scholarly journals Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition

2022 ◽  
Author(s):  
Yihsuan S. Tsai ◽  
Mark G. Woodcock ◽  
Salma H. Azam ◽  
Leigh B. Thorne ◽  
Krishna L. Kanchi ◽  
...  
Keyword(s):  
Clinical Resistance

scholarly journals Pediatric Septic Arthritis of the Knee Due to a Multi-Sensitive Streptococcus pyogenes Strain Responsive to Clindamycin—A Case Report

Children ◽  
2021 ◽  
Vol 8 (3) ◽  
pp. 189
Author(s):  
Giada Maria Di Pietro ◽  
Irene Maria Borzani ◽  
Sebastiano Aleo ◽  
Samantha Bosis ◽  
Paola Marchisio ◽  
...  
Keyword(s):  
Septic Arthritis ◽  
Streptococcus Pyogenes ◽  
Antibiotic Sensitivity ◽  
Antimicrobial Treatment ◽  
Antibiotic Regimen ◽  
Hematogenous Spread ◽  
Clinical Resistance ◽  
Antibiotic Sensitivity Test ◽  
Clinical Conditions

Septic arthritis is an inflammatory process usually generated by a bacterial infection. The knee is one of the most frequently involved joints. The etiology varies depending on age, and hematogenous spread remains the primary cause in children. Herein, we report a case of a previously healthy three-year-old female who was referred to our institution for acute swelling of her right knee. After a clinical and radiological diagnosis of septic arthritis, an empirical treatment with a combination of cefotaxime and clindamycin was initiated. The isolation of a multi-sensitive Streptococcus pyogenes strain from the joint’s effusion prompted the discontinuation of clindamycin and the usage of cefotaxime alone. One week later, an ultrasound was executed due to worsening in the patient’s clinical conditions, and an organized corpuscular intra-articular effusion with diffuse synovial thickening was revealed. Cefotaxime was therefore replaced with clindamycin, which improved the symptoms. Despite the antibiotic sensitivity test having revealed a microorganism with sensitivity to both cephalosporin and clindamycin, clinical resistance to cefotaxime was encountered and a shift in the antimicrobial treatment was necessary to ensure a full recovery. This case study confirms that an antibiotic regimen based solely on a susceptibility test may be ineffective for such cases.

scholarly journals Epigenetic mechanisms in breast cancer therapy and resistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Liliana Garcia-Martinez ◽  
Yusheng Zhang ◽  
Yuichiro Nakata ◽  
Ho Lam Chan ◽  
Lluis Morey
Keyword(s):  
Breast Cancer ◽  
Therapy Response ◽  
Disease Recurrence ◽  
Therapeutic Resistance ◽  
Breast Cancers ◽  
Epigenetic Factors ◽  
Breast Cancer Therapy ◽  
Resistant Phenotype ◽  
Early Adoption ◽  
Clinical Resistance

AbstractThe majority of breast cancers express the estrogen receptor (ERα) and agents targeting this pathway represent the main treatment modality. Endocrine therapy has proven successful in the treatment of hormone-responsive breast cancer since its early adoption in the 1940s as an ablative therapy. Unfortunately, therapeutic resistance arises, leading to disease recurrence and relapse. Recent studies increased our understanding in how changes to the chromatin landscape and deregulation of epigenetic factors orchestrate the resistant phenotype. Here, we will discuss how the epigenome is an integral determinant in hormone therapy response and why epigenetic factors are promising targets for overcoming clinical resistance.

scholarly journals BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia

Cancer Cell ◽  
2014 ◽  
Vol 26 (3) ◽  
pp. 428-442 ◽  
Author(s):  
Matthew S. Zabriskie ◽  
Christopher A. Eide ◽  
Srinivas K. Tantravahi ◽  
Nadeem A. Vellore ◽  
Johanna Estrada ◽  
...  
Keyword(s):  
Kinase Domain ◽  
Clinical Resistance ◽  
Ph Chromosome

Relevance of Aromatase Inhibitors in Breast Cancer Treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Ankita Sood ◽  
Damanpreet Kaur Lang ◽  
Rajwinder Kaur ◽  
Balraj Saini ◽  
Sandeep Arora
Keyword(s):  
Breast Cancer ◽  
Aromatase Inhibitors ◽  
Breast Tissue ◽  
Positive Impact ◽  
Treatment Options ◽  
Living Standards ◽  
Efficacious Treatment ◽  
Clinical Resistance ◽  
Steroidal Aromatase Inhibitors ◽  
Near Future

: Efficacious treatment for breast cancer is still a challenge despite the presence of various treatment options. Aromatase enzyme present in the breast tissue is responsible for estrogen formation from androgens. Aromatase inhibitors manifest remarkably ameliorated therapeutic efficacy as compared to the current therapeutic options available and exhibit a better safety profile as compared to the other drugs. Clinical resistance to aromatase inhibitors is perceived as a lack of growth inhibition by aromatase inhibitors treatment and cancer therapy becomes ineffective in causing a decrease in the size of the tumor. Naturally extracted aromatase inhibitors have a huge positive impact on vitality and living standards. This review article highlights the particulars about the currently approved steroidal and non-steroidal aromatase inhibitors for clinical use, adverse effects associated with their use and approach to tackling the problem, various strategies to overcome aromatase inhibitors resistance, information on the synthesis of various peculiar aromatase inhibitors which can prove as highly efficient and potent drugs in the near future and the drugs of natural and semi-synthetic origin which can demonstrate to be more efficient, potent and less-toxic than conventional therapy.

Point mutation or overexpression of A. fumigatus cyp51B, encoding lanosterol 14α-sterol demethylase, leads to triazole resistance.

2021 ◽  
Author(s):  
Mariana Handelman ◽  
Zohar Meir ◽  
Jennifer Scott ◽  
Yona Shadkchan ◽  
Wei Liu ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Point Mutation ◽  
Clinical Isolate ◽  
Recipient Strain ◽  
Antifungal Treatment ◽  
Ergosterol Biosynthesis ◽  
Common Cause ◽  
Clinical Resistance

Aspergillus fumigatus is the most common cause of invasive fungal mold infections in immunocompromised individuals. Current antifungal treatment relies heavily on the triazole antifungals which inhibit fungal Erg11/Cyp51 activity and subsequent ergosterol biosynthesis. However, resistance, due primarily to cyp51 mutation, is rapidly increasing. A. fumigatus contains two Cyp51 isoenzymes, Cyp51A and Cyp51B. Overexpression and mutation of Cyp51A is a major cause of triazole resistance in A. fumigatus . The role of Cyp51B in generating resistance is unclear. Here we show that overexpression or mutation of cyp51B results in triazole resistance. We demonstrate that introduction of a G457S Cyp51B mutation identified in a resistant clinical isolate, results in voriconazole resistance in the naïve recipient strain. Our results indicate that mutations in cyp51B resulting in clinical resistance do exist and should be monitored.

scholarly journals Extracellularly oxidative activation and inactivation of matured prodrug for cryptic self-resistance in naphthyridinomycin biosynthesis

2018 ◽  
Vol 115 (44) ◽  
pp. 11232-11237 ◽  
Author(s):  
Yue Zhang ◽  
Wan-Hong Wen ◽  
Jin-Yue Pu ◽  
Man-Cheng Tang ◽  
Liwen Zhang ◽  
...  
Keyword(s):  
Assembly Line ◽  
Antibiotic Biosynthesis ◽  
Bond Functionalization ◽  
Gram Positive Bacteria ◽  
Self Defense ◽  
Clinical Resistance ◽  
Reactive Chemicals ◽  
Peptide Synthetase ◽  
Oxidative Activation ◽  
Temporal And Spatial

Understanding how antibiotic-producing bacteria deal with highly reactive chemicals will ultimately guide therapeutic strategies to combat the increasing clinical resistance crisis. Here, we uncovered a distinctive self-defense strategy featured by a secreted oxidoreductase NapU to perform extracellularly oxidative activation and conditionally overoxidative inactivation of a matured prodrug in naphthyridinomycin (NDM) biosynthesis from Streptomyces lusitanus NRRL 8034. It was suggested that formation of NDM first involves a nonribosomal peptide synthetase assembly line to generate a prodrug. After exclusion and prodrug maturation, we identified a pharmacophore-inactivated intermediate, which required reactivation by NapU via oxidative C-H bond functionalization extracellularly to afford NDM. Beyond that, NapU could further oxidatively inactivate the NDM pharmacophore to avoid self-cytotoxicity if they coexist longer than necessary. This discovery represents an amalgamation of sophisticatedly temporal and spatial shielding mode conferring self-resistance in antibiotic biosynthesis from Gram-positive bacteria.

scholarly journals Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Wiley A. Schell ◽  
A. M. Jones ◽  
Katyna Borroto-Esoda ◽  
Barbara D. Alexander
Keyword(s):  
Candida Glabrata ◽  
Antifungal Agents ◽  
Candida Parapsilosis ◽  
Candida Krusei ◽  
Wild Type ◽  
Content Type ◽  
Clinical Resistance ◽  
Excellent Activity ◽  
Candida Lusitaniae

ABSTRACT SCY-078 in vitro activity was determined for 178 isolates of resistant or susceptible Candida albicans, Candida dubliniensis, Candida glabrata, Candida krusei, Candida lusitaniae, and Candida parapsilosis, including 44 Candida isolates with known genotypic (FKS1 or FKS2 mutations), phenotypic, or clinical resistance to echinocandins. Results were compared to those for anidulafungin, caspofungin, micafungin, fluconazole, and voriconazole. SCY-078 was shown to have excellent activity against both wild-type isolates and echinocandin- and azole-resistant isolates of Candida species.

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