Goodyear

Progesterone Receptor Inhibits Aromatase and Inflammatory Response Pathways in Breast C... - 0 views

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    Progesterone receptor (PR) shown to provide an important anti-inflammatory role in breast cancer in this study.  PR shown to increase NF-kappaB inhibitor IkBalpha, shown to inhibit aromatase activity, shown to inhibit COX-2 expression and shown to inhibit HER-2/neu expression.
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Nathan Goodyear

Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-... - 0 views

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    Olive Oil helps in Breast Cancer therapy
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