An Enzymatically Cleavable Tripeptide Linker for Maximizing the Therapeutic Index of Antibody-Drug Conjugates

Valine-citrulline is a protease-cleavable linker commonly used in many drug delivery systems, including antibody-drug conjugates (ADC) for cancer therapy. However, its suboptimal in vivo stability can cause various adverse effects such as neutropenia and hepatotoxicity, leading to dose delays or treatment discontinuation. Here, we report that glutamic acid-glycine-citrulline (EGCit) linkers have the potential to solve this clinical issue without compromising the ability of traceless drug release and ADC therapeutic efficacy. We demonstrate that our EGCit ADC resists neutrophil protease-mediated degradation and spares differentiating human neutrophils. Notably, our anti-HER2 ADC shows almost no sign of blood and liver toxicity in healthy mice at 80 mg kg-1. In contrast, at the same dose level, the FDA-approved anti-HER2 ADCs Kadcyla and Enhertu show increased levels of serum alanine aminotransferase and aspartate aminotransferase and morphologic changes in liver tissues. Our EGCit conjugates also exert greater antitumor efficacy in multiple xenograft tumor models compared with Kadcyla and Enhertu. This linker technology could substantially broaden the therapeutic windows of ADCs and other drug delivery agents, providing clinical options with improved efficacy and safety

Phase 2 Study of Neoadjuvant Enzalutamide and Paclitaxel for Luminal Androgen Receptor-Enriched TNBC: Trial Results and Insights Into “ARness”

Luminal androgen receptor (LAR)-enriched triple-negative breast cancer (TNBC) is a distinct subtype. The efficacy of AR inhibitors and the relevant biomarkers in neoadjuvant therapy (NAT) are yet to be determined. We tested the combination of the AR inhibitor enzalutamide (120 mg daily by mouth) and paclitaxel (80 mg/m2 weekly intravenously) (ZT) for 12 weeks as NAT for LAR-enriched TNBC. Eligibility criteria included a percentage of cells expressing nuclear AR by immunohistochemistry (iAR) of at least 10% and a reduction in sonographic volume of less than 70% after four cycles of doxorubicin and cyclophosphamide. Twenty-four patients were enrolled. Ten achieved a pathologic complete response or residual cancer burden-I. ZT was safe, with no unexpected side effects. An iAR of at least 70% had a positive predictive value of 0.92 and a negative predictive value of 0.97 in predicting LAR-enriched TNBC according to RNA-based assays. Our data support future trials of AR blockade in early-stage LAR-enriched TNBC

EFFECTS OF STABILIZATION EXERCISE USING A BALL ON MUTIFIDUS CROSS-SECTIONAL AREA IN PATIENTS WITH CHRONIC LOW BACK PAIN

The purpose of this study was to compare the effects of lumbar stabilization exercises using balls to the effects of general lumbar stabilization exercises with respect to changes in the cross section of the multifidus (MF), weight bearing, pain, and functional disorders in patients with non-specific chronic low back pain. Twelve patients participated in either a 8 week (3 days per week) stabilization exercise program using balls and control group (n = 12). The computer tomography (CT) was used to analyze MF cross-sectional areas (CSA) and Tetrax balancing scale was used to analyze left and right weight bearing differences. Both groups had significant changes in the CSA of the MF by segment after training (p < 0.05) and the experimental group showed greater increases at the L4 (F = 9.854, p = 0.005) and L5 (F = 39. 266, p = 0.000). Both groups showed significant decreases in weight bearing, from 9.25% to 5.83% in the experimental group and from 9.33% to 4.25% in the control group (p < 0.05), but did not differ significantly between the two groups. These results suggests that stabilization exercises using ball can increases in the CSA of the MF segments, improvement in weight bearing, pain relief, and recovery from functional disorders, and the increases in the CSA of the MF of the L4 and L5 segments for patients with low back pai

ATR Inhibitor BAY 1895344 Inhibited Proliferation of Triple-Negative Breast Cancer Cells In Vitro by Arresting Cell Cycle Progression and Inducing Apoptosis

https://openworks.mdanderson.org/sumexp21/1102/thumbnail.jp

Experimental and Theoretical Analysis of Flexural Properties of Mortar Beam Reinforced with Coated Carbon-Fiber Textile

The flexural behavior of mortar beams reinforced with coated carbon-fiber textile was experimentally analyzed in this study. Accordingly, pull-out and bending tests were performed on textile-reinforced mortar (TRM) beam specimens. The experimental results demonstrated the superior bond performance of the coated carbon-fiber textile. The TRM beam exhibited sufficient ductility even after the occurrence of flexural cracks. In addition, a theoretical analysis method for predicting the flexural behavior of a TRM beam was established based on the experimentally determined bond behaviors of the textile reinforcement in cementitious materials. The analysis demonstrated that the bending behavior of the TRM beam was reasonably predicted. The results of this study can serve as basic data for the structural application of textile-reinforced cementitious composites

ONC201 and an MEK Inhibitor Trametinib Synergistically Inhibit the Growth of Triple-Negative Breast Cancer Cells

Triple-negative breast cancer (TNBC) is a heterogeneous group of estrogen, progesterone, and HER2-negative breast cancers with poor clinical outcomes. The imipridone ONC201 is a G-protein-coupled dopamine receptor D2 modulator and an allosteric agonist of the mitochondrial protease caseinolytic protease P(ClpP), which induces apoptosis. Here, we aimed to develop a novel ONC201-based combination therapy targeting TNBC. We performed a reverse-phase protein array analysis of ONC201-treated/-untreated and -sensitive/-resistant cell lines to identify potential predictive biomarkers. A principal component analysis using measured protein expression levels, the apoptosis score (AS), and heatmaps of all the measured protein and AS-related protein expression levels did not show a clear correlation between the expression levels of a specific protein and ONC201 efficacy. Three-dimensional RNA interference kinome-wide library screening revealed the MAPK and PI3K/Akt pathways as potential synergistic therapeutic partners. The combination with the MEK inhibitor trametinib successfully inhibited the growth of both ONC201-sensitive/-resistant TNBC cell lines. The baseline ClpP level correlated with the efficacy of single-agent ONC201. Single and combination therapy increased caspase 3/7 activity. The predictive biomarkers and a detailed mechanism of synergy beyond an induction of caspase activation should be tested for translation into future studies

Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance

Intratumor heterogeneity in breast cancer can limit the clinical success of antibody-drug conjugates (ADCs). In this study, the authors develop dual payload Her2-ADCs that show potent anti-tumor activity against heterogeneous breast tumors in vivo

PI3K and MAPK Pathways as Targets for Combination with the Pan-HER Irreversible Inhibitor Neratinib in HER2-Positive Breast Cancer and TNBC by Kinome RNAi Screening

Human epidermal growth factor receptor (EGFR) 2 (HER2) is overexpressed/amplified in about 25% of all breast cancers, and EGFR is overexpressed in up to 76% and amplified in up to 24% of triple-negative breast cancers (TNBC). Here, we aimed to identify inhibitors that may enhance the anti-tumor activity of neratinib for HER2+ breast cancer and TNBC. By conducting a non-biased high-throughput RNA interference screening, we identified PI3K/AKT/mTOR and MAPK as two potential inhibitory synergistic canonical pathways. We confirmed that everolimus (mTOR inhibitor) and trametinib (MEK inhibitor) enhances combinatorial anti-proliferative effects with neratinib under anchorage-independent growth conditions (p &lt; 0.05). Compared to single agent neratinib, the combination therapies significantly enhanced tumor growth inhibition in both SUM190 HER2+ breast cancer (neratinib plus everolimus, 77%; neratinib plus trametinib, 77%; p &lt; 0.0001) and SUM149 TNBC (neratinib plus everolimus, 71%; neratinib plus trametinib, 81%; p &lt; 0.0001) xenograft models. Compared to single-agent neratinib, everolimus, or trametinib, both everolimus plus neratinib and trametinib plus neratinib significantly suppressed proliferation marker Ki67 and enhanced antitumor efficacy by activating the apoptosis pathway shown by increased Bim and cleaved-PARP expression. Taken together, our data justify new neratinib-based combinations for both HER2+ breast cancer and TNBC

Negative Cellular Effects of Urban Particulate Matter on Human Keratinocytes Are Mediated by P38 MAPK and NF-κB-dependent Expression of TRPV 1

Urban particulate matter (UPM) exerts negative effects on various human organs. Transient receptor potential vanilloid 1 (TRPV1) is a polymodal sensory transducer that can be activated by multiple noxious stimuli. This study aimed to explore the effects of the UPM 1648a on the expression of TRPV1, and its regulatory mechanisms in HaCaT cells. UPM enhanced TRPV 1 promoter-luciferase reporter activity. UPM also increased expression of the TRPV 1 gene as evidenced by increased mRNA and protein levels of TRPV 1. In addition, elucidation of the underlying mechanism behind the UPM-mediated effects on TRPV 1 expression revealed that UPM can upregulate expression of the TRPV1 gene by activating activator protein-1 (AP-1) and nuclear factor kappa B (NF-&kappa;B). The UPM treatment also altered Ca2+ influx and cell proliferation, as well as production of interleukin-8 (IL-8), tumor necrosis factor-&alpha; (TNF-&alpha;), and interleukin-1&beta; (IL-1&beta;). In addition, these UPM-induced effects were attenuated by SB203580 and ammonium pyrrolidinedithiocarbamate (PDTC). However, SP600125 and PD98059 did not alter the UPM-induced effects. Taken together, these findings indicate that UPM upregulates expression of the TRPV 1 gene, which is mediated by the p38 mitogen-activated protein kinase (MAPK) and NF-&kappa;B signaling pathways and suggest that UPM is a potential irritant that can induce skin processes such as aging and inflammatory responses