Mitochondrial C1QBP is essential for T cell antitumor function by maintaining mitochondrial plasticity and metabolic fitness.

The metabolic stress present in the tumor microenvironment of many cancers can attenuate T cell antitumor activity, which is intrinsically controlled by the mitochondrial plasticity, dynamics, metabolism, and biogenesis within these T cells. Previous studies have reported that the complement C1q binding protein (C1QBP), a mitochondrial protein, is responsible for maintenance of mitochondrial fitness in tumor cells; however, its role in T cell mitochondrial function, particularly in the context of an antitumor response, remains unclear. Here, we show that C1QBP is indispensable for T cell antitumor immunity by maintaining mitochondrial integrity and homeostasis. This effect holds even when only one allele of C1qbp is functional. Further analysis of C1QBP in the context of chimeric antigen receptor (CAR) T cell therapy against the murine B16 melanoma model confirmed the cell-intrinsic role of C1QBP in regulating the antitumor functions of CAR T cells. Mechanistically, we found that C1qbp knocking down impacted mitochondrial biogenesis via the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha signaling pathway, as well as mitochondrial morphology via the phosphorylation of mitochondrial dynamics protein dynamin-related protein 1. In summary, our study provides a novel mitochondrial target to potentiate the plasticity and metabolic fitness of mitochondria within T cells, thus improving the immunotherapeutic potential of these T cells against tumors.

C1QBP regulates mitochondrial plasticity to impact tumor progression and antitumor immune response.

Mitochondrial plasticity including mitochondrial dynamics, metabolic flexibility, and mitochondrial quality control, impact tumor cells' progression and determine immune cells' fate. Complement C1q binding protein (C1QBP) plays an indispensable role through regulating mitochondrial morphology, metabolism, and autophagy. C1QBP promotes mitochondrial plasticity to impact tumor metastasis and their therapeutic response. At the same time, C1QBP is involved in regulating immune cells' maturation, differentiation, and effector function through the enhancement of mitochondrial function. In this regard, manipulation of C1QBP has been shown to adjust the competitive balance between tumor cells and immune cells. In the course of evolution, mitochondrial plasticity has endowed numerous advantages against the relentless microenvironment of tumors. In this current review, we summarize the current knowledge of the mechanism of C1QBP regulation of cancer and immunity. We explain this process in vision of potentially new anticancer therapies.

Second Language Proficiency Modulates the Dependency of Bilingual Language Control on Domain-General Cognitive Control.

The relationship between bilingual language control and domain-general cognitive control has been a hot topic in the research field of bilingualism. Previous studies mostly examined the correlation between performances of bilinguals in language control tasks and that in domain-general cognitive control tasks and came to the conclusions that they overlap, partially overlap, or are qualitatively different. These contradictory conclusions are possibly due to the neglect of the moderating effect of second language (L2) proficiency, that is, the relationship between bilingual language control and domain-general cognitive control might vary with the L2 proficiency of bilinguals. To examine this hypothesis, we recruited 36 unbalanced Chinese-English bilinguals to perform the Simon task (to assess domain-general cognitive control), Oxford Placement Test (to assess L2 proficiency), and picture naming tasks in single-and dual-language contexts (to evoke local and global language control). We find that Simon scores positively predicted switching costs in bilinguals with low L2 proficiency, but not in bilinguals with high L2 proficiency. Furthermore, Simon scores positively predicted mixing costs in bilinguals with high L2 proficiency, but not in bilinguals with low L2 proficiency. These results verify the moderating effect of L2 proficiency on the relationship between bilingual language control and domain-general cognitive control, that is, bilinguals with more proficient L2 rely on domain-general cognitive control less for local language control and more for global language control. This may imply a shift from local to global for the dependency of bilingual language control on domain-general cognitive control during the L2 development of bilinguals.

Complement C1q binding protein regulates T cells' mitochondrial fitness to affect their survival, proliferation, and anti-tumor immune function.

T cells survival, proliferation, and anti-tumor response are closely linked to their mitochondrial health. Complement C1q binding protein (C1QBP) promotes mitochondrial fitness through regulation of mitochondrial metabolism and morphology. However, whether C1QBP regulates T cell survival, proliferation, and anti-tumor immune function remains unclear. Our data demonstrated that C1QBP knockdown induced the accumulation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential to impair T cell mitochondrial fitness. At the same time, C1QBP insufficiency reduced the recruitment of the anti-apoptotic proteins, including Bcl-2 and Bcl-XL, and repressed caspase-3 activation and poly (ADP-ribose) polymerase cleavage, which consequently accelerated the T cell apoptotic process. In contrast, C1QBP knockdown rendered T cells with relatively weaker proliferation due to the inhibition of AKT/mTOR signaling pathway. To investigate the exact role of C1QBP in anti-tumor response, C1QBP+/- and C1QBP+/+ mice were given a subcutaneous injection of murine MC38 cells. We found that C1QBP deficiency attenuated T cell tumor infiltration and aggravated tumor-infiltrating T lymphocytes (TIL) exhaustion. Moreover, we further clarified the potential function of C1QBP in chimeric antigen receptor (CAR) T cell immunotherapy. Our data showed that C1QBP+/- CAR T cells exhibited relatively weaker anti-tumor response than the corresponding C1QBP+/+ CAR T cells. Given that C1QBP knockdown impairs T cells' anti-apoptotic capacity, proliferation as well as anti-tumor immune function, development of the strategy for potentiation of T cells' mitochondrial fitness through C1QBP could potentially optimize the efficacy of the related immunotherapy.

microRNA-133b represses the progression of lung cancer through inhibiting SOX9/ß-catenin signaling pathway.

MicroRNA-133b (miR-133b) has been shown to be down-regulated in lung cancer and functions as a tumor repressor. However, the underlying mechanisms of miR-133b in lung cancer are not clear. SOX9, a member of SOX family, serves as an oncogene in lung cancer by activating b-catenin signaling and was identified to be a direct target of miR-133b in breast cancer. Based on these data, the current study was performed to explore whether SOX9/b-catenin signaling is implicated in miR-133b-meditaed lung cancer repression. MiR-133b expression in lung cancer tissues and cells were detected by RT-PCR. CCK-8, colony formation, flow cytometry, transwell chamber and in vivo assays were carried out to determine cell proliferation, colony formation, apoptosis, cell cycle, invasion, and tumorigenesis. We found that miR-133b expression was decreased in lung cancer tissues and cells. Up-regulation of miR-133b reduced cell proliferation and colony formation, induced cell apoptosis and G0/G1 phase arrest, and decreased cell invasion. Besides, miR-133b up-regulation decreased the expression of b-catenin and SOX9. Cell viability inhibition and apoptosis promotion induced by miR-133b up-regulation were all impaired when SOX9 was up-regulated. Furthermore, miR-133b over-expression repressed the tumorigenesis of lung cancer cells with smaller tumor size and lower Ki-67 expression. Taken together, this study clarifies that miR-133b represses lung cancer progression by inhibiting SOX9/b-catenin signaling.

Overexpression of microRNA-34a Attenuates Proliferation and Induces Apoptosis in Pituitary Adenoma Cells via SOX7.

Pituitary adenomas constitute one of the most common intracranial tumors and are typically benign. However, the role of the tumor suppressor microRNA-34a (miR-34a), which is implicated in other cancers, in pituitary adenoma pathogenesis remains largely unknown. miR-34a expression was compared between GH4C1 cancer cells and normal cells derived from the pituitary gland of Rattus norvegicus, and the effects of miR-34a on GH4C1 cell proliferation and apoptosis were examined. miR-34a target genes were identified and analyzed computationally. The mRNA levels of the miR-34a target genes were measured using qRT-PCR, and the protein levels of the differentially expressed targets were assessed by western blotting. miR-34a expression was significantly lower in GH4C1 cells, whereas miR-34a overexpression significantly inhibited GH4C1 cell proliferation and promoted cell apoptosis though SRY-box 7 (SOX7). Our data facilitate the development of a better understanding of the pathogenesis and treatment of pituitary adenomas by elucidating the crucial role of miR-34a in the development of pituitary adenomas.

Establishment of a spinal cord injury model in adult rats by an electrocircuit-controlled impacting device and its pathological observations.

One of the crucial challenges in medicine is the treatment and rehabilitation of spinal cord injury (SCI). In this study, we established a stable and reproducible acute spinal cord injury model in adult rats. The SCI was inflicted by our self-innovated spinal cord impact device controlled by electrical circuit. The Basso, Beattie, and Bresnahan Locomotor Rating Scale (BBB) score, electrophysiology, histological, and immunohistochemical changes after SCI were observed. The BBB score of the injured rats began to increase from the 3rd day of SCI and reached at the score 7.2 ± 1.3 at the 28th day. The latency of cortical somatosensory evoked potentials (CSEP) was not observed 2 and 6 h after injury, but appeared 24 h after injury which was significantly prolonged. It recovered from day 3 gradually to 27.3 ± 2.7 ms on day 28. H&E staining showed that the structure of gray and white matter was disrupted after the SCI. The result also showed dramatic neuron degenerations, cellular swelling, and the proliferation of glial cells. The immunohistochemical analysis showed that the expression of neuron specific enolase (NSE) and neurofilament 200 (NF200) started lowering at 2 h and dropped to the bottom at 24 h. Their expression rebound from day 3 and yet to the original level at day 28 (P < 0.05). The number of cells expressing glial fibrillary acidic protein (GFAP) hiked from day 3, peaked at day 14, and began recovering from day 28 (P < 0.05). The changes of NSE, NF200, GFAP, and CSEP were significantly associated with the BBB score (P < 0.05). In conclusion, our self-innovated device can reproduce the injury model stably. The changes of NSE, NF, and GFAP after spinal cord injury reflect the characteristics of pathological change, which are closely associated with the functional recovery from the spinal cord injury.

[Guiding value of brain tissue oxygenation plus intracranial pressure monitoring in severe traumatic brain injury patients].

OBJECTIVE: To elucidate the effectiveness of brain tissue oxygenation (PbtO2) plus intracranial pressure (ICP) monitoring and targeted therapy in patients of severe traumatic brain injury (TBI). METHODS: A total of 46 patients with severe TBI (Glasgow coma scale, GCS scale ≤ 8) admitted at Jiangyin People's Hospital from June 2009 to June 2012 were divided randomly into 2 groups and evaluated prospectively.Patients undergoing ICP plus PbtO2 monitoring were compared with controls with ICP monitoring alone.Therapies of both patient groups were attempted to maintain an ICP < 20 mm Hg and a cerebral perfusion pressure (CPP) ≥ 60 mm Hg.Among those with PbtO2 monitoring, oxygenation was maintained at a level of ≥ 20 mm Hg.The scores of Glasgow outcome scale (GOS) were compared between two groups at Month 6 post-injury. RESULTS: The mean daily ICP and CPP levels were similar in each group.The mortality rate was 21.7% in patients with ICP monitoring alone and the favorable outcome rate was 47.8%.However, those receiving combined management had a significantly reduced mortality rate of 8.7% and good outcome rate of 65.2% (P < 0.05). CONCLUSION: The combined use of both ICP and PbtO2 may be associated with reduced mortality and improved outcome in patients with severe TBI.

Examination of the relationship between chromosome abnormality in pituitary adenomas and tumor invasiveness by normal karyotype analysis and interphase fluorescence staining.

To study the potential relationship between chromosome abnormality and tumor invasiveness in pituitary adenomas. To use conventional R-band cytogenetic karyotype analysis and interphase fluorescence in situ hybridization using centromeric probe of chromosomes 8, 9, and 11 to detect chromosome abnormality in 30 cases of pituitary adenoma. All chromosomes except chromosomes 4, 16, and Y show significant variation between invasive and noninvasive pituitary adenomas. Chromosomes 8 and 12 display some type of numeric alteration in all endocrine subtypes of pituitary adenoma. Numeric alterations in chromosomes 9, 11, and 19 are more frequently detected in invasive pituitary adenomas compared with noninvasive tumors. Numeric alterations in chromosomes are common in all endocrine subtype pituitary adenomas. Furthermore, chromosome numbers are significantly different in invasive and noninvasive pituitary adenomas. On the basis of our study and literature review, we conclude that while chromosomes 8 and 12 may play important roles in the occurrence of pituitary adenomas, chromosomes 9, 11, and 19 may be specifically associated with invasiveness.