scholarly journals Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2358
Author(s):  
Jose J. G. Marin ◽  
Paula Sanchon-Sanchez ◽  
Candela Cives-Losada ◽  
Sofía del Carmen ◽  
Jesús M. González-Santiago ◽  
...  
Keyword(s):  
Small Molecules ◽  
Poor Response ◽  
Genetic Alterations ◽  
New Drugs ◽  
Tyrosine Kinase Receptors ◽  
Surgical Removal ◽  
Mechanisms Of Resistance ◽  
Standard Chemotherapy ◽  
The Poor ◽  
Available Information

Despite the crucial advances in understanding the biology of cholangiocarcinoma (CCA) achieved during the last decade, very little of this knowledge has been translated into clinical practice. Thus, CCA prognosis is among the most dismal of solid tumors. The reason is the frequent late diagnosis of this form of cancer, which makes surgical removal of the tumor impossible, together with the poor response to standard chemotherapy and targeted therapy with inhibitors of tyrosine kinase receptors. The discovery of genetic alterations with an impact on the malignant characteristics of CCA, such as proliferation, invasiveness, and the ability to generate metastases, has led to envisage to treat these patients with selective inhibitors of mutated proteins. Moreover, the hope of developing new tools to improve the dismal outcome of patients with advanced CCA also includes the use of small molecules and antibodies able to interact with proteins involved in the crosstalk between cancer and immune cells with the aim of enhancing the immune system’s attack against the tumor. The lack of effect of these new therapies in some patients with CCA is associated with the ability of tumor cells to continuously adapt to the pharmacological pressure by developing different mechanisms of resistance. However, the available information about these mechanisms for the new drugs and how they evolve is still limited.

Surgery and metastases of stomach cancer in liver

2020 ◽  
pp. 21-24
Author(s):  
F. M. Dzhuraev ◽  
S. L. Gutorov ◽  
E. I. Borisova ◽  
G. G. Khakimova
Keyword(s):  
Gastric Cancer ◽  
Liver Metastases ◽  
Lymphovascular Invasion ◽  
Peritoneal Dissemination ◽  
Surgical Removal ◽  
Relapse Free Survival ◽  
Cancer Markers ◽  
Free Survival ◽  
The Poor ◽  
Isolated Liver

Liver metastases of gastric cancer determine the poor prognosis. Until now The expediency of their surgical removal has been controversial. However, according to a number of studies, the removal of potentially operable isolated liver metastases allows a significant increase of overall and relapse-free survival in some cases. The review is dedicated to the analysis of prognostic factors that allow selecting patients for surgical removal of liver metastases of gastric cancer. The main criteria are: effective perioperative chemotherapy; stage under T4, N0, absence of lymphovascular invasion, absence of peritoneal dissemination, number less than 3, size up to 4 cm, localization of metastases in one lobe, low level of cancer markers CA 19-9 and CEA.

scholarly journals Diversity-oriented synthesis derived indole based spiro and fused small molecules kills artemisinin-resistant Plasmodium falciparum

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Akshaykumar Nayak ◽  
Himani Saxena ◽  
Chandramohan Bathula ◽  
Tarkeshwar Kumar ◽  
Souvik Bhattacharjee ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Small Molecules ◽  
New Drugs ◽  
Developmental Cycle ◽  
Oxygen Species ◽  
Compound Library ◽  
Diversity Oriented Synthesis ◽  
Resistant Strains ◽  
Acid Catalyzed

Abstract Background Despite numerous efforts to eradicate the disease, malaria continues to remain one of the most dangerous infectious diseases plaguing the world. In the absence of any effective vaccines and with emerging drug resistance in the parasite against the majority of anti-malarial drugs, the search for new drugs is urgently needed for effective malaria treatment. Methods The goal of the present study was to examine the compound library, based on indoles generated through diversity-oriented synthesis belonging to four different architecture, i.e., 1-aryltetrahydro/dihydro-β-carbolines and piperidine/pyrrolidine-fused indole derivatives, for their in vitro anti-plasmodial activity. Trifluoroacetic acid catalyzed transformation involving tryptamine and various aldehydes/ketones provided the library. Results Among all the compounds screened, 1-aryltetrahydro-β-carbolines 2 and 3 displayed significant anti-plasmodial activity against both the artemisinin-sensitive and artemisinin-resistant strain of Plasmodium falciparum. It was observed that these compounds inhibited the overall parasite growth in intra-erythrocytic developmental cycle (IDC) via reactive oxygen species-mediated parasitic death and thus could be potential anti-malarial compounds. Conclusion Overall the compounds 2 and 3 identified in this study shows promising anti-plasmodial activity that can kill both artemisinin-sensitive and artemisinin-resistant strains of P. falciparum.

Polysialogangliosides Expressed by Amelanotic Melanoma: A Possible Explanation for the Poor Response to Anti-monosialoganglioside Antibody 202 in a Patient with Melanoma

1995 ◽  
Vol 22 (2) ◽  
pp. 81-87
Author(s):  
Sumiko Hamanaka ◽  
Takahisa Ota ◽  
Chidori Asagami ◽  
Toshikazu Gondo ◽  
Yasunori Yamaguchi ◽  
...  
Keyword(s):  
Poor Response ◽  
Amelanotic Melanoma ◽  
The Poor

scholarly journals Drug Discovery Firms and Business Alliances for Sustainable Innovation

2021 ◽  
Vol 13 (7) ◽  
pp. 3599
Author(s):  
Yoshimi Harada ◽  
Huayi Wang ◽  
Kota Kodama ◽  
Shintaro Sengoku
Keyword(s):  
Drug Discovery ◽  
Initial Public Offering ◽  
New Drugs ◽  
Pharmaceutical Companies ◽  
Pharmaceutical Firms ◽  
Significant Research ◽  
Public Offering ◽  
Platform Leadership ◽  
Available Information ◽  
Startup Firms

Biotech startup firms developing pharmaceutical seeds from scientific and technological innovation are burdened by significant Research & Development (R&D) expenses, long-term R&D operations, and low probability of R&D success. To address these challenges while sustainably creating innovations and new drugs, business alliances with existing pharmaceutical companies are one of the most important issues on the management agenda. The present study explores the necessity and significance of business alliances with pharmaceutical companies for the development of drug-discovery by Japanese biotech startup firms under high uncertainty. This study investigates the types of alliances to understand the origins of sustainability of these creative activities. First, we investigate and analyze the details of the partnership and its impact on the products under development based on the publicly available information of 16 drug discovery biotech startup firms in Japan that had become public since 2010. As a result, all firms continued their operations with the funds obtained from the business alliances with pharmaceutical firms at the time of their initial public offering (IPO). In addition, 56% of these firms’ alliance projects (n = 73) were seeded-out, and 32% seeded-in, indicating that they had adopted flexible alliance strategies not limited to seed-out ones. For sustainable going concern of the biotech startup business, it is valuable to consider multiple strategic options: “in-licensing and value up”, “best-in-class”, “platform leadership” and “first-in-class” depending on the characteristics of seeds and environmental restrictions.

scholarly journals Multimodal genetic features correlate with poor response to neoadjuvant chemoradiotherapy and high recurrence risk in Chinese patients with stage IB-IIA cervical cancer

2020 ◽  
Author(s):  
Yuchun Wei ◽  
Chuqing Wei ◽  
Chen Liang ◽  
Ning Liu ◽  
Zhenhao Fang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Neoadjuvant Therapy ◽  
Disease Free Survival ◽  
Poor Response ◽  
Recurrence Risk ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Free Survival ◽  
Caucasian Patients ◽  
Disease Free

Abstract Background Response of cervical cancer patients to neoadjuvant therapy differs from person to person. It remains unclear whether genetic alterations can predict response to neoadjuvant therapy and disease-free survival in cervical cancer.Methods 62 Chinese patients with stage IB-IIA cervical cancer were included in this study. Pre-treatment tumor tissues were profiled using a targeted next-generation sequencing assay. Genetic alterations were compared with those identified in the Western populations using the TCGA database. Pathological response and disease-free survival (DFS) were evaluated and their correlations with genetic alterations were analyzed.Results Genetic alterations in PIK3CA were prevalent in both Chinese and Caucasian populations. The mutation frequencies of TERT, POLD1, NOS2, and FGFR3 were significantly higher in Chinese patients whereas RPTOR, EGFR, and TP53 were frequently mutated in Caucasian patients. Germline mutations were identified in 13 out of 62 Chinese patients and 57% of them occurred in DNA repair genes, such as BRCA1/2, TP53 and PALB2. High tumor mutation burden (TMB), TP53 polymorphism (rs1042522) and KEAP1 mutations were found to be associated with poor response to neoadjuvant therapy. KEAP1 mutations, PIK3CA-SOX2 co-amplification, TERC amplification and TYMS polymorphism were associated with higher relapse rates of cervical cancer.Conclusion The similarity and difference of mutation landscape of Chinese and Caucasian patients suggested genetic background played a role in shaping the architecture of cervical cancer mutations. The associations of mutation feature of cervical cancer with patient response and tumor recurrence risk provided rationale to further validate and explore potential biomarkers for cervical cancer patients.

scholarly journals Metformin as Potential Therapy for High-Grade Glioma

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 210 ◽  
Author(s):  
Marek Mazurek ◽  
Jakub Litak ◽  
Piotr Kamieniak ◽  
Bartłomiej Kulesza ◽  
Katarzyna Jonak ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Cancer ◽  
Endometrial Carcinoma ◽  
Mechanism Of Action ◽  
High Grade Glioma ◽  
New Drugs ◽  
High Grade ◽  
First Line ◽  
The Poor

Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug used as the first-line medication in the treatment of type 2 diabetes. The recent years have brought many observations showing metformin in its new role. The drug, commonly used in the therapy of diabetes, may also find application in the therapy of a vast variety of tumors. Its effectiveness has been demonstrated in colon, breast, prostate, pancreatic cancer, leukemia, melanoma, lung and endometrial carcinoma, as well as in gliomas. This is especially important in light of the poor options offered to patients in the case of high-grade gliomas, which include glioblastoma (GBM). A thorough understanding of the mechanism of action of metformin can make it possible to discover new drugs that could be used in neoplasm therapy.

scholarly journals Quantitative Analysis of Retinal Microvascular Perfusion and Novel Biomarkers of the Treatment Response in Diabetic Macular Edema

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Young Gun Park ◽  
Young-Hoon Park
Keyword(s):  
Macular Edema ◽  
Treatment Response ◽  
Subgroup Analysis ◽  
Poor Response ◽  
Flow Ratio ◽  
The Poor ◽  
Poor Treatment ◽  
Capillary Plexus ◽  
Intravitreal Dexamethasone ◽  
Response Group

Purpose. We aimed to assess the changes of retinal microvascular parameters using optical coherence tomography angiography (OCTA) between diabetes macular edema (DME) and controls. We assessed the changes between the baseline microvascular parameters and final treatment response in patients with DME, initially treated with intravitreal dexamethasone (DEX) implant followed by antivascular endothelial growth factor (VEGF) injections on an as-needed basis. Methods. This retrospective study included 90 DME patients and 24 healthy control subjects. All subjects had their best-corrected visual acuity (BCVA) and central macular thickness (CMT) measured at baseline and after 12 months. Vessel density (VD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) and the deep/superficial flow ratio at baseline were analyzed. A subgroup analysis was used to compare the treatment response. A poor-response group was defined by five or more retreatments at 12 months. Results. BCVA and CMT showed a significant improvement at 12 months (all p < 0.001 ). The VD in the whole and parafoveal areas of the DCP was significantly reduced in DME patients compared to that in controls (all p < 0.05 ). The DCP/SCP flow ratio was also significantly reduced in the DME group ( 1.08 ± 0.03 vs. 1.05 ± 0.02 , p = 0.001 ). In the subgroup analysis, the VD in the foveal and whole DCP areas was significantly lower in the poor-response group than that in the good-response group ( p = 0.043 and p = 0.048 , respectively). The DCP/SCP flow ratio was also significantly lower in the poor-response group ( p = 0.011 ). Conclusion. DME correlated with significant retinal microvascular impairment in the DCP. A decreased DCP/SCP flow ratio was observed in patients with DME that exhibited a poor treatment response. Retinal microvascular parameters could predict the treatment response in DME and help optimize clinical outcomes.

scholarly journals PROMISCUOUS 2.0: a resource for drug-repositioning

2020 ◽  
Vol 49 (D1) ◽  
pp. D1373-D1380
Author(s):  
Kathleen Gallo ◽  
Andrean Goede ◽  
Andreas Eckert ◽  
Barbara Moahamed ◽  
Robert Preissner ◽  
...  
Keyword(s):  
Side Effects ◽  
Small Molecules ◽  
User Experience ◽  
Drug Target ◽  
Drug Repositioning ◽  
Dynamic Network ◽  
Structural Similarity ◽  
New Drugs ◽  
Entry Level ◽  
Development Costs

Abstract The development of new drugs for diseases is a time-consuming, costly and risky process. In recent years, many drugs could be approved for other indications. This repurposing process allows to effectively reduce development costs, time and, ultimately, save patients’ lives. During the ongoing COVID-19 pandemic, drug repositioning has gained widespread attention as a fast opportunity to find potential treatments against the newly emerging disease. In order to expand this field to researchers with varying levels of experience, we made an effort to open it to all users (meaning novices as well as experts in cheminformatics) by significantly improving the entry-level user experience. The browsing functionality can be used as a global entry point to collect further information with regards to small molecules (∼1 million), side-effects (∼110 000) or drug-target interactions (∼3 million). The drug-repositioning tab for small molecules will also suggest possible drug-repositioning opportunities to the user by using structural similarity measurements for small molecules using two different approaches. Additionally, using information from the Promiscuous 2.0 Database, lists of candidate drugs for given indications were precomputed, including a section dedicated to potential treatments for COVID-19. All the information is interconnected by a dynamic network-based visualization to identify new indications for available compounds. Promiscuous 2.0 is unique in its functionality and is publicly available at http://bioinformatics.charite.de/promiscuous2.

scholarly journals The Pharmaceutical Industry in 2019. An Analysis of FDA Drug Approvals from the Perspective of Molecules

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 745 ◽  
Author(s):  
Beatriz G. de la Torre ◽  
Fernando Albericio
Keyword(s):  
Natural Products ◽  
Pharmaceutical Industry ◽  
Small Molecules ◽  
Chemical Structure ◽  
New Drugs ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
The Us ◽  
New Chemical Entities ◽  
Antibody Drug

During 2019, the US Food and Drug Administration (FDA) approved 48 new drugs (38 New Chemical Entities and 10 Biologics). Although this figure is slightly lower than that registered in 2018 (59 divided between 42 New Chemical Entities and 17 Biologics), a year that broke a record with respect to new drugs approved by this agency, it builds on the trend initiated in 2017, when 46 drugs were approved. Of note, three antibody drug conjugates, three peptides, and two oligonucleotides were approved in 2019. This report analyzes the 48 new drugs of the class of 2019 from a strictly chemical perspective. The classification, which was carried out on the basis of chemical structure, includes the following: Biologics (antibody drug conjugates, antibodies, and proteins); TIDES (peptide and oligonucleotides); drug combinations; natural products; and small molecules.

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