No abstract

No abstract

Colorectal cancer is one of the leading causes of cancer death worldwide. According to global genomic status, colorectal cancer can be classified into two main types: microsatellite-stable and microsatellite-instable tumors. Moreover, the two subtypes also exhibit different responses to chemotherapeutic agents through distinctive molecular mechanisms. Recently, mitochondrial DNA depletion has been shown to induce apoptotic resistance in microsatellite-instable colorectal cancer. However, the effects of altered mitochondrial DNA copy number on the progression of microsatellite-stable colorectal cancer, which accounts for the majority of colorectal cancer, remain unclear. In this study, we systematically investigated the functional role of altered mitochondrial DNA copy number in the survival and metastasis of microsatellite-stable colorectal cancer cells. Moreover, the underlying molecular mechanisms were also explored. Our results demonstrated that increased mitochondrial DNA copy number by forced mitochondrial transcription factor A expression significantly facilitated cell proliferation and inhibited apoptosis of microsatellite-stable colorectal cancer cells both in vitro and in vivo. Moreover, we demonstrated that increased mitochondrial DNA copy number enhanced the metastasis of microsatellite-stable colorectal cancer cells. Mechanistically, the survival advantage conferred by increased mitochondrial DNA copy number was caused in large part by elevated mitochondrial oxidative phosphorylation. Furthermore, treatment with oligomycin significantly suppressed the survival and metastasis of microsatellite-stable colorectal cancer cells with increased mitochondrial DNA copy number. Our study provides evidence supporting a possible tumor-promoting role for mitochondrial DNA and uncovers the underlying mechanism, which suggests a potential novel therapeutic target for microsatellite-stable colorectal cancer.

Aberrant expression of MicroRNAs (miRNAs) has been implicated in several types of cancer. As a direct target gene of p53, miR-34a has been suggested to mediate the tumor suppressor function of p53. Ether à go-go 1 (Eag1) channel is overexpressed in a variety of cancers and plays important roles in cancer progression. However, the link between miR-34a and Eag1 in cancer is unclear. In this study, we used human osteosarcoma as the model to demonstrate that miR-34a was significantly downregulated in osteosarcoma tissues and cell lines compared with normal brain tissues and osteoblastic cell line. Next we evaluated the role of miR-34a in the regulation of osteosarcoma cell proliferation by CCK-8 and colony formation assays. The results showed that overexpression of miR-34a inhibited the proliferation of MG-63 and Saos-2 cells. Furthermore, xenograft nude mice model showed that miR-34a inhibited osteosarcoma growth in vivo. Mechanistically, we found that overexpression of miR-34a led to decreased Eag1 expression in osteosarcoma cells while inhibition of miR-34a increased Eag1 expression. Taken together, our results suggest that miR-34a could inhibit osteosarcoma growth via the down regulation of Eag1 expression.

Background— Phase-contrast x-ray imaging using an x-ray interferometer has great potential to reveal the structures inside soft tissues, because the sensitivity of this method to hydrogen, carbon, nitrogen, and oxygen is ≈1000 times higher than that of the absorption-contrast x-ray method. Imaging of vessels is very important to understand the vascular distribution of organs and tumors, so the possibility of selective angiography based on phase contrast is examined with a physiological material composed of low-atomic-number elements. Methods and Results— Phase-contrast x-ray imaging was performed with a synchrotron x-ray source. Differences in refractive index, dδ, of physiological saline, lactated Ringer’s solution, 5% glucose, artificial blood such as pyridoxylated hemoglobin–polyoxyethylene conjugate, and perfluorotributylamine were measured. Because the dδ of physiological saline has highest contrast, it was used for the phase-contrast x-ray imaging of vessel, and this was compared with absorption-contrast x-ray images. Vessels >0.03 mm in diameter of excised liver from rats and a rabbit were revealed clearly in phase-contrast x-ray imaging, whereas the vessel could not be revealed at all by the absorption-contrast x-ray image. Absorption-contrast x-ray images with iodine microspheres depicted only portal veins >0.1 mm in diameter with nearly the same x-ray dose as the present phase-contrast x-ray imaging. Conclusions— Phase-contrast x-ray imaging explored clear depiction of the vessels using physiological saline with small doses of x-rays.

Purpose: Immunotherapy offers a second-line option for patients with metastatic urothelial carcinoma (mUC) who failed standard therapy, but the biomarkers for predicting response remain to be explored. This study aims to evaluate the safety, efficacy, and correlative biomarker of toripalimab in patients with previously treated mUC. Patients and Methods: Patients with mUC received toripalimab 3 mg/kg Q2W. Clinical response was assessed every 8 weeks by an independent review committee per RECIST v1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated. Results: Among the intention-to-treat population (n = 151), 85% of the patients experienced treatment-related adverse event (TRAE) and 20% experienced grade 3 and above TRAE. The objective response rate (ORR) was 26% with a disease control rate (DCR) of 45%. The median duration of response, progression-free survival (PFS), and overall survival (OS) were 19.7 months [95% confidence interval (CI): 13.9–not estimable], 2.3 months (95% CI, 1.8–3.6), and 14.4 months (95% CI, 9.3–23.1), respectively. Both PD-L1+ and TMB-high (10 mutations/Mb as the cutoff) patients had better ORR than PD-L1− patients (42% vs. 17%, P = 0.002) and TMB-low patients (48% vs. 22%, P = 0.014), respectively. The TMB-high group also showed better PFS (12.9 vs. 1.8 months, P < 0.001) and OS (not reached versus 10.0 months, P = 0.018) than the TMB-low group. Conclusions: Toripalimab has demonstrated encouraging clinical activity in the second-line treatment of mUC with a manageable safety profile. PD-L1 expression and TMB were two independent biomarkers in the study.

No abstract

ObjectiveThis study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer.DesignPatient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment.ResultsWe found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour progression. These effects were associated with stable cell-cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single-cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors.ConclusionsTogether, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy.