Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR−/lo). Xenograft modeling demonstrates that AR+ CRPC is enzalutamide-sensitive but AR−/lo CRPC is resistant. Genome editing-derived AR+ and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR+/hi and AR−/lo CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR−/lo PCa cells/clones.

Rationale: Mesenchymal stromal cells (MSCs) are emerging as a novel therapeutic strategy for the acute ischemic stroke (AIS). However, the poor targeted migration and low engraftment in ischemic lesions restrict their treatment efficacy. The ischemic brain lesions express a specific chemokine profile, while cultured MSCs lack the set of corresponding receptors. Thus, we hypothesize that overexpression of certain chemokine receptor might help in MSCs homing and improve therapeutic efficacy. Methods: Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we identified that CCL2 is one of the most highly expressed chemokines in the ipsilateral hemisphere. Then, we genetically transduced the corresponding receptor, CCR2 to the MSCs and quantified the cell retention of MSCCCR2 compared to the MSCdtomato control. Results: MSCCCR2 exhibited significantly enhanced migration to the ischemic lesions and improved the neurological outcomes. Brain edema and blood-brain barrier (BBB) leakage levels were also found to be much lower in the MSCCCR2-treated rats than the MSCdtomato group. Moreover, this BBB protection led to reduced inflammation infiltration and reactive oxygen species (ROS) generation. Similar results were also confirmed using the in vitro BBB model. Furthermore, genome-wide RNA sequencing (RNA-seq) analysis revealed that peroxiredoxin4 (PRDX4) was highly expressed in MSCs, which mainly contributed to their antioxidant impacts on MCAO rats and oxygen-glucose deprivation (OGD)-treated endothelium. Conclusion: Taken together, this study suggests that overexpression of CCR2 on MSCs enhances their targeted migration to the ischemic hemisphere and improves the therapeutic outcomes, which is attributed to the PRDX4-mediated BBB preservation.

An increased PTS was identified to be an independent anatomic risk factor of increased (≥6 mm) anterior subluxation of the lateral compartment in acute noncontact ACL injuries. For patients with obviously increased anterior tibial subluxation of the lateral compartment after ACL injuries, the PTS should be measured.

Abnormal cancer antioxidant capacity is considered as a potential mechanism of tumor malignancy. Modulation of oxidative stress status is emerging as an anti-cancer treatment. Our previous studies have found that Nestin-knockdown cells were more sensitive to oxidative stress in non-small cell lung cancer (NSCLC). However, the molecular mechanism by which Nestin protects cells from oxidative damage remains unclear. Here, we identify a feedback loop between Nestin and Nrf2 maintaining the redox homeostasis. Mechanistically, the ESGE motif of Nestin interacts with the Kelch domain of Keap1 and competes with Nrf2 for Keap1 binding, leading to Nrf2 escaping from Keap1-mediated degradation, subsequently promoting antioxidant enzyme generation. Interestingly, we also map that the antioxidant response elements (AREs) in the Nestin promoter are responsible for its induction via Nrf2. Taken together, our results indicate that the Nestin–Keap1–Nrf2 axis regulates cellular redox homeostasis and confers oxidative stress resistance in NSCLC.

Radiation-induced oral mucositis affects patient quality of life and reduces tolerance to cancer therapy. Unfortunately, traditional treatments are insufficient for the treatment of mucositis and might elicit severe side effects. Due to their immunomodulatory and anti-inflammatory properties, the transplantation of mesenchymal stem cells (MSCs) is a potential therapeutic strategy for mucositis. However, systemically infused MSCs rarely reach inflamed sites, impacting their clinical efficacy. Previous studies have demonstrated that chemokine axes play an important role in MSC targeting. By systematically evaluating the expression patterns of chemokines in radiation/chemical-induced oral mucositis, we found that CXCL2 was highly expressed, whereas cultured MSCs negligibly express the CXCL2 receptor CXCR2. Thus, we explored the potential therapeutic benefits of the transplantation of CXCR2-overexpressing MSCs (MSCsCXCR2) for mucositis treatment. Indeed, MSCsCXCR2 exhibited enhanced targeting ability to the inflamed mucosa in radiation/chemical-induced oral mucositis mouse models. Furthermore, we found that MSCCXCR2 transplantation accelerated ulcer healing by suppressing the production of pro-inflammatory chemokines and radiogenic reactive oxygen species (ROS). Altogether, these findings indicate that CXCR2 overexpression in MSCs accelerates ulcer healing, providing new insights into cell-based therapy for radiation/chemical-induced oral mucositis.

Emerging evidence has revealed that Nestin not only serves as a biomarker for multipotent stem cells, but also regulates cell proliferation and invasion in various tumors. However, the mechanistic contributions of Nestin to cancer pathogenesis are still unknown. In the present study, previously thought to reside exclusively in the cytoplasm, Nestin can also be found in the nucleus and participate in protecting tumor cells against cellular senescence. Specifically, we reveal that Nestin has a nuclear localization signal (aa318–aa347) at the downstream of rod domain. We then find nuclear Nestin could interact with lamin A/C. Mechanistic investigations demonstrate that Nestin depletion results in the activation of cyclin-dependent kinase 5 (Cdk5), which causes the phosphorylation of lamin A/C (mainly at S392 site) and its subsequent translocation to the cytoplasm for degradation. The findings establish a role for nuclear Nestin in tumor senescence, which involves its nucleus-localized form and interaction with lamin A/C.

Whether elevated beat-to-beat blood pressure variability (BPV) has an influence on vascular elasticity is confounded and poorly understood. This study hypothesized that the increased BPV could have an adverse effect on the vascular elasticity, as estimated by total arterial compliance (TAC), independent of blood pressure (BP) values. Beat-to-beat BP and TAC were measured in 81 hypertensive patients (experimental population) and in 80 normal adults (control population). Beat-to-beat BPV was assessed by standard deviation (SD), average real variability (ARV), residual standard deviation (RSD) and variation independent of mean (VIM). In experimental population, systolic BPV (SBPV) showed a significant correlation with TAC (SD, r = −0.326, p < 0.001; ARV, r = −0.277, p = 0.003; RSD, r = −0.382, p < 0.001; VIM, r = −0.274, p = 0.003); similarly, SD, RSD and VIM of diastolic BP (DBP) also showed explicit correlation with TAC (r = −0.255, p = 0.006; r = −0.289, p = 0.002; r = −0.219, p = 0.019; respectively). However, in the control population, neither SBPV nor diastolic BPV (DBPV) showed a significant correlation with TAC. Furthermore, in the experimental population, VIM of systolic BP (SBP) was also a determinant of TAC (β = −0.100, p = 0.040) independent of average SBP, DBP, age and body mass index. In conclusion, these data imply that beat-to-beat BPV, especially SBPV, shows an independent correlation with vascular elasticity in hypertensive population.

The purpose of this study was to investigate the incidence and clinical characteristics of the “diagonal” lesion. A total of 273 consecutive patients with combined posterolateral corner (PLC) and posterior cruciate ligament (PCL) injuries were retrospectively analyzed. All preoperative knee joint evaluations were reviewed including the computed tomography, the anteroposterior (AP) view, the lateral view, the full-length long-standing AP view, and the physical examination results with the patient under anesthesia. Twenty-six patients (9.5%) were verified as having the “diagonal” lesions. The anteromedial impingement fractures could be categorized into small (small fracture group, n = 7) and large (large fracture group, n = 19). The PCL injuries were classified into grade 2 (n = 22) and grade 3 (n = 4). The PLC injuries could be classified into type A (n = 3), type B (n = 8), and type C (n = 15) according to the Fanelli's classification system. Notably, there were 20 chronic cases. Among them, 14 (70%) had varus deformities. The proportion of patients with varus deformity in the large fracture group was significantly higher than that of the small fracture group (p = 0.026). In this study, the incidence of the “diagonal” lesions was 9.5%. Patients who had larger fracture size tended to develop subsequent varus deformity of the lower extremity. It was important for us to recognize the PCL/PLC injuries and to fully reduce the large bony fracture during the initial treatment of the “diagonal” lesions to prevent the residual instability and varus deformity.