Double Blockage Research Articles

Abstract P4-12-14: Assessing patients perceptions on hormone therapy for breast cancer: Insights from a Brazilian patient group

Abstract Introduction Breast cancer has a high incidence in the population, and it still is a major cause of mortality among women. About 2/3 of these tumors express hormone receptor which are important therapeutical targets for both adjuvant and metastatic settings. Hormone therapy (HT) is an important strategy for adjuvant treatment in breast cancer, enhancing disease-free and overall survival. But the side effects of this strategy are multiple, especially by mimicking or intensifying menopausal symptoms, which can substantially compromise quality of life of patients. Moreover, treatment of women with breast cancer is rising both in intensity and extension, maximizing hormone deprivation effects. Another major factor is patient adherence as it is known that about 50% of women don’t complete the whole treatment. Bad adherence occurs mainly because side effects are poorly controlled, either being neglected or less valued during medical check-ups. Outside clinical trials, there is not enough data of patients’ perceptions about HT. Objective To evaluate adherence, side effects and medical care perceptions of breast cancer patients in use of HT. Method A questionnaire was developed and applied online to users of Oncoguia, an NGO for cancer patient’s advocacy. The adhesion was volunteer and individual data were not identified. Primarily qualitative analysis was performed to identify patterns in no meeting needs of patients using HT for breast cancer. Results 310 answers were submitted from February to July of 2020. 84.1% of patients (261) referred having used HT. Tamoxifen was used in 47.5% of these, aromatase inhibitor in 29% and double blockage in 8.1%. Related to orientation about side effects, 43.2% consider they were properly orientated, 25% superficially and 11.2% weren’t oriented. 50% of women who previously didn’t exercise started physical activities after HT. Of those who were previously active, 73,4% kept regular exercises during HT. Considering weight gain, 63% of women who didn’t have prior problems experienced trouble with weight gain; and in those who already had issues with weight there were persistence in 71.7%. For patients with normal libido before HT, 42,9% noticed reduction and 36,4% of them considered the libido absent after onset of treatment. When vaginal dryness was addressed, 75% of women had it as a new symptom. Hot flashes onset on 86.5% of women who previously didn’t present it.Humor distress wise 67.9% of patients considered they developed irritability, prior inexistent, in use of HT. Depression or depressive episodes were related by 45.5% of patients without personal history of these disturbers and by 65.2% of patients with depressive personal history.When asked about how much the symptoms interfered in their daily lives, 45.2% consider a huge/considerable interference, 32% a little interference and only 5.8% of women considered symptoms didn’t interfere on their daily lives. Discussion Bringing patients to the center of treatment, more than aiming better therapeutic results, also includes listening to their needs and perceptions about it. Outside clinical trials, there is few information about adherence to HT and factors that leads to HT drop. Surveys applied to oncologic communities may reveal concerns and perceptions that can be differently influenced by local characteristics. This kind of survey can open a window of opportunity for actions directly focused on patients demands. Conclusion Real life data has the potential to direct educational actions for patients and health professionals, according to the specifics perceptions of patient community, aiming for adherence and consequent better treatment results. Citation Format: Marina S Montemor, Lycia TV Neumann, Anna CA Siqueira, Luciana HC Barros, Solange M Sanches. Assessing patients perceptions on hormone therapy for breast cancer: Insights from a Brazilian patient group [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-12-14.

The Hermeneutical Task of Postcolonial African Philosophy: Construction and Deconstruction

Meta philosophical issues surround the topic of African philosophy. What should be counted as African philosophy, and what makes African philosophy so notable has long been a matter of reflection by African and African descended thinkers? One stance taken by African thinkers leans toward ascribing philosophical status to the collective worldviews of Africans embedded in their traditions, language, and culture. By criticizing ethnophilosophy as being unanimous and uncritical, professional philosophers epitomize a philosophy to be a universal, individualized, and reflective enterprise. This tendency of appropriating cultural traits as philosophical and thereby tending to emphasize particularity by ethnophilosophers on the one hand and the universalist claim by professional philosophers puts African philosophy in a dilemma and whereby makes it counterproductive to the neocolonial liberation struggle. The article's central argument is that African philosophical hermeneutics is a panacea for the 'double blockage' that the philosophers currently look into contemporary African philosophy. African hermeneutics is the extension of German and French hermeneutical tradition with the works of Heidegger, Gadamer, and Ricœur. Hermeneutics is a mediation between culture and philosophy and also universality and particularity.

Inhibitive effect of loureirin B plus capsaicin on tetrodotoxin-resistant sodium channel

OBJECTIVETo investigate whether the effect of loureirin B plus capsaicin on tetrodotoxin-resistant (TTX-R) sodium channel. METHODSBy using whole-cell patch-clamp recordings, in acutely isolated dorsal root ganglion (DRG) neurons, the combined effects of loureirin B and capsaicin on TTX-R sodium channel were observed. Based on the data, the interaction between loureirin B and capsaicin in their modulation on TTX-R sodium channel was assessed. RESULTSLoureirin B could not induce transient inward TRPV1 current. Capsazepine, a transient receptor potential vanilloid l (TRPV1) antagonist, could not attenuate the block of 0.64 mmol/L loureirin B on TTX-R sodium channel. There was no significant difference (P > 0.05) between IC50 of loureirin B (0.37 mmol/L) on TTX-R sodium channel in capsaicin-sensitive DRG neurons and that (0.38 mmol/L) in capsaicin-insensitive DRG neurons. However, there was a significant difference (P < 0.05) between the IC50 of capsaicin (0.28 μmol/L) on TTX-R sodium channel in capsaicin-sensitive DRG neurons and that (52.24 μmol/L) in capsaicin-insensitive DRG neurons. Four combinations composed of various concentrations of loureirin B and capsaicin could all inhibit TTX-R sodium currents but have different interactions between loureirin B and capsaicin. CONCLUSIONLoureirin B plus capsaicin could produce double blockage on TRPV1 and modulation on TTX-R sodium channel. The action of loureirin B on TTX-R sodium channel was independent of TRPV1 but similar with that of capsaicin on TTX-R sodium channel in capsaicin-insensitive DRG neurons.

Efficient elimination of pancreatic cancer stem cells by hedgehog/GLI inhibitor GANT61 in combination with mTOR inhibition.

BackgroundPancreatic cancer is one of the most lethal malignancies. The innovative treatments are required and now the cancer stem cells (CSCs) are expected to be an effective target for novel therapies. Therefore we investigated the significance of hedgehog (Hh) signaling in the maintenance of CSC-like properties of pancreatic cancer cells, in order to discover the key molecules controlling their unique properties.MethodsHuman pancreatic cancer cell lines, Capan-1, PANC-1, MIA PaCa-2 and Capan-1 M9 were used for our experiments in DMEM/F12 medium containing 10 % fetal bovine serum. Sphere formation assay, immunofluorescence staining, flow cytometric analysis and MTT cell viability assay were performed to investigate molecular signals and the efficacy in the treatment of pancreatic cancer cells.ResultsInhibition of the Hh pathway significantly reduced the expression of stem cell marker CD133 and sphere formation, an index of self-renewal capacity, demonstrating the suppression of CSC-like properties. Moreover, the GLI inhibitor GANT61 induced greater reduction in sphere formation and cell viability of pancreatic cancer cells than the smoothened (SMO) inhibitor cyclopamine. This suggests that GLI transcription factors, but not SMO membrane protein, are the key molecules in the Hh pathway. The treatment using GANT61 in combination with the inhibition of mTOR, which is another key molecule in pancreatic CSCs, resulted in the efficient reduction of cell viability and sphere formation of an inhibitor-resistant cell line, showing the strong efficacy and wide range applicability to pancreatic CSC-like cells.ConclusionsThus, this novel combination treatment could be useful for the control of pancreatic cancer by targeting pancreatic CSCs. This is the first report of the efficient elimination of pancreatic cancer stem-like cells by the double blockage of Hh/GLI and mTOR signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0534-2) contains supplementary material, which is available to authorized users.

Immunotherapy in non-small cell lung cancer: evolution of knowledge and clinical advances

Lung cancer represent the leading cause of cancer related-death worldwide. Although cytotoxic chemotherapy and targeted agents improved survival, the median overall survival for patients with metastatic disease remains poor. Docetaxel is still the corner stone of the second-line treatment, although associated with an unfavourable safety profile. Recent advances in the understanding of cancer immune escape system lead to the development of novel immunotherapies agent that can restore patient's immune response to cancer cells. Unlike vaccines, immune checkpoints inhibitors have shown promising results in non-small cell lung cancer patients. Especially, nivolumab and pembrolizumab, monoclonal antibodies against PD-1, provides as single agent therapy in chemotherapy refractory patients objective response rates ranging from 15%-25%, the majority of which arose quickly and were ongoing 1 year after starting treatment. Furthermore, the toxicity profile differs from that of cytotoxic chemotherapy and is much better tolerated. PD-L1 expression is a promising biomarker for selection and stratification of patients, although its prognostic and predictive role remains to be defined. Several trials are currently ongoing to define the role of immune checkpoint inhibitors in the treatment of patients with non-small cell lung cancer, their combination with cytotoxic chemotherapy or targeted agents and the efficacy and safety of double blockage of PD-1/PD-L1 and CTLA4. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating immune checkpoint inhibitors and NSCLC, considering the measured outcomes as progression free survival (PFS), overall survival (OS), and the overall response rate (ORR).

Prevention of Early Inflammatory Reaction By Double Blockage of TNFα and IL-1β in Clinical Autologous Islet Transplantation for Chronic Pancreatitis.

Prevention of Early Inflammatory Reaction By Double Blockage of TNFα and IL-1β in Clinical Autologous Islet Transplantation for Chronic Pancreatitis.

Blood Transcriptions in Clinical Islet Cell Transplantation with T Cell Depletion and Antiinflammatory Protocol

Introduction: Allogeneic islet cell transplantation (ICT) is a promising treatment for patients with brittle type 1 diabetes. Recent reports have demonstrated that T cell depletiing immunosuppression protocol could improve islet engraftment as well as prolong graft function. We have implemented the T cell depletion plus antiinflammatory (TCD-AI) protocol using antithymocyte globulin (ATG) and double blockage of IL-1β and TNF-α. Global investigation of peripheral blood transcriptions is helpful for understanding systemic responses as well as discovering diagnostic biomarkers. Modular level analysis for cDNA microarray allows effective interpretation on the background determination with multiple immunologic disease populations (1). In this study, peripheral blood transcriptions were measured to explore systemic biological response for early phase of ICT with TCD-AI protocol. Methods: Five islet recipients received TCD-AI protocol with ATG for induction, along with anakinra and etanercept. Peripheral blood samples were collected on the screening day (baseline), post-transplant days 4, 7, 14, 28 and 42. Isolated RNA were hybridized on to Illumina HumanHT-12 v4 BeadChip. Probe-level differential gene expression analysis was conducted using mixed model adjusting for correlation for longitudinal data to compare between baseline and post-transplant samples. A false discovery rate of 0.1 was used to account for multiple testing. Modular analysis of gene expressions were employed with previously determined sets of genes (1). Results: Four patients (80%) achieved insulin independence after single islet infusion and the median duration of insulin independence is 17.5 months (range: 4-36 months) as of the analysis. The number of genes that were expressed with significant difference (p< 0.05) are 866, 465, 492, 160, 353 and 80 on day 4, 7, 14, 21, 28 and 42 after transplant when compare to baseline. Modular analysis of cDNA microarray on day 4 revealed upregulated modules annotated as interferon responses (M3.4), inflammation (M4.2), myeloid lineage (M4.6) and cell cycle (M6.13), and downregulated modules as coagulation cascade (M3.6), T-cells (M4.1 and M6.15), lymphoid lineage (M4.7 and M6.9) and cytotoxicity (M4.15) (Figure 1). Among these modules, T-cells (M4.1 and M6.19) and cytotoxicity (M4.15) modules were downregulated throughout the study period.[Figure 1]Figure 1. Blood transcriptional fingerprints with islet recipients receiving TCD-AI protocol. Relative changes in whole blood gene expressions with islet recipients for day 4 to 42, compared to baseline. Colored spots represent the percentage of significantly upregulated (red) or downregulated (blue) transcripts (p< 0.002). Conclusion: Gene expression modules annotated as T-cells and cytotoxicity were downregulated in early phase of ICT, suggesting that effective control of cellular immune response as the background mechanism of improved outcome of TCD-AI protocol. (1) Chaussabel D, et al. Immunity 2008;29:150-164.

New therapeutic targets for ACE inhibitors and angiotensin receptor blockers

Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) posses multiple beneficial effects such as cardioprotection, cerebroprotection, nephroprotection which provide opportunity to select the most suitable drug for the target vascular bed (e.g. coronary, or cerebral circulation). In some clinical settings, combined therapy ACE-I with ARB (double blockage of the renin-angiotensin-aldosteron system) may appear the most effective. These drugs (especially ARB) may successfully prevent atrial fibrillation and play a protective role in metabolic syndrome. Recently, it has been demonstrated that losartan is able to inhibit vasodilatation of the aorta in Marfan syndrome, which might prevent sudden death due to aorta rupture. An increasing role of ARB is most beneficial in hipotensive therapy (inhibition/regression of hypertension-related organ damage). With particular interest, results of the ONTARGET study are being awaited. This study is focused on the effect of double blockage (ramipril and telmisartan) on reduction of the occurrence of myocardial infarction, stroke, and heart failure.

Improving Efficacy of Clinical Islet Transplantation with Iodixanol-Based Islet Purification, Thymoglobulin Induction, and Blockage of IL-1β and TNF-α

Poor efficacy is one of the issues for clinical islet transplantation. Recently, we demonstrated that pancreatic ductal preservation significantly improved the success rate of islet isolation; however, two transplants were necessary to achieve insulin independence. In this study, we introduced iodixanol-based purification, thymoglobulin induction, and double blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression to improve the efficacy of clinical islet transplantation. Nine clinical-grade human pancreata were procured. Pancreatic ductal preservation was performed using ET-Kyoto solution in all cases. When the isolated islets met the clinical criteria, they were transplanted. We utilized two methods of immunosuppression and anti-inflammation. The first protocol prescribed daclizumab for induction, then sirolimus and tacrolimus to maintain immunosuppression. The second protocol used thymoglobulin for induction and tacrolimus and mycophenolate mofetil to maintain immunosuppression. Eternacept and anakinra were administered as anti-inflammatory drugs. The total amount of insulin required, HbA1c, and the SUITO index were determined to analyze and compare the results of transplantation. All isolated islet preparations (9/9) met the criteria for clinical transplantation, and they were transplanted into six type 1 diabetic patients. All patients achieved insulin independence with normal HbA1c levels; however, the first protocol required two islet infusions (N = 3) and the second protocol only required a single infusion (N = 3). The average SUITO index, at 1 month after a single-donor islet transplantation, was significantly higher in the second protocol (49.6 ± 8.3 vs. 19.3 ± 6.3, p < 0.05). Pancreatic ductal preservation, iodixanol-based purification combined with thymoglobulin induction, and blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression dramatically improved the efficacy of clinical islet transplantations. This protocol enabled us to perform successful single-donor islet transplantations. Further large-scale studies are necessary to confirm these results and clarify the mechanism of each component.

Effects of Multiblocking and Axial Gap Distance on Performance of Partial Admission Turbines: A Numerical Analysis

In this paper, the effects of axial gap distance between the first stage stator and rotor blades and multiblocking on aerodynamics and performance of partial admission turbines are analyzed numerically. The selected test case is a two stage axial steam turbine with low reaction blades operating with compressed air. The multiblocking effect is studied by blocking the inlet annulus of the turbine in a single arc and in two opposing blocked arcs, each having the same admission degree. The effect of axial gap distance between the first stage stator and rotor blades is studied while varying the axial gap by 20% compared with the design gap distance. Finally, full admission turbine is modeled numerically for comparison. Performance of various computational cases showed that the first stage efficiency of the two stage partial admission turbine with double blockage was better than that of the single blockage turbine; however, the extra mixing losses of the double blockage turbine caused the efficiency to deteriorate in the downstream stage. It was shown that the two stage partial admission turbine with smaller axial gap than the design value had better efficiency of the first stage due to lower main flow and leakage flow interactions; however, the efficiency at the second stage decreased faster compared with the other cases. Numerical computations showed that the parameters, which increased the axial force of the first stage rotor wheel for the partial admission turbine, were longer blocked arc, single blocked arc, and reduced axial gap distance between the first stage stator and rotor blades.