What happens to macromolecules ? What drives the structure-activity relationship and stability for antibody-drug conjugates (ADCs)? These interrelated questions are increasingly relevant due to the re-emerging importance of ADCs as an impactful therapeutic modality and the gaps that exist in our understanding of ADC structural determinants that underlie ADC stability. Complex macromolecules, such as ADCs, may undergo changes due to their intricate structure as biotransformations may occur on the linker, the payload, and/or at the modified conjugation site. Furthermore, the dissection of ADC metabolism presents a substantial analytical challenge due to the difficulty in the identification or quantification of minor changes on a large macromolecule.
View Article and Find Full Text PDFWound Repair Regen
November 2024
The Wound Healing Society guidelines for the treatment of arterial insufficiency ulcers were originally published in 2006, with the last update in 2014. These guidelines provided recommendations, along with their respective levels of evidence, on seven categories: diagnosis, surgery, infection control, wound bed preparation, dressings, adjuvant therapy and long-term maintenance. Over the last 9 years, additional literature regarding these aspects of arterial ulcer management has been published.
View Article and Find Full Text PDFPreviously we reported that a novel αvβ6-specific peptide-drug conjugate (SG3299) could eliminate established human pancreatic ductal adenocarcinoma (PDAC) xenografts. However the development of effective therapies for PDAC, which is an essential need, must show efficacy in relevant immunocompetent animals. Previously we reported that the KPC mouse transgenic PDAC model that closely recapitulates most stages of development of human PDAC, unlike in humans, failed to express αvβ6 on their tumours or metastases.
View Article and Find Full Text PDFA young male patient presented with an incidental finding of a large supraglottic vascular lesion. The lesion was initially noted during intubation 4 years ago. Although originally listed for elective excision, there was a significant delay and at the time of surgery, the lesion proved too large to remove and a significant threat to the patient's airway.
View Article and Find Full Text PDFObjective: Primary hyperparathyroidism is a common endocrine disorder, with 80% of all cases usually caused by one single hyperfunctioning parathyroid adenoma. Conventional imaging modalities for the diagnostic work-up of primary hyperparathyroidism (PHPT) include ultrasound of the neck, 99mTc-sestamibi scintigraphy, and four-dimensional computed tomography (4D-CT). However, the role of other imaging modalities, such as 11C-methionine PET/CT, in the care pathway for PHPT is currently unclear.
View Article and Find Full Text PDFDespite advances by recently approved antibody-drug conjugates in treating advanced gastric cancer patients, substantial limitations remain. Here, several key obstacles are overcome by developing a first-in-class ultrasmall (sub-8-nanometer (nm)) anti-human epidermal growth factor receptor 2 (HER2)-targeting drug-immune conjugate nanoparticle therapy. This multivalent fluorescent core-shell silica nanoparticle bears multiple anti-HER2 single-chain variable fragments (scFv), topoisomerase inhibitors, and deferoxamine moieties.
View Article and Find Full Text PDFIntrathyroidal parathyroid adenomas (IPAs) are a rare cause of primary hyperparathyroidism. They are often difficult to localize preoperatively and intraoperatively, making diagnosis and treatment challenging. Current data on IPAs are sparse and fragmented in the literature.
View Article and Find Full Text PDFThis review aimed to examine the relationship between TP53 mutational status, as determined by genomic sequencing, and survival in squamous cell carcinoma of the head and neck. The databases Medline, Embase, Web of Science (core collection), Scopus and Cochrane Library were searched from inception to April 2021 for studies assessing P53 status and survival. Qualitative analysis was carried out using the REMARK criteria.
View Article and Find Full Text PDFPurpose: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models.
Experimental Design: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies.
Antibody-drug conjugate (ADC) research has typically focused on the release of highly potent cytotoxic agents to achieve antitumor efficacy. However, recently approved ADCs trastuzumab deruxtecan and sacituzumab govitecan release lower-potency topoisomerase inhibitors. This has prompted interest in ADCs that release lower-potency cytotoxic drugs to potentially enhance therapeutic index and reduce unwanted toxicity.
View Article and Find Full Text PDFRaf Kinase Inhibitory Protein (RKIP) maintains cellular robustness and prevents the progression of diseases such as cancer and heart disease by regulating key kinase cascades including MAP kinase and protein kinase A (PKA). Phosphorylation of RKIP at S153 by Protein Kinase C (PKC) triggers a switch from inhibition of Raf to inhibition of the G protein coupled receptor kinase 2 (GRK2), enhancing signaling by the β-adrenergic receptor (β-AR) that activates PKA. Here we report that PKA-phosphorylated RKIP promotes β-AR-activated PKA signaling.
View Article and Find Full Text PDFPurpose: Primary: To determine the rate of occult cervical metastases in primary temporal bone squamous cell carcinomas (TBSSC). Secondary: to perform a subgroup meta-analysis of the risk of occult metastases based on the clinical stage of the tumour and its risk based on corresponding levels of the neck.
Methods: A systematic review and meta-analysis of papers searched through Medline, Cochrane, Embase, Scopus and Web of Science up to November 2021 to determine the pooled rate of occult lymph node/parotid metastases.
Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia driven by excess parathyroid hormone (PTH) secretion. PHPT is a common endocrine condition with a prevalence of 1 to 7 cases per 1000 adults. PHPT typically presents in the fifth or sixth decade and shows significant female preponderance.
View Article and Find Full Text PDFHuman papillomavirus (HPV)-positive (HPV) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the UICC/AJCC staging system separates HPV OPSCC from its HPV-negative (HPV) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes.
View Article and Find Full Text PDFNasopharyngeal carcinoma (NPC) is a malignant epithelial tumor, most commonly located in the pharyngeal recess and endemic to parts of Asia. It is often detected at a late stage which is associated with poor prognosis (5-year survival rate of 63%). Treatment for this malignancy relies predominantly on radiotherapy and/or systemic chemotherapy, which can be associated with significant morbidity and impaired quality of life.
View Article and Find Full Text PDFObjective: It has been suggested that the presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment is associated with a better prognosis in different types of cancer. In this systematic review and meta-analysis, we investigated the prognostic role of CD4+ and CD8+ TILs in head and neck squamous cell carcinoma (HNSCC).
Methods: PubMed, Cochrane, Embase, Scopus, and Web of Science were searched up to September 2020.
Resistance to antibody-drug conjugates (ADCs) has been observed in both preclinical models and clinical studies. However, mechanisms of resistance to pyrrolobenzodiazepine (PBD)-conjugated ADCs have not been well characterized and thus, this study was designed to investigate development of resistance to PBD dimer warheads and PBD-conjugated ADCs. We established a PBD-resistant cell line, 361-PBDr, by treating human breast cancer MDA-MB-361 cells with gradually increasing concentrations of SG3199, the PBD dimer released from the PBD drug-linker tesirine.
View Article and Find Full Text PDFEur Arch Otorhinolaryngol
July 2021
Background And Aims: Squamous cell carcinoma (SCC) of the temporal bone is a rare malignancy accounting for only 0.2% of head and neck cancers. There is currently no clear consensus on staging or common approach to management.
View Article and Find Full Text PDF: The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% for decades because no effective therapies have been identified. Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an αvβ6-specific peptide-drug conjugate (PDC) for therapy of PDAC.
View Article and Find Full Text PDFNow is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.
View Article and Find Full Text PDFAntibody-drug conjugates (ADCs) are an emerging class of biopharmaceutical products for oncology, with the cytotoxic pyrrolobenzodiazepine (PBD) family of "warheads" well-established in the clinic. While PBDs offer high potency, they are also characterized by their hydrophobicity, which can make formulation of the ADC challenging. Several approaches have been investigated to improve the physicochemical properties of PBD-containing ADCs, and herein a supramolecular approach was explored using cucurbit[8]uril (CB[8]).
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