Medicine Approach Research Articles

Biological synthesis of Nanoparticles from Medicinal Plants: Recent Studies

In a recent trend, nanotechnology has been developed to be an important field of research in various fields like medicinal chemistry, pharmaceuticals and all. On the other hand, compared to chemical method of synthesis, method of synthesis of nanoparticles by green method is simple, effective & ecofriendly. Plant extracts are obtained from the plant, creep, cereals, etc. generally natural extracts are prepared by decoction method or solid powder formation method. The natural extracts are very much effective in the medicinal approach. The study of Nano sized particles towards natural extracts has given a novel way in the field of medicines. So from the nanomaterials of natural extracts, one can expect still good effective results. As we know that preparation of nanoparticles through green approach is one of the good selections in the view of betterment of ecology. Therefore by taking aqueous extracts of medicinal plants’ parts and metal ions, nanoparticles can be synthesized. The plant extract and metal ions are taken in a fixed ratio and keep at room temperature for the reduction. The Changes in the Color confirmed the formation of nanoparticles. Further, the synthesized nanoparticles were characterized by UV, EPMA, XRD and FTIR data.

In memoriam Prof. Dr. Ferenc Garzuly (1937-2021)

Ferenc Garzuly passed away after a long and productive life at the age of 84. He worked for almost 60 years at the Markusovszky University Teaching Hospital, where primarily led the laboratory of neuropathology and the department of neurology, but transferred to the department of pathology after his retirement. By authoring several books on rare diseases, he greatly enriched the case-based tea-ching approach in medicine. He described the Hun-garian type of transthyretin mutation causing the familial me-nin-go-cerebrovascular amyloidosis phenotype. The presentation of a special phenotype of Fabry disease associated with megadolichobasilar anomaly and a novel mutation in the alpha-galactosidase-A gene is also associated with his name.

Dermatology and Randomized Control Trials.

Well-designed and rigorously conducted randomized controlled trial (RCT) can produce most valid and precise scientific evidence. Any intervention, be it systemic or topical medicine, dermatology procedure needs to be tested for its efficacy in improving particular disease condition and RCT should come into mind of investigator. The biggest strength of RCT lies in two self-explanatory factors; they are randomized and controlled. Randomization of study subjects eliminates selection and confounding bias and controlling of study condition improves the internal and external validity of findings. “Blinding” eliminates assessment bias. If one starts a comparative study without stating proper hypothesis, he/she would end up collecting lots of data which does not make sense. PICOT format helps in formulating research question. Writing a detailed protocol based on hypothesis describing in detail methodology, sample size calculation, randomization method, and blinding procedure up to statistical analysis plan is very important step in planning of RCT. Trials registered prospectively contribute to transparency of the trial and are considered to reduce the publication bias by reducing selective publication of positive outcomes. Adverse events can occur at any time during conduct of an RCT and should be reported and kept track of. Physical injury resulting from clinical trial participation is entitled to financial compensation. During preparation of final manuscript of study, the CONSORT guidelines must be followed to improve the quality of reporting of RCTs. Clinical trials provide evidence-based approach in medicine and a designed and well-implemented trial can alter clinical dermatology practice for a healthier tomorrow.

The Two Great Healing Traditions: Issues, Opportunities, and Recommendations for an Integrated First Nations Healthcare System in Canada

ABSTRACT The First Nations in Manitoba, Canada, are calling for active recognition and incorporation of holistic traditional healing and medicine ways and approaches by the mainstream healthcare system that has hitherto tended to ignore all but biomedical approaches. This request for recognition requires elaboration on areas of opportunity for collaboration that could positively influence both Indigenous and allopathic medicine. We discuss pathways to an integrated healthcare system as community-based primary healthcare transformation. A community-based participatory research approach was used to engage eight Manitoba First Nations communities. One hundred and eighty-three (183) in-depth, semi-structured key informant interviews were completed in all communities. Grounded theory guided data analysis using NVivo 10 software. We learned that increased recognition and incorporation of traditional healing and medical methods would enhance a newly envisioned funded health system. Elders and healers will be meaningfully involved in the delivery of community-based primary health care. Funding for traditional healing and medicines are necessary components of primary health care. An overall respect for Indigenous health knowledge would aid transformation in community-based primary health care. Recognition of and respect for traditional healing, healers, medicines, therapies, and approaches is also recommended as part of addressing the legacy and intergenerational impact of assimilative policies including Indian residential schools as the Truth and Reconciliation Commission of Canada has stated in its Calls to Action.

POTENTIALS OF SHORT RECORDING OF HEART RATE VARIABILITY IN DISPLAYING SYSTEMIC INFORMATIONAL ENERGY PROCESSES OF THE HUMAN BODY DURING CLINICAL EXAMINATION OF PATIENTS WITH NON-COMMUNICABLE DISEASES

The article highlights the issues on the improvement of diagnosis and treatment of non-communicable diseases by applying the approaches of systemic medicine and the latest technologies. The aim of the study is to assess the clinical and diagnostic capabilities of a short recording of heart rate variability in displaying systemic informational energy processes of the human body. There has been a necessity to increase the effectiveness of measures for the prevention and treatment of non-communicable diseases in Ukraine through the early diagnosis and the introduction of the latest science-based technologies into medical practice and the development of a scientific concept of magnetoelectrochemical metabolism. An open-label, non-randomized controlled trial was performed. The study of the wave characteristics of the heart rate in functionally healthy respondents of different levels of physical fitness was one of its components. Main group 1 (n=171) and control group 2 (patients with non-communicable diseases and concomitant diseases, n=76) were examined by the method of short recording of heart rate variability using spectral analysis of wave parameters of the heart rate and variation heart rate monitoring. Clinically significant objective signs of changes in the functional state of the patients in group 2 in comparison with the individuals having good functional health status were identified. The significant difference between the indicators of the functional state in the subgroups of the individuals with good functional health has proven the significant clinical sensitivity of the method and the potentials of its applying as an objective tool for structured clinical examination of the health status, as well as for assessment of the therapeutic efficacy in the dynamics of managing patients with non-communicable diseases and determining their prognosis. The method of short recording of heart rate variability can be included into the procedure of objective structured clinical examination of patients with non-communicable diseases.

Light‐Controlled Cell‐Cycle Arrest and Apoptosis

AbstractCell‐cycle interference by small molecules has widely been used to study fundamental biological mechanisms and to treat a great variety of diseases, most notably cancer. However, at present only limited possibilities exist for spatio‐temporal control of the cell cycle. Here we report on a photocaging strategy to reversibly arrest the cell cycle at metaphase or induce apoptosis using blue‐light irradiation. The versatile proteasome inhibitor MG132 is photocaged directly at the reactive aldehyde function effectively masking its biological activity. Upon irradiation reversible cell‐cycle arrest in the metaphase is demonstrated to take place in vivo. Similarly, apoptosis can efficiently be induced by irradiation of human cancer cells. With the developed photopharmacological approach spatio‐temporal control of the cell cycle is thus enabled with very high modulation, as caged MG132 shows no effect on proliferation in the dark. In addition, full compatibility of photo‐controlled uncaging with dynamic microscopy techniques in vivo is demonstrated. This visible‐light responsive tool should be of great value for biological as well as medicinal approaches in need of high‐precision targeting of the proteasome and thereby the cell cycle and apoptosis.

Light-Controlled Cell-Cycle Arrest and Apoptosis.

Cell‐cycle interference by small molecules has widely been used to study fundamental biological mechanisms and to treat a great variety of diseases, most notably cancer. However, at present only limited possibilities exist for spatio‐temporal control of the cell cycle. Here we report on a photocaging strategy to reversibly arrest the cell cycle at metaphase or induce apoptosis using blue‐light irradiation. The versatile proteasome inhibitor MG132 is photocaged directly at the reactive aldehyde function effectively masking its biological activity. Upon irradiation reversible cell‐cycle arrest in the metaphase is demonstrated to take place in vivo. Similarly, apoptosis can efficiently be induced by irradiation of human cancer cells. With the developed photopharmacological approach spatio‐temporal control of the cell cycle is thus enabled with very high modulation, as caged MG132 shows no effect on proliferation in the dark. In addition, full compatibility of photo‐controlled uncaging with dynamic microscopy techniques in vivo is demonstrated. This visible‐light responsive tool should be of great value for biological as well as medicinal approaches in need of high‐precision targeting of the proteasome and thereby the cell cycle and apoptosis.

Determination of Beck Depression Inventory Scores of the Patients in a Hemodialysis Center: Evaluation with a Holistic Approach

Aim/ Background: The holistic approach in medicine refers to addressing an individual as a whole. Family physicians should be familiar with psychological as well as physical problems of their hemodialysis patients. This study aims to measure depressive mood levels of patients in a hemodialysis center, and to investigate the potential risk factors with a holistic approach. Method: This study was conducted on patients receiving treatment at a private hemodialysis center. During the hemodialysis session, the patients’s blood samples were taken, and serum phosphorus, creatinine, albumin, and hematocrit levels were measured. A semi-structured questionnaire form was used to investigate the sociodemographic characteristics and the Beck Depression Inventory (BDI) was used to determine depressive mood level of the patients. Results: This study was conducted on a sample of 88 patients (33 female, 55 male). The mean BDI scores were 16.7±9.8, and when the cut-off point of BDl was taken as 15, the rate of depressive mood was %56.8 for hemodialysis patients. We evaluated the duration of illness, family structure, educational level, having non-renal comorbid disease, employment status, economic status, and also blood creatinine, albumin, phosphorus, and hematocrit levels. The mean BDI score was significantly lower in patients who lived in simple nuclear families with fewer than six individuals at home. Conclusion: The holistic approach is essential, especially in chronic disease follow-up in primary healthcare. Family support and psychological evaluation with a holistic approach are vital for hemodialysis patients.

O exercício da escrita e da escuta como instrumentos de aprimoramento da prática clínica

INTRODUÇÃO: O exercício da escrita e da escuta contribuem para a prática médica de forma ímpar. O recebimento da história do paciente se dá por uma escuta atenta que, para isso, precisa ser treinada. Assim, a escrita é a ferramenta primordial nesse processo. A medicina hoje assume um carácter cada vez mais tecnicista. DISCUSSÃO: A aproximação da Medicina e das ciências humanas, que para alguns, parece ser inconciliável, ganha espaço na Medicina Narrativa de Rita Charon, através deste exercício cíclico e inesgotável de escrever e escutar. Os livros são capazes de nos fornecer recursos interpretativos e proporcionar um posicionamento mais atento e perspicaz aos comportamentos do paciente de falar ou até mesmo ao se manter em silêncio. Assim que se apreende o que foi escutado, a escrita vem como diálogo consigo mesmo para entender com maior profundidade o que acabamos de experienciar. Entrando nesse complexo enredo do paciente, através da imaginação, abre-se o caminho para desenvolver empatia com o emissor e abre espaço para reflexão do médico em relação ao que ele vivencia. É essencial possuir um arsenal teórico e literário para se conectar com as vivências e o lugar social do paciente. CONCLUSÃO: A medicina não é em si ciência, por isso pressupõe a interpretação, a qual surge também da boa escuta e escrita. Desta forma, essas capacidades promovem uma relação médico(a)-paciente mais horizontal e menos paternalista dando o protagonismo ao paciente sobre si mesmo e sua dor.

Similarity Learning Algorithm Selection for Chronic Renal Failure Patients Treatment Strategy Optimization

One of the main methods on which the personalized approach in medicine is based is finding a pair of patients who are similar in the properties of the disease. The objective of the study is to select the most effective similarity learning instrument amongst three options anaemia treatment and phosphorus-calcium balance recovery in dialysis patients, ranked according to the highest similarity to the particular patient. As soon as methods for comparing instruments will achieve the goal, the algorithm of weight tagging is used, modified by the authors by adding more weights values to important features — the cosine measure, the soft cosine measure, considering the similarity of drug alternative and their bioavailability. As a metric that evaluates the quality of algorithms, a combined metric is used that takes into account the quality of treatment classification as effective and the rank order of the greatest correspondence of therapy to a specific patient. As a result, using the opinions of nephrologists as experts, it was shown that the best measure of similarity is the soft cosine measure.

Initial response of ovarian tissue transcriptome to vitrification or microwave-assisted dehydration in the domestic cat model

BackgroundLong term preservation of living ovarian tissues is a critical approach in human reproductive medicine as well as in the conservation of rare animal genotypes. Compared to single cell preservation, optimization of protocols for tissues is highly complex because of the diversity of cells responding differently to non-physiological conditions. Using the prepubertal domestic cat as a model, the objective was to study immediate effects of vitrification or microwave-assisted dehydration on the global transcriptome dynamics in the ovarian cortex. RNA sequencing was performed on ovarian tissues (n = 6 individuals) from different conditions: fresh tissue after dissection (F), vitrified/warmed tissue (V), tissue dehydrated for 5 min (D5) or 10 min (D10) followed by rehydration. Differential gene expression analysis was performed for comparison pairs V vs. F, D10 vs. F, D5 vs. F and D10 vs. D5, and networks were built based on results of functional enrichment and in silico protein-protein interactions.ResultsThe impact of the vitrification protocol was already measurable within 20 min after warming and involved upregulation of the expression of seven mitochondrial DNA genes related to mitochondrial respiration. The analysis of D10 vs. F revealed, 30 min after rehydration, major downregulation of gene expression with enrichment of in silico interacting genes in Ras, Rap1, PI3K-Akt and MAPK signaling pathways. However, comparison of D5 vs. F showed negligible effects of the shorter dehydration protocol with two genes enriched in Ras signaling. Comparison of D10 vs. D5 showed downregulation of only seven genes. Vitrification and dehydration protocols mainly changed the expression of different genes and functional terms, but some of the differentially expressed genes formed a major in silico protein-protein interaction cluster enriched for mitochondrial respiration and Ras/MAPK signaling pathways.ConclusionsOur results showed, for the first time, different effects of vitrification and microwave-assisted dehydration protocols on the global transcriptome of the ovarian cortex (using the domestic cat as a biomedical model). Acquired data and networks built on the basis of differentially expressed genes (1) can help to better understand stress responses to non-physiological stresses and (2) can be used as directions for future preservation protocol optimizations.

Abstract 14044: Engineering Bioactive Nanoparticles to Rejuvenate Vascular Progenitor Cells

Introduction: Fetal exposure to gestational diabetes mellitus (GDM) predisposes children to future health complications including hypertension and cardiovascular disease. A key mechanism by which these complications occur is through stress-induced dysfunction of vascular progenitor cells, including endothelial colony-forming cells (ECFCs). In particular, overexpression of transgelin (TAGLN), also known as SM22α, in GDM-ECFCs is associated with actin cytoskeletal rearrangement, which results in reduced cell migration and impaired vasculogenesis. We hypothesized that bioactive nanoparticles (NPs) conjugated on the surface of GDM-ECFCs can provide a sustained pseudo-autocrine stimulation to improve in vitro and in vivo vasculogenesis. Methods & Results: We designed multilamellar lipid NPs with an average size of 147±63 nm in diameter to deliver small molecules SB-431542 (TGF-β inhibitor) directly to the surface of GDM-ECFCs. Bioactive NPs can be robustly conjugated to the surface of ECFCs using thiol-maleimide coupling without altering cell viability and key progenitor phenotypes. By controlling the release kinetic of TGF-β inhibitor from the NPs, we can normalize TAGLN expression and improve cell migration, a critical key step in establishing functional vascular networks. Moreover, bioactive NPs can restore the vasculogenic potential of GDM-ECFCs in both 2D Matrigel and 3D collagen assays. Finally, when transplanted into immunodeficient mice, GDM-ECFCs conjugated with bioactive NPs exhibit robust de novo blood vessel formation with high engraftment rate, comparable to normal ECFCs. Conclusions: Collectively, these findings highlight a simple, yet promising strategy to rejuvenate GDM-ECFCs and improve their therapeutic potentials, which can be clinically-translated to address various cardiovascular complications, as well as toward a range of approaches in tissue repair and regenerative medicine.

Formula omitted]-index: A referential index for encrypted genomic databases

Huge DBMSs storing genomic information are being created and engineerized for doing large-scale, comprehensive and in-depth analysis of human beings and their diseases. This paves the way for significant new approaches in medicine, but also poses major challenges for storing, processing and transmitting such big amounts of data in compliance with recent regulations concerning user privacy. We designed and implemented ER-index, a new full-text index in minute space which was optimized for pattern-search on compressed and encrypted genomic data using a reference sequence, and that complements a previous index for reference-free genomics. Thanks to a multi-user and multiple-keys encryption model, a single ER-index can store the sequences related to a large population of individuals so that users may perform search operations directly on compressed data and only on the sequences to which they were granted access.Tests performed of three different computing platforms show that the ER-index get very good compression ratios and search times, outperforming in many cases a reference tool that was proved nearly-optimal in time and space and does not implement encryption.The ER-index C++ source code plus scripts and data to assess the tool performance are available at: https://github.com/EncryptedIndexes/erindex.

Overview of Cold Atmospheric Plasma in Wounds Treatment

Cold atmospheric plasma (CAP), a room temperate ionised gas, known as the fourth state of matter is an ionised gas and can be produced from argon, helium, nitrogen, oxygen or air at atmospheric pressure and low temperatures. CAP has become a new promising way for many biomedical applications, such as disinfection, cancer treatment, root canal treatment, wound healing, and other medical applications. Among these applications, investigations of plasma for skin wound healing have gained huge success both in vitro and in vivo experiments without any known significant negative effects on healthy tissues. The development of CAP devices has led to novel therapeutic strategies in wound healing, tissue regeneration and skin infection management. CAP consists of a mixture of multitude of active components such as charged particles, electric field, UV radiation, and reactive gas species which can act synergistically. CAP has lately been recognized as an alternative approach in medicine for sterilization of wounds by its antiseptic effects and promotion of wound healing by stimulation of cell proliferation and migration of wound related skin cells. With respect to CAP applications in medicine, this review focuses particularly on the potential of CAP and the known molecular basis for this action. We summarize the available literature on the plasma devices developed for wound healing, the current in vivo and in vitro use of CAP, and the mechanism behind it as well as the biosafety issues.

Constitutional characteristics of the body surface area in women of different somatotypes

The aim of the study is to determine the features of the skin area in Kyrgyz women population in view of their constitutional groups and somatotypes.Material and methods. We studied the physical status of 1028 Kyrgyz women of different age groups – the juvenile age group (n=310), the 1st adulthood age group (n=310), and the 2nd adulthood age group (n=410) living in Osh and its neighborhood applying anthropometric and bioimpedance methods. Statistical data processing was performed by statistical programs Microsoft Excel and the package STATISTICA 6.0. The differences between the two compared values were determined by the Student's criterion and they were considered significant at p<0.05. Results. The performed study revealed the constitutional and somatotypological features of the skin area in the juvenile and both periods of adulthood in the female population. The body surface area is minimal in women of leptosomic group and maximum in megalosomic one. Somatotypological specificity is determined by the minimum value of this indicator in women of asthenic and stenoplastic types and by the maximum value in representatives of the euriplastic tall type. There is the tendency to increase the body skin area from the juvenile to the 2nd period of adulthood, which is typical for women of all somatotypes and constitutional groups. Conclusion. The area of the skin is one of the indicators of human physical development, which has somatotypological specificity in representatives of various constitutional groups of the studied women population. The presented materials on the constitutional and typological features of the women’s physical status in relative norm conditions can serve as one of the bases for further development of a personalized approach in clinical medicine.

Abstract A28: Identification of NGLY1-mediated protein deglycosylation as a vulnerable point in melanoma

Abstract Although NGLY1 is known as a pivotal enzyme that catalyzes the deglycosylation of denatured glycoproteins, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited. While studying the NGLY1 deficiency-caused neurodevelopmental variations in patients with a congenital deglycosylation disorder, we made an intriguing discovery that the expression of NGLY1 appears to be dysregulated in human melanoma cells. We have examined how NGLY1 expression affects viability, tumor growth, and responses to therapeutic agents in melanoma cells and an animal model. Molecular mechanisms contributing to NGLY1 suppression-induced anticancer responses were revealed by systems biology and chemical biology studies. Using computational and medicinal chemistry-assisted approaches, we established novel NGLY1-inhibitory small molecules. Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumors. NGLY1 knockdown caused melanoma cell death and tumor growth retardation. Targeting NGLY1 in melanoma cells induced pleiotropic responses, predominantly stress signaling-associated apoptosis and cytokine surges, which synergize with the antimelanoma activity of standard chemotherapy and targeted therapy agents. Pharmacologic and molecular biology tools that inactivate NGLY1 elicited highly similar responses in melanoma cells. Unlike normal cells, melanoma cells presented distinct responses and high vulnerability to NGLY1 suppression. Our work demonstrated the significance of NGLY1 in melanoma cells, provided mechanistic insights into how NGLY1 inactivation leads to eradication of melanoma with limited impact on normal cells, and suggested that targeting NGLY1 represents a novel antimelanoma strategy with the opportunity of a broad therapeutic window. Citation Format: Victor Lin, Ashwini Zolekar, Nigam Mishra, Yin Ying Ho, Hamed Hayatshahi, Abhishek Parab, Rohit Sampat, Xiaoyan Liao, Peter Hoffmann, Jin Liu, Kyle Emmitte, Yu-Chieh Wang. Identification of NGLY1-mediated protein deglycosylation as a vulnerable point in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A28.

Legacy of COVID‐19 – the opportunity to enhance surgical services for patients with colorectal disease

The COVID-19 crisis has undoubtedly taken a toll on the care of patients with colorectal disease. Elective services, be that face to face contact, endoscopy or operating all but ceased during the pandemic.

Investigation the importance of metabolism on body weight and glucose for 8.5 years using GH-Method: math-physical medicine (No. 300)

The author uses GH-method: math-physical medicine (MPM) approach to investigate three sets of correlation between: Weight vs. Metabolism Index Glucose vs. Metabolism Index Weight vs. Glucose – Weight is measured in early mornings and Glucose consists of daily average glucose, including both fasting plasma glucose (FPG) and three postprandial plasma glucose (PPG). He utilized time-series analysis on both his “daily data” and his “annual data” for comparison. His selected study period was 8.5 years (3,124 days) from 1/1/2012 through 7/23/2020. The reason for this specific time period was due to his weight (M1) and glucose (M2) data collection starting on 1/1/2012 along with the calculation of his metabolism index (MI) values. It is clear that, through his sophisticated math-physical medicine of metabolism and then statistical method of time-series analysis, all of these three biomarkers, weight, glucose, and metabolism index are proven to be highly correlated to each other. The following order ranking of correlation coefficients remained to be true between daily data and annual data: M1&MI > M2&MI > M1&M2 Daily : 84% > 72% > 61% Annual : 91% > 81% > 67% In other words, if you manage your metabolism (4 medical conditions and 6 lifestyle details) by controlling your disease conditions and monitoring your lifestyle details, your body weight and glucose will reduce accordingly. The author’s analyses is based on his personal biomarkers of two million data within 8.5 years (3,124 days) has further proven a simple and clean conclusion that has already been observed by many clinical physicians and healthcare professionals from their patients.

Abstract 2328: Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York

Abstract Advances in sequencing technologies have revolutionized our approaches in medicine. However, our current knowledge about the molecular attributes of cancer has primarily been derived from patients of European descent. The overall aims of Polyethnic-1000 are to study the variability of somatic profiles and the effects of genetic ancestry on cancer biology and to bring genomic innovation to under-represented ethnic groups in the diverse patient population of New York City.A dynamic research platform is being created, involving the New York Genome Center, academic centers and partnering hospitals in the New York City region. In an initial retrospective study, the infrastructure, sample workflow, analysis and data sharing policies within the consortium have been developed. Whole-exome and RNA sequencing has been performed on 146 samples from self-identified non-white cancer patients treated at 14 different centers. Genetic ancestry estimation was performed at the super-population and population level using the 1000Genomes references. Data from over 24 tumor types were shared with our collaborators and the somatic variants were made available through our local installation of cBioPortal. Using the knowledge gained during the first stage, we are designing a prospective study to demonstrate our capacity to obtain samples from patients of varied ethnicities and to allow the formation of cohorts of interest for particular cancer types and particular ethnicities, with uniform consent for germline and somatic sequencing and return of results for potentially actionable mutations.By establishing a collaborative network, Polyethnic-1000 will deepen our understanding of the contributions that ethnicities make to the incidence and biology of cancers, potentially improving outcomes for patients who currently lack access to the most recent advances in medical science. Citation Format: Nicolas Robine, Fieke Froeling, Benjamin Hubert, Timothy Chu, Ashlea Chandler, Michael C. Zody, Dayna M. Oschwald, Harold E. Varmus, Charles Sawyers, David Tuveson. Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2328.

Abstract 5676: Preclinical evaluation of estrogen receptor coregulator binding inhibitor ERX-245 in breast cancer

Abstract Background: Breast cancer (BC) is the most common cancer in American women. Majority of BC (70%) is estrogen receptor alpha (ERα) positive and these tumors initially respond to ER-targeted therapy, however, acquired therapy-resistance limit the utility of ERα-targeted therapy using aromatase inhibitors and antiestrogens. Importantly, both therapy-sensitive and therapy-resistant tumors retain ESR1 signaling, via interaction with critical oncogenic coregulator proteins. We recently developed a small organic molecule, ESR1 coregulator binding inhibitor ERX-11. The objective of this study is to develop better analogues of ERX-11 using medicinal chemistry approaches. Methods: Virtual screening of a quarter million compounds and medicinal chemistry approaches were used to design new analogues of ERX-11 and identified ERX-245 as potent analogue. Effect of ERX-245 was evaluated in vitro using multiple BC models that express wild type (WT) ERα (MCF-7, ZR-75) and BC models with acquired resistance (MCF-7-Tam, MCF-7-LTLT). Mechanistic studies were performed using RNA-Seq, Western blotting, qRT-PCR and reporter gene assays. The in vivo efficacy of ERX-245 was examined using xenograft, and xenograft-derived explant (XDEx) models. Results: We initially performed an intensive virtual screening of a quarter million compounds and selected several candidates that showed strong binding energy to ERα. We then designed and developed several analogues of ERX-11 using modeled structural interactions. Using this approach, we identified ERX-245 as a potential lead compound for interaction with ERα. Like the parental ERX-11, ERX-245 significantly reduced the cell viability of both WT and therapy-resistant BC cells with an IC50 of 300-500 nM with minimal activity in ER-negative models such as TNBC cells. In long-term colony formation assays, ERX-245 significantly reduced the colony formation ability of both ER-WT and therapy-resistant BC cells. In ERE reporter assays, ERX-245 significantly reduced the estrogen-mediated reporter activity. ERX-245 significantly reduced the invasion of endocrine-resistant BC cells. RNA sequencing revealed unique pathways blocked by ERX-245. PK studies indicated that ERX-245 is more polar and has better solubility and pharmacokinetic properties compared to ERX-11. Treatment of ERX-245 decreased the proliferation and increased apoptosis (TUNEL staining) in xenograft derived explant (XDEx) models. ERX-245 also showed potent activity against WT-ERα and therapy-resistant xenograft models. Conclusions: Collectively, these results suggest that the ERX-11 analogue ERX-245 has potential to therapeutically target endocrine therapy resistant BC. Citation Format: Suryavathi Viswanadhapalli, Shihong Ma, Tae Kyung Lee, Xihui Liu, Kara Kassees, Uday P. Pratap, Junhao Liu, Weiwei Tang, Rajeshwar R. Tekmal, Jung-Mo Ahn, Ganesh V. Raj, Ratna K. Vadlamudi. Preclinical evaluation of estrogen receptor coregulator binding inhibitor ERX-245 in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5676.