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Annals of Oncology : Official Journal... Nov 2019Numerous phase I trials testing immune checkpoint inhibitors (CPI)-based combinations are currently being conducted to improve response rates observed with single... (Review)
Review
BACKGROUND
Numerous phase I trials testing immune checkpoint inhibitors (CPI)-based combinations are currently being conducted to improve response rates observed with single agents. However, methodology varies across studies, especially regarding the use of dose escalation.
MATERIALS AND METHODS
A literature search was conducted in Pubmed and major oncology meetings libraries for phase I trials reported between 2011 and 2018, containing at least one CPI [CLTA-4 blocking antibody or a PD(L)1 blocking antibody] plus at least one second agent (e.g. tyrosine kinase inhibitor, chemotherapy). Dose escalation schemes, target doses and recommended phase II doses (RP2D) were captured in our database for each study. Combination RP2D (combo-RP2D) was compared with target dose.
RESULTS
We identified 113 different studies comprising a total of 120 individual cohorts. The backbone was an anti- cytotoxic T-lymphocyte antigen 4 (CTLA-4) in 40 cohorts and an anti-PD(L)1 in 80 cohorts. Dose escalation was used for the CPI in 29 (24%) cohorts [11% for anti-PD(L)1 and 50% for anti-CTLA-4] and for the second agent in 55 cohorts (46%). For 31 s agents (26%), the combo-RP2D was significantly lower than the expected target dose. Failure to reach the target dose was explained by the type of second agent form (e.g. small molecules versus monoclonal antibodies) (P < 0.001) and the choice of trial design for the second agent by investigators.
CONCLUSION
Design of studies investigating new CPI-based combinations must consider the type of second agent. Dose escalation is required for combinations with small molecules but is unnecessary with vaccine/virus/dendritic therapies and monoclonal antibodies.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; CTLA-4 Antigen; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Humans; Maximum Tolerated Dose; Neoplasms; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Research Design; Treatment Outcome
PubMed: 31435659
DOI: 10.1093/annonc/mdz286 -
Dermatology Online Journal Jul 2021Periungual pyogenic granulomas are benign vascular tumors that present as painful, round, spontaneously bleeding lesions composed of rapidly proliferating capillaries...
Periungual pyogenic granulomas are benign vascular tumors that present as painful, round, spontaneously bleeding lesions composed of rapidly proliferating capillaries and excess tissue. The vast majority of pyogenic granulomas are caused by physical trauma or infectious agents and they may resolve spontaneously. Herein, we highlight a very rare case of periungual pyogenic granulomas induced by the regularly prescribed oral retinoid acitretin during treatment for congenital palmoplantar keratoderma. This unique case showed that it is feasible to continue acitretin therapy in the presence of pyogenic granuloma development if proper dose reduction and topical therapies are utilized. The patient's lesions resolved within two weeks of this protocol's initiation and the pyogenic granulomas did not recur over the course of a six-month follow-up observation period. In addition, we performed a systematic review of the literature using PubMed databases for the clinical features and treatments in other reported acitretin-induced pyogenic granuloma cases; we compiled a comprehensive list of other prescription drugs known to cause pyogenic granulomas up-to-date.
Topics: Acitretin; Administration, Oral; Adult; Anti-Bacterial Agents; Clobetasol; Glucocorticoids; Granuloma, Pyogenic; Humans; Keratoderma, Palmoplantar; Keratolytic Agents; Male; Mupirocin; Nail Diseases
PubMed: 34391333
DOI: 10.5070/D327754369 -
Journal of Oral Science 2020The purpose of this study was to evaluate the influence of various polishing protocols on the surface roughness of polyetheretherketone (PEEK) and identify an effective...
The purpose of this study was to evaluate the influence of various polishing protocols on the surface roughness of polyetheretherketone (PEEK) and identify an effective polishing method of dental prostheses at the chairside. The PEEK specimens were assigned to seven groups with different protocols: no additional polishing (NT); polishing using a rubber point (C); polishing using "silky shine" (S); polishing using "aqua blue paste" (A); protocol C followed by protocol S (CS); protocol C followed by protocol A (CA); and protocol C followed by protocols S and A (CSA). The surface roughness (Sa and Ra) of the polished surfaces was measured. The surface roughness decreased in the following order of groups: NT, C, S, CS, CSA, CA, and A. In Groups C and S, wide deep pits formed by abrasive grains of SiC paper were observed, whereas only fine linear structures were observed on the surface in other groups. With respect to the polishing protocol of PEEK, clinically acceptable surface roughness was obtained using a soft polishing brush and agent for more than 3 min.
Topics: Benzophenones; Dental Polishing; Ketones; Materials Testing; Polyethylene Glycols; Polymers; Surface Properties
PubMed: 31996521
DOI: 10.2334/josnusd.18-0473 -
World Journal of Gastroenterology Aug 2014While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20%, the administration of combinations of... (Review)
Review
While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20%, the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival. However, the side effects of systemic therapy such as myelotoxicity, neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients. Therefore, biomarkers that would be instrumental in the choice of optimal type, combination and dose of drugs for an individual patient are urgently needed. The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells, healthy tissues and by the presence and quantity of the drug targets. Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome. The aim of this review was to summarize published data on associations of gene and protein expression, and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens. Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biotransformation; Camptothecin; Colorectal Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pharmacogenetics; Phenotype; Precision Medicine; Treatment Outcome
PubMed: 25132748
DOI: 10.3748/wjg.v20.i30.10316 -
Cancer Reports (Hoboken, N.J.) Sep 2023Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized... (Review)
Review
BACKGROUND
Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup.
RECENT FINDINGS
Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing. Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed.
CONCLUSION
Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.
Topics: Humans; Neoplasms; Polymorphism, Genetic
PubMed: 37150853
DOI: 10.1002/cnr2.1830 -
Bio-protocol Dec 2021The engineering of poxvirus genomes is fundamental to primary and applied virology research. Indeed, recombinant poxviruses form the basis for many novel vaccines and...
The engineering of poxvirus genomes is fundamental to primary and applied virology research. Indeed, recombinant poxviruses form the basis for many novel vaccines and virotherapies but producing and purifying these viruses can be arduous. In recent years, CRISPR/Cas9 has become the favoured approach for genome manipulation due to its speed and high success rate. However, recent data suggests poxvirus genomes are not repaired well following Cas9 cleavage. As a result, CRISPR/Cas9 is inefficient as an editing tool, but very effective as a programmable selection agent. Here, we describe protocols for the generation and enrichment of recombinant vaccinia viruses using targeted Cas9 as a selection tool. This novel use of Cas9 is a simple addition to current homologous recombination-based methods that are widespread in the field, facilitating implementation in laboratories already working with poxviruses. This is also the first method that allows for isolation of new vaccinia viruses in less than a fortnight, without the need to incorporate a marker gene or manipulation of large poxvirus genomes and reactivation with helper viruses. Whilst this protocol describes applications for laboratory strains of vaccinia virus, it should be readily adaptable to other poxviruses. Graphic abstract: Pipeline for Cas9 selection of recombinant poxviruses.
PubMed: 35087929
DOI: 10.21769/BioProtoc.4270 -
Cureus Dec 2020An alliance of established experts on critical care, Front Line COVID-19 Critical Care Alliance (FLCCC), has published two protocols for treatment of COVID-19. The first...
An alliance of established experts on critical care, Front Line COVID-19 Critical Care Alliance (FLCCC), has published two protocols for treatment of COVID-19. The first one, methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+), is intended for hospital and intensive care unit treatment of pulmonary phases of the disease. It is based on affordable, commonly available components: anti-inflammatory corticosteroids (methylprednisolone, "M"), high-dose vitamin C infusion (ascorbic acid, "A"), vitamin B1 (thiamine, "T"), anticoagulant heparin ("H"), antiparasitic agent ivermectin, and supplemental components ("+") including melatonin, vitamin D, elemental zinc, and magnesium. The MATH+ protocol has received scarce attention due to the World Health Organization (WHO) advising against the use of corticosteroids in the beginning of the pandemic. In addition, randomized controlled clinical trials were required as a condition for adoption of the protocol. As the hospital mortality rate of MATH+ treated patients was approximately a quarter of the rate of patients receiving a standard of care, the authors of the protocol considered performing such trials unethical. Other parties have later performed clinical trials with corticosteroids and anticoagulants, which has led to a more widespread adoption of these components. In October 2020, ivermectin was upgraded from an optional component to an essential component of the protocol. According to the authors, ivermectin is considered the first agent effective for both prophylaxis (prevention) of COVID-19 and for treatment of all phases of COVID-19 including outpatient treatment of the early symptomatic phase. Therefore, at the end of October 2020, a separate ivermectin-based I-MASK+ protocol for prophylaxis and early outpatient treatment of COVID-19 was published.
PubMed: 33532161
DOI: 10.7759/cureus.12403 -
Frontiers in Bioengineering and... 2022Regenerative endodontic procedures have been described for over a decade as a paradigm shift in the treatment of immature necrotic permanent teeth, owing to their... (Review)
Review
Regenerative endodontic procedures have been described for over a decade as a paradigm shift in the treatment of immature necrotic permanent teeth, owing to their ability to allow root maturation with subsequent enhancement of the tooth's fracture resistance in addition to the potential for regeneration of vital intracanal tissues. Concomitantly, minimally invasive endodontics is another rising concept with the main concern of preservation of tooth structure. Stemming from their potential to preserve the original tooth structure, both regenerative and minimally invasive endodontics could be considered as two revolutionary sciences with one common goal. Achieving this goal would entail not only employing the appropriate strategies to recreate the ideal regenerative niche but modifying existing concepts and protocols currently being implemented in regenerative endodontics to address two important challenges affecting the outcome of these procedures; conservation of tooth structure and achieving effective disinfection. Therefore, the search for new biomimetic cell-friendly disinfecting agents and strategies is crucial if such a novel integratory concept is to be foreseen in the future. This could be attainable by advocating a new merged concept of "minimally invasive regenerative endodontic procedures (MIREPs)," through modifying the clinical protocol of REPs by incorporating a minimally invasive access cavity design/preparation and biomimetic disinfection protocol, which could enhance clinical treatment outcomes and in the future; allow for personalized disinfection/regeneration protocols to further optimize the outcomes of MIREPs. In this review, we aim to introduce this new concept, its realization and challenges along with future perspectives for clinical implementation.
PubMed: 35211465
DOI: 10.3389/fbioe.2022.837639 -
BMC Oral Health May 2022To evaluate the effect of amalgam contamination, different surface treatments, and adhesive protocols on dentin microleakage to bulk-fill composite resin material.
BACKGROUND
To evaluate the effect of amalgam contamination, different surface treatments, and adhesive protocols on dentin microleakage to bulk-fill composite resin material.
METHODS
Forty teeth were fixed in (polyvinyl siloxane) PVS molds, and the Class II cavities were placed on mesial and distal aspects. Thirty teeth were restored by amalgam and thermocycled to 10,000 cycles (5 and 55 °C, 30-s dwell time). The rest were restored with Filtek one Bulk Fill composite without amalgam predecessor. Samples were divided into: G1 (dentin pretreated with 2% chlorhexidine gluconate), G2 (0.5 mm of dentin was removed), G3 (no surface modification), and G4 (control, where composite was bonded to sound dentin without amalgam predecessor.). Single Bond Universal Adhesive system was used to bond the composite material, by using the etch-and-rinse protocol in the mesial cavity preparation and self-etch protocol in the distal. Specimens underwent thermocycling for 5000 cycles, then embedded in silver nitrate and sectioned for stereomicroscope examination. Descriptive statistics, Mann-Whitney U test, and Kruskal-Wallis test were used to analyze the results at p < 0.05.
RESULTS
The highest microleakage score values (4.00) were found in the G2, and G4 in etch-and-rinse protocol. While the lowest scores were found in G2 when using self-etching protocol (1.5). Lower microleakage values were associated with the chlorhexidine treatment group for both adhesive protocols. No significant differences were found between amalgam contaminated and non-contaminated groups.
CONCLUSIONS
Amalgam contamination did not affect microleakage. Self-etching adhesive protocol significantly reduced microleakage for all groups irrespective of the surface treatment. Chlorhexidine pretreatment improved microleakage for both adhesive protocols but had no significant effect.
Topics: Chlorhexidine; Composite Resins; Dental Cavity Preparation; Dental Cements; Dental Leakage; Dental Restoration, Permanent; Dentin; Dentin-Bonding Agents; Humans; Materials Testing; Resin Cements
PubMed: 35585533
DOI: 10.1186/s12903-022-02214-1 -
Current Protocols Nov 2023Replication timing is significantly correlated with gene expression and chromatin organization, changes dynamically during cell differentiation, and is altered in...
Replication timing is significantly correlated with gene expression and chromatin organization, changes dynamically during cell differentiation, and is altered in diseased states. Genome-wide analysis of replication timing is performed in actively replicating cells by Repli-seq. Current methods for Repli-seq require cells to be fixed in large numbers. This is a barrier for sample types that are sensitive to fixation or are in very limited numbers. In this article, we outline optimized methods to process live cells and intact nuclei for Repli-seq. Our protocol enables the processing of a smaller number of cells per sample and reduces processing time and sample loss while obtaining high-quality data. Further, for samples that tend to form clumps and are difficult to dissociate into a single-cell suspension, we also outline methods for isolation, staining, and processing of nuclei for Repli-seq. The Repli-seq data obtained from live cells and intact nuclei are comparable to those obtained from the standard protocols. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Live cell isolation and staining Alternate Protocol: Nuclei isolation and staining.
Topics: Coloring Agents; Cell Nucleus; DNA Replication Timing; Cell Separation; Genome
PubMed: 38009262
DOI: 10.1002/cpz1.945