Prolyl hydroxylase domain 2 (PHD2) is the primary oxygen sensing enzyme involved in hydroxylation of hypoxia-inducible factor (HIF). Under normoxic conditions, PHD2 hydroxylates specific proline residues in HIF-1α and HIF-2α, promoting their ubiquitination and subsequent proteasomal degradation. Although PHD2 activity decreases in hypoxia, notable residual activity persists, but its function in these conditions remains unclear. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) targets proteins with phosphorylated serine/threonine-proline (pSer/Thr-Pro) motifs. As PHD2 contains several pSer/Thr-Pro motifs, it may be a potential substrate of Pin1. In the present study, we found Pin1 and PHD2 interactions in human breast cancer MDA-MB-231 cells. The breast cancer tissue array revealed higher levels of PHD2 and Pin1 in tumors compared to adjacent normal tissues. Through liquid chromatography-tandem mass spectrometry spectrometry, three phosphorylation sites (S125, T168, and S174) on PHD2 were identified, with serine 125 as the main site for Pin1 binding. As a new Pin1 binding partner, oncogenic PHD2 could be a potential therapeutic target for breast cancer treatment.

Prolyl hydroxylase domain 2 (PHD2) is the primary oxygen sensing enzyme involved in hydroxylation of hypoxia-inducible factor (HIF). Under normoxic conditions, PHD2 hydroxylates specific proline residues in HIF-1α and HIF-2α, promoting their ubiquitination and subsequent proteasomal degradation. Although PHD2 activity decreases in hypoxia, notable residual activity persists, but its function in these conditions remains unclear. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) targets proteins with phosphorylated serine/threonine-proline (pSer/Thr-Pro) motifs. As PHD2 contains several pSer/Thr-Pro motifs, it may be a potential substrate of Pin1. In the present study, we found Pin1 and PHD2 interactions in human breast cancer MDA-MB-231 cells. The breast cancer tissue array revealed higher levels of PHD2 and Pin1 in tumors compared to adjacent normal tissues. Through liquid chromatography-tandem mass spectrometry spectrometry, three phosphorylation sites (S125, T168, and S174) on PHD2 were identified, with serine 125 as the main site for Pin1 binding. As a new Pin1 binding partner, oncogenic PHD2 could be a potential therapeutic target for breast cancer treatment.

Prolyl hydroxylase domain 2 (PHD2) is the primary oxygen sensing enzyme involved in hydroxylation of hypoxia-inducible factor (HIF). Under normoxic conditions, PHD2 hydroxylates specific proline residues in HIF-1α and HIF-2α, promoting their ubiquitination and subsequent proteasomal degradation. Although PHD2 activity decreases in hypoxia, notable residual activity persists, but its function in these conditions remains unclear. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) targets proteins with phosphorylated serine/threonine-proline (pSer/Thr-Pro) motifs. As PHD2 contains several pSer/Thr-Pro motifs, it may be a potential substrate of Pin1. In the present study, we found Pin1 and PHD2 interactions in human breast cancer MDA-MB-231 cells. The breast cancer tissue array revealed higher levels of PHD2 and Pin1 in tumors compared to adjacent normal tissues. Through liquid chromatography-tandem mass spectrometry spectrometry, three phosphorylation sites (S125, T168, and S174) on PHD2 were identified, with serine 125 as the main site for Pin1 binding. As a new Pin1 binding partner, oncogenic PHD2 could be a potential therapeutic target for breast cancer treatment.

Purpose: GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). Materials and Methods: Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. Results: RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0). Conclusion GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

Background: and Purpose Accurate classification of ischemic stroke subtype is important for effective secondary prevention of stroke. We used diffusion-weighted image (DWI) and atrial fibrillation (AF) data to train a deep learning algorithm to classify stroke subtype. Methods: Model development was done in 2,988 patients with ischemic stroke from three centers by using U-net for infarct segmentation and EfficientNetV2 for subtype classification. Experienced neurologists (n=5) determined subtypes for external test datasets, while establishing a consensus for clinical trial datasets. Automatically segmented infarcts were fed into the model (DWI-only algorithm). Subsequently, another model was trained, with AF included as a categorical variable (DWI+AF algorithm). These models were tested: (1) internally against the opinion of the labeling experts, (2) against fresh external DWI data, and (3) against clinical trial dataset. Results: In the training-and-validation datasets, the mean (±standard deviation) age was 68.0±12.5 (61.1% male). In internal testing, compared with the experts, the DWI-only and the DWI+AF algorithms respectively achieved moderate (65.3%) and near-strong (79.1%) agreement. In external testing, both algorithms again showed good agreements (59.3%–60.7% and 73.7%–74.0%, respectively). In the clinical trial dataset, compared with the expert consensus, percentage agreements and Cohen’s kappa were respectively 58.1% and 0.34 for the DWI-only vs. 72.9% and 0.57 for the DWI+AF algorithms. The corresponding values between experts were comparable (76.0% and 0.61) to the DWI+AF algorithm. Conclusion Our model trained on a large dataset of DWI (both with or without AF information) was able to classify ischemic stroke subtypes comparable to a consensus of stroke experts.

Celosia cristata , belongs to Amaranthaceae family, has been utilized in many traditional medicinal systems to treat hemostasis, eye and mouth inflammation, and gynecological diseases. The various physiological investigations on C. cristata have documented its antibacterial, antioxidant, antifungal, and antihepatotoxic properties. During the research program aimed at isolating bioactive constituents from the medicinal plants, the aerial parts of C. cristata were extracted using 80% EtOH, then sequentially partitioned with n-hexane, CH 2 Cl 2 , and EtOAc. The CH 2 Cl 2 -soluble fraction demonstrated inhibitory effects on nitric oxide production in LPS-induced RAW 264.7 cells, with an IC50 value of 24.7 μg/mL. The CH 2 Cl 2 -soluble fraction was subjected to a series of chromatographic techniques, such as Sephadex LH-20 column chromatography, MPLC, and preparative HPLC. As a result, seven known norisoprenoids (1–7) were isolated, and the structures were determined through the analysis of spectroscopic data, especially 1D NMR, 2D NMR, and HR-ESI-MS. Dehydrovomifoliol (2), 3-hydroxy-4,7-megastigmadien-9-one (6), and 9-hydroxy-4,7-megastigmadien-3-one (7) exhibited inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 macrophages with IC50 values of 17.7–24.4 μM.

Hericium erinaceus, also known as lion’s mane mushroom, is an edible and medicinal mushroom that belongs to the family Hericiaceae. We previously reported hericene A as an anti-diabetic constituent of H. erinaceus and the effect of cultivation substrates on its content was investigated. As the continuation, the contents of five major compounds such as hericenes A-D, which exerted α-glucosidase inhibitory activity, together with ergosterol were investigated depending on cultivation stages. H. erinaceus was cultured for 25 days (5 stages) to induce fruiting bodies, and the contents of the compounds at each stage were quantified. All the five compounds were detected in fruiting body by HPLC analysis. Among the hericene derivatives in the mushroom, the content of hericene A was the highest, followed by hericene C and the content of hericenes B and D was relative low. All four hericene derivatives present in the highest content at stage 4 whereas the content of ergosterol was highest at stage 5. The highest α-glucosidase inhibitory activity of H. erinaceus was measured at stage 4, which correlates with the contents of hericene derivatives. Conclusively, H. erinaceus with better efficacy and high content of active constituents can be secured by the optimization of cultivation conditions.