ResearchPad - short-review https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[The safety, immunological benefits, and efficacy of ginseng in organ transplantation]]> https://www.researchpad.co/article/Nb1e3dd69-cf2d-4691-947e-7a4d5f96f42a Korean ginseng (Panax ginseng) is associated with a variety of therapeutic effects, including antioxidative, anti-inflammatory, vasorelaxative, antiallergic, antidiabetic, and anticancer effects. Accordingly, the use of ginseng has reached an all-time high among members of the general public. However, the safety and efficacy of ginseng in transplant recipients receiving immunosuppressant drugs have still not been elucidated. Transplantation is the most challenging and complex of surgical procedures and may require causation for the use of ginseng. In this regard, we have previously examined the safety, immunological benefits, and protective mechanisms of ginseng with respect to calcineurin inhibitor-based immunosuppression, which is the most widely used regimen in organ transplantation. Using an experimental model of calcineurin inhibitor-induced organ injury, we found that ginseng does not affect drug levels in the peripheral blood and tissue, favorably regulates immune response, and protects against calcineurin inhibitor-induced nephrotoxicity and pancreatic islet injury. On the basis of our experimental studies and a review of the related literature, we propose that ginseng may provide benefits in organ transplant recipients administered calcineurin inhibitors. Through the present review, we aimed to briefly discuss our current understanding of the therapeutic benefits of ginseng related to transplant patient survival.

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<![CDATA[Ginsenosides: potential therapeutic source for fibrosis-associated human diseases]]> https://www.researchpad.co/article/N88eb504e-b11f-40cb-b1e6-02f90fbd4147

Tissue fibrosis is an eventual pathologic change of numerous chronic illnesses, which is characterized by resident fibroblasts differentiation into myofibroblasts during inflammation, coupled with excessive extracellular matrix deposition in tissues, ultimately leading to failure of normal organ function. Now, there are many mechanistic insights into the pathogenesis of tissue fibrosis, which facilitate the discovery of effective antifibrotic drugs. Moreover, many chronic diseases remain a significant clinical unmet need. For the past five years, many research works have undoubtedly addressed the functional dependency of ginsenosides in different types of fibrosis and the successful remission in various animal models treated with ginsenosides. Caveolin-1, interleukin, thrombospondin-1 (TSP-1), liver X receptors (LXRs), Nrf2, microRNA-27b, PPARδ-STAT3, liver kinase B1 (LKB1)-AMPK, and TGF-β1/Smads are potential therapy targeting using ginsenosides. Ginsenosides can play a targeting role and suppress chronic inflammatory response, collagen deposition, and epithelial–mesenchymal transition (EMT), as well as myofibroblast activation to attenuate fibrosis. In this report, our aim was to focus on the therapeutic prospects of ginsenosides in fibrosis-related human diseases making use of results acquired from various animal models. These findings should provide important therapeutic clues and strategies for the exploration of new drugs for fibrosis treatment.

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<![CDATA[Exploring the computational methods for protein-ligand binding site prediction]]> https://www.researchpad.co/article/Nd7494747-7c03-47d7-b650-b7056be1d819

Proteins participate in various essential processes in vivo via interactions with other molecules. Identifying the residues participating in these interactions not only provides biological insights for protein function studies but also has great significance for drug discoveries. Therefore, predicting protein–ligand binding sites has long been under intense research in the fields of bioinformatics and computer aided drug discovery. In this review, we first introduce the research background of predicting protein–ligand binding sites and then classify the methods into four categories, namely, 3D structure-based, template similarity-based, traditional machine learning-based and deep learning-based methods. We describe representative algorithms in each category and elaborate on machine learning and deep learning-based prediction methods in more detail. Finally, we discuss the trends and challenges of the current research such as molecular dynamics simulation based cryptic binding sites prediction, and highlight prospective directions for the near future.

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<![CDATA[Recent Advances in Transition-Metal-Catalyzed, Directed Aryl C–H/N–H Cross-Coupling Reactions]]> https://www.researchpad.co/article/5c7eb0a4d5eed0c4848a572c

Amination and amidation of aryl compounds using a transition-metal-catalyzed cross-coupling reaction typically involves prefunctionalization or preoxidation of either partner. In recent years, a new class of transition-metal-catalyzed cross-dehydrogenative coupling reaction has been developed for the direct formation of aryl C–N bonds. This short review highlights the substantial progress made for ortho -C–N bond formation via transition-metal-catalyzed chelation-directed aryl C–H activation and gives an overview of the challenges that remain for directed meta - and para -selective reactions.

1 Introduction

2 Intramolecular C–N Cross-Dehydrogenative Coupling

2.1 Nitrogen Functionality as Both Coupling Partner and Directing Group

2.2 Chelating-Group-Directed Intramolecular C–N Bond Formation

3 Intermolecular C–N Cross-Dehydrogenative Coupling

3.1 ortho -C–N Bond Formation

3.1.1 Copper-Catalyzed Reactions

3.1.2 Other Transition-Metal-Catalyzed Reactions

3.2 meta - and para -C–N Bond Formation

4 C–N Cross-Dehydrogenative Coupling of Acidic C–H Bonds

5 Conclusions

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<![CDATA[50 Years of Zweifel Olefination: A Transition-Metal-Free Coupling]]> https://www.researchpad.co/article/5c7eb0a6d5eed0c4848a573c

The Zweifel olefination is a powerful method for the stereoselective synthesis of alkenes. The reaction proceeds in the absence of a transition-metal catalyst, instead taking place by iodination of vinyl boronate complexes. Pioneering studies into this reaction were reported in 1967 and this short review summarizes developments in the field over the past 50 years. An account of how the Zweifel olefination was modified to enable the coupling of robust and air-stable boronic esters is presented followed by a summary of current state of the art developments in the field, including stereodivergent olefination and alkynylation. Finally, selected applications of the Zweifel olefination in target-oriented synthesis are reviewed.

1 Introduction

2.1 Zweifel Olefination of Vinyl Boranes

2.2 Zweifel Olefination of Vinyl Borinic Esters

2.3 Extension to Boronic Esters

3.1 Introduction of an Unsubstituted Vinyl Group

3.2 Coupling of α-Substituted Vinyl Partners

3.3 Syn Elimination

4 Zweifel Olefination in Natural Product Synthesis

5 Conclusions and Outlook

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<![CDATA[ASCO Congress 2018: melanoma treatment]]> https://www.researchpad.co/article/5c2d3f5fd5eed0c484df3e55

Summary

The 2018 ASCO Annual Meeting provided a closer look on the details of studies already presented. In melanoma, the interest was on neoadjuvant treatment options with high pathological response rates as well as updates on large phase III studies in stage IV disease. Further new targets were discussed focusing on additional drugs to a PD-1 backbone treatment.

Another focus was on Merkel cell carcinoma and basal cell carcinomas, giving new data on PD-1 antibody treatments as well as on vismodegib as neoadjuvant therapy.

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<![CDATA[ASCO 2018: highlights of urothelial cancer and prostate cancer]]> https://www.researchpad.co/article/5c2d3f68d5eed0c484df4108

Summary

Prostate cancer and urothelial carcinoma are the two most common urological cancers. The aim of this short review is to highlight abstracts from this year’s ASCO Annual Meeting. The phase III SPCG-13 trial showed no difference in biochemical disease-free survival by the addition of docetaxel after primary radiation therapy of localized high-risk prostate cancer. In bone dominant metastatic castration resistant prostate cancer, the phase II radium-223 dose escalation study concluded that the currently used dose with 6 cycles of 55 kBq/kg remains the standard of care. The PARP inhibitor olaparib plus abiraterone provided a significant benefit in radiological progression-free survival compared with abiraterone alone, independent of homologous recombination repair (HRR) mutation status. In localized muscle-invasive urothelial carcinoma, two phase II trials (ABACUS and PURE-01) exploring the pathological complete remission rate of atezolizumab and pembrolizumab prior to cystectomy in cisplatin-unfit or cisplatin-fit patients are presented. Novel targeted therapies such as fibroblast growth factor receptor (FGFR) inhibitors or monoclonal antibodies against nectin-4 confirmed astonishing objective response rates in heavily pretreated metastatic urothelial carcinoma (mUC) patients, resulting in a median overall survival (OS) up to 13.8 months. Finally, updated 1‑year and 2‑year OS survival rates of pembrolizumab and atezolizumab in the first line setting of mUC are presented.

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<![CDATA[ASCO 2018 NSCLC highlights—combination therapy is key]]> https://www.researchpad.co/article/5c2d3f73d5eed0c484df4457

Summary

Non-small cell lung cancer (NSCLC) treatment was booming at this year’s ASCO 2018 meeting as several well-performed phase III trials with practice-changing potential were presented. Thereby immune checkpoint blockade (ICB) consolidated its major role in the treatment of NSCLC patients without genetic alterations and extended its use by showing impressive data on ICB combination therapies (mainly combined with chemotherapy). Furthermore the role of predictive biomarkers for ICB therapy (Programmed death-ligand 1 [PD-L1] expression, tumor mutational burden [TMB] testing and others) have been further developed and blood-based tests were presented with promising data revealing the potential of this minimally invasive method for treatment monitoring and guidance in the future. Nevertheless the best biomarker is still elusive and future research is ongoing and might be a multimodal approach combining different modalities. No major studies concerning new genetic alterations or innovative targets were presented and the focus in genetic driven NSCLC was the evaluation of combinational approaches (e.g. in epidermal growth factor receptor [EGFR] mutation positve patients, EGFR tyrosine kinase inhibitor [TKI] plus anti-angiogenic agent or chemotherapy backbone). The presented results showed some benefit for the combinational approach; however toxicity might be an issue and further validation is necessary. Summarizing, ASCO 2018 showed that combinational approaches will be the future standard treatment in NSCLC and that biomarker identification is more heterogeneous and complex than anticipated, but presented next generation techniques may pave the way to a more personalized cancer therapy.

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<![CDATA[ASCO 2018 highlights: metastatic breast cancer]]> https://www.researchpad.co/article/5c2d3f6fd5eed0c484df4341

Summary

This article reviews the clinically most relevant presentations at the American Society of Clinical Oncology (ASCO) annual meeting 2018 on the topic of metastatic breast cancer. In the randomized placebo-controlled phase 3 trial MONALEESA-3, testing ribociclib vs. placebo in combination with fulvestrant in postmenopausal women or men with hormone receptor-positive (HR+) and HER2-negative (HER2−) advanced breast cancer (ABC), an increase of median progression-free survival (PFS) from 12.8 months to 20.5 months by the addition of the CDK4/6 inhibitor was reported (HR 0.59; P > 0.01). Taselisib, an alpha specific PI3K inhibitor, was tested in combination with fulvestrant in pretreated HR+/HER2− ABC patients with PIK3CA mutations in the placebo-controlled phase 3 trial SANDPIPER. PFS was significantly longer (7.4 months vs 5.4 months; HR 0.70, P < 0.01) but severe adverse events were more frequent (32% and 9%) in the taselisib group. In triple-negative breast cancer, the AKT inhibitor capivasertib (AZD5363) was combined with paclitaxel as first-line treatment in the placebo-controlled phase 2 trial PAKT. In patients with altered PIK3CA, AKT1 or PTEN, median PFS increased from 3.7 months to 9.3 months (HR 0.30; two-sided P = 0.01). No treatment effect was shown in the non-altered group. The most common adverse events attributed to capivasertib were diarrhea, fatigue and stomatitis. Results of two phase I trials of trastuzumab antibody-drug conjugates (ADCs) indicated HER2 as a non-oncogenic surface target in breast cancer patients expressing HER2.

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<![CDATA[ASCO 2018: highlights in HER2-positive metastatic breast cancer]]> https://www.researchpad.co/article/5c2d3f64d5eed0c484df3ff9

Summary

At the 2018 ASCO Annual Meeting, data from several interesting studies in HER2-positive metastatic breast cancer were presented. While not immediately practice changing, these trials indicate the future directions of drug development in this field. Early phase studies with novel antibody-drug conjugates (ADCs) such as trastuzumab-deruxtecan and trastuzumab-duocarmazine suggest relevant clinical activity of these drugs in pretreated patients; in addition, these ADCs may offer activity in low HER2-expressing tumours as well. ZW25, a bispecific HER2-directed antibody targeting the extracellular domains 2 and 4, showed excellent tolerability and considerable single-agent activity. A combination of T‑DM1 with the tyrosine-kinase inhibitor neratinib yielded high response rates, while a study of trastuzumab plus durvalumab reported disappointing results. Although formally negative, overall survival data from the PHEREXA trial suggest clinical activity of dual HER2-inhibition with trastuzumab and pertuzumab in patients with prior trastuzumab treatment for advanced disease. A combined analysis of two tucatinib studies showed that systemic therapy is active when continued in case of isolated central nervous system progression and stable extracranial disease after local therapy of brain metastases; finally, a small prospective observation in asymptomatic patients with reduced left ventricular ejection fraction suggests that anti-HER2 treatment may be reasonably safe in this population.

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<![CDATA[Short review of biparametric prostate MRI]]> https://www.researchpad.co/article/5c2d3f6bd5eed0c484df423b

Summary

Magnetic resonance imaging (MRI) of the prostate has become the gold standard for visualization of prostate cancer. Prostate MRI is usually performed as multiparametric MRI (mpMRI). Since mpMRI has several drawbacks, a biparametric MRI (bpMRI) of the prostate has been proposed. Many studies have been published on mpMRI and bpMRI in recent years. This short review offers an overview of the latest developments in this rapidly evolving field of research.

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<![CDATA[Soluble HLA Class I Molecules/CD8 Ligation Trigger Apoptosis of CD8 Cells by Fas/Fas-Ligand Interaction]]> https://www.researchpad.co/article/5c04bf4ad5eed0c4847b5492 ]]> <![CDATA[The Behaviour of Cs, Co, and Sr Radionuclides in Marine Environmental Sediment]]> https://www.researchpad.co/article/5c04bf65d5eed0c4847b579f

This work describes experimental investigations and modelling studies on the sorption of radionuclides Cs, Co, and Sr by certain marine sediments within Egypt. The chemical composition of the marine sediments was determined. The soluble salts were measured for the sediments and the concentrations of the released cations, Al, Fe, and Si, were measured for the sediment materials in 0.1 M NaClO4 aqueous solution at different hydrogen ion concentrations. The two main factors that control the uptake of the radionuclides onto the sediment are the pH and the exchangeable capacities of the sediment materials. Surface complex model was used to estimate the surface charge densities and the electric surface potential of the marine sediment materials. These two parameters were calculated at the surface capacity sites of the sediment materials. The desorption of the adsorbed cations was determined by means of selective consecutive extraction tests using different chemical reagents including (1) 1 M MgCl2 (pH 7), (2) 1 M ammonium oxalate (pH 3-5), (3) 0.04 M NH2OH,HCl in 25% acetic acid (pH 3-4), (4) H2O2 in 5% HNO3(pH 2-3), and (5) digestion with nitric acid followed by hydrofluoric and perchloric acids (pH 2).

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<![CDATA[Towards an anti-fibrotic therapy for scleroderma: targeting myofibroblast differentiation and recruitment]]> https://www.researchpad.co/article/5989da3dab0ee8fa60b88a2d

Background

In response to normal tissue injury, fibroblasts migrate into the wound where they synthesize and remodel new extracellular matrix. The fibroblast responsible for this process is called the myofibroblast, which expresses the highly contractile protein α-smooth muscle actin (α-SMA). In normal tissue repair, the myofibroblast disappears. Conversely, abnormal myofibroblast persistence is a key feature of fibrotic dieases, including scleroderma (systemic sclerosis, SSc). Myofibroblasts can be derived from differentiation of local resident fibroblasts or by recruitment of microvascular pericytes.

Clinical problem addressed

Controlling myofibroblast differentiation and persistence is crucial for developing anti-fibrotic therapies targeting SSc.

Basic science advances

Insights have been recently generated into how the proteins transforming growth factor β (TGFβ), endothelin-1 (ET-1), connective tissue growth factor (CCN2/CTGF) and platelet derived growth factor (PDGF) contribute to myofibroblast differentiation and pericyte recruitment in general and to the persistent myofibroblast phenotype of lesional SSc fibroblast, specifically.

Relevance to clinical care

This minireview summarizes recent findings pertinent to the origin of myofibroblasts in SSc and how this knowledge might be used to control the fibrosis in this disease.

Conclusions

TGFβ, ET-1, CCN2 and PDGF are likely to cooperate in driving tissue repair and fibrogenic responses in fibroblasts. TGFβ, ET-1 and CCN2 appear to contribute to myofibroblast differentiation; PDGF appears to be involved with pericyte recruitment. Thus, different therapeutic strategies may exist for targeting the multisystem fibrotic disorder SSc.

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<![CDATA[Hepatic wound repair]]> https://www.researchpad.co/article/5989dae0ab0ee8fa60bbbb71

Background

Human chronic liver diseases (CLDs) with different aetiologies rely on chronic activation of wound healing that represents the driving force for fibrogenesis progression (throughout defined patterns of fibrosis) to the end stage of cirrhosis and liver failure.

Issues

Fibrogenesis progression has a major worldwide clinical impact due to the high number of patients affected by CLDs, increasing mortality rate, incidence of hepatocellular carcinoma and shortage of organ donors for liver transplantation.

Basic science advances

Liver fibrogenesis is sustained by a heterogeneous population of profibrogenic hepatic myofibroblasts (MFs), the majority being positive for α smooth muscle actin (αSMA), that may originate from hepatic stellate cells and portal fibroblasts following a process of activation or from bone marrow-derived cells recruited to damaged liver and, in a method still disputed, by a process of epithelial to mesenchymal transition (EMT) involving cholangiocytes and hepatocytes. Recent experimental and clinical data have identified, at tissue, cellular and molecular level major profibrogenic mechanisms: (a) chronic activation of the wound-healing reaction, (b) oxidative stress and related reactive intermediates, and (c) derangement of epithelial-mesenchymal interactions.

Clinical care relevance

Liver fibrosis may regress following specific therapeutic interventions able to downstage or, at least, stabilise fibrosis. In cirrhotic patients, this would lead to a reduction of portal hypertension and of the consequent clinical complications and to an overall improvement of liver function, thus extending the complication-free patient survival time and reducing the need for liver transplantation.

Conclusion

Emerging mechanisms and concepts related to liver fibrogenesis may significantly contribute to clinical management of patients affected by CLDs.

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<![CDATA[Interstitial fluid: the overlooked component of the tumor microenvironment?]]> https://www.researchpad.co/article/5989dab0ab0ee8fa60bab3ea

Background

The interstitium, situated between the blood and lymph vessels and the cells, consists of a solid or matrix phase and a fluid phase, together constituting the tissue microenvironment. Here we focus on the interstitial fluid phase of tumors, i.e., the fluid bathing the tumor and stromal cells. Novel knowledge on this compartment may provide important insight into how tumors develop and how they respond to therapy.

Results

We discuss available techniques for interstitial fluid isolation and implications of recent findings with respect to transcapillary fluid balance and uptake of macromolecular therapeutic agents. By the development of new methods it is emerging that local gradients exist in signaling substances from neoplastic tissue to plasma. Such gradients may provide new insight into the biology of tumors and mechanistic aspects linked to therapy. The emergence of sensitive proteomic technologies has made the interstitial fluid compartment in general and that of tumors in particular a highly valuable source for tissue-specific proteins that may serve as biomarker candidates. Potential biomarkers will appear locally at high concentrations in the tissue of interest and will eventually appear in the plasma, where they are diluted.

Conclusions

Access to fluid that reliably reflects the local microenvironment enables us to identify substances that can be used in early detection and monitoring of disease.

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