A perspective on the application of macrocyclic design strategies in antitumor drugs.

The macrocyclization of inhibitors has become gradually favored as a new approach for drug design in the field of anticancer agents, since the recent approvals of lorlatinib, pacritinib, and repotrectinib, and feasibility of macrocyclic modification to improve inhibitor drug-like properties has also been confirmed. Macrocycles are receiving increasing attention due to their enhanced binding affinity, target selectivity, and pharmacokinetic properties through conformational constraints. Therefore, this review summarizes various strategies for improving drug-like properties in macrocyclization and structural optimization, and reveals that macrocyclization is a new favorable strategy for drug design, aiming to provide insights for the drug discovery in different targets.

Structure-Guided Discovery of Novel -(Substituted Thiazol-2-yl)--(4-Substituted phenyl)pyrimidine-2,4-Diamines as Potent CDK2 and CDK9 Dual Inhibitors with High Oral Bioavailability.

CDK2 and CDK9 play pivotal roles in cell cycle progression and gene transcription, respectively, making them promising targets for cancer treatment. Herein, we discovered a series of -(substituted thiazol-2-yl)--(4-substituted phenyl)pyrimidine-2,4-diamines as highly potent CDK2/9 dual inhibitors. Especially, compound significantly inhibited CDK2 (IC = 0.

Targeting hyperactive mitochondria in activated HSCs and inhibition of liver fibrogenesis in mice using sorafenib complex micelles.

Liver fibrosis is a pathological condition marked by the excessive buildup of extracellular matrix primarily resulting from the transformation of quiescent hepatic stellate cells (HSCs) to myofibroblastic (MF) phenotype and their resultant over-expansion. Activated HSCs completely rely on their hyperactive mitochondria to supply the energy and biomass for their rapid proliferation and collagen secretion, so an intervention targeting their mitochondria can effectively restrict their pathological amplification and contribution to liver fibrosis. Here we tried sorafenib, a drug that plays anticancer roles by inducing the disruption and loss of mitochondrial functions, to reach an antifibrotic goal.

Perioperative and mid-term outcomes of robotic-assisted versus video-assisted minimally invasive esophagectomy for esophageal cancer: a retrospective propensity-matched analysis of 842 patients.

Aim: Comparing the safety, effectiveness, and mid-term survival rates of robot-assisted minimally invasive esophagectomy (RAMIE) and video-assisted minimally invasive esophagectomy (VAMIE).

Methods: A total of 842 patients undergoing minimally invasive esophagectomy were analyzed, including 694 patients in VAMIE group and 148 in RAMIE group. PSM analysis was applied to generate matched pairs for further comparison.

Corrigendum: Patchouli alcohol improved diarrhea-predominant irritable bowel syndrome by regulating excitatory neurotransmission in the myenteric plexus of rats.

[This corrects the article DOI: 10.3389/fphar.2022.

Confounder balancing in adversarial domain adaptation for pre-trained large models fine-tuning.

The excellent generalization, contextual learning, and emergence abilities in the pre-trained large models (PLMs) handle specific tasks without direct training data, making them the better foundation models in the adversarial domain adaptation (ADA) methods to transfer knowledge learned from the source domain to target domains. However, existing ADA methods fail to account for the confounder properly, which is the root cause of the source data distribution that differs from the target domains. This study proposes a confounder balancing method in adversarial domain adaptation for PLMs fine-tuning (CadaFT), which includes a PLM as the foundation model for a feature extractor, a domain classifier and a confounder classifier, and they are jointly trained with an adversarial loss.

[Experimental study of improved sclerotherapy injection in rat model of vertebral arteriocervical spondylopathy].

Objective: To improve the rat model of cervical spondylosis of vertebral artery type (CSA) induced by injecting sclerosing agent. To evaluate the efficacy of injecting sclerosing agent to induce CSA.

Methods: Forty Health SPF SD rats(20 males and 20 females), were randomly divided into two groups:the model group (20) and the blank group (20).

Patchouli alcohol improved diarrhea-predominant irritable bowel syndrome by regulating excitatory neurotransmission in the myenteric plexus of rats.

Irritable bowel syndrome (IBS) is usually associated with chronic gastrointestinal disorders. Its most common subtype is accompanied with diarrhea (IBS-D). The enteric nervous system (ENS) modulates major gastrointestinal motility and functions whose aberration may induce IBS-D.

The Effects of Patchouli Alcohol on Diarrhea-Predominant Irritable Bowel Syndrome are Correlated with Phenotypic Plasticity in Myenteric Neurons and the Targeted Regulation of Myosin Va.

Patchouli alcohol (PA) has been widely used for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) in traditional Chinese medicine, and the related mechanism remains to be fully understood. Our previous study has indicated that PA significantly reduced visceral sensitivity and defecation area in IBS-D rats. In this study, we prepared an IBS-D rat model and observed the dynamic intestinal motility and colonic longitudinal muscle and myenteric plexus (LMMP) neurons, as well as their subtypes at D14, D21, and D28.

LncRNA C9orf139 can regulate the progression of esophageal squamous carcinoma by mediating the miR-661/HDAC11 axis.

Increasing evidence has indicated that long non-coding RNAs (LncRNAs) play multiple functions in the development of cancer and function as indicators of diagnosis and prognosis. This aim of this study was to investigate the roles LncRNA C9orF139 had in the progression of esophageal squamous carcinoma (ESCC). We found C9orf139 was highly expressed in ESCC and knock down the expression of C9orf139 significantly suppressed cell proliferation, promoted apoptosis, and inhibited migration and invasion.

Efficacy of sternocleidomastoid muscle flap in reducing anastomotic mediastinal/pleural cavity leak.

Background: Anastomotic mediastinal/pleural cavity leak (AMPCL) is a life-threatening postoperative complication after esophagectomy. The objective of this study was to find a safe and effective surgical method to reduce the incidence of AMPCL.

Methods: A total of 223 patients who underwent surgery in Fujian Medical University Union Hospital from May 2020 to October 2021 were enrolled in this study.

A nomogram to predict the recurrence-free survival and analyze the utility of chemotherapy in stage IB non-small cell lung cancer.

Background: Large part of patients of stage IB non-small cell lung cancer (IB NSCLC) may suffer recurrence after surgery. This study is to determine risk factors and establish a nomogram for postoperative recurrence and to provide a reference for adjuvant chemotherapy selection in patients with stage IB NSCLC.

Methods: A total of 394 patients with postoperative stage IB NSCLC who visited Fujian Medical University Union Hospital between January 2010 and June 2016 were selected.

Neoadjuvant sintilimab plus chemotherapy for locally advanced esophageal squamous cell carcinoma: a single-arm, single-center, phase 2 trial (ESONICT-1).

Background: To investigate the safety and feasibility of combining neoadjuvant sintilimab (Innovent Biologics, Suzhou, China) and chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC).

Methods: The study was an investigator-initiated, open-label, non-randomized, single-arm, single-center phase 2 trial. Patients aged between 18 to 75 years with locally advanced ESCC were eligible for neoadjuvant immunochemotherapy (nICT).

Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and Y-DOTA.

Pretargeted radioimmunotherapy (PRIT) has been investigated as a multi-step approach to decrease relapse and toxicity for high-risk acute myeloid leukemia (AML). Relevant factors including endogenous biotin and immunogenicity, however, have limited the use of PRIT with an anti-CD45 antibody streptavidin conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine and anti-human CD45 bispecific antibody constructs using 30F11 and BC8 antibodies, respectively, combined with an anti-yttrium (Y)-DOTA single-chain variable fragment (C825) to capture a radiolabeled ligand.

The α-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model.

Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones.

CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies.

Pretargeted radioimmunotherapy (PRIT) has demonstrated remarkable efficacy targeting tumor antigens, but immunogenicity and endogenous biotin blocking may limit clinical translation. We describe a new PRIT approach for the treatment of multiple myeloma (MM) and other B-cell malignancies, for which we developed an anti-CD38-bispecific fusion protein that eliminates endogenous biotin interference and immunogenic elements. In murine xenograft models of MM and non-Hodgkin lymphoma (NHL), the CD38-bispecific construct demonstrated excellent blood clearance and tumor targeting.

Venetoclax Synergizes with Radiotherapy for Treatment of B-cell Lymphomas.

Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation.

Pretargeting with bispecific fusion proteins facilitates delivery of nanoparticles to tumor cells with distinct surface antigens.

Tumor heterogeneity, which describes the genetically and phenotypically distinct subpopulations of tumor cells present within the same tumor or patient, presents a major challenge to targeted delivery of diagnostic and/or therapeutic agents. An ideal targeting strategy should deliver a given nanocarrier to the full diversity of cancer cells, which is difficult to achieve with conventional ligand-conjugated nanoparticles. We evaluated pretargeting (i.

Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers.

Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7), with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825).

Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models.

Purpose: Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs.

Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model.

α-Emitting radionuclides deposit a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD). To evaluate this hypothesis, (211)At-labeled 1F5 monoclonal antibody (mAb) (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to (211)At-labeled 1F5 mAb were evident in the MRD setting.

A preclinical model of CD38-pretargeted radioimmunotherapy for plasma cell malignancies.

The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on malignant plasma cells.