Pharmacological basis and new insights of taxifolin: A comprehensive review.

Recombinant antibodies such as nanobodies are progressively demonstrating to be a valid alternative to conventional monoclonal antibodies also for clinical applications. Furthermore, they do not solely represent a substitute for monoclonal antibodies but their unique features allow expanding the applications of biotherapeutics and changes the pattern of disease treatment. Nanobodies possess the double advantage of being small and simple to engineer. This combination has promoted extremely diversified approaches to design nanobody-based constructs suitable for particular applications. Both the format geometry possibilities and the functionalization strategies have been widely explored to provide macromolecules with better efficacy with respect to single nanobodies or their combination. Nanobody multimers and nanobody-derived reagents were developed to image and contrast several cancer diseases and have shown their effectiveness in animal models. Their capacity to block more independent signaling pathways simultaneously is considered a critical advantage to avoid tumor resistance, whereas the mass of these multimeric compounds still remains significantly smaller than that of an IgG, enabling deeper penetration in solid tumors. When applied to CAR-T cell therapy, nanobodies can effectively improve the specificity by targeting multiple epitopes and consequently reduce the side effects. This represents a great potential in treating malignant lymphomas, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma and solid tumors. Apart from cancer treatment, multispecific drugs and imaging reagents built with nanobody blocks have demonstrated their value also for detecting and tackling neurodegenerative, autoimmune, metabolic, and infectious diseases and as antidotes for toxins. In particular, multi-paratopic nanobody-based constructs have been developed recently as drugs for passive immunization against SARS-CoV-2 with the goal of impairing variant survival due to resistance to antibodies targeting single epitopes. Given the enormous research activity in the field, it can be expected that more and more multimeric nanobody molecules will undergo late clinical trials in the next future. Systematic Review Registration

https://www.frontiersin.org/articles/10.3389/fimmu.2021.838082/pdf

Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment

Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.

VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment

The plasma glycoprotein von Willebrand factor (VWF) is exclusively synthesized in endothelial cells (ECs) and megakaryocytes, the precursor cells of platelets. Its primary function lies in hemostasis. However, VWF is much more than just a “fishing hook” for platelets and a transporter for coagulation factor VIII. VWF is a true multitasker when it comes to its many roles in cellular processes. In ECs, VWF coordinates the formation of Weibel–Palade bodies and guides several cargo proteins to these storage organelles, which control the release of hemostatic, inflammatory and angiogenic factors. Leukocytes employ VWF to assist their rolling on, adhesion to and passage through the endothelium. Vascular smooth muscle cell proliferation is supported by VWF, and it regulates angiogenesis. The life cycle of platelets is accompanied by VWF from their budding from megakaryocytes to adhesion, activation and aggregation until the end in apoptosis. Some tumor cells acquire the ability to produce VWF to promote metastasis and hide in a shell of VWF and platelets, and even the maturation of osteoclasts is regulated by VWF. This review summarizes the current knowledge on VWF’s versatile cellular functions and the resulting pathophysiological consequences of their dysregulation.

The Manifold Cellular Functions of von Willebrand Factor.

Angiogenesis is involved in physiological and pathological processes in the body. Tumor angiogenesis is a key factor associated with tumor growth, progression, and metastasis. Therefore, there is great interest in developing antiangiogenic strategies. Hypoxia is the basic initiating factor of tumor angiogenesis, which leads to the increase of vascular endothelial growth factor (VEGF), angiopoietin (Ang), hypoxia-inducible factor (HIF-1), etc. in hypoxic cells. The pathways of VEGF and Ang are considered to be critical steps in tumor angiogenesis. A number of antiangiogenic drugs targeting VEGF/VEGFR (VEGF receptor) or ANG/Tie2, or both, are currently being used for cancer treatment, or are still in various stages of clinical development or preclinical evaluation. This article aims to review the mechanisms of angiogenesis and tumor angiogenesis and to focus on new drugs and strategies for the treatment of antiangiogenesis. However, antitumor angiogenic drugs alone may not be sufficient to eradicate tumors. The molecular chaperone heat shock protein 90 (HSP90) is considered a promising molecular target. The VEGFR system and its downstream signaling molecules depend on the function of HSP90. This article also briefly introduces the role of HSP90 in angiogenesis and some HSP90 inhibitors.

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Novel Drugs with High Efficacy against Tumor Angiogenesis

Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model

Brain metastases (BM) are an ever-increasing challenge in oncology, threatening quality of life and survival of many cancer patients. The majority of BM originate from lung adenocarcinoma, and stage III patients have a risk of 40-50% to develop BM in the first years of disease onset. As therapeutic options are limited, prevention of their occurrence is an attractive concept. Here we investigated whether Nintedanib (BIBF 1120), a tyrosine kinase inhibitor (TKI) targeting the VEGF pathway approved for lung adenocarcinoma, and the dual anti-VEGF-A/Ang2 nanobody BI836880 have the potential to prevent BM formation. A mouse model of brain metastasis from lung adenocarcinoma was used in which tumor cells were injected intracardially. Metastases formation occurred inside and outside of the brain and was followed by MRI, IVIS, and immunohistochemistry. BM were reduced in volume and number by both Nintedanib and the dual anti-VEGF-A/Ang2 nanobody, which translated into improved survival. Both compounds were able to normalize cerebral blood vessels at the site of brain metastatic lesions. Extracranial metastases, however, were not reduced, and meningeal metastases only partially. Interestingly, unspecific control IgG also lead to brain vessel normalization and reduction of brain and meningeal metastases. This data indicates a brain-specific group effect of antiangiogenic compounds with respect to metastasis prevention, most likely by preventing an early angiogenic switch. Thus, Nintedanib and BI836880 are promising candidates for future BM preventive study concepts in lung adenocarcinoma patients.

/pdf/nintedanib-and-a-bi-specific-anti-vegf-ang2-nanobody-56n0fa1sm0.pdf

Nintedanib and a bi-specific anti-VEGF/Ang2 nanobody selectively prevent brain metastases of lung adenocarcinoma cells

Focusing on the eye signs of Alport syndrome in a 40-year-old man who previously had a kidney transplant and hearing loss

Fungal keratitis due to Fusarium species is known to be typical of developing countries; however, with the increasing use of contact lenses a rise of Fusarium keratitis has been observed in Germany.In a monocentric retrospective study, we analyzed all patients who presented to our university eye hospital with infectious keratitis between January 2011 and December 2021 and had a proof of Fusarium species in either microscopy, culture or PCR.We could identify 13 patients with a proof of Fusarium species. A significant increase of cases in 2021 was observed. In 76.9% of our cases the patients were female and in 76.9% the patients had a history of prior contact lens use. In only 4 cases the initial corneal sample gave a positive result for Fusarium. On average the suspicion of fungal keratitis arose 13.1 days after onset of symptoms, correct diagnosis was achieved after 14.6 days. All isolated specimens showed resistance against at least one of the common fungicides. In 70% of our cases treatment with penetrating keratoplasty was necessary. The patients showed a 57.1% recurrence rate after penetrating keratoplasty. In 80% of our cases best documented visual acuity after Fusarium keratitis was ≤ 0.4.Due to difficult detection and a high resistance rate to common antifungals, Fusarium keratitis is prone to delayed diagnosis and limited treatment outcomes. Whenever risk factors are present and infectious keratitis does not respond to antibiotics, antimycotic treatment must be initiated. Early keratoplasty may be necessary.HINTERGRUND: Galt die mykotische Keratitis durch Fusarien in Industrienationen bisher als Seltenheit, so ist in den letzten Jahren ein Anstieg der Fusarien-Keratitiden auch in Deutschland zu verzeichnen. Anhand der folgenden Studie möchten wir gegenüber dem klinischen Krankheitsbild sensibilisieren sowie diagnostische und therapeutische Möglichkeiten aufzeigen.In dieser monozentrischen, retrospektiven Fallserie wurden alle Patienten der Universitäts-Augenklinik Heidelberg im Zeitraum von 2011 bis 2021 eingeschlossen, bei denen ein mikrobiologischer Nachweis von Fusarium Spezies gelang.Insgesamt 13 Fälle mit mikrobiologischem Nachweis von Fusarium Spezies konnten identifiziert werden, auffällig war eine Häufung im Jahr 2021. Die Patienten waren zu 76,9 % weiblich und zu 76,9 % Kontaktlinsenträger. Nur in 4 Fällen gelang die Erregeridentifizierung aus dem initialen Hornhautabradat. Die durchschnittliche Dauer bis zur Verdachtsdiagnose einer mykotischen Genese betrug 13,1 Tage, die mittlere Dauer bis zum Erregernachweis 14,6 Tage ab Symptombeginn. Alle getesteten Erreger wiesen Resistenzen gegen mindestens ein gängiges Antimykotikum auf. Die Therapie mittels perforierender Keratoplastik war bei 70 % der Fälle erforderlich, in 57,1 % kam es dabei zu einem Rezidiv. In 80 % betrug der beste dokumentierte Visus nach Fusarien-Keratitis in unserer Fallserie ≤ 0,4.Bei erschwerten Nachweismöglichkeiten und hoher Resistenzlage kommt es bei der Fusarien-Keratitis meist zu einem verspäteten Therapiebeginn mit reduzierter Visusprognose. Bei Vorliegen von Risikofaktoren und Nicht-Ansprechen auf Antibiotika muss frühzeitig eine antimykotische Therapie eingeleitet und ggf. eine Keratoplastik erwogen werden. 

/pdf/fusarium-keratitis-an-upcoming-threat-in-germany-24rip6vb.pdf

Bogdana Kovalchuk

Papers

Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model

Nintedanib and a bi-specific anti-VEGF/Ang2 nanobody selectively prevent brain metastases of lung adenocarcinoma cells

Focusing on the eye signs of Alport syndrome in a 40-year-old man who previously had a kidney transplant and hearing loss

[Fusarium Keratitis-an upcoming threat in Germany?]