scholarly journals Proteolysis Targeting Chimeras With Reduced Off-targets

2021 ◽  
Author(s):  
Tuan M Nguyen ◽  
Arghya Deb ◽  
Praveen Kokkonda ◽  
Vedagopuram Sreekanth ◽  
Praveen K Tiwari ◽  
...  
Keyword(s):  
Side Effects ◽  
Protein Degradation ◽  
High Throughput ◽  
Normal Development ◽  
Nucleophilic Aromatic Substitution ◽  
Aromatic Substitution ◽  
E3 Ligases ◽  
Current Design ◽  
Design Paradigm

Proteolysis Targeting Chimeras (PROTACs), a class of heterobifunctional molecules that recruit target proteins to E3 ligases, have gained traction for targeted protein degradation. However, pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other targets, such as zinc-finger (ZF) proteins, that hold key functions in normal development and disease progression. This off-target degradation of pomalidomide-based PROTACs raises concerns about their therapeutic applicability and long-term side effects. Therefore, there is a crucial need to develop rules for PROTAC design that minimize off-target degradation. In this study, we developed a high-throughput platform that interrogates the off-target degradation of ZF domains and discovered, using this platform, that PROTACs with the current design paradigm induce significant degradation of several ZF proteins. To identify new rules for PROTAC design, we generated a rationalized library of pomalidomide analogs with distinct exit vector modifications on the C4 and C5 positions of the phthalimide ring and profiled their propensities for ZF protein degradation. We found that modifications on the C5 position with nucleophilic aromatic substitution (SNAr) reduce off-target ZF degradation. We applied our newfound design principles on a previously developed ALK oncoprotein-targeting PROTAC and generated PROTACs with enhanced potency and minimal off-target degradation. We envision the reported off-target profiling platform and pomalidomide analogs will find utility in the design of specific PROTACs.

High-Throughput Experimentation and Continuous Flow Evaluation of Nucleophilic Aromatic Substitution Reactions

2020 ◽  
Vol 22 (4) ◽  
pp. 184-196 ◽  
Author(s):  
Zinia Jaman ◽  
David L. Logsdon ◽  
Botond Szilágyi ◽  
Tiago J. P. Sobreira ◽  
Deborah Aremu ◽  
...  
Keyword(s):  
High Throughput ◽  
Continuous Flow ◽  
Nucleophilic Aromatic Substitution ◽  
Aromatic Substitution ◽  
Substitution Reactions ◽  
High Throughput Experimentation

Concise Synthesis of Furo[2,3-b]indolines via [3,3]-Sigmatropic Rearrangement of N-Alkenyloxyindoles

Synlett ◽  
2020 ◽  
Author(s):  
Laura L. Anderson ◽  
Michael Shevlin ◽  
Neil A. Strotman
Keyword(s):  
High Throughput ◽  
Conjugate Addition ◽  
Sigmatropic Rearrangement ◽  
Nucleophilic Aromatic Substitution ◽  
Aromatic Substitution ◽  
Synthetic Route ◽  
High Throughput Experimentation ◽  
Activated Alkynes

A concise new synthetic route to furo[2,3-b]indolines has been developed by taking advantage of the reactivity of N-alkenyloxyindole intermediates. These compounds spontaneously undergo [3,3]-sigmatropic rearrangement followed by cyclization to form hemiaminals as single diastereomers. Tin-promoted N-hydroxyindole formation followed by conjugate addition to activated alkynes provides simple and modular access to a diverse array of N-alkenyloxyindoles and their corresponding furo[2,3-b]indolines. Microscale high-throughput experimentation was used to facilitate investigation of the scope and tolerance of this transformation and related studies on the nucleophilic aromatic substitution and rearrangement of N-hydroxyindoles with halogenated arenes have also been evaluated.

Cutaneous ulcers following hydroxyurea therapy

Phlebologie ◽  
2004 ◽  
Vol 33 (06) ◽  
pp. 202-205 ◽  
Author(s):  
K. Hartmann ◽  
S. Nagel ◽  
T. Erichsen ◽  
E. Rabe ◽  
K. H. Grips ◽  
...  
Keyword(s):  
Side Effects ◽  
Side Effect ◽  
Antineoplastic Agent ◽  
Limited Time ◽  
Myeloproliferative Diseases ◽  
Dermatological Side Effects ◽  
Chronic Myeloproliferative Diseases ◽  
Hydroxyurea Therapy

SummaryHydroxyurea (HU) is usually a well tolerated antineoplastic agent and is commonly used in the treatment of chronic myeloproliferative diseases. Dermatological side effects are frequently seen in patients receiving longterm HU therapy. Cutaneous ulcers have been reported occasionally.We report on four patients with cutaneous ulcers whilst on long-term hydroxyurea therapy for myeloproliferative diseases. In all patients we were able to reduce the dose, or stop HU altogether and their ulcers markedly improved. Our observations suggest that cutaneous ulcers should be considered as possible side effect of long-term HU therapy and healing of the ulcers can be achieved not only by cessation of the HU treatment, but also by reducing the dose of hydroxyurea for a limited time.

Long-term side effects following pneumonectomy: A case report and review of the literature

2019 ◽  
Author(s):  
BA Högerle ◽  
EL Bulut ◽  
L Klotz ◽  
F Eichhorn ◽  
M Eichhorn ◽  
...  
Keyword(s):  
Case Report ◽  
Side Effects ◽  
Review Of The Literature

scholarly journals Machine learning meets mechanistic modelling for accurate prediction of experimental activation energies

2021 ◽  
Author(s):  
Kjell Jorner ◽  
Tore Brinck ◽  
Per-Ola Norrby ◽  
David Buttar
Keyword(s):  
Machine Learning ◽  
Activation Energies ◽  
Accurate Prediction ◽  
Nucleophilic Aromatic Substitution ◽  
Aromatic Substitution ◽  
Mechanistic Modelling

Hybrid reactivity models, combining mechanistic calculations and machine learning with descriptors, are used to predict barriers for nucleophilic aromatic substitution.

Long-Term Follow-Up of Early Cochlear Implant Device Activation

2021 ◽  
pp. 1-11
Author(s):  
Stefanie Bruschke ◽  
Uwe Baumann ◽  
Timo Stöver
Keyword(s):  
Speech Recognition ◽  
Side Effects ◽  
Cochlear Implant ◽  
Surgical Techniques ◽  
Control Group ◽  
First Year ◽  
Safe Procedure ◽  
Sound Processor

Background: The cochlear implant (CI) is a standard procedure for the treatment of patients with severe to profound hearing loss. In the past, a standard healing period of 3–6 weeks occurred after CI surgery before the sound processor was initially activated. Advancements of surgical techniques and instruments allow an earlier initial activation of the processor within 14 days after surgery. Objective: Evaluation of the early CI device activation after CI surgery within 14 days, comparison to the first activation after 4–6 weeks, and assessment of the feasibility and safety of the early fitting over a 12 month observation period were the objectives of this study. Method: In a prospective study, 127 patients scheduled for CI surgery were divided into early fitting group (EF, n = 67) and control group (CG, n = 60). Individual questionnaires were used to evaluate medical and technical outcomes of the EF. Medical side effects, speech recognition, and follow-up effort were compared with the CG within the first year after CI surgery. Results: The early fitting was feasible in 97% of the EF patients. In the EF, the processor was activated 25 days earlier than in the CG. No major complications were observed in either group. At the follow-up appointments, side effects such as pain and balance problems occurred with comparable frequency in both groups. At initial fitting, the EF showed a significantly higher incidence of medical minor complications (p < 0.05). When developing speech recognition within the first year of CI use, no difference was observed. Furthermore, the follow-up effort within the first year after CI surgery was comparable in both groups. Conclusions: Early fitting of the sound processor is a feasible and safe procedure with comparable follow-up effort. Although more early minor complications were observed in the EF, there were no long-term wound healing problems caused by the early fitting. Regular inspection of the magnet strength is recommended as part of the CI follow-up since postoperative wound swelling must be expected. The early fitting procedure enabled a clear reduction in the waiting time between CI surgery and initial sound processor activation.

scholarly journals Rituximab-Containing Risk-Adapted Treatment Strategy in Nodular Lymphocyte Predominant Hodgkin Lymphoma: 7-Years Follow-Up

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1760
Author(s):  
Novella Pugliese ◽  
Marco Picardi ◽  
Roberta Della Pepa ◽  
Claudia Giordano ◽  
Francesco Muriano ◽  
...  
Keyword(s):  
Side Effects ◽  
Hodgkin Lymphoma ◽  
Prognostic Score ◽  
Single Agent ◽  
Response To Therapy ◽  
Baseline Risk ◽  
Historical Cohort ◽  
Treatment Groups

Background: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare variant of HL that accounts for 5% of all HL cases. The expression of CD20 on neoplastic lymphocytes provides a suitable target for novel treatments based on Rituximab. Due to its rarity, consolidated and widely accepted treatment guidelines are still lacking for this disease. Methods: Between 1 December 2007 and 28 February 2018, sixteen consecutive newly diagnosed adult patients with NLPHL received Rituximab (induction ± maintenance)-based therapy, according to the baseline risk of German Hodgkin Study Group prognostic score system. The treatment efficacy and safety of the Rituximab-group were compared to those of a historical cohort of 12 patients with NLPHL who received Doxorubicin, Bleomycin, Vinblastine, Dacarbazine (ABVD) chemotherapy followed by radiotherapy (RT), if needed, according to a similar baseline risk. The primary outcome was progression-free survival (PFS) and secondary outcomes were overall survival (OS) and side-effects (according to the Common Terminology Criteria for Adverse Events, v4.03). Results: After a 7-year follow-up (range, 1–11 years), PFS was 100% for patients treated with the Rituximab-containing regimen versus 66% for patients of the historical cohort (p = 0.036). Four patients in the latter group showed insufficient response to therapy. The PFS for early favorable and early unfavorable NLPHLs was similar between treatment groups, while a better PFS was recorded for advanced-stages treated with the Rituximab-containing regimen. The OS was similar for the two treatment groups. Short- and long-term side-effects were more frequently observed in the historical cohort. Grade ≥3 neutropenia was more frequent in the historical cohort compared with the Rituximab-group (58.3% vs. 18.7%, respectively; p = 0.03). Long-term non-hematological toxicities were observed more frequently in the historical cohort. Conclusion: Our results confirm the value of Rituximab in NLPHL therapy and show that Rituximab (single-agent) induction and maintenance in a limited-stage, or Rituximab with ABVD only in the presence of risk factors, give excellent results while sparing cytotoxic agent- and/or RT-related damage. Furthermore, Rituximab inclusion in advanced-stage therapeutic strategy seems to improve PFS compared to conventional chemo-radiotherapy.

Physiological Pacing: A New Road to Future

2021 ◽  
pp. 263246362097804
Author(s):  
Vanita Arora ◽  
Pawan Suri
Keyword(s):  
Side Effects ◽  
Fibrous Tissue ◽  
Cardiac Pacing ◽  
His Bundle ◽  
Anatomy And Physiology ◽  
Long Term Follow Up ◽  
Pacing Lead ◽  
The Right

Anatomy and physiology are the basis of human body functioning and as we have progressed in management of various diseases, we have understood that physiological intervention is always better than an anatomical one. For more than 50 years, a standard approach to permanent cardiac pacing has been an anatomical placement of transvenous pacing lead at the right ventricular apex with a proven benefit of restoring the rhythm. However, the resultant ventricular dyssynchrony on the long-term follow-up in patients requiring more than 40% ventricular pacing led to untoward side effects in the form of heart failure and arrhythmias. To counter such adverse side effects, a need for physiological cardiac pacing wherein the electrical impulse be transmitted directly through the normal conduction system was sought. His bundle pacing (HBP) with an intriguing alternative of left bundle branch pacing (LBBP) is aimed at restoring such physiological activation of ventricles. HBP is safe, efficacious, and feasible; however, localization and placement of a pacing lead at the His bundle is challenging with existing transvenous systems due to its small anatomic size, surrounding fibrous tissue, long-learning curve, and the concern remains about lead dislodgement and progressive electrical block distal to the HBP lead. In this article, we aim to take the reader through the challenging journey of HBP with focus upon the hardware and technique, selective versus nonselective HBP, indications and potential disadvantages, and finally the future prospects.

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