Humanized dual-targeting antibody-drug conjugates specific to MET and RON receptors as a pharmaceutical strategy for the treatment of cancers exhibiting phenotypic heterogeneity.

Cancer heterogeneity, characterized by diverse populations of tumorigenic cells, involves the occurrence of differential phenotypes with variable expressions of receptor tyrosine kinases. Aberrant expressions of mesenchymal-epithelial transition (MET) and recepteur d'origine nantais (RON) receptors contribute to the phenotypic heterogeneity of cancer cells, which poses a major therapeutic challenge. This study aims to develop a dual-targeting antibody-drug conjugate (ADC) that can act against both MET and RON for treating cancers with high phenotypic heterogeneity.

Drug exposure during pregnancy: Current understanding and approaches to measure maternal-fetal drug exposure.

Prescription drug use is prevalent during pregnancy, yet there is limited knowledge about maternal-fetal safety and efficacy of this drug use because pregnant individuals have historically been excluded from clinical trials. Underrepresentation has resulted in a lack of data available to estimate or predict fetal drug exposure. Approaches to study fetal drug pharmacology are limited and must be evaluated for feasibility and accuracy.

Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients.

This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development.

Examination of Complementary Medicine for Treating Urinary Tract Infections Among Pregnant Women and Children.

Urinary tract infections (UTIs) are a significant clinical problem that pregnant women and children commonly experience. is the primary causative organism, along with several other gram-negative and gram-positive bacteria. Antimicrobial drugs are commonly prescribed to treat UTIs in these patients.

Antibody-drug Conjugate PCMC1D3-Duocarmycin SA as a Novel Therapeutic Entity for Targeted Treatment of Cancers Aberrantly Expressing MET Receptor Tyrosine Kinase.

Background: Aberrant expression of the MET receptor tyrosine kinase is an oncogenic determinant and a drug target for cancer therapy. Currently, antibody-based biotherapeutics targeting MET are under clinical trials.

Objective: Here, we report the preclinical and therapeutic evaluation of a novel anti-MET antibody- drug conjugate PCMC1D3-duocarmycin SA (PCMC1D3-DCM) for targeted cancer therapy.

Duocarmycin-based antibody-drug conjugates as an emerging biotherapeutic entity for targeted cancer therapy: Pharmaceutical strategy and clinical progress.

Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the development of antibody-drug conjugates (ADCs). Currently, more than 15 duocarmycin-based ADCs have been studied preclinically, and some of them such as SYD985 have been granted Fast-Track Designation status.

MET and RON receptor tyrosine kinases in colorectal adenocarcinoma: molecular features as drug targets and antibody-drug conjugates for therapy.

Advanced colorectal adenocarcinoma (CRAC), featured by distinctive histopathological appearance, distant organ metastasis, acquired chemoresistance, and tumorigenic stemness is a group of heterogeneous cancers with unique genetic signatures and malignant phenotypes. Treatment of CRAC is a daunting task for oncologists. Currently, various strategies including molecular targeting using therapeutic monoclonal antibodies, small molecule kinase inhibitors and immunoregulatory checkpoint therapy have been applied to combat this deadly disease.

Progress and challenge in development of biotherapeutics targeting MET receptor for treatment of advanced cancer.

Advanced epithelial cancers such as gastric, lung, and pancreatic tumors are featured by invasive proliferation, distant metastasis, acquired chemoresistance, and tumorigenic stemness. For the last decade, molecular-targeted therapies using therapeutic antibodies, small molecule kinase inhibitors and immune-checkpoint blockades have been applied for these diseases with significant clinical benefits. Nevertheless, there is still a large gap to achieve curative outcomes.

Immune Responses and Performance Are Influenced by Respiratory Vaccine Antigen Type and Stress in Beef Calves.

The study objective was to determine if a combined weaning and transportation stress model affected performance, antibody, endocrine, or hematological responses to modified-live virus (MLV) or killed virus (KV) respiratory vaccination in beef steers. In total, 48 calves (Day 0 BW = 226 ± 6.2 kg) from a single origin were used in a 2 × 2 factorial to evaluate main effects of stress model, vaccine type, and their interaction, resulting in four treatments ( = 12/treatment) including non-stress control (C) with KV (CKV), C with MLV (CMLV), stress model implementation (S) with KV (SKV), and S with MLV (SMLV).

Antibody-drug conjugates targeting RON receptor tyrosine kinase as a novel strategy for treatment of triple-negative breast cancer.

Treatment of triple-negative breast cancer (TNBC) is a challenge to oncologists. Currently, the lack of effective therapy has fostered a major effort to discover new targets and therapeutics to combat this disease. The recepteur d'origine nantais (RON) receptor has been implicated in the pathogenesis of TNBC.

RON receptor tyrosine kinase in pancreatic ductal adenocarcinoma: Pathogenic mechanism in malignancy and pharmaceutical target for therapy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis and high mortality. Molecular aberrations associated with PDAC pathogenesis and progression have been extensively investigated. Nevertheless, these findings have not been translated into clinical practice.

Hypospadias surgery in England: Higher volume centres have lower complication rates.

Introduction: Hypospadias surgery has progressed steadily over recent years. There remains considerable variation in the operative management of boys with hypospadias in the UK, and it is therefore difficult to identify acceptable standards with regards to reoperation rates.

Objective: To determine the frequency of reoperations and complications from all centres performing hypospadias surgery in England and to identify variables that influence outcome.

A comparison of alternative strategies for cost-effective water quality management in lakes.

Roughly 45% of the assessed lakes in the United States are impaired for one or more reasons. Eutrophication due to excess phosphorus loading is common in many impaired lakes. Various strategies are available to lake residents for addressing declining lake water quality, including septic system upgrades and establishing riparian buffers.