Synergistic Antimicrobial and Antioxidant Properties of Coccinia grandis (L.) Voigt, Clerodendrum inerme (L.) Gaertn. and Acanthus ebracteatus Vahl. Extracts and Their Potential as a Treatment for Xerosis Cutis

2020 ◽  
Vol 27 (6) ◽  
pp. 410-420
Author(s):  
Chayanin Pratoomsoot ◽  
Nalin Wongkattiya ◽  
Donruedee Sanguansermsri
Keyword(s):  
Treatment Options ◽  
Antioxidant Properties ◽  
Unmet Need ◽  
Epidermal Keratinocytes ◽  
Minimal Bactericidal Concentration ◽  
Herbal Extracts ◽  
Cell Viability Assay ◽  
Local Skin ◽  
Coccinia Grandis ◽  
Acanthus Ebracteatus

<b><i>Background:</i></b> A common health condition among older persons is xerosis cutis. Topical corticosteroid treatments are ­associated with side effects. There is an unmet need for her­bal treatment alternatives. <i>Coccinia grandis</i>, <i>Clerodendrum inerme</i> and <i>Acanthus ebracteatus</i> are used to treat skin con­ditions in Thai traditional medicine. This study aimed to investigate their antimicrobial and antioxidant properties, synergistic properties as well as their cytotoxicity. <b><i>Methods:</i></b> ­Ethanolic herbal extracts were used to perform minimal ­inhibitory (MIC) and minimal bactericidal concentration (MBC) assays on common skin pathogens. Synergistic anti­microbial activity was evaluated by a chequerboard assay. Antioxidant and synergistic properties were assessed by a 1,1-diphenyl-2-picrylhydrazyl assay. Cytotoxicity was tested on normal adult human primary epidermal keratinocytes. <b><i>Results:</i></b> All extracts showed an inhibitory effect on growth of all microorganisms tested. MIC and MBC values ranged from 0.0625 to 32 mg/mL and from 0.0625 to &#x3e;256 mg/mL, respectively. <i>A. ebracteatus</i> extract markedly demonstrated bactericidal activity against an methicillin-resistant <i>Staphylococcus aureus</i> strain. Additive antimicrobial activity was observed (fractional inhibitory concentration index values: 0.75–1). All extracts possessed antioxidant properties (IC<sub>50</sub> values: 0.12–0.25 mg/L). However, antagonism was observed with paired extract combinations (combination index values: 1.025–1.455). The cell viability assay confirmed that herbal extracts were not cytotoxic. <b><i>Conclusions:</i></b> Our results provide early findings of pharmacological activities to support a novel choice of herbal combinations as potential local skin treatment options for xerosis cutis.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

Phase II study of cabozantinib (cabo) combined with pembrolizumab (pembro) in metastatic or recurrent gastric and gastroesophageal adenocarcinoma (GEC) to overcome resistance to checkpoint inhibitors.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS253-TPS253
Author(s):  
Farshid Dayyani ◽  
Chloe Thomas ◽  
Gwendolyn Ung ◽  
Thomas H Taylor
Keyword(s):  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Objective Response ◽  
Unmet Need ◽  
Primary Objective ◽  
Phase 2 ◽  
Open Label ◽  
Secondary Resistance ◽  
Phase 2 Trial ◽  
Number Of Patients

TPS253 Background: GEC is the third leading cause of cancer mortality and the fifth most common malignancy worldwide. Fluoropyrimidine and platinum-based combinations are the most commonly used 1L treatment regimens. There are few standard treatment options after 1st line regimens. In the 3L+ GEC Keynote-059 trial, objective response rate (ORR) with Pembro was 15.5% in PD-L1(+) vs. 6.4% in PD-L1(-) tumors. While the responses were durable, the 6-months PFS (6-PFS) was only 14.1% and the median PFS was 2.0 mo. This highlights the remaining unmet need for the majority of patients who either are refractory or develop disease progression following treatment with PD-1 inhibitors in GEC. Cabo plus checkpoint inhibitors have shown clinical benefit in various cancers including hepatocellular, renal cell (RCC), urothelial and castration-resistant prostate cancers. In the CheckMate-9ER trial, Cabo+Nivolumab improved both OS and PFS vs sunitinib in 1L RCC. In patients with RCC who had progression on anti-PD1 inhibitor treatment, Cabo showed promising activity with an ORR of 33% and DCR of 79% (ESMO 2018, abstract 3793). Hypothesis: Based on preclinical and clinical observations, Cabo might contribute to overcoming primary or secondary resistance to PD-1 blockade in GEC. Methods: Prospective, open label, non-randomized phase 2 trial. Eligibility: Diagnosis of GEC, 2+ line of treatment including previous fluoropyrimidine/platinum, ECOG 0-2, adequate organ function, prior checkpoint inhibitor if tumor PD-L1 CPS≥10%. Treatment: Cabozantinib 40mg PO daily, Pembrolizumab 200 mg IV on day 1 of 21d cycle. Primary objective: Feasibility of the combination and estimate of efficacy. Primary endpoint:PFS-6. Secondary objectives: OS, ORR, adverse events. Total number of patients to be enrolled N = 27. Current enrollment (Sep 2020) N = 10. Statistics: If the PFS-6 is > 25%, the study would be regarded as positive, in which case it is planned to expand patient enrollment into a larger single arm phase 2 trial with additional sites to establish the efficacy of the regimen. Clinical trial information: NCT04164979.

scholarly journals Intratumoural immunotherapies for unresectable and metastatic melanoma: current status and future perspectives

2020 ◽  
Vol 123 (6) ◽  
pp. 885-897
Author(s):  
Mark R. Middleton ◽  
Christoph Hoeller ◽  
Olivier Michielin ◽  
Caroline Robert ◽  
Caroline Caramella ◽  
...  
Keyword(s):  
Immune Response ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Unmet Need ◽  
Systemic Exposure ◽  
Oncolytic Viruses ◽  
Current Status ◽  
Local Concentration ◽  
Major Step

Abstract The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma. The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response. Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies. Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation. This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents. The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs. Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment.

scholarly journals Identifying Biomarkers to Pair with Targeting Treatments within Triple Negative Breast Cancer for Improved Patient Stratification

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1864 ◽  
Author(s):  
Holly Tovey ◽  
Maggie Chon U. Cheang
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
High Throughput Sequencing ◽  
Triple Negative ◽  
Treatment Options ◽  
Unmet Need ◽  
Growth Factor Receptor ◽  
Parp Inhibitors ◽  
Genetic Features ◽  
The Uk

The concept of precision medicine has been around for many years and recent advances in high-throughput sequencing techniques are enabling this to become reality. Within the field of breast cancer, a number of signatures have been developed to molecularly sub-classify tumours. Notable examples recently approved by National Institute for Health and Care Excellence in the UK to guide treatment decisions for oestrogen receptors (ER)+ human epidermal growth factor receptor 2 (HER2)- patients include Prosigna® test, EndoPredict®, and Oncotype DX®. However, a population of still unmet need are those with triple negative breast cancer (TNBC). Accounting for 15–20% of patients, this population has comparatively poor prognosis and as yet no targeted treatment options. Studies have shown that some patients with TNBC respond favourably to DNA damaging drugs (carboplatin) or agents which inhibit DNA damage response (poly ADP ribose polymerase (PARP) inhibitors). Known to be a heterogeneous population, there is a need to identify further TNBC patients who may benefit from these treatments. A number of signatures have been identified based on association with treatment response or specific genetic features/pathways however many of these were not restricted to TNBC patients and as of yet are not common practice in the clinic.

scholarly journals Development of humanized tri-specific nanobodies with potent neutralization for SARS-CoV-2

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jianbo Dong ◽  
Betty Huang ◽  
Bo Wang ◽  
Allison Titong ◽  
Sachith Gallolu Kankanamalage ◽  
...  
Keyword(s):  
Computer Aided Design ◽  
Treatment Options ◽  
Unmet Need ◽  
Spike Protein ◽  
Therapeutic Antibodies ◽  
Human Igg1 ◽  
Vhh Antibodies ◽  
Phage Libraries ◽  
Aided Design ◽  
Potent Neutralization

Abstract SARS-CoV-2 is a newly emergent coronavirus, which has adversely impacted human health and has led to the COVID-19 pandemic. There is an unmet need to develop therapies against SARS-CoV-2 due to its severity and lack of treatment options. A promising approach to combat COVID-19 is through the neutralization of SARS-CoV-2 by therapeutic antibodies. Previously, we described a strategy to rapidly identify and generate llama nanobodies (VHH) from naïve and synthetic humanized VHH phage libraries that specifically bind the S1 SARS-CoV-2 spike protein, and block the interaction with the human ACE2 receptor. In this study we used computer-aided design to construct multi-specific VHH antibodies fused to human IgG1 Fc domains based on the epitope predictions for leading VHHs. The resulting tri-specific VHH-Fc antibodies show more potent S1 binding, S1/ACE2 blocking, and SARS-CoV-2 pseudovirus neutralization than the bi-specific VHH-Fcs or combination of individual monoclonal VHH-Fcs. Furthermore, protein stability analysis of the VHH-Fcs shows favorable developability features, which enable them to be quickly and successfully developed into therapeutics against COVID-19.

scholarly journals Systemic lupus erythematosus and diffuse alveolar hemorrhage, etiology and novel treatment strategies

Lupus ◽  
2020 ◽  
Vol 29 (4) ◽  
pp. 355-363 ◽  
Author(s):  
N K Al-Adhoubi ◽  
J Bystrom
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Treatment Options ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Diffuse Alveolar Hemorrhage ◽  
Alveolar Hemorrhage ◽  
Factor Vii ◽  
Systemic Lupus ◽  
Mesenchymal Stem Cell Therapy

Diffuse alveolar hemorrhage is a severe respiratory complication of systemic lupus erythematosus. The illness develops over hours to a few days and is the systemic lupus erythematosus-associated syndrome with highest mortality. Although no specific symptoms have been identified, a number of features are associated with diffuse alveolar hemorrhage, with a drop in blood hemoglobin the most prominent. Dyspnea, blood-stained sputum, diffuse infiltrates identified by chest imaging, elevated single breath-diffusing capacity for monoxide, thrombocytopenia and C3 hypocomplementemia are other commonly reported signs of diffuse alveolar hemorrhage. The etiology is not completely understood but many patients develop diffuse alveolar hemorrhage concomitant with lupus nephritis, suggesting immune complex-driven pathology. Biopsy studies have identified both cases with capillaritis and a bland non-inflammatory phenotype. An animal model of diffuse alveolar hemorrhage has indicated requirement of B lymphocytes and complement receptor-mediated apoptotic body phagocytosis by monocytes as part of the pathogenesis. This review will discuss considerations when diagnosing the condition and available therapies. Infections and other causes of hemorrhage have to be excluded as these require different treatment strategies. Methylprednisolone and cyclophosphamide remain the most commonly used therapies. Plasmapheresis and rituximab are other beneficial treatment options. A few studies have also considered intrapulmonary Factor VII therapy, extracorporeal membrane oxygenation and mesenchymal stem cell therapy. There is an unmet need of better definition of diffuse alveolar hemorrhages etiology and pathology for development of improved treatment strategies.

The human α-defensin-derived peptide HD5(1-9) inhibits cellular attachment and entry of human cytomegalovirus

2019 ◽  
Author(s):  
Rebecca Böffert ◽  
Ramona Businger ◽  
Hannes Preiß ◽  
Dirk Ehmann ◽  
Vincent Truffault ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Human Cytomegalovirus ◽  
Treatment Options ◽  
Unmet Need ◽  
Severe Illness ◽  
Natural Occurrence ◽  
Natural Defense ◽  
Cellular Attachment ◽  
Arginine Residues ◽  
Low Toxicity

ABSTRACTHuman cytomegalovirus (HCMV) infection causes severe illness in newborns and immunocompromised patients. Since treatment options are limited there is an unmet need for new therapeutic approaches. Defensins are cationic peptides, produced by various human tissues, which serve as antimicrobial effectors of the immune system. Furthermore, some defensins are proteolytically cleaved, resulting in the generation of smaller fragments with increased activity. Together, this led us to hypothesize that defensin-derived peptides are natural human inhibitors of virus infection with low toxicity. We screened several human defensin HNP4- and HD5-derived peptides and found HD5(1-9) to be antiviral without toxicity at high concentrations. HD5(1-9) inhibited HCMV cellular attachment and thereby entry and was active against primary as well as a multiresistant HCMV isolate. Moreover, cysteine and arginine residues were identified to mediate the antiviral activity of HD5(1-9). Altogether, defensin-derived peptides, in particular HD5(1-9), qualify as promising candidates for further development as a novel class of HCMV entry inhibitors.AUTHOR SUMMARYDefensins are peptides produced by various human organs which take part in the natural defense against pathogens. Recently, it has been shown that defensins are further cleaved to smaller peptides that have high intrinsic anti-microbial activity. We here challenged the hypothesis that these peptides might have antiviral activity, and due to their presumably natural occurrence, low toxicity. Indeed, we found one peptide fragment that turned out to block the attachment of the human cytomegalovirus (HCMV) to cells. Furthermore, this peptide did not show toxicity in various cellular assays or impede the embryonic development of zebrafish at the concentrations used to block HCMV. This is important, since HCMV is one of the most important viral congenital infections. Altogether, our results hold promise for the development of a new class of antivirals against HCMV.

scholarly journals Select β-Lactam Combinations Exhibit Synergy againstMycobacterium abscessus In Vitro

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Elizabeth Story-Roller ◽  
Emily C. Maggioncalda ◽  
Gyanu Lamichhane
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Mycobacterium Abscessus ◽  
Nontuberculous Mycobacterium ◽  
Pulmonary Infections ◽  
Content Type ◽  
Resistant Mutants ◽  
Lactamase Inhibitor ◽  
Selection Of

ABSTRACTMycobacterium abscessusis a nontuberculous mycobacterium that causes invasive pulmonary infections in patients with structural lung disease.M. abscessusis intrinsically resistant to several classes of antibiotics, and an increasing number of strains isolated from patients exhibit resistance to most antibiotics considered for treatment of infections by this mycobacterium. Therefore, there is an unmet need for new regimens with improved efficacy to treat this disease. Synthesis of the essential cell wall peptidoglycan inM. abscessusis achieved via two enzyme classes,l,d- andd,d-transpeptidases, with each class preferentially inhibited by different subclasses of β-lactam antibiotics. We hypothesized that a combination of two β-lactams that comprehensively inhibit the two enzyme classes will exhibit synergy in killingM. abscessus. Paired combinations of antibiotics tested forin vitrosynergy againstM. abscessusincluded dual β-lactams, a β-lactam and a β-lactamase inhibitor, and a β-lactam and a rifamycin. Of the initial 206 combinations screened, 24 pairs exhibited synergy. A total of 13/24 pairs were combinations of two β-lactams, and 12/24 pairs brought the MICs of both drugs to within the therapeutic range. Additionally, synergistic drug pairs significantly reduced the frequency of selection of spontaneous resistant mutants. These novel combinations of currently available antibiotics may offer viable immediate treatment options against highly-resistantM. abscessusinfections.

scholarly journals Ca2+ Channel Toolkit in Neuroendocrine Tumors

2019 ◽  
Vol 110 (1-2) ◽  
pp. 147-154
Author(s):  
Alessandra Fiorio Pla ◽  
Dimitra Gkika
Keyword(s):  
Neuroendocrine Tumors ◽  
Transient Receptor Potential ◽  
Treatment Options ◽  
Unmet Need ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
The Body ◽  
Neuroendocrine Cells ◽  
Neoplastic Progression ◽  
Ca2 Channels

Neuroendocrine tumors (NET) constitute a heterogeneous group of malignancies with various clinical presentations and growth rates but a common origin in neuroendocrine cells located all over the body. NET are a relatively low-frequency disease mostly represented by gastroenteropancreatic (GEP) and bronchopulmonary tumors (pNET); on the other hand, an increasing frequency and prevalence have been associated with NET. Despite great efforts in recent years, the management of NET is still a critical unmet need due to the lack of knowledge of the biology of the disease, the lack of adequate biomarkers, late presentation, the relative insensitivity of imaging modalities, and a paucity of predictably effective treatment options. In this context Ca2+ signals, being pivotal molecular devices in sensing and integrating signals from the microenvironment, are emerging to be particularly relevant in cancer, where they mediate interactions between tumor cells and the tumor microenvironment to drive different aspects of neoplastic progression (e.g., cell proliferation and survival, cell invasiveness, and proangiogenetic programs). Indeed, ion channels represent good potential pharmacological targets due to their location on the plasma membrane, where they can be easily accessed by drugs. The present review aims to provide a critical and up-to-date overview of NET development integrating Ca2+ signal involvement. In this perspective, we first give an introduction to NET and Ca2+ channels and then describe the different families of Ca2+ channels implicated in NET, i.e., ionotropic receptors, voltage-dependent Ca2+ channels, and transient receptor potential channels, as well as intracellular Ca2+ channels and their signaling molecules.

scholarly journals Antiproliferative Effects of an Analog of Curcumin in Hep-2 cells: A Comparative Study with Curcumin

2013 ◽  
Vol 8 (2) ◽  
pp. 1934578X1300800 ◽  
Author(s):  
Mohankumar Kumaravel ◽  
Pajaniradje Sankar ◽  
Periyasamy Latha ◽  
Chellakan S Benson ◽  
Rajagopalan Rukkumani
Keyword(s):  
Cell Proliferation ◽  
Curcuma Longa ◽  
Antioxidant Properties ◽  
Active Principle ◽  
Cell Cycle Distribution ◽  
Curcumin Analog ◽  
Cell Viability Assay ◽  
Chemopreventive Agents ◽  
Viability Assay ◽  
Cell Counts

Curcumin, the major active principle of Curcuma longa, is one of the promising, plant-derived, chemopreventive agents being studied for its anticarcinogenic and antioxidant properties. Hence, in our study, we aimed at testing the antiproliferative efficacy of an o-hydroxyl substituted analog of curcumin, bis demethoxy curcumin analog (BDMC-A), and comparing its efficacy with that of curcumin. BDMC-A was synthesised with a yield of 78% and 98% purity. Hep-2 cells and the MTT cell viability assay were used to examine cell proliferation. LDH assay and cell counts were performed to assess the cytotoxicity and anti-proliferative effects of the compound, respectively. Flow cytometry followed by Western blot were performed to investigate the cell cycle distribution. BDMC-A inhibited cell proliferation at a much lower concentration (IC50 20 μM) than curcumin (IC50 50 μM). Similar effects were observed in the LDH release and cell count assays. Flow cytometric studies using propidium iodide showed accumulation of cells in the G0/G1 phase and the arrest was further confirmed by immunoblotting of protein cyclin D1. BDMC-A was more potent in inhibiting the cells at a lower dose when compared with curcumin. Our results showed that the analog of curcumin is likely to possess more efficacy compared with curcumin in inhibiting cancer.

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