PROteolysis-Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives.

Leukemia is a heterogeneous group of life-threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long-term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy.

Proteolysis-Targeting Chimeras (PROTACs) targeting the BCR-ABL for the treatment of chronic myeloid leukemia - a patent review.

Introduction: PROteolysis-TArgeting Chimeras (PROTACs) allow the selective degradation of a protein of interest (POI) by the ubiquitin-proteasome system (UPS). With this unique mechanism of action, the research and development of PROTACs that target the Breakpoint Cluster Region Abelson (BCR-ABL) tyrosine kinase (TK) has been increasing dramatically, as they are promising molecules in the treatment of Chronic Myeloid Leukemia (CML), one of the main hematological malignancies, which results from an uncontrolled myeloproliferation due to the constitutive activation of BCR-ABL.

Areas Covered: This review summarizes the patents/applications published in the online databases like Espacenet or World Intellectual Property Organization regarding PROTACs that promote BCR-ABL degradation.

Recent advances in oridonin derivatives with anticancer activity.

Cancer is a leading cause of mortality responsible for an estimated 10 million deaths worldwide in 2020, and its incidence has been rapidly growing over the last decades. Population growth and aging, as well as high systemic toxicity and chemoresistance associated with conventional anticancer therapies reflect these high levels of incidence and mortality. Thus, efforts have been made to search for novel anticancer drugs with fewer side effects and greater therapeutic effectiveness.

MDM2-Based Proteolysis-Targeting Chimeras (PROTACs): An Innovative Drug Strategy for Cancer Treatment.

Proteolysis-targeting chimeras (PROTACs) are molecules that selectively degrade a protein of interest (POI). The incorporation of ligands that recruit mouse double minute 2 (MDM2) into PROTACs, forming the so-called MDM2-based PROTACs, has shown promise in cancer treatment due to its dual mechanism of action: a PROTAC that recruits MDM2 prevents its binding to p53, resulting not only in the degradation of POI but also in the increase of intracellular levels of the p53 suppressor, with the activation of a whole set of biological processes, such as cell cycle arrest or apoptosis. In addition, these PROTACs, in certain cases, allow for the degradation of the target, with nanomolar potency, in a rapid and sustained manner over time, with less susceptibility to the development of resistance and tolerance, without causing changes in protein expression, and with selectivity to the target, including the respective isoforms or mutations, and to the cell type, overcoming some limitations associated with the use of inhibitors for the same therapeutic target.

Corneal transplantation in aniridia-related keratopathy with a two-year follow-up period, an uncommon disease with precarious course.

Purpose: The purpose of this study is to study the frequency, surgical transplantation technique and outcome in patients with aniridia-related keratopathy (ARK) with two-year follow-up period.

Methods: A retrospective registry-study including all ARK cases performed in Sweden and Denmark between 2001 and 2016 and registered in the Swedish Cornea Transplant Registry.

Results: A total of 36 eyes of 26 patients were subjected to corneal transplantation due to ARK during 2001 to 2016.

Current clinical practice in corneal crosslinking for treatment of progressive keratoconus in four Nordic countries.

Purpose: To evaluate clinical practice in the diagnosis and treatment of progressive keratoconus with corneal crosslinking (CXL) in four Nordic countries.

Methods: A questionnaire was sent to all centres at which keratoconus patients are evaluated and CXL is performed in Sweden, Denmark, Norway and Iceland. Nineteen of 20 centres participated.

Aniridia-related keratopathy relevant cell signaling pathways in human fetal corneas.

We aimed to study aniridia-related keratopathy (ARK) relevant cell signaling pathways [Notch1, Wnt/β-catenin, Sonic hedgehog (SHH) and mTOR] in normal human fetal corneas compared with normal human adult corneas and ARK corneas. We found that fetal corneas at 20 weeks of gestation (wg) and normal adult corneas showed similar staining patterns for Notch1; however 10-11 wg fetal corneas showed increased presence of Notch1. Numb and Dlk1 had an enhanced presence in the fetal corneas compared with the adult corneas.

Dose Administration Aid Service in Community Pharmacies: Characterization and Impact Assessment.

Adherence to therapies is a primary determinant of treatment success. Lack of medication adherence is often associated with medical and psychosocial issues due to complications from underlying conditions and is an enormous waste of medical resources. Dose Administration Aid Service (DAAS) can be seen as part of the solution, allowing individual medicine doses to be organized according to the dosing schedule determined by the patient's prescriber.

An inter-day assessment of the ABC parameters in the evaluation of progressive keratoconus.

The progression of keratoconus is commonly determined by comparing the results of corneal tomographic measurements on different occasions. However, investigations on the repeatability of measurements are commonly performed within the same day, thus not taking the inter-day variation into account. The effect of keratoconus disease severity on the measurement error is also seldom considered.

Gene expression profile of extraocular muscles following resection strabismus surgery.

This paper aims to identify key biological processes triggered by resection surgery in the extraocular muscles (EOMs) of a rabbit model of strabismus surgery by studying changes in gene expression. Resection surgery was performed in the superior rectus of 16 rabbits and a group of non-operated rabbits served as control. Muscle samples were collected from groups of four animals 1, 2, 4 and 6 weeks after surgery and processed for RNA-sequencing and immunohistochemistry.

Altered Signaling Pathways in Aniridia-Related Keratopathy.

Purpose: To study the Notch1, Wnt/beta-catenin, sonic hedgehog (SHH), and mammalian target of rapamycin (mTOR) cell signaling pathways in naïve and surgically treated corneas of aniridia cases with advanced aniridia-related keratopathy (ARK).

Methods: Two naïve corneal buttons from patients with advanced ARK submitted to penetrating keratoplasty for the first time, one corneal button from an ARK patient that had undergone a keratolimbal allograft (KLAL), two corneal buttons from ARK patients who had previously undergone centered or decentered transplantation, and two adult healthy control corneas were processed for immunohistochemistry in this descriptive study. Antibodies specific against elements of the Notch1 (Notch1; Dlk1; Numb), Wnt/beta-catenin (Wnt5a; Wnt7a; beta-catenin), SHH (glioma-associated oncogene homolog [Gli1]; Hes1), and mTOR (mTOR1; ribosomal protein S6 [rpS6]) signaling pathways were used as well as antibodies against PAX6 and keratin 13 (Krt13).

Aniridia-related keratopathy: Structural changes in naïve and transplanted corneal buttons.

Background: To study structural changes in naïve and surgically treated corneas of aniridia patients with advanced aniridia-related keratopathy (ARK).

Methods And Findings: Two naïve corneal buttons from patients with advanced ARK submitted to penetrating keratoplasty for the first time, one corneal button from an ARK patient that had undergone a keratolimbal allograft (KLAL), two corneal buttons from ARK patients who had previously undergone centered or decentered transplantation and were now retransplanted and two adult healthy donor control corneas were processed for immunohistochemistry. Antibodies against extracellular matrix components in the stroma and in the epithelial basement membrane (collagen I and IV, collagen receptor α11 integrin and laminin α3 chain), markers of fibrosis, wound healing and vascularization (fibronectin, tenascin-C, vimentin, α-SMA and caveolin-1), cell division (Ki-67) and macrophages (CD68) were used.

Composition, Architecture, and Functional Implications of the Connective Tissue Network of the Extraocular Muscles.

Purpose: We examined the pattern and extent of connective tissue distribution in the extraocular muscles (EOMs) and determined the ability of the interconnected connective tissues to disseminate force laterally.

Methods: Human EOMs were examined for collagens I, III, IV, and VI; fibronectin; laminin; and elastin using immunohistochemistry. Connective tissue distribution was examined with scanning electron microscopy.

Exophiala phaeomuriformis keratitis in a subarctic climate region: a case report.

Purpose: To report a case of Exophiala phaeomuriformis mycotic keratitis in a patient from a subarctic climate region. Dematiaceous fungi (black yeasts) have been gaining importance as corneal keratitis and ulcer causative agents in certain regions, but no cases have been described in Scandinavia.

Methods: Case report of a patient with a persistent corneal erosion that eventually presented a brown-pigmented infiltrate.

CHOROIDAL THICKNESS IN DIABETIC PATIENTS WITHOUT DIABETIC RETINOPATHY.

Purpose: To compare choroidal thickness (CT) between diabetic patients without diabetic retinopathy and a nondiabetic group. To explore how CT relates to disease duration, mean arterial pressure, glycemia, glycosylated hemoglobin, intraocular pressure, and ocular pulse amplitude.

Methods: Choroidal thickness was assessed using a spectral-domain optical coherence tomography and enhanced depth mode at 13 locations (subfoveal and 3 measurements 500 μm apart in 4 directions-nasal, temporal, superior, and inferior).

Open-Angle Glaucoma: Drug Development Pipeline during the Last 20 Years (1995-2015).

Objectives: To analyse drug development for open-angle glaucoma during the last 20 years.

Methods: Research was performed by referring to clinical trials registered at the International Clinical Trials Registry Platform (ICTRP). A search for the condition "open-angle glaucoma" with the intervention "drug" was performed.

Macular Ganglion Cell Layer and Peripapillary Retinal Nerve Fibre Layer Thickness in Patients with Unilateral Posterior Cerebral Artery Ischaemic Lesion: An Optical Coherence Tomography Study.

The purpose of this study is to evaluate the macular ganglion cell layer (GCL) and peripapillary retinal nerve fibre layer (RNFL) thickness in patients with unilateral posterior cerebral artery (PCA) ischaemic lesions using spectral-domain optical coherence tomography (SD-OCT). A prospective, case-control study of patients with unilateral PCA lesion was conducted in the neuro-ophthalmology clinic of Centro Hospitalar Lisboa Central. Macular and peripapillary SD-OCT scans were performed in both eyes of each patient.

Diabetic choroidopathy: a review of the current literature.

Diabetic retinopathy is an increasingly prevalent disease, and a leading contributor to the burden of all-cause blindness worldwide. In addition to retinal changes, choroidal abnormalities are common in patients with diabetes. The first studies concerning this vascular structure were based on histologic, indocyanine angiography and laser Doppler flowmetry techniques, but the development of new optical coherence tomography (OCT) technologies and imaging software for enhanced depth imaging (EDI)-OCT in recent years has made it possible to provide more detailed images of the choroidal anatomy and topography.

Retinal Ganglion Cell Layer Analysis by Optical Coherence Tomography in Toxic and Nutritional Optic Neuropathy.

Objective: To analyze the retinal ganglion cell layer (RGL) by optical coherence tomography (OCT) in toxic and nutritional optic neuropathy and to correlate its thickness and volume with functional damage.

Methods: We conducted an observational cross-sectional study in healthy subjects and in patients with toxic optic neuropathy observed in the Neuro-Ophthalmology Department of Central Lisbon Hospital Center. Complete ophthalmologic examination, OCT (Heidelberg Spectralis), and automated static perimetry were performed.

The impact of multifocal intraocular lens in retinal imaging with optical coherence tomography.

Multifocal intraocular lenses (MF IOLs) have concentric optical zones with different dioptric power, enabling patients to have good visual acuity at multiple focal points. However, several optical limitations have been attributed to this particular design. The purpose of this study is to access the effect of MF IOLs design on the accuracy of retinal optical coherence tomography (OCT).

Choroidal Thickness in Nonarteritic Anterior Ischaemic Optic Neuropathy: A Study with Optical Coherence Tomography.

Nonarteritic anterior ischemic optic neuropathy (NA-AION) is the most common nonglaucomatous optic neuropathy in adults over 50 years of age. It is usually related to cardiovascular risk factors. The primary objective of this study was to evaluate choroidal thickness in patients with chronic NA-AION, and the secondary objective was to evaluate macular thickness in these patients.