Evaluation of the antioxidant impact of ginger-based kombucha on the murine breast cancer model

2017 ◽  
Vol 15 (1) ◽  
Author(s):  
Samaneh Salafzoon ◽  
Hamideh Mahmoodzadeh Hosseini ◽  
Raheleh Halabian
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Sod Activity ◽  
Antioxidant Agents ◽  
Kombucha Tea ◽  
Before And After ◽  
Abnormal Metabolism ◽  
Liver And Kidney ◽  
Tumor Homogenate ◽  
The Impact

AbstractBackgroundAbnormal metabolism is a common event in cancerous cells. For example, the increase of reactive oxygen species (ROS) production, particularly due to aerobic respiration during invasive stage, results in cancer progression. Herein, the impact of kombucha tea prepared from ginger on the alteration of antioxidant agents was assessed in the breast cancer animal model.MethodsTwo types of kombucha tea with or without ginger were administered to BALB/c mice before and after tumor challenge. Superoxide dismutase (SOD), catalase, glutathione (GSH) and malondialdehyde (MDA) were evaluated in tumor, liver and kidney.ResultsAdministration of kombucha ginger tea significantly decreased catalase activity as well as GSH and MDA level in tumor homogenate (p<0.001). A significant decrease in SOD activity and increase in MDA quantity was determined in the kidney which had received kombucha ginger tea (pConclusionsThe consumption of kombucha prepared from ginger could exert minor antioxidant impacts by balancing multi antioxidant factors in different tissues in the breast cancer models.

scholarly journals Boosting GWAS using biological networks: A study on susceptibility to familial breast cancer

2021 ◽  
Vol 17 (3) ◽  
pp. e1008819
Author(s):  
Héctor Climente-González ◽  
Christine Lonjou ◽  
Fabienne Lesueur ◽  
Dominique Stoppa-Lyonnet ◽  
Nadine Andrieu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Biological Networks ◽  
Familial Breast Cancer ◽  
Association Studies ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Functional Relationships ◽  
Network Methods ◽  
The Impact

Genome-wide association studies (GWAS) explore the genetic causes of complex diseases. However, classical approaches ignore the biological context of the genetic variants and genes under study. To address this shortcoming, one can use biological networks, which model functional relationships, to search for functionally related susceptibility loci. Many such network methods exist, each arising from different mathematical frameworks, pre-processing steps, and assumptions about the network properties of the susceptibility mechanism. Unsurprisingly, this results in disparate solutions. To explore how to exploit these heterogeneous approaches, we selected six network methods and applied them to GENESIS, a nationwide French study on familial breast cancer. First, we verified that network methods recovered more interpretable results than a standard GWAS. We addressed the heterogeneity of their solutions by studying their overlap, computing what we called the consensus. The key gene in this consensus solution was COPS5, a gene related to multiple cancer hallmarks. Another issue we observed was that network methods were unstable, selecting very different genes on different subsamples of GENESIS. Therefore, we proposed a stable consensus solution formed by the 68 genes most consistently selected across multiple subsamples. This solution was also enriched in genes known to be associated with breast cancer susceptibility (BLM, CASP8, CASP10, DNAJC1, FGFR2, MRPS30, and SLC4A7, P-value = 3 × 10−4). The most connected gene was CUL3, a regulator of several genes linked to cancer progression. Lastly, we evaluated the biases of each method and the impact of their parameters on the outcome. In general, network methods preferred highly connected genes, even after random rewirings that stripped the connections of any biological meaning. In conclusion, we present the advantages of network-guided GWAS, characterize their shortcomings, and provide strategies to address them. To compute the consensus networks, implementations of all six methods are available at https://github.com/hclimente/gwas-tools.

Breast Cancer Stage at Presentation in Ohio: The Effect of Medicaid Expansion and the Affordable Care Act

2020 ◽  
Vol 86 (3) ◽  
pp. 195-199
Author(s):  
Dan Kirkpatrick ◽  
Margaret Dunn ◽  
Rebecca Tuttle
Keyword(s):  
Breast Cancer ◽  
Affordable Care Act ◽  
Advanced Disease ◽  
Disease Stage ◽  
Cancer Stage ◽  
Medicaid Expansion ◽  
Cancer Data ◽  
Before And After ◽  
The Affordable Care Act ◽  
The Impact

Patients presenting with localized breast cancer have a five-year survival of 99 per cent, whereas survival falls to 27 per cent in advanced disease. This obviates the importance of early diagnosis and treatment. Our study evaluates the impact of Ohio's Medicaid expansion and the passage of the Affordable Care Act (ACA) on the stage at which Ohioans were diagnosed with breast cancer. Data were collected for 3056 patients presenting with breast cancer between 2006 and 2016 in the Dayton area. Patients were divided into groups based on cancer stage. The percentage of patients presenting with advanced disease (stage 3 or 4) was compared both before and after ACA implementation and Ohio Medicaid expansion. These results were also compared with statewide data maintained by the Ohio Department of Health. Compared with pre-ACA, the number of uninsured patients post-ACA was noted to fall 83 per cent, the number of patients presenting with Medicaid increased by five times, and the proportion of patients younger than 65 years presenting with breast cancer increased by approximately 7 per cent. These changes notwithstanding, no difference was identified in the percentage of patients presenting with advanced breast cancer before and after ACA implementation or Ohio Medicaid expansion ( P = 0.56). Statewide data similarly demonstrated no change ( P = 0.88). Improved insurance access had a smaller-than-anticipated impact on the stage at which Ohioans presented with breast cancer. As significant morbidity and mortality can be avoided by earlier presentation, additional research is appropriate to identify factors affecting patients’ decision to seek breast cancer screening and care.

scholarly journals The Extracellular Matrix and Vesicles Modulate the Breast Tumor Microenvironment

2020 ◽  
Vol 7 (4) ◽  
pp. 124 ◽  
Author(s):  
Jun Yang ◽  
Gokhan Bahcecioglu ◽  
Pinar Zorlutuna
Keyword(s):  
Breast Cancer ◽  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Signaling Molecules ◽  
Clinical Applications ◽  
Breast Cancer Progression ◽  
Multiple Roles ◽  
Biophysical Properties ◽  
The Impact

Emerging evidence has shown multiple roles of the tumor microenvironment (TME) components, specifically the extracellular matrix (ECM), in breast cancer development, progression, and metastasis. Aside from the biophysical properties and biochemical composition of the breast ECM, the signaling molecules are extremely important in maintaining homeostasis, and in the breast TME, they serve as the key components that facilitate tumor progression and immune evasion. Extracellular vesicles (EVs), the mediators that convey messages between the cells and their microenvironment through signaling molecules, have just started to capture attention in breast cancer research. In this comprehensive review, we first provide an overview of the impact of ECM in breast cancer progression as well as the alterations occurring in the TME during this process. The critical importance of EVs and their biomolecular contents in breast cancer progression and metastasis are also discussed. Finally, we discuss the potential biomedical or clinical applications of these extracellular components, as well as how they impact treatment outcomes.

Impact of copayment elimination on annual and biennial screening mammography utilization among rural U.S. women.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6503-6503
Author(s):  
Jeffrey M. Peppercorn ◽  
Stephanie B. Wheeler ◽  
Kevin Houck ◽  
Bercedis Peterson ◽  
Victor Villagra ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Rural Women ◽  
Age Groups ◽  
Screening Mammography ◽  
Prior History ◽  
Insurance Claims ◽  
Financial Barriers ◽  
Before And After ◽  
Insurance Claims Data ◽  
The Impact

6503 Background: Early detection of breast cancer through mammography screening leads to earlier stage at diagnosis and improved survival. Previous research has shown that rural American women are less likely to receive screening mammography compared to their urban counterparts. Copayments for mammography are a potential barrier to screening, and elimination of copayments may improve screening rates. We examined annual (aSMU) and biennial (bSMU) screening mammography utilization and the impact of copayment elimination among rural U.S. women. Methods: Using the insurance claims database of the National Rural Electric Cooperative Association (NRECA), which insures over 100,000 electrical workers and their families nationally, we identified all women ages 40 to 64 with no prior history of invasive breast cancer or DCIS (based on ICD-9 codes) and captured claims for aSMU and bSMU between 1999 and 2009. Changes in screening over time were assessed for the periods before and after NRECA elimination of copayments for screening mammography in January, 2006. Chi-squared tests were used to compare aSMU and bSMU rates by age group. All p-values are two-sided. Results: During this time period, over 20,000 women ages 40 to 64 received health insurance through NRECA each year. From 1999 to 2009, aSMU increased from 38.1% to 49.5%, while bSMU increased from 57.2% to 68.1%. Screening increased significantly following elimination of copayments in 2006 (p = 0.0004). Specifically, for the period 2006-2007 compared to 2004-2005, the percentage of women undergoing at least biennial screening increased from 60.9 to 68.8% (p < 0.0001), with absolute differences in screening by age ranging from an increase of 5.3% among women 40-45, to 10% among women 60 – 64. Conclusions: Evaluation of insurance claims data from rural US populations reveals that a large percentage of rural women ages 40 to 64 do not undergo even biennial breast cancer screening. Elimination of copayments improves both annual and biennial screening rates in all age groups, but does not eliminate all barriers. Further investigation is ongoing to understand financial and non-financial barriers to screening and attitudes towards current screening recommendations.

scholarly journals Influence of Social Determinants, Lifestyle, Emotional Well-Being and the Use of Unconventional Therapies in Breast Cancer Progression in a Cohort of Women in Barcelona: Protocol for the DAMA Cohort (Preprint)

2017 ◽  
Author(s):  
Rosa Puigpinos-Riera ◽  
Xavier Continente ◽  
Gemma Serral ◽  
Xavi Bargalló ◽  
Montserrat Doménech ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Social Determinants ◽  
Breast Cancer Survivors ◽  
Well Being ◽  
Lifestyle Changes ◽  
Convenience Sample ◽  
Informed Consent Form ◽  
Clinical Records ◽  
The Impact

BACKGROUND Breast cancer continues to be the most commonly diagnosed cancer in women. Breast cancer survivors face numerous problems, especially after completing the first year of intense treatment. We present the protocol for an ongoing study to analyze the impact of a series of factors on breast cancer survival related to lifestyle, emotional well-being, and use of complementary and alternative medicine (CAM). OBJECTIVE We aim to analyze the influence of social determinants, lifestyle changes, emotional well-being, and use of CAM in the progression of breast cancer in women diagnosed with breast cancer between 2003 and 2013 in Barcelona, Spain. METHODS We will perform a mixed cohort study (prospective and retrospective) of women diagnosed with breast cancer, created using a convenience sample in which we study the evolution of the disease (relapse, death, or remaining disease-free). Once identified, we sent the women information about the study and an informed consent form that they are required to sign in order to participate; a total of 2235 women were recruited. We obtained the following information from all participants: sociodemographic profile via a phone interview, and a self-administered survey of information about the study’s objectives (lifestyles, emotional well-being, health care services, and the use of CAM). Lastly, we examined clinical records to obtain data on the tumor at the time of diagnosis, the treatment received, the occurrence of relapses (if any), and the tumor typology. We present data on the women’s social profile based on descriptive data obtained from the telephone interview (welcome survey). RESULTS Based on the welcome survey, which was completed by 2712 women, 14.42% (391/2712) of respondents were <50 years of age, 45.50% (1234/2712) were between 50 and 65 years of age, and 40.08% (1087/2712) were >65 years of age. A total of 43.69% (1185/2712) belonged to the highest social classes (I and II), 31.27% (848/2712) to the middle class (III), and 23.49% (637/2712) to the working classes (IV and V). Approximately 22.71% (616/2712) lived alone, 38.31% (1039/2712) lived with one person, and 38.97% (1057/2712) lived with two or more people. CONCLUSIONS We obtained information from a large cohort of women, but this study has limitations related to the convenience sampling strategy, one of which is reduced representativeness. Conversely, being a self-administered survey, the study introduces biases, especially from respondents that answered on paper. However, the information that the study provides will serve as the basis for designing future interventions aimed at improving the knowledge gaps indicated for women with breast cancer.

scholarly journals The Effect of Intraoperative Radiotherapy on Breast Cancer: Focus on the Levels of Angiogenic Factors

2021 ◽  
Author(s):  
Nahid Nafisi ◽  
Maryam Mohammadlou ◽  
Mohammad Esmaeil Akbari ◽  
Seyed Rabie Mahdavi ◽  
Maryam Sheikh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Linear Regression Analysis ◽  
Intraoperative Radiotherapy ◽  
Angiogenic Factors ◽  
Breast Cancer Patients ◽  
Risk Of Death ◽  
Post Surgery ◽  
Before And After ◽  
The Impact

Abstract Objective: Angiogenesis is one of the hallmarks of cancers that is involved in tumor progression. Angiogenic factors induce the formation of new blood vessels and tumor extension, and finally reduce the survival of patients. Intraoperative radiotherapy (IORT), in which radiation is delivered to the tumor bed can kill cells and change tumor microenvironment. Here, we compared the impact of IORT on the levels of angiogenic factors in the blood and surgical wound fluids (SWF) of the breast cancer patients. Patients and Methods: Blood and drained wound fluid (WF) samples were collected from the breast cancer patients before and after surgery, followed by quantification of the amounts of TGF-β, EGF, FGF, VEGF and DLL4 in the patients using ELISA.Results: Our results were indicative of significant differences between the pre-surgery and post-surgery serum levels of EGF, DLL4 and VEGF. In addition, linear regression analysis showed the significant impact of IORT, vascular invasion and lymph node (LN) involvement on the difference between TGF-β levels in the blood before and after surgery-IORT. According to the outcomes of multivariate analysis, IORT changed the levels of EGF and FGF in the blood and WF. Furthermore, logistic regression analyses showed that TGF-β and EGF can be used as predictor markers of the late-stage and LN involvement of the disease. Interestingly, IORT was able to reduce the risk of death and the recurrence rate of disease. Conclusions: In summary, IORT is a safe and effective treatment that can affect angiogenesis and improve the survival of breast cancer patients.

scholarly journals Activation of epithelial-mesenchymal transition process during breast cancer progression – the impact of molecular subtype and stromal composition

2021 ◽  
Author(s):  
Aleksandra Markiewicz ◽  
Justyna Topa ◽  
Marta Popęda ◽  
Jolanta Szade ◽  
Jarosław Skokowski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Nodes ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Ki 67 ◽  
Mesenchymal Transition ◽  
Metastatic Colonization ◽  
The Impact

Breast cancer (BC) is a heterogeneous disease with different molecular subtypes, which can be defined by oestrogen (ER), progesterone (PR) and human epidermal growth factor (HER2) receptors’ status as luminal, HER2+ and triple negative (TNBC). Molecular subtypes also differ in their epithelial-mesenchymal phenotype, which might be related to their aggressiveness, as activation of the epithelial-mesenchymal transition (EMT) is linked with increased ability of cancer cells to survive and metastasize. Nevertheless, the reverse process of mesenchymal-epithelial transition was shown to be required to sustain metastatic colonization. In this study we aimed to analyse activation of the EMT process in primary tumours (PT), which have (N+) or have not (N–) colonized the lymph nodes, as well as the lymph nodes metastases (LNM) themselves in 88 BC patients. We showed that luminal N– PT have the lowest activation of the EMT process (27%), in comparison to N+ PT (48%, p=0.06). On the other hand, TNBC do not show statistically significant EMT activation at the stage before lymph colonization (N–, 83%) and after colonization of the lymph nodes (N+, 63%, p=0.58). TNBC are also the least plastic (unable to change the EMT phenotype) in terms of turning EMT on or off between matched PT and LNM (0% EMT plasticity in TNBC vs 36% plasticity in luminal tumours). Moreover, in TNBC activation of EMT was correlated with increased cell division rate of the PT– in mesenchymal TNBC PT median Ki-67 was 45% in comparison to 10% in epithelial TNBC PT (p=0.002), whereas in PT of luminal subtypes Ki-67 did not differ between epithelial and mesenchymal phenotypes. Profiling of immunotranscriptome of epithelial and mesenchymal luminal BC with Nanostring technology revealed that N– PT with epithelial phenotype were enriched in inflammatory response signatures, whereas N+ mesenchymal cancers showed elevated MHC class II antigen presentation. Overall, activation of EMT changes during cancer progression and metastatic colonization of the lymph nodes depending on the PT molecular subtype and is related to differences in stromal signatures. Activation of EMT is associated with colonizing phenotype in luminal PT and proliferative phenotype of TNBC.

scholarly journals Impact of 2013 ASCO/CAP guidelines on various HER2 reporting categories in breast cancer by fluorescent in-situ hybridization and Immunohistochemistry: A meta-analysis with systematic review

2020 ◽  
Vol 5 ◽  
pp. 14-26 ◽  
Author(s):  
Sunil Pasricha ◽  
Smita Asthana ◽  
Satyanarayana Labani ◽  
Uma Kailash ◽  
Abhinav Srivastav ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Meta Analysis ◽  
Pooled Analysis ◽  
Paired Data ◽  
Treatment Benefit ◽  
Before And After ◽  
Primary Test ◽  
The Cost ◽  
The Impact

Objective: The ASCO/CAP guidelines for reporting HER2 in breast cancer, first released in 2007, aimed to standardize the reporting protocol, and were updated in 2013 and 2018, to ensure right treatment. Several studies have analyzed the changes attributed to 2013 updated guidelines, and majority of them found increase in positive and equivocal cases. However, the precise implication of these updated guidelines is still contentious, in spite of the latest update (2018 guidelines) addressing some of the issues. We conducted systematic review and meta- analysis to see the impact of 2013 guidelines on various HER2 reporting categories by both FISH and IHC. Materials and Methods: After extensively searching the pertinent literature, 16 studies were included for the systematic review. We divided our approach in three strategies: (1) Studies in which breast cancer cases were scored for HER2 by FISH or IHC as a primary test concurrently by both 2007 and 2013 guidelines, (2) Studies in which HER2 results were equivocal by IHC and were followed by reflex-FISH test by both 2007 and 2013 guidelines, and (3) Studies in which trends of HER2 reporting were compared in the two periods before and after implementation of updated 2013 guidelines. All the paired data in these respective categories was pooled and analyzed statistically to see the overall impact of the updated guidelines. Results: In the first category, by pooled analysis of primary FISH testing there has been a significant increase in the equivocal cases (P < 0.001) and positive cases (P = 0.037). We also found 8.3% and 0.8% of all the negative cases from 2007 guidelines shifted to equivocal and positive categories, respectively. Similarly by primary IHC testing there has been a significant increase in both equivocal cases (P < 0.001) and positive cases (P = 0.02). In the second category of reflex-FISH testing there was a substantial increase in the equivocal cases (P < 0.0001); however there is insignificant decrease (10% to 9.7%; P = 0.66) in the amplified cases. In the third approach for evaluating the trend, with the implementation of 2013 guidelines, there was increase in the equivocal category (P = 0.025) and positive category (P = 0.0088) by IHC. By FISH test also there was significant increase in the equivocal category (P < 0.001) while the increase in the positive category was non-significant (P = 0.159). Conclusions: The updated 2013 guidelines has significantly increased the positive and equivocal cases using primary FISH or IHC test and with further reflex testing, thereby increasing the double equivocal cases and increasing the cost and delaying the decision for definite management. However, whether the additional patients becoming eligible for HDT will derive treatment benefit needs to be answered by further large clinical trials.

scholarly journals Impact of Primary Care Delay on Progression of Breast Cancer in a Black African Population: A Multicentered Survey

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Olayide Agodirin ◽  
Samuel Olatoke ◽  
Ganiyu Rahman ◽  
Julius Olaogun ◽  
Oladapo Kolawole ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Primary Care ◽  
Cancer Progression ◽  
Clustering Analysis ◽  
Short Interval ◽  
Tumor Stage ◽  
Stage Migration ◽  
Patient Journey ◽  
Low Middle Income Countries ◽  
The Impact

Background. Reports are scanty on the impact of long primary care interval in breast cancer. Exploratory reports in Nigeria and other low-middle-income countries suggest detrimental impact. The primary aim was to describe the impact of long primary care interval on breast cancer progression, and the secondary aim was to describe the factors perceived by patients as the reason(s) for long intervals. Method. Questionnaire-based survey was used in 9 Nigerian tertiary institutions between May 2017 and July 2018. The study hypothesis was that the majority of patients stayed >30 days, and the majority experienced stage migration in primary care interval. Assessment of the impact of the length of interval on tumor stage was done by survival analysis technique, and clustering analysis was used to find subgroups of the patient journey. Results. A total of 237 patients presented to primary care personnel with tumor ≤5cm (mean 3.4±1.2cm). A total of 151 (69.3%, 95% CI 62.0-75.0) stayed >30 days in primary care interval. Risk of stage migration in primary care interval was 49.3% (95% CI 42.5%-56.3%). The most common reasons for long intervals were symptom misinformation and misdiagnosis. Clustering analysis showed 4 clusters of patients’ experience and journey: long interval due to distance, long interval due to misinformation, long interval due to deliberate delaying, and not short interval—prepared for treatment. Conclusion. The majority of patients stayed longer than 30 days in primary care interval. Long primary care interval was associated with a higher risk of stage migration, and more patients reported misinformation and misdiagnosis as reasons for a long interval.

Characterization of the tumor immune microenvironment (TIM) with multiplex immunohistochemistry (mIHC) in patients with breast cancer following treatment with MK-2206.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12109-e12109
Author(s):  
Douglas Kanter Marks ◽  
Robyn Denise Gartrell ◽  
Margueritta El Asmar ◽  
Thomas Hart ◽  
Yan Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Akt Inhibitor ◽  
Immune Microenvironment ◽  
Immune Biomarkers ◽  
Tumor Immune Microenvironment ◽  
Before And After ◽  
Infiltrating Lymphocytes ◽  
The Impact

e12109 Background: The PAM (PI3K/Akt/mTOR) signaling pathway has been implicated in the oncogenesis of multiple solid malignancies, including breast cancer (BC). Our aim is to characterize the TIM in a series of patients with operable stage I-III BC treated with MK-2206, an allosteric Akt inhibitor within a presurgical trial. In NCT01319539 , patients received 2 doses of MK-2206 with first dose at day -9 and second at day -2 from surgery. Methods: mIHC was performed using immune biomarkers (DAPI, CD3, CD8, CD4, FOXP3, CD68, Pancytokeratin) on full section (4uM) tissue slides from core biopsy specimens and postsurgical specimens of 10 patients - 5 treated with MK-2206, 5 paired controls. Images were taken using Vectra, a novel pathology workstation and analyzed using inForm software to perform cell classification and phenotyping. T- tests were used to compare biomarker changes before and after MK-2206. Results: Our preliminary analysis demonstrates that patients treated with MK-2206 exhibited an increase in median cytotoxic T-cells (CD3CD8+) density, as compared to the control population , which was statistically significant (87% vs.0.2%, p < 0.05). We did not identify a change in macrophage (CD68) or T helper/T reg (CD4/CD4FOXP3+) density following MK-2206 treatment in this small cohort. We are currently expanding our myeloid panel as well as performing additional tissue analysis to validate our findings. As data is exploratory no correction was made for multiple comparisons. Conclusions: Tumor infiltrating lymphocytes (TILs) are both prognostic of overall survival as well as predictive of response to neoadjuvant chemotherapy in BC. At present, there are currently both FDA approved therapies, as well as agents in clinical development that exert antineoplastic activity through the PAM pathway. Investigations that endeavour to understand the impact of these therapies on the tumor immune microenvironment may lead to both an increased understanding of the bioactivity of these agents and potentially identify aspects of the immune response which can be exploited in future therapeutics.

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