Biomedicines

15 pages, 3232 KiB

Open AccessArticle

RICTOR Affects Melanoma Tumorigenesis and Its Resistance to Targeted Therapy

by Ahlem Jebali, Maxime Battistella, Céleste Lebbé and Nicolas Dumaz

Biomedicines 2021, 9(10), 1498; https://doi.org/10.3390/biomedicines9101498 - 19 Oct 2021

Cited by 14 | Viewed by 2741

The network defined by phosphatidylinositol-3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) plays a major role in melanoma oncogenesis and has been implicated in BRAF inhibitor resistance. The central role of RICTOR (rapamycin-insensitive companion of mTOR) in this pathway has only recently [...] Read more.

The network defined by phosphatidylinositol-3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) plays a major role in melanoma oncogenesis and has been implicated in BRAF inhibitor resistance. The central role of RICTOR (rapamycin-insensitive companion of mTOR) in this pathway has only recently begun to be unraveled. In the present study, we assessed the role of mTORC2/RICTOR in BRAF-mutated melanomas and their resistance to BRAF inhibition. We showed that RICTOR was significantly overexpressed in melanoma and associated with bad prognoses. RICTOR overexpression stimulated melanoma-initiating cells (MICs) with ‘stemness’ properties. We also showed that RICTOR contributed to melanoma resistance to BRAF inhibitors and rendered the cells very sensitive to mTORC2 inhibition. We highlighted a connection between mTORC2/RICTOR and STAT3 in resistant cells and revealed an interaction between RAS and RICTOR in resistant melanoma, which, when disrupted, impeded the proliferation of resistant cells. Therefore, as a key signaling node, RICTOR contributes to BRAF-dependent melanoma development and resistance to therapy and, as such, is a valuable therapeutic target in melanoma. Full article

(This article belongs to the Special Issue Targeted Therapies for Cancer)

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12 pages, 310 KiB

Open AccessReview

Strategies Targeting Type 2 Inflammation: From Monoclonal Antibodies to JAK-Inhibitors

by Andrea Matucci, Emanuele Vivarelli, Francesca Nencini, Enrico Maggi and Alessandra Vultaggio

Biomedicines 2021, 9(10), 1497; https://doi.org/10.3390/biomedicines9101497 - 19 Oct 2021

Cited by 16 | Viewed by 3978

Abstract

Bronchial asthma and its frequent comorbidity chronic rhinosinusitis (CRS), are characterized by an inflammatory process at lower and upper respiratory tract, with a variability in terms of clinical presentations (phenotypes) and distinct underpin pathophysiological mechanisms (endotypes). Based on the characteristics of inflammation, bronchial [...] Read more.

Bronchial asthma and its frequent comorbidity chronic rhinosinusitis (CRS), are characterized by an inflammatory process at lower and upper respiratory tract, with a variability in terms of clinical presentations (phenotypes) and distinct underpin pathophysiological mechanisms (endotypes). Based on the characteristics of inflammation, bronchial asthma can be distinguished into type 2 (eosinophilic) or nontype 2 (noneosinophilic) endotypes. In type 2 asthma endotype, the pathogenic mechanism is sustained by an inflammatory process driven by Th2 cells, type 2 innate lymphoid cells (ILC2) and type 2 cytokines, which include interleukin (IL)-4, IL-5, IL-9 and IL-13. The definition of asthma and chronic rhinusinusitis phenotype/endotype is crucial, taking into account the availability of novel biologic agents, such as monoclonal antibodies targeting the classical type 2 cytokines. Recently, new therapeutic strategies have been proposed and analyzed in preliminary clinical trials. Among them Janus kinase (JAK) inhibitors, now largely used for the treatment of other chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases, is receiving great relevance. The rationale of this strategy derives from the data that JAK is a tyrosine kinase involved in the signaling of T cell receptor and of several cytokines that play a role in allergic respiratory disease, such as IL-2, IL-4 and IL-9. In this review, we discuss whether treatment with biological agents and JAK inhibitors may be equally effective in controlling type 2 inflammatory process in both asthma and CRS. Full article

(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)

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Graphical abstract

28 pages, 6366 KiB

Open AccessReview

Impact of Protein Corona on the Biological Identity of Nanomedicine: Understanding the Fate of Nanomaterials in the Biological Milieu

by Md Habban Akhter, Habibullah Khalilullah, Manish Gupta, Mohamed A. Alfaleh, Nabil A. Alhakamy, Yassine Riadi and Shadab Md

Biomedicines 2021, 9(10), 1496; https://doi.org/10.3390/biomedicines9101496 - 19 Oct 2021

Cited by 36 | Viewed by 4283

Abstract

Nanoparticles (NPs) in contact with a biological medium are rapidly comprehended by a number of protein molecules resulting in the formation of an NP–protein complex called protein corona (PC). The cell sees the protein-coated NPs as the synthetic identity is masked by protein [...] Read more.

Nanoparticles (NPs) in contact with a biological medium are rapidly comprehended by a number of protein molecules resulting in the formation of an NP–protein complex called protein corona (PC). The cell sees the protein-coated NPs as the synthetic identity is masked by protein surfacing. The PC formation ultimately has a substantial impact on various biological processes including drug release, drug targeting, cell recognition, biodistribution, cellular uptake, and therapeutic efficacy. Further, the composition of PC is largely influenced by the physico-chemical properties of NPs viz. the size, shape, surface charge, and surface chemistry in the biological milieu. However, the change in the biological responses of the new substrate depends on the quantity of protein access by the NPs. The PC-layered NPs act as new biological entities and are recognized as different targeting agents for the receptor-mediated ingress of therapeutics in the biological cells. The corona-enveloped NPs have both pros and cons in the biological system. The review provides a brief insight into the impact of biomolecules on nanomaterials carrying cargos and their ultimate fate in the biological milieu. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Target Identification and Drug Discovery 2.0)

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12 pages, 1859 KiB

Open AccessArticle

Weight Gain after Interferon-Free Treatment of Chronic Hepatitis C—Results from the German Hepatitis C-Registry (DHC-R)

by Bernhard Schlevogt, Klaus H. W. Boeker, Stefan Mauss, Hartwig Klinker, Renate Heyne, Ralph Link, Karl-Georg Simon, Christoph Sarrazin, Yvonne Serfert, Michael P. Manns and Heiner Wedemeyer

Biomedicines 2021, 9(10), 1495; https://doi.org/10.3390/biomedicines9101495 - 19 Oct 2021

Cited by 11 | Viewed by 2178

Abstract

Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term [...] Read more.

Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (−0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases)

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42 pages, 4982 KiB

Open AccessReview

Footprints of microRNAs in Cancer Biology

by Yaashini Rajasegaran, Adam Azlan, Aliaa Arina Rosli, Mot Yee Yik, Khor Kang Zi, Narazah Mohd Yusoff and Emmanuel Jairaj Moses

Biomedicines 2021, 9(10), 1494; https://doi.org/10.3390/biomedicines9101494 - 19 Oct 2021

Cited by 12 | Viewed by 4094

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs involved in post-transcriptional gene regulation. Over the past years, various studies have demonstrated the role of aberrant miRNA expression in the onset of cancer. The mechanisms by which miRNA exerts its cancer-promoting or inhibitory effects are apparent [...] Read more.

MicroRNAs (miRNAs) are short non-coding RNAs involved in post-transcriptional gene regulation. Over the past years, various studies have demonstrated the role of aberrant miRNA expression in the onset of cancer. The mechanisms by which miRNA exerts its cancer-promoting or inhibitory effects are apparent through the various cancer hallmarks, which include selective proliferative advantage, altered stress response, vascularization, invasion and metastasis, metabolic rewiring, the tumor microenvironment and immune modulation; therefore, this review aims to highlight the association between miRNAs and the various cancer hallmarks by dissecting the mechanisms of miRNA regulation in each hallmark separately. It is hoped that the information presented herein will provide further insights regarding the role of cancer and serve as a guideline to evaluate the potential of microRNAs to be utilized as biomarkers and therapeutic targets on a larger scale in cancer research. Full article

(This article belongs to the Special Issue MicroRNA in Solid Tumor and Hematological Diseases 2.0)

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15 pages, 4060 KiB

Open AccessArticle

Styrene Maleic Acid Copolymer-Based Micellar Formation of Temoporfin (SMA@ mTHPC) Behaves as A Nanoprobe for Tumor-Targeted Photodynamic Therapy with A Superior Safety

by Jun Fang, Shanghui Gao, Rayhanul Islam, Hinata Nema, Rina Yanagibashi, Niho Yoneda, Natsumi Watanabe, Yuki Yasuda, Naoki Nuita, Jian-Rong Zhou and Kazumi Yokomizo

Biomedicines 2021, 9(10), 1493; https://doi.org/10.3390/biomedicines9101493 - 19 Oct 2021

Cited by 10 | Viewed by 3033

Abstract

Tumor-targeted photodynamic therapy (PDT) using polymeric photosensitizers is a promising anticancer therapeutic strategy. Previously, we developed several polymeric nanoprobes for PDT using different polymers and PDT agents. In the study, we synthesized a styrene maleic acid copolymer (SMA) micelle encapsulating temoporfin (mTHPC) that [...] Read more.

Tumor-targeted photodynamic therapy (PDT) using polymeric photosensitizers is a promising anticancer therapeutic strategy. Previously, we developed several polymeric nanoprobes for PDT using different polymers and PDT agents. In the study, we synthesized a styrene maleic acid copolymer (SMA) micelle encapsulating temoporfin (mTHPC) that is a clinically used PDT drug, SMA@mTHPC, with a hydrodynamic size of 98 nm, which showed high water solubility. SMA@mTHPC maintained stable micelle formation in physiological aqueous solutions including serum; however, the micelles could be disrupted in the presence of detergent (e.g., Tween 20) as well as lecithin, the major component of cell membrane, suggesting micelles will be destroyed and free mTHPC will be released during intracellular uptake. SMA@mTHPC showed a pH-dependent release profile, for which a constant release of ≈20% per day was found at pH 7.4, and much more release occurred at acidic pH (e.g., 6.5, 5.5), suggesting extensive release of free mTHPC could occur in the weak acidic environment of a tumor and further during internalization into tumor cells. In vitro cytotoxicity assay showed a lower cytotoxicity of SMA@mTHPC than free mTHPC; however, similar in vivo antitumor effects were observed by both SMA@mTHPC and free THPC. More importantly, severe side effects (e.g., body weight loss, death of the mice) were found during free mTHPC treatment, whereas no apparent side effects were observed for SMA@mTHPC. The superior safety profile of SMA@mTHPC was mostly due to its micelle formation and the enhanced permeability and retention (EPR) effect-based tumor accumulation, as well as the tumor environment-responsive release properties. These findings suggested SMA@mTHPC may become a good candidate drug for targeted PDT with high safety. Full article

(This article belongs to the Topic Photodynamic Therapy)

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13 pages, 1269 KiB

Open AccessArticle

The Association between Use of ICS and Psychiatric Symptoms in Patients with COPD—A Nationwide Cohort Study of 49,500 Patients

by Alexander Jordan, Pradeesh Sivapalan, Josefin Eklöf, Jakob B. Vestergaard, Howraman Meteran, Mohamad Isam Saeed, Tor Biering-Sørensen, Anders Løkke, Niels Seersholm and Jens Ulrik Stæhr Jensen

Biomedicines 2021, 9(10), 1492; https://doi.org/10.3390/biomedicines9101492 - 18 Oct 2021

Cited by 4 | Viewed by 2892

Abstract

Psychiatric side effects are well known from treatment with systemic corticosteroids. It is, however, unclear whether inhaled corticosteroids (ICS) have psychiatric side effects in patients with COPD. We conducted a nationwide cohort study in all Danish COPD outpatients who had respiratory medicine specialist-verified [...] Read more.

Psychiatric side effects are well known from treatment with systemic corticosteroids. It is, however, unclear whether inhaled corticosteroids (ICS) have psychiatric side effects in patients with COPD. We conducted a nationwide cohort study in all Danish COPD outpatients who had respiratory medicine specialist-verified COPD, age ≥40 years, and no previous cancer. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder were assessed by Cox proportional hazards models. We observed a dose-dependent increase in the risk of antidepressant-use with ICS cumulated dose (HR 1.05, 95% CI 1.03–1.07, p = 0.0472 with low ICS exposure, HR 1.10, 95% CI 1.08–1.12, p < 0.0001 with medium exposure, HR 1.15, 95% CI 1.11–1.15, p < 0.0001 with high exposure) as compared to no ICS exposure. We found a discrete increased risk of admission to psychiatric hospitals in the medium and high dose group (HR 1.00, 95% CI 0.98–1.03, p = 0.77 with low ICS exposure, HR 1.07, 95% CI 1.05–1.10, p < 0.0001 with medium exposure, HR 1.13, 95% CI 1.10–1.15, p < 0.0001 with high exposure). The association persisted when stratifying for prior antidepressant use. Thus, exposure to ICS was associated with a small to moderate increase in antidepressant-use and psychiatric admissions. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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17 pages, 1602 KiB

Open AccessReview

The Impact of Steatosis on Chronic Hepatitis C Progression and Response to Antiviral Treatments

by Phumelele Yvonne Siphepho, Yi-Ting Liu, Ciniso Sylvester Shabangu, Jee-Fu Huang, Chung-Feng Huang, Ming-Lun Yeh, Ming-Lung Yu and Shu-Chi Wang

Biomedicines 2021, 9(10), 1491; https://doi.org/10.3390/biomedicines9101491 - 17 Oct 2021

Cited by 20 | Viewed by 4582

Abstract

Metabolic derangement is characteristic in patients with hepatitis C virus (HCV) infection. Aside from established liver injury, various extrahepatic metabolic disorders impact the natural history of the disease, clinical outcomes, and the efficacy of antiviral therapy. The presence of steatosis, recently redefined as [...] Read more.

Metabolic derangement is characteristic in patients with hepatitis C virus (HCV) infection. Aside from established liver injury, various extrahepatic metabolic disorders impact the natural history of the disease, clinical outcomes, and the efficacy of antiviral therapy. The presence of steatosis, recently redefined as metabolic-associated fatty liver disease (MAFLD), is a common feature in HCV-infected patients, induced by host and/or viral factors. Most chronic HCV-infected (CHC) patients have mild steatosis within the periportal region of the liver with an estimated prevalence of 40% to 86%. Indeed, this is higher than the 19% to 50% prevalence observed in patients with other chronic liver diseases such as chronic hepatitis B (CHB). The histological manifestations of HCV infection are frequently observed in genotype 3 (G-3), where relative to other genotypes, the prevalence and severity of steatosis is also increased. Steatosis may independently influence the treatment efficacy of either interferon-based or interferon-free antiviral regimens. This review aimed to provide updated evidence of the prevalence and risk factors behind HCV-associated steatosis, as well as explore the impact of steatosis on HCV-related outcomes. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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11 pages, 852 KiB

Open AccessArticle

Transcranial versus Direct Cortical Stimulation for Motor-Evoked Potentials during Resection of Supratentorial Tumors under General Anesthesia (The TRANSEKT-Trial): Study Protocol for a Randomized Controlled Trial

by Tammam Abboud, Thomas Asendorf, Jutta Heinrich, Katharina Faust, Sandro M. Krieg, Kathleen Seidel, Dorothee Mielke, Cordola Matthies, Florian Ringel, Veit Rohde and Andrea Szelényi

Biomedicines 2021, 9(10), 1490; https://doi.org/10.3390/biomedicines9101490 - 16 Oct 2021

Cited by 7 | Viewed by 2597

Abstract

Background: Monitoring of motor function during surgery for supratentorial tumors under general anesthesia applies either transcranial electrical stimulation (TES) or direct cortical stimulation (DCS) to elicit motor-evoked potentials. To date, there is no guideline that favor one method over the other. Therefore, we [...] Read more.

Background: Monitoring of motor function during surgery for supratentorial tumors under general anesthesia applies either transcranial electrical stimulation (TES) or direct cortical stimulation (DCS) to elicit motor-evoked potentials. To date, there is no guideline that favor one method over the other. Therefore, we designed this randomized study to compare between both methods regarding the prediction of postoperative motor deficits and extent of tumor resection. Methods: This is a multicenter (six centers in Germany and one in Switzerland), double blind, parallel group, exploratory, randomized controlled clinical trial. Patients without or with mild paresis, who are scheduled for surgical resection of motor-eloquent brain tumors under general anesthesia will be randomized to surgical resection under TES or surgical resection under DCS. The primary endpoint is sensitivity and specificity in prognosis of motor function 7 days after surgery. The main secondary endpoint is the extent of tumor resection. The study is planned to include 120 patients within 2 years. Discussion: The present exploratory study should compare TES and DCS regarding sensitivity and specificity in predicting postoperative motor deficit and extent of tumor resection to calculate the required number of patients in a confirmatory trial to test the superiority of one method over the other. Full article

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14 pages, 2399 KiB

Open AccessArticle

Pulsed Radiofrequency Upregulates Serotonin Transporters and Alleviates Neuropathic Pain-Induced Depression in a Spared Nerve Injury Rat Model

by Kuo-Hsing Ma, Cheng-Yi Cheng, Wei-Hung Chan, Shih-Yu Chen, Li-Ting Kao, Chun-Sung Sung, Dueng-Yuan Hueng and Chun-Chang Yeh

Biomedicines 2021, 9(10), 1489; https://doi.org/10.3390/biomedicines9101489 - 16 Oct 2021

Cited by 4 | Viewed by 2985

Abstract

Neuropathic pain (NP) is difficult to treat due to complex pathophysiological mechanisms. Pulsed radiofrequency (RRF) has been used widely with neuromodulation effect in refractory chronic pain treatment. A recent study found that PRF treatment may decrease chronic pain-related anxiety-depressant symptoms in patients, even [...] Read more.

Neuropathic pain (NP) is difficult to treat due to complex pathophysiological mechanisms. Pulsed radiofrequency (RRF) has been used widely with neuromodulation effect in refractory chronic pain treatment. A recent study found that PRF treatment may decrease chronic pain-related anxiety-depressant symptoms in patients, even though the mechanisms are unclear. Additionally, accumulated evidence has shown serotonin uptake is correlated with various neuropsychiatric diseases. Therefore, we investigated the effects and underlying mechanisms of PRF on depression-like behaviors, resulting from spared nerve injury (SNI)-induced NP. We examined the indexes of mechanical allodynia, cold allodynia, depression-like behavior, and blood cytokines by dynamic plantar aesthesiometry, acetone spray test, forced swimming test, and ProcartaPlex multiplex immunoassays in male Wistar rats, respectively. Serotonin transporters (SERTs) in rat brains were examined by using 4-[18F]-ADAM/PET imaging. We found that specific uptake ratios (SURs) of SERTs were significantly decreased in the brain regions of the thalamus and striatum in rats with SNI-induced NP and depression-like behaviors. Additionally, the decrease in SERT density was correlated with the development of a depression-like behavior indicated by the forced swimming test results and pronounced IL-6 cytokines. Moreover, we demonstrated that PRF application could modulate the descending serotoninergic pathway to relieve pain and depression behaviors. Full article

(This article belongs to the Section Cell Biology and Pathology)

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14 pages, 1258 KiB

Open AccessArticle

Capillary Electrophoresis–Mass Spectrometry with Multisegment Injection and In-Capillary Preconcentration for High-Throughput and Sensitive Determination of Therapeutic Decapeptide Triptorelin in Pharmaceutical and Biological Matrices

by Juraj Piešťanský, Ivana Čižmárová, Ondrej Štefánik, Michaela Matušková, Andrea Horniaková, Petra Majerová and Peter Mikuš

Biomedicines 2021, 9(10), 1488; https://doi.org/10.3390/biomedicines9101488 - 16 Oct 2021

Cited by 11 | Viewed by 2265

Abstract

A capillary electrophoresis–tandem mass spectrometry method with a multisegment injection and an in-capillary field-enhanced sample stacking for determination of therapeutic peptide triptorelin in pharmaceutical and biological matrices was developed. The CE separation conditions were optimized in order to obtain maximal separation efficiency, analytical [...] Read more.

A capillary electrophoresis–tandem mass spectrometry method with a multisegment injection and an in-capillary field-enhanced sample stacking for determination of therapeutic peptide triptorelin in pharmaceutical and biological matrices was developed. The CE separation conditions were optimized in order to obtain maximal separation efficiency, analytical signal intensity and stability, and minimal adsorption of the analyzed peptide onto the capillary wall (1 M formic acid—HFo, pH 1.88). The implementation of the field-enhanced sample injection into CE improved the value of limit of detection 50 times while the multisegment injection increased the sample throughput three times in comparison to a conventional CE approach. The proposed method was characterized by favorable performance parameters, such as linearity (r² ≥ 0.99), limit of detection (5 ng mL⁻¹ in water matrix, 25 ng mL⁻¹ in plasma matrix), precision (relative standard deviation, 1.5–9.4% for intraday and 2.3–11.9% for interday reproducibility), or accuracy (relative errors in the range of 80–109%). The FDA-validated method was successfully applied to the analysis of triptorelin in the commercial drug Diphereline^® 0.1 mg (powder for injection) and in spiked human plasma samples. Favorable performance parameters along with proven application potentialities indicate the usefulness of the proposed method for its routine use in drug quality control laboratories and for clinical analysis, such as determination of triptorelin levels in plasma (for pharmacokinetic study). Full article

(This article belongs to the Special Issue Pharmacokinetics and Therapeutic Drug Monitoring)

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16 pages, 7280 KiB

Open AccessArticle

Zoledronate Bound to Ceramics Increases Ectopic Bone Volume Induced by rhBMP6 Delivered in Autologous Blood Coagulum in Rats

by Nikola Stokovic, Natalia Ivanjko, Igor Erjavec, Anita Breski, Mihaela Peric and Slobodan Vukicevic

Biomedicines 2021, 9(10), 1487; https://doi.org/10.3390/biomedicines9101487 - 16 Oct 2021

Cited by 4 | Viewed by 2483

Abstract

Autologous bone graft substitute (ABGS) containing rhBMP6 in autologous blood coagulum (ABC) with synthetic ceramics is a novel therapeutic solution for bone repair. The aim of this study was to investigate whether the application of Zoledronate (ZOL) with ABGS might enhance the properties [...] Read more.

Autologous bone graft substitute (ABGS) containing rhBMP6 in autologous blood coagulum (ABC) with synthetic ceramics is a novel therapeutic solution for bone repair. The aim of this study was to investigate whether the application of Zoledronate (ZOL) with ABGS might enhance the properties of newly formed bone. The effect of ZOL on bone induction was tested in a rat subcutaneous implant model. ZOL bound to synthetic ceramics was added into ABGS implants, and the quantity, quality, and longevity of the induced bone were assessed by micro-CT, histomorphometry, and histology over a period of 365 days. Local use of ZOL in the ABGS implants with ceramics had no influence on the bone volume (BV) on day 14 but subsequently significantly increased BV on days 35, 50, 105, 140, and 365 compared to the control implants. Locally applied ZOL had a similar effect in all of the applied doses (2–20 µg), while its systemic use on stimulating the BV of newly induced bone by ABGS depended on the time of application. BV was increased when ZOL was applied systemically on day 14 but had no effect when applied on day 35. The administration of ZOL bound to ceramics in ABGS increased and maintained the BV over a period of one year, offering a novel bone tissue engineering strategy for treating bone defects and spinal fusions. Full article

(This article belongs to the Topic Animal Model in Biomedical Research)

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29 pages, 443 KiB

Open AccessReview

Overview of Acute Ischemic Stroke Evaluation and Management

by Tasneem F. Hasan, Hunaid Hasan and Roger E. Kelley

Biomedicines 2021, 9(10), 1486; https://doi.org/10.3390/biomedicines9101486 - 16 Oct 2021

Cited by 39 | Viewed by 8684

Abstract

Stroke is a major contributor to death and disability worldwide. Prior to modern therapy, post-stroke mortality was approximately 10% in the acute period, with nearly one-half of the patients developing moderate-to-severe disability. The most fundamental aspect of acute stroke management is “time is [...] Read more.

Stroke is a major contributor to death and disability worldwide. Prior to modern therapy, post-stroke mortality was approximately 10% in the acute period, with nearly one-half of the patients developing moderate-to-severe disability. The most fundamental aspect of acute stroke management is “time is brain”. In acute ischemic stroke, the primary therapeutic goal of reperfusion therapy, including intravenous recombinant tissue plasminogen activator (IV TPA) and/or endovascular thrombectomy, is the rapid restoration of cerebral blood flow to the salvageable ischemic brain tissue at risk for cerebral infarction. Several landmark endovascular thrombectomy trials were found to be of benefit in select patients with acute stroke caused by occlusion of the proximal anterior circulation, which has led to a paradigm shift in the management of acute ischemic strokes. In this modern era of acute stroke care, more patients will survive with varying degrees of disability post-stroke. A comprehensive stroke rehabilitation program is critical to optimize post-stroke outcomes. Understanding the natural history of stroke recovery, and adapting a multidisciplinary approach, will lead to improved chances for successful rehabilitation. In this article, we provide an overview on the evaluation and the current advances in the management of acute ischemic stroke, starting in the prehospital setting and in the emergency department, followed by post-acute stroke hospital management and rehabilitation. Full article

(This article belongs to the Special Issue Stroke—Pathophysiology and New Therapeutic Strategies)

21 pages, 5148 KiB

Open AccessArticle

Surface Modification of Porous Polyethylene Implants with an Albumin-Based Nanocarrier-Release System

by Jonas Eckrich, Niklas Hoormann, Erik Kersten, Keti Piradashvili, Frederik R. Wurm, Martin Heller, Sven Becker, Toni Anusic, Juergen Brieger and Sebastian Strieth

Biomedicines 2021, 9(10), 1485; https://doi.org/10.3390/biomedicines9101485 - 16 Oct 2021

Cited by 2 | Viewed by 2352

Abstract

Background: Porous polyethylene (PPE) implants are used for the reconstruction of tissue defects but have a risk of rejection in case of insufficient ingrowth into the host tissue. Various growth factors can promote implant ingrowth, yet a long-term gradient is a prerequisite for [...] Read more.

Background: Porous polyethylene (PPE) implants are used for the reconstruction of tissue defects but have a risk of rejection in case of insufficient ingrowth into the host tissue. Various growth factors can promote implant ingrowth, yet a long-term gradient is a prerequisite for the mediation of these effects. As modification of the implant surface with nanocarriers may facilitate a long-term gradient by sustained factor release, implants modified with crosslinked albumin nanocarriers were evaluated in vivo. Methods: Nanocarriers from murine serum albumin (MSA) were prepared by an inverse miniemulsion technique encapsulating either a low- or high-molar mass fluorescent cargo. PPE implants were subsequently coated with these nanocarriers. In control cohorts, the implant was coated with the homologue non-encapsulated cargo substance by dip coating. Implants were consequently analyzed in vivo using repetitive fluorescence microscopy utilizing the dorsal skinfold chamber in mice for ten days post implantation. Results: Implant-modification with MSA nanocarriers significantly prolonged the presence of the encapsulated small molecules while macromolecules were detectable during the investigated timeframe regardless of the form of application. Conclusions: Surface modification of PPE implants with MSA nanocarriers results in the alternation of release kinetics especially when small molecular substances are used and therefore allows a prolonged factor release for the promotion of implant integration. Full article

(This article belongs to the Special Issue Early Biological Reactions on Biomaterials Determining Long-Term Tissue Regeneration Effects)

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12 pages, 2039 KiB

Open AccessReview

Insights into Potential Pathogenesis and Treatment Options for Immune-Checkpoint Inhibitor-Related Pneumonitis

by Hiroyuki Ando, Kunihiro Suzuki and Toyoshi Yanagihara

Biomedicines 2021, 9(10), 1484; https://doi.org/10.3390/biomedicines9101484 - 16 Oct 2021

Cited by 14 | Viewed by 4034

Abstract

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to [...] Read more.

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to release the brakes on the immune system, thereby enhancing immune anti-tumor responses. On the other hand, unlike conventional chemotherapies, ICIs can cause specific side effects, called immune-related adverse events (irAEs). These toxicities may affect various organs, including the lungs. ICI-related pneumonitis (ICI-pneumonitis) is not the most frequent adverse event, but it is serious and can be fatal. In this review, we summarize recent findings regarding ICI-pneumonitis, with a focus on potential pathogenesis and treatment. Full article

(This article belongs to the Special Issue Treatment for Pulmonary Fibrosis)

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13 pages, 3040 KiB

Open AccessArticle

Heat Shock Cognate 70 kDa Protein Is the Target of Tetradecyl 2,3-Dihydroxybenzoate for Neuritogenic Effect in PC12 Cells

by Lihong Cheng, Yanhui Wang, Lan Xiang and Jianhua Qi

Biomedicines 2021, 9(10), 1483; https://doi.org/10.3390/biomedicines9101483 - 16 Oct 2021

Cited by 3 | Viewed by 2950

Abstract

Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from gentisides with a remarkable neuritogenic activity. However, the target of ABG-001 is yet to be defined to date. In this study, the potential target of ABG-001 was investigated via an activity-based protein profiling (ABPP) [...] Read more.

Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from gentisides with a remarkable neuritogenic activity. However, the target of ABG-001 is yet to be defined to date. In this study, the potential target of ABG-001 was investigated via an activity-based protein profiling (ABPP) analysis, which is a chemical proteomic method for target identification by using chemical probes. Results indicated that the potential target proteins of ABG-001 were heat shock cognate 70 kDa protein (Hsc70), 78 kDa glucose-regulated protein (GRP78), and 14-3-3 theta protein. Then, the potential target of ABG-001 was confirmed by using inhibitors, the cellular thermal shift assay (CETSA) and small-interfering RNA (siRNA) analysis. The inhibitor of Hsc70 and siRNA significantly decreased the neurite outgrowth induced by ABG-001. Furthermore, ABG-001 induced neurite outgrowth was reduced by siRNA against Hsc70, and the results of CETSA suggested that Hsc70 showed a significant thermal stability-shifted effect upon ABG-001 treatment. These results indicated that Hsc70 is the target protein of ABG-001 in PC12 cells. Full article

(This article belongs to the Special Issue Bioactive Natural Products and Synthetic Small Molecules as Potential Investigational Treatments for Neurodegenerative Diseases)

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15 pages, 299 KiB

Open AccessArticle

New-Onset Psoriatic Arthritis under Biologics in Psoriasis Patients: An Increasing Challenge?

by Matteo Megna, Sonia Sofia Ocampo-Garza, Luca Potestio, Giuseppina Fontanella, Lucia Gallo, Sara Cacciapuoti, Angelo Ruggiero and Gabriella Fabbrocini

Biomedicines 2021, 9(10), 1482; https://doi.org/10.3390/biomedicines9101482 - 15 Oct 2021

Cited by 36 | Viewed by 3815

Abstract

Psoriasis and psoriatic arthritis (PsA) development is sustained by tumor necrosis factor (TNF)α, interleukin (IL)17, and IL23; hence, biologics targeting those cytokines represent useful therapeutic weapons for both conditions. Nevertheless, biologics strongly reduce PsA risk; several studies reported the possibility of new-onset PsA [...] Read more.

Psoriasis and psoriatic arthritis (PsA) development is sustained by tumor necrosis factor (TNF)α, interleukin (IL)17, and IL23; hence, biologics targeting those cytokines represent useful therapeutic weapons for both conditions. Nevertheless, biologics strongly reduce PsA risk; several studies reported the possibility of new-onset PsA during biologic therapy for psoriasis. The aim of this 1-year prospective study is to evaluate the prevalence of paradoxical PsA in psoriasis patients under biologic therapy and review the existing literature. For each patient, age, sex, psoriasis duration, psoriasis severity, comorbidities, and previous and current psoriasis treatments were collected, and each subject was screened for PsA using the Early ARthritis for Psoriatic patient (EARP) questionnaire every 3 months for 1 year. New-onset PsA was diagnosed in 10 (8.5%) out of 118 patients (three male, 30.0%; mean age 44.5 years) involving every different biologic class (anti-TNF, anti-IL12/23, anti-IL17, and anti-IL23). No significant risk factor for new-onset PsA was identified; no significant difference was found comparing patients who developed PsA and subjects who did not develop PsA regarding psoriasis severity, past/current therapies, and comorbidities. Clinicians must keep in mind the possibility of PsA onset also in patients undergoing biologics so that PsA screening should be strongly recommended at each follow-up. Full article

(This article belongs to the Special Issue Immune-Mediated Skin Diseases: From Pathophysiology to Novel Therapeutic Approaches)

17 pages, 1327 KiB

Open AccessReview

The Role of Omics Approaches to Characterize Molecular Mechanisms of Rare Ovarian Cancers: Recent Advances and Future Perspectives

by Yashwanth Subbannayya, Riccardo Di Fiore, Silvana Anna Maria Urru and Jean Calleja-Agius

Biomedicines 2021, 9(10), 1481; https://doi.org/10.3390/biomedicines9101481 - 15 Oct 2021

Cited by 8 | Viewed by 3967

Abstract

Rare ovarian cancers are ovarian cancers with an annual incidence of less than 6 cases per 100,000 women. They generally have a poor prognosis due to being delayed diagnosis and treatment. Exploration of molecular mechanisms in these cancers has been challenging due to [...] Read more.

Rare ovarian cancers are ovarian cancers with an annual incidence of less than 6 cases per 100,000 women. They generally have a poor prognosis due to being delayed diagnosis and treatment. Exploration of molecular mechanisms in these cancers has been challenging due to their rarity and research efforts being fragmented across the world. Omics approaches can provide detailed molecular snapshots of the underlying mechanisms of these cancers. Omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, can identify potential candidate biomarkers for diagnosis, prognosis, and screening of rare gynecological cancers and can aid in identifying therapeutic targets. The integration of multiple omics techniques using approaches such as proteogenomics can provide a detailed understanding of the molecular mechanisms of carcinogenesis and cancer progression. Further, omics approaches can provide clues towards developing immunotherapies, cancer recurrence, and drug resistance in tumors; and form a platform for personalized medicine. The current review focuses on the application of omics approaches and integrative biology to gain a better understanding of rare ovarian cancers. Full article

(This article belongs to the Special Issue The Omics Techniques in Obstetrical Pathologies)

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8 pages, 780 KiB

Open AccessCommunication

The Slower Antibody Response in Myelofibrosis Patients after Two Doses of mRNA SARS-CoV-2 Vaccine Calls for a Third Dose

by Fabio Fiorino, Anna Sicuranza, Annalisa Ciabattini, Adele Santoni, Gabiria Pastore, Martina Simoncelli, Jacopo Polvere, Sara Galimberti, Stefano Auddino, Claudia Baratè, Francesca Montagnani, Vincenzo Sammartano, Monica Bocchia and Donata Medaglini

Biomedicines 2021, 9(10), 1480; https://doi.org/10.3390/biomedicines9101480 - 15 Oct 2021

Cited by 19 | Viewed by 2550

Abstract

Immunization with mRNA SARS-CoV-2 vaccines has been highly recommended and prioritized in fragile subjects, including patients with myelofibrosis (MF). Available data on the vaccine immune response developed by MF patients and the impact of ruxolitinib treatment are still too fragmented to support an [...] Read more.

Immunization with mRNA SARS-CoV-2 vaccines has been highly recommended and prioritized in fragile subjects, including patients with myelofibrosis (MF). Available data on the vaccine immune response developed by MF patients and the impact of ruxolitinib treatment are still too fragmented to support an informed decision on a third dose for this category of subjects. Here, we show that 76% of MF patients develop spike-specific IgG after the second mRNA SARS-CoV-2 vaccine dose, but the response has a slower kinetics compared to healthy subjects, suggesting a reduced capability of their immune system to promptly react to vaccination. A reduced ACE2/RBD binding inhibition activity of spike-specific antibodies was also observed, especially in ruxolitinib-treated patients. Our results, showing slow kinetics of antibody responses in MF patients following vaccination with mRNA SARS-CoV-2 vaccines, support the need for a third vaccine dose. Full article

(This article belongs to the Special Issue Immunology in COVID-19 Disease: From Pathophysiology to Novel Therapeutic Approaches)

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11 pages, 1355 KiB

Open AccessArticle

The Dynamic Change of Immune Checkpoints and CD14+ Monocytes in Latent Tuberculosis Infection

by Ping-Huai Wang, Ming-Fang Wu, Chi-Yu Hsu, Shu-Yung Lin, Ya-Nan Chang, Ho-Shen Lee, Yu-Feng Wei and Chin-Chung Shu

Biomedicines 2021, 9(10), 1479; https://doi.org/10.3390/biomedicines9101479 - 15 Oct 2021

Cited by 12 | Viewed by 2149

Abstract

Controlling latent tuberculosis infection (LTBI) is important for preventing tuberculosis (TB). However, the immune regulation of LTBI remains uncertain. Immune checkpoints and CD14+ monocytes are pivotal for immune defense but have been scarcely studied in LTBI. We prospectively enrolled participants with LTBI and [...] Read more.

Controlling latent tuberculosis infection (LTBI) is important for preventing tuberculosis (TB). However, the immune regulation of LTBI remains uncertain. Immune checkpoints and CD14+ monocytes are pivotal for immune defense but have been scarcely studied in LTBI. We prospectively enrolled participants with LTBI and controls from January 2017 to December 2019. We measured their CD14+ monocytes and the expression of immune checkpoints, including programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and T cell immunoglobulin mucin domain-containing-3 (TIM3) on T lymphocytes in peripheral blood mononuclear cells before and after LTBI treatment. A total of 87 subjects were enrolled, including 29 IGRA-negative healthy controls (HC), 58 in the LTBI group (19 without chronic kidney disease (non-CKD), and 39 with end-stage renal disease (ESRD)). All PD-1, CTLA-4, and TIM3 on lymphocytes and monocytes were higher in the LTBI group than that in the HC group. Total CD14+ monocytes were higher and PD-L2+CD14+ over monocytes were lower in patients with LTBI-non-CKD than that in the HC group. After LTBI treatment, CD14+ monocytes, TIM3+ on CD4+ and monocytes, and CTLA-4 on lymphocytes decreased significantly. Multivariable logistic regression indicated that CD14+ monocytes was an independent factor for LTBI-non-CKD from the HC group, whereas PD-L2+CD14+ monocytes and TIM3+ monocytes were significant for LTBI-ESRD from the HC group. In conclusion, LTBI status was associated with increasing CD14+ monocytes plus low PD-L2 expression. By contrast, increased expression of immune checkpoints over all immune cells might be due to Mycobacterium tuberculosis related immune exhaustion, which decreased after treatment. Full article

(This article belongs to the Special Issue Tuberculosis and Latent Tuberculosis Infection: Molecular Basis and Translational Research)

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12 pages, 316 KiB

Open AccessReview

Liquid Biopsy as a Tool for the Characterisation and Early Detection of the Field Cancerization Effect in Patients with Oral Cavity Carcinoma

by Elisabeth Pérez-Ruiz, Vanesa Gutiérrez, Marta Muñoz, Javier Oliver, Marta Sánchez, Laura Gálvez-Carvajal, Antonio Rueda-Domínguez and Isabel Barragán

Biomedicines 2021, 9(10), 1478; https://doi.org/10.3390/biomedicines9101478 - 15 Oct 2021

Cited by 5 | Viewed by 2435

Abstract

Oral squamous cell carcinoma (OSCC) constitutes approximately 25% of all head and neck cancer, for which the consumption of tobacco and alcohol are the main associated risk factors. The field cancerization effect of OSCC is one of the main reasons for the poor [...] Read more.

Oral squamous cell carcinoma (OSCC) constitutes approximately 25% of all head and neck cancer, for which the consumption of tobacco and alcohol are the main associated risk factors. The field cancerization effect of OSCC is one of the main reasons for the poor survival rates associated with this disease. Despite some advances, its ccharacterization and early diagnosis continue to challenge modern oncology, and the goal of improving the prognosis remains to be achieved. Among new early diagnostic tools for OSCC that have been proposed, liquid biopsy appears to be an ideal candidate, as studies have shown that the analysis of blood and saliva provides promising data for the early detection of relapses or second tumours. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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13 pages, 1392 KiB

Open AccessArticle

Genomic Characterization of Serotype III/ST-17 Group B Streptococcus Strains with Antimicrobial Resistance Using Whole Genome Sequencing

by Jen-Fu Hsu, Ming-Horng Tsai, Lee-Chung Lin, Shih-Ming Chu, Mei-Yin Lai, Hsuan-Rong Huang, Ming-Chou Chiang, Peng-Hong Yang and Jang-Jih Lu

Biomedicines 2021, 9(10), 1477; https://doi.org/10.3390/biomedicines9101477 - 15 Oct 2021

Cited by 7 | Viewed by 2271

Abstract

Background: Antibiotic-resistant type III/ST-17 Streptococcus agalactiae (group B Streptococcus, GBS) strain is predominant in neonatal invasive GBS diseases. We aimed to investigate the antibiotic resistance profiles and genetic characteristics of type III/ST-17 GBS strains. Methods: A total of 681 non-duplicate GBS isolates [...] Read more.

Background: Antibiotic-resistant type III/ST-17 Streptococcus agalactiae (group B Streptococcus, GBS) strain is predominant in neonatal invasive GBS diseases. We aimed to investigate the antibiotic resistance profiles and genetic characteristics of type III/ST-17 GBS strains. Methods: A total of 681 non-duplicate GBS isolates were typed (MLST, capsular types) and their antibiotic resistances were performed. Several molecular methods (WGS, PCR, sequencing and sequence analysis) were used to determine the genetic context of antibiotic resistant genes and pili genes. Results: The antibiotic resistant rates were significantly higher in type Ib (90.1%) and type III (71.1%) GBS isolates. WGS revealed that the loss of PI-1 genes and absence of ISSag5 was found in antibiotic-resistant III/ST-17 GBS isolates, which is replaced by a ~75-kb integrative and conjugative element, ICESag37, comprising multiple antibiotic resistance and virulence genes. Among 190 serotype III GBS isolates, the most common pilus island was PI-2b (58.4%) alone, which was found in 81.3% of the III/ST-17 GBS isolates. Loss of PI-1 and ISSag5 was significantly associated with antibiotic resistance (95.5% vs. 27.8%, p < 0.001). The presence of ICESag37 was found in 83.6% of all III/ST-17 GBS isolates and 99.1% (105/106) of the antibiotic-resistant III/ST-17 GBS isolates. Conclusions: Loss of PI-1 and ISSag5, which is replaced by ICESag37 carrying multiple antibiotic resistance genes, accounts for the high antibiotic resistance rate in III/ST-17 GBS isolates. The emerging clonal expansion of this hypervirulent strain with antibiotic resistance after acquisition of ICESag37 highlights the urgent need for continuous surveillance of GBS infections. Full article

(This article belongs to the Section Gene and Cell Therapy)

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38 pages, 2331 KiB

Open AccessEditor’s ChoiceReview

Antitumoral Activities of Curcumin and Recent Advances to ImProve Its Oral Bioavailability

by Marta Claudia Nocito, Arianna De Luca, Francesca Prestia, Paola Avena, Davide La Padula, Lucia Zavaglia, Rosa Sirianni, Ivan Casaburi, Francesco Puoci, Adele Chimento and Vincenzo Pezzi

Biomedicines 2021, 9(10), 1476; https://doi.org/10.3390/biomedicines9101476 - 14 Oct 2021

Cited by 43 | Viewed by 4819

Abstract

Curcumin, a main bioactive component of the Curcuma longa L. rhizome, is a phenolic compound that exerts a wide range of beneficial effects, acting as an antimicrobial, antioxidant, anti-inflammatory and anticancer agent. This review summarizes recent data on curcumin’s ability to interfere with [...] Read more.

Curcumin, a main bioactive component of the Curcuma longa L. rhizome, is a phenolic compound that exerts a wide range of beneficial effects, acting as an antimicrobial, antioxidant, anti-inflammatory and anticancer agent. This review summarizes recent data on curcumin’s ability to interfere with the multiple cell signaling pathways involved in cell cycle regulation, apoptosis and the migration of several cancer cell types. However, although curcumin displays anticancer potential, its clinical application is limited by its low absorption, rapid metabolism and poor bioavailability. To overcome these limitations, several curcumin-based derivatives/analogues and different drug delivery approaches have been developed. Here, we also report the anticancer mechanisms and pharmacokinetic characteristics of some derivatives/analogues and the delivery systems used. These strategies, although encouraging, require additional in vivo studies to support curcumin clinical applications. Full article

(This article belongs to the Special Issue Therapeutic Potential of Plant Secondary Metabolites in the Treatment of Diseases and Drug Development)

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14 pages, 632 KiB

Open AccessArticle

Associations between SNPs in Intestinal Cholesterol Absorption and Endogenous Cholesterol Synthesis Genes with Cholesterol Metabolism

by Maite M. Schroor, Fatma B. A. Mokhtar, Jogchum Plat and Ronald P. Mensink

Biomedicines 2021, 9(10), 1475; https://doi.org/10.3390/biomedicines9101475 - 14 Oct 2021

Cited by 11 | Viewed by 2827

Abstract

Single nucleotide polymorphisms (SNPs) have been associated with cholesterol metabolism and may partly explain large inter-individual variability in intestinal cholesterol absorption and endogenous cholesterol synthesis rates. This cross-sectional study therefore examined whether SNPs in genes encoding for proteins involved in intestinal cholesterol absorption [...] Read more.

Single nucleotide polymorphisms (SNPs) have been associated with cholesterol metabolism and may partly explain large inter-individual variability in intestinal cholesterol absorption and endogenous cholesterol synthesis rates. This cross-sectional study therefore examined whether SNPs in genes encoding for proteins involved in intestinal cholesterol absorption (ABCG5, ABCG8, and NPC1L1) and endogenous cholesterol synthesis (CYP51A1, DHCR7, DHCR24, HMGCR, HSD17B7, LBR, and MSMO1) were associated with intestinal cholesterol absorption markers (total cholesterol (TC) standardized campesterol and sitosterol levels), an endogenous cholesterol synthesis marker (TC-standardized lathosterol levels), and serum low-density lipoprotein cholesterol (LDL-C) concentrations in a European cohort. ABCG5 (rs4245786) and the tag SNP ABCG8 (rs4245791) were significantly associated with serum campesterol and/or sitosterol levels. In contrast, NPC1L1 (rs217429 and rs217416) were significantly associated with serum lathosterol levels. The tag SNP in HMGCR (rs12916) and a SNP in LBR (rs12141732) were significantly associated with serum LDL-C concentrations. SNPs in the cholesterol absorption genes were not associated with serum LDL-C concentrations. SNPs in CYP51A1, DHCR24, HSD17B7, and MSMO1 were not associated with the serum non-cholesterol sterols and LDL-C concentrations. Given the variable efficiency of cholesterol-lowering interventions, the identification of SNPs associated with cholesterol metabolism could be a step forward towards personalized approaches. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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12 pages, 840 KiB

Open AccessArticle

Transcriptomic Characterization of Postmolar Gestational Choriocarcinoma

by Constance Collet, Jonathan Lopez, Christophe Battail, Fabienne Allias, Mojgan Devouassoux-Shisheboran, Sophie Patrier, Nicolas Lemaitre, Touria Hajri, Jérôme Massardier, Benoit You, François Mallet, François Golfier, Nadia Alfaidy and Pierre-Adrien Bolze

Biomedicines 2021, 9(10), 1474; https://doi.org/10.3390/biomedicines9101474 - 14 Oct 2021

Cited by 5 | Viewed by 2418

Abstract

The human placenta shares properties with solid tumors, such as rapid growth, tissue invasion, cell migration, angiogenesis, and immune evasion. However, the mechanisms that drive the evolution from premalignant proliferative placental diseases—called hydatidiform moles—to their malignant counterparts, gestational choriocarcinoma, as well as the [...] Read more.

The human placenta shares properties with solid tumors, such as rapid growth, tissue invasion, cell migration, angiogenesis, and immune evasion. However, the mechanisms that drive the evolution from premalignant proliferative placental diseases—called hydatidiform moles—to their malignant counterparts, gestational choriocarcinoma, as well as the factors underlying the increased aggressiveness of choriocarcinoma arising after term delivery compared to those developing from hydatidiform moles, are unknown. Using a 730-gene panel covering 13 cancer-associated canonical pathways, we compared the transcriptomic profiles of complete moles to those of postmolar choriocarcinoma samples and those of postmolar to post-term delivery choriocarcinoma. We identified 33 genes differentially expressed between complete moles and postmolar choriocarcinoma, which revealed TGF-β pathway dysregulation. We found the strong expression of SALL4, an upstream regulator of TGF-β, in postmolar choriocarcinoma, compared to moles, in which its expression was almost null. Finally, there were no differentially expressed genes between postmolar and post-term delivery choriocarcinoma samples. To conclude, the TGF-β pathway appears to be a crucial step in the progression of placental malignancies. Further studies should investigate the value of TGF- β family members as biomarkers and new therapeutic targets. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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12 pages, 2504 KiB

Open AccessArticle

Unprecedented Monoterpenoid Polyprenylated Acylphloroglucinols with a Rare 6/6/5/4 Tetracyclic Core, Enhanced MCF-7 Cells’ Sensitivity to Camptothecin by Inhibiting the DNA Damage Response

by Xiang-Zhong Liu, Mi Zhou, Chun-Chun Du, Hong-Hong Zhu, Xi Lu, Shou-Lun He, Guang-Hui Wang, Ting Lin, Wen-Jing Tian and Hai-Feng Chen

Biomedicines 2021, 9(10), 1473; https://doi.org/10.3390/biomedicines9101473 - 14 Oct 2021

Cited by 5 | Viewed by 2431

Abstract

(±)-Hypersines A–C (1–3), the three pairs of enantiomerically pure monoterpenoid polyprenylated acylphloroglucinols with an unprecedented 6/6/5/4 fused ring system, were isolated from Hypericum elodeoides. Their structures, including absolute configurations, were elucidated by comprehensive spectroscopic data, single-crystal X-ray diffraction, [...] Read more.

(±)-Hypersines A–C (1–3), the three pairs of enantiomerically pure monoterpenoid polyprenylated acylphloroglucinols with an unprecedented 6/6/5/4 fused ring system, were isolated from Hypericum elodeoides. Their structures, including absolute configurations, were elucidated by comprehensive spectroscopic data, single-crystal X-ray diffraction, and quantum chemical calculations. The plausible, biosynthetic pathway of 1–3 was proposed. Moreover, the bioactivity evaluation indicated that 1a might be a novel DNA damage response inhibitor, and could enhance MCF-7 cell sensitivity to the anticancer agent, camptothecin. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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25 pages, 1745 KiB

Open AccessReview

Comparative Cancer Cell Signaling in Muscle-Invasive Urothelial Carcinoma of the Bladder in Dogs and Humans

by Maria Malvina Tsamouri, Thomas M. Steele, Maria Mudryj, Michael S. Kent and Paramita M. Ghosh

Biomedicines 2021, 9(10), 1472; https://doi.org/10.3390/biomedicines9101472 - 14 Oct 2021

Cited by 6 | Viewed by 3410

Abstract

Muscle-invasive urothelial carcinoma (MIUC) is the most common type of bladder malignancy in humans, but also in dogs that represent a naturally occurring model for this disease. Dogs are immunocompetent animals that share risk factors, pathophysiological features, clinical signs and response to chemotherapeutics [...] Read more.

Muscle-invasive urothelial carcinoma (MIUC) is the most common type of bladder malignancy in humans, but also in dogs that represent a naturally occurring model for this disease. Dogs are immunocompetent animals that share risk factors, pathophysiological features, clinical signs and response to chemotherapeutics with human cancer patients. This review summarizes the fundamental pathways for canine MIUC initiation, progression, and metastasis, emerging therapeutic targets and mechanisms of drug resistance, and proposes new opportunities for potential prognostic and diagnostic biomarkers and therapeutics. Identifying similarities and differences between cancer signaling in dogs and humans is of utmost importance for the efficient translation of in vitro research to successful clinical trials for both species. Full article

(This article belongs to the Topic Cancer Biology and Therapy)

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18 pages, 1074 KiB

Open AccessReview

Novel Concepts in Systemic Sclerosis Pathogenesis: Role for miRNAs

by Iulia Szabo, Laura Muntean, Tania Crisan, Voicu Rednic, Claudia Sirbe and Simona Rednic

Biomedicines 2021, 9(10), 1471; https://doi.org/10.3390/biomedicines9101471 - 14 Oct 2021

Cited by 17 | Viewed by 2574

Abstract

Systemic sclerosis (SSc) is a rare connective tissue disease with heterogeneous clinical phenotypes. It is characterized by the pathogenic triad: microangiopathy, immune dysfunction, and fibrosis. Epigenetic mechanisms modulate gene expression without interfering with the DNA sequence. Epigenetic marks may be reversible and their [...] Read more.

Systemic sclerosis (SSc) is a rare connective tissue disease with heterogeneous clinical phenotypes. It is characterized by the pathogenic triad: microangiopathy, immune dysfunction, and fibrosis. Epigenetic mechanisms modulate gene expression without interfering with the DNA sequence. Epigenetic marks may be reversible and their differential response to external stimuli could explain the protean clinical manifestations of SSc while offering the opportunity of targeted drug development. Small, non-coding RNA sequences (miRNAs) have demonstrated complex interactions between vasculature, immune activation, and extracellular matrices. Distinct miRNA profiles were identified in SSc skin specimens and blood samples containing a wide variety of dysregulated miRNAs. Their target genes are mainly involved in profibrotic pathways, but new lines of evidence also confirm their participation in impaired angiogenesis and aberrant immune responses. Research approaches focusing on earlier stages of the disease and on differential miRNA expression in various tissues could bring novel insights into SSc pathogenesis and validate the clinical utility of miRNAs as biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Frontiers of Targeted Therapy and Predictors of Treatment Response in Systemic Sclerosis)

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15 pages, 3731 KiB

Open AccessArticle

Network Analysis Integrating microRNA Expression Profiling with MRI Biomarkers and Clinical Data for Prostate Cancer Early Detection: A Proof of Concept Study

by Valeria Panebianco, Paola Paci, Martina Pecoraro, Federica Conte, Giorgia Carnicelli, Zein Mersini Besharat, Giuseppina Catanzaro, Elena Splendiani, Alessandro Sciarra, Lorenzo Farina, Carlo Catalano and Elisabetta Ferretti

Biomedicines 2021, 9(10), 1470; https://doi.org/10.3390/biomedicines9101470 - 14 Oct 2021

Cited by 7 | Viewed by 2807

Abstract

The MRI of the prostate is the gold standard for the detection of clinically significant prostate cancer (csPCa). Nonetheless, MRI still misses around 11% of clinically significant disease. The aim was to comprehensively integrate tissue and circulating microRNA profiling, MRI biomarkers and clinical [...] Read more.

The MRI of the prostate is the gold standard for the detection of clinically significant prostate cancer (csPCa). Nonetheless, MRI still misses around 11% of clinically significant disease. The aim was to comprehensively integrate tissue and circulating microRNA profiling, MRI biomarkers and clinical data to implement PCa early detection. In this prospective cohort study, 76 biopsy naïve patients underwent MRI and MRI directed biopsy. A sentinel sample of 15 patients was selected for a pilot molecular analysis. Weighted gene coexpression network analysis was applied to identify the microRNAs drivers of csPCa. MicroRNA–target gene interaction maps were constructed, and enrichment analysis performed. The ANOVA on ranks test and ROC analysis were performed for statistics. Disease status was associated with the underexpression of the miRNA profiled; a correlation was found with ADC (r = −0.51, p = 0.02) and normalized ADC values (r = −0.64, p = 0.002). The overexpression of miRNAs from plasma was associated with csPCa (r = 0.72; p = 0.02), and with PI-RADS assessment score (r = 0.73; p = 0.02); a linear correlation was found with biomarkers of diffusion and perfusion. Among the 800 profiled microRNA, eleven were identified as correlating with PCa, among which miR-548a-3p, miR-138-5p and miR-520d-3p were confirmed using the RT-qPCR approach on an additional cohort of ten subjects. ROC analysis showed an accuracy of >90%. Provided an additional validation set of the identified miRNAs on a larger cohort, we propose a diagnostic paradigm shift that sees molecular data and MRI biomarkers as the prebiopsy triage of patients at risk for PCa. This approach will allow for accurate patient allocation to biopsy, and for stratification into risk group categories, reducing overdiagnosis and overtreatment. Full article

(This article belongs to the Special Issue Non-coding RNAs in Health and Disease)

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16 pages, 734 KiB

Open AccessArticle

Link between History of Childhood Maltreatment and Emotion Dysregulation in Adults Suffering from Attention Deficit/Hyperactivity Disorder or Borderline Personality Disorder

by Eva Rüfenacht, Eléonore Pham, Rosetta Nicastro, Karen Dieben, Roland Hasler, Sébastien Weibel and Nader Perroud

Biomedicines 2021, 9(10), 1469; https://doi.org/10.3390/biomedicines9101469 - 14 Oct 2021

Cited by 9 | Viewed by 3751

Abstract

Childhood maltreatment (CM) may have a long-term effect on emotion regulation. This study aimed to explore the relationship between CM and emotion dysregulation (ED) in a heterogeneous population. Four hundred seventy French-speaking outpatients (N = 279 ADHD, N = 70 BPD, N [...] Read more.

Childhood maltreatment (CM) may have a long-term effect on emotion regulation. This study aimed to explore the relationship between CM and emotion dysregulation (ED) in a heterogeneous population. Four hundred seventy French-speaking outpatients (N = 279 ADHD, N = 70 BPD, N = 60 ADHD + BPD, N = 61 clinical controls) completed the Emotion Reactivity Scale (ERS), the Cognitive Emotional Regulation Questionnaire (CERQ), the Childhood Trauma Questionnaire (CTQ), and the Relationship Scales Questionnaire (RSQ). Reports of childhood maltreatment experiences were significantly associated with increased levels of emotion reactivity in all our groups and in the whole population, with a greater use of non-adaptive cognitive emotion regulation strategies and insecure attachment patterns. Emotional abuse showed the strongest effect. Further analysis indicated that an anxious attachment style significantly mediated the relationship between CM and the use of non-adaptive cognitive emotion regulation strategies and emotion reactivity. The results of our study suggest an impact of CM on ED and a potentially marked effect of emotional abuse. They also indicate a potentially mediating role of insecure attachment in the relationship between a history of childhood abuse and emotion reactivity and a higher use of non-adaptive cognitive emotion regulation strategies in adulthood. Full article

(This article belongs to the Special Issue Neurodevelopmental Disorders: From Pathophysiology to Novel Therapeutic Approaches)

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