INK4 Tumor Suppressor Proteins Mediate Resistance to CDK4/6 Kinase Inhibitors

Proteïnes supressores de tumors; Inhibidors de la quinasaProteínas supresoras de tumores; Inhibidores de la quinasaTumor suppressor proteins; Kinase inhibitorsCyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identified several genetic alterations (e.g., FAT1, PTEN, or ARID1A loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18INK4C). In vitro binding and kinase assays together with physical modeling reveal that the p18INK4C–cyclin D–CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects in vivo, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance. Significance: CDK4/6 kinase activation represents a common mechanism by which oncogenic signaling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6–INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases.The Chandarlapaty lab has received generous funding support for this research from the Cancer Couch Foundation, the Shen Family Fund, the Smith Fund for Cancer Research, the Breast Cancer Research Foundation, an NIH Cancer Center Support Grant (P30 CA008748), and NIH R01234361. Q. Li has received support from Translational Research Oncology Training Fellowship (MSKCC) made possible by the generous contribution of First Eagle Investment Management. V. Serra reports grants from the Susan G. Komen Foundation (CCR15330331) and Instituto de Salud Carlos III (CPII19/00033) during the conduct of the study and grants from Novartis, Genentech, and AstraZeneca outside the submitted work. The Chodera laboratory receives or has received funding from multiple sources, including the NIH and an NIH Cancer Center Support Grant (P30 CA008748), the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, Vir Biotechnology, Bayer, XtalPi, Foresite Laboratories, the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award, and the Sloan Kettering Institute. J. Guo acknowledges support from NIH grant R01 GM121505. J.D. Chodera acknowledges support from NIH grant P30 CA008748, NIH grant R01 GM121505, and NIH grant R01 GM132386. A complete funding history for the Chodera lab can be found at http://choderalab.org/funding, including complete funding information and grant numbers. The authors thank Dr. Marie Will and Madeline Dorso for helpful comments on the manuscript and Dr. Zhan Yao for helpful advice on the kinase assays

A RG-II type polysaccharide purified from Aconitum coreanum and their anti-inflammatory activity

Korean mondshood root polysaccharides (KMPS) isolated from the root of Aconitum coreanum (Lévl.) Rapaics have shown anti-inflammatory activity, which is strongly influenced by their chemical structures and chain conformations. However, the mechanisms of the anti-inflammatory effect by these polysaccharides have yet to be elucidated. A RG-II polysaccharide (KMPS-2E, Mw 84.8 kDa) was isolated from KMPS and its chemical structure was characterized by FT-IR and NMR spectroscopy, gas chromatography–mass spectrometry and high-performance liquid chromatography. The backbone of KMPS-2E consisted of units of [→6) -β-D-Galp (1→3)-β-L-Rhap-(1→4)-β-D-GalpA-(1→3)-β-D-Galp-(1→] with the side chain →5)-β-D-Arap (1→3, 5)-β-D-Arap (1→ attached to the backbone through O-4 of (1→3,4)-L-Rhap. T-β-D-Galp is attached to the backbone through O-6 of (1→3,6)-β-D-Galp residues and T-β-D-Ara is connected to the end group of each chain. The anti-inflammatory effects of KMPS-2E and the underlying mechanisms using lipopolysaccharide (LPS) - stimulated RAW 264.7 macrophages and carrageenan-induced hind paw edema were investigated. KMPS-2E (50, 100 and 200 µg/mL) inhibits iNOS, TLR4, phospho-NF-κB–p65 expression, phosphor-IKK, phosphor-IκB-α expression as well as the degradation of IκB-α and the gene expression of inflammatory cytokines (TNF-α, IL-1β, iNOS and IL-6) mediated by the NF-κB signal pathways in macrophages. KMPS-2E also inhibited LPS-induced activation of NF-κB as assayed by electrophorectic mobility shift assay (EMSA) in a dose-dependent manner and it reduced NF-κB DNA binding affinity by 62.1% at 200µg/mL. In rats, KMPS-2E (200 mg/kg) can significantly inhibit carrageenan-induced paw edema as ibuprofen (200 mg/kg) within 3 h after a single oral dose. The results indicate that KMPS-2E is a promising herb-derived drug against acute inflammation

Influence of Non-Constant Hygrothermal Parameters on Heat and Moisture Transfer in Rammed Earth Walls

As environment-friendly building materials, earth materials are attracting significant attention because of their favorable hygrothermal properties. In this study, the earth materials in northwest Sichuan were tested and curves of thermal conductivity and water vapor permeability with relative humidity were obtained. The function curves and constants of the two coefficients were substituted into the verified nonstationary model of heat and moisture transfer in rammed earth walls and indoor air for calculation. The difference in the calculation results when the hygrothermal parameters are functions and constants were analyzed, and the influence of the non-constant hygrothermal parameters on the heat and moisture transfer in rammed earth walls, was obtained. The test results show that thermal conductivity is linearly related to moisture content, and water vapor permeability has a small variation in the relative humidity range of 0–60% and increases exponentially above 60%. The calculation results indicate that the non-constant hygrothermal parameters have little influence on the internal surface temperature of the rammed earth walls and Mianyang City’s indoor air temperature and humidity during the summer and winter. The heat transfer on the internal surface will be underestimated by using a non-constant for the hygrothermal parameter when the moisture content of the wall is low, and vice versa. In hot-humid areas or seasons with large differences in temperature and humidity between indoors and outdoors, non-constant hygrothermal parameters have a more obvious effect on heat transfer on the internal surface of the wall. The results of this study demonstrate the necessity of parameter testing

Influence of Non-Constant Hygrothermal Parameters on Heat and Moisture Transfer in Rammed Earth Walls

As environment-friendly building materials, earth materials are attracting significant attention because of their favorable hygrothermal properties. In this study, the earth materials in northwest Sichuan were tested and curves of thermal conductivity and water vapor permeability with relative humidity were obtained. The function curves and constants of the two coefficients were substituted into the verified nonstationary model of heat and moisture transfer in rammed earth walls and indoor air for calculation. The difference in the calculation results when the hygrothermal parameters are functions and constants were analyzed, and the influence of the non-constant hygrothermal parameters on the heat and moisture transfer in rammed earth walls, was obtained. The test results show that thermal conductivity is linearly related to moisture content, and water vapor permeability has a small variation in the relative humidity range of 0–60% and increases exponentially above 60%. The calculation results indicate that the non-constant hygrothermal parameters have little influence on the internal surface temperature of the rammed earth walls and Mianyang City’s indoor air temperature and humidity during the summer and winter. The heat transfer on the internal surface will be underestimated by using a non-constant for the hygrothermal parameter when the moisture content of the wall is low, and vice versa. In hot-humid areas or seasons with large differences in temperature and humidity between indoors and outdoors, non-constant hygrothermal parameters have a more obvious effect on heat transfer on the internal surface of the wall. The results of this study demonstrate the necessity of parameter testing

Structure-aware deep model for MHC-II peptide binding affinity prediction

Abstract The prediction of major histocompatibility complex (MHC)-peptide binding affinity is an important branch in immune bioinformatics, especially helpful in accelerating the design of disease vaccines and immunity therapy. Although deep learning-based solutions have yielded promising results on MHC-II molecules in recent years, these methods ignored structure knowledge from each peptide when employing the deep neural network models. Each peptide sequence has its specific combination order, so it is worth considering adding the structural information of the peptide sequence to the deep model training. In this work, we use positional encoding to represent the structural information of peptide sequences and validly combine the positional encoding with existing models by different strategies. Experiments on three datasets show that the introduction of position-coding information can further improve the performance built upon the existing model. The idea of introducing positional encoding to this field can provide important reference significance for the optimization of the deep network structure in the future

A rare, large, well-differentiated liposarcoma in the hypopharynx of a female: A case report

A liposarcoma is a common soft tissue sarcoma found in adults; however, liposarcomas in the hypopharynx are extremely rare. Here, we report a large liposarcoma originating from the piriform sinus in a female; this is the fifth reported liposarcoma of the hypopharynx in a female, and the first (to our knowledge) liposarcoma in a female that was larger than 20 cm in its largest diameter. The mass was removed using suspension laryngoscopy and diagnosed as a well-differentiated liposarcoma. No recurrence was evident 14 months after surgery. Keywords: Liposarcoma, Hypopharynx, Piriform sinus, Endoscop

Point-wise spatial network for identifying carcinoma at the upper digestive and respiratory tract

Abstract Problem Artificial intelligence has been widely investigated for diagnosis and treatment strategy design, with some models proposed for detecting oral pharyngeal, nasopharyngeal, or laryngeal carcinoma. However, no comprehensive model has been established for these regions. Aim Our hypothesis was that a common pattern in the cancerous appearance of these regions could be recognized and integrated into a single model, thus improving the efficacy of deep learning models. Methods We utilized a point-wise spatial attention network model to perform semantic segmentation in these regions. Results Our study demonstrated an excellent outcome, with an average mIoU of 86.3%, and an average pixel accuracy of 96.3%. Conclusion The research confirmed that the mucosa of oral pharyngeal, nasopharyngeal, and laryngeal regions may share a common appearance, including the appearance of tumors, which can be recognized by a single artificial intelligence model. Therefore, a deep learning model could be constructed to effectively recognize these tumors