Guozi Yang

STAT3 induces muscle stem cell differentiation by interaction with myoD

Signal transducers and activators of transcription (STAT) family proteins transduce pivotal biological effects of various cytokines and hormones. STAT3 proteins are known to play a central role in the regulation of growth, differentiation, and survival of many types of cells. However, the function of STAT3 in myogenesis still remains largely unknown. We now provided direct evidence that STAT3 could induce myogenic differentiation and this effect might be mediated by interaction with MyoD--the essential transcription factor during myogenic differentiation. Furthermore, leukemia inhibitory factor (LIF) might be the upstream factor which activated JAK2/STAT3 pathway to stimulate muscle cell differentiation. Taken together, these results provide a molecular basis for further understanding of the muscle regeneration mechanism.

Identification of complement C3f-desArg and its derivative for acute leukemia diagnosis and minimal residual disease assessment.

Therapeutic conditions for acute leukemia (AL) mainly rely on diagnosis and detection of minimal residual disease (MRD). However, no serum biomarker has been available for clinicians to make diagnosis of AL and assessment of MRD. In this study, we performed bead fractionation/MALDI‐TOF‐MS analysis on sera from patients with AL. Support vector machine algorithm was used to obtain diagnostic model that discriminated proteomic spectra of patients with AL from that of controls. Twenty‐six features with p<0.00001 had optimal discriminatory performance, with 97% sensitivity and 100% specificity. Statistical analysis revealed that two peptides with m/z 1778 and 1865 were gradually decreased in their relative intensities with increase of remission degree. Moreover, the peptide with m/z 1865 was also found to be correlated with AL types. With FT‐ICR‐MS detection, both the peptides were identified as fragments of complement C3f. Linear regression analysis showed that the combined use of them could discriminate PML/RARα positive M3 from molecular remission M3. Two fragments of complement C3f were significantly correlated with MRD levels and could be used for clinical practice in MRD assessment.

Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics

It has been generally accepted that both natural and man‐made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low‐dose radiation (LDR) are different from those of high‐dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti‐cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application.

Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: A prospective and single-arm study

The prognosis of leptomeningeal metastasis (LM) from solid tumors is extremely poor, especially for patients with adverse prognostic factors. In this phase II clinical trial, we evaluated the efficacy and safety of intrathecal chemotherapy (IC) combined with concomitant involved‐field radiotherapy (IF‐RT) for treating LM from solid tumors with adverse prognostic factors. Fifty‐nine patients with LM from various solid tumors were enrolled between May 2010 and December 2014. Concurrent therapy consisted of concomitant IC (methotrexate 12.5–15 mg and dexamethasone 5 mg, weekly) and IF‐RT (whole brain and/or spinal canal RT, 40 Gy/20f). For patients with low Karnofsky performance status (KPS) score and radiotherapy intolerance, induction IC (1–3 times) was given before concurrent therapy. Thirty‐eight patients (64.4%) received subsequent treatments. All patients were followed up at least 6 months after LM diagnosis or until death. Primary endpoint evaluated was clinical response rate. Secondary endpoints were overall survival (OS) and safety. The pathological types included lung cancer (n = 42), breast cancer (n = 11) and others (n = 6). Median KPS score was 40 (range 20–70). Fifty‐one patients (86.4%) completed concurrent therapy. The overall response rate was 86.4% (51/59). OS ranged from 0.4 to 36.7 months (median 6.5 months), and 1‐year‐survival rate was 21.3%. Treatment‐related adverse events mainly included acute meningitis, chronic‐delayed encephalopathy, radiculitis, myelosuppression and mucositis. Twelve patients (20.3%) had grade III–V toxic reactions. We concluded that IC combined with concomitant IF‐RT, with significant efficacy and acceptable toxicity, may be an optimal therapeutic option for treatment of LM from solid tumors with adverse prognostic factors. LM, in which cancer cells spread to membranes enveloping the brain and spinal cord, is a devastating complication of solid cancers. Existing LM therapies center on IC. In this prospective clinical study, the authors combined intrathecal methotrexate with involved‐field radiotherapy in a concomitant regimen, showing that the approach can potentially improve quality of life for patients with adverse prognostic factors. Concurrent radiotherapy‐bolstered IC by contributing to prolonged remission of neurological symptoms and increasing OS. The findings suggest that the concomitant regimen could be an optimal treatment option for LM.

Low-Dose Ionizing Radiation Induces Direct Activation of Natural Killer Cells and Provides a Novel Approach for Adoptive Cellular Immunotherapy

Recent evidence indicates that limited availability and cytotoxicity have restricted the development of natural killer (NK) cells in adoptive cellular immunotherapy (ACI). While it has been reported that low-dose ionizing radiation (LDIR) could enhance the immune response in animal studies, the influence of LDIR at the cellular level has been less well defined. In this study, the authors aim to investigate the direct effects of LDIR on NK cells and the potential mechanism, and explore the application of activation and expansion of NK cells by LDIR in ACI. The authors found that expansion and cytotoxicity of NK cells were markedly augmented by LDIR. The levels of IFN-γ and TNF-α in the supernatants of cultured NK cells were significantly increased after LDIR. Additionally, the effect of the P38 inhibitor (SB203580) significantly decreased the expanded NK cell cytotoxicity, cytokine levels, and expression levels of FasL and perforin. These findings indicate that LDIR induces a direct expansion and activation of NK cells through possibly the P38-MAPK pathway, which provides a potential mechanism for stimulation of NK cells by LDIR and a novel but simplified approach for ACI.

Hormetic Response to Low-Dose Radiation: Focus on the Immune System and Its Clinical Implications

The interrelationship between ionizing radiation and the immune system is complex, multifactorial, and dependent on radiation dose/quality and immune cell type. High-dose radiation usually results in immune suppression. On the contrary, low-dose radiation (LDR) modulates a variety of immune responses that have exhibited the properties of immune hormesis. Although the underlying molecular mechanism is not fully understood yet, LDR has been used clinically for the treatment of autoimmune diseases and malignant tumors. These advancements in preclinical and clinical studies suggest that LDR-mediated immune modulation is a well-orchestrated phenomenon with clinical potential. We summarize recent developments in the understanding of LDR-mediated immune modulation, with an emphasis on its potential clinical applications.

Distinct biological effects of low-dose radiation on normal and cancerous human lung cells are mediated by ATM signaling

Low-dose radiation (LDR) induces hormesis and adaptive response in normal cells but not in cancer cells, suggesting its potential protection of normal tissue against damage induced by conventional radiotherapy. However, the underlying mechanisms are not well established. We addressed this in the present study by examining the role of the ataxia telangiectasia mutated (ATM) signaling pathway in response to LDR using A549 human lung adenocarcinoma cells and HBE135-E6E7 (HBE) normal lung epithelial cells. We found that LDR-activated ATM was the initiating event in hormesis and adaptive response to LDR in HBE cells. ATM activation increased the expression of CDK4/CDK6/cyclin D1 by activating the AKT/glycogen synthase kinase (GSK)-3β signaling pathway, which stimulated HBE cell proliferation. Activation of ATM/AKT/GSK-3β signaling also increased nuclear accumulation of nuclear factor erythroid 2-related factor 2, leading to increased expression of antioxidants, which mitigated cellular damage from excessive reactive oxygen species production induced by high-dose radiation. However, these effects were not observed in A549 cells. Thus, the failure to activate these pathways in A549 cells likely explains the difference between normal and cancer cells in terms of hormesis and adaptive response to LDR.

Validating the pivotal role of the immune system in low-dose radiation-induced tumor inhibition in Lewis lung cancer-bearing mice

Although low‐dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR‐induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high‐dose radiation (HDR) of 1 Gy. Additionally, the LDR‐induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR‐activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR‐induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice.

Alterations of MicroRNA Expression in the Liver, Heart, and Testis of Mice Upon Exposure to Repeated Low-Dose Radiation

MicroRNAs (miRs), which regulate target gene expression at the post-transcriptional level, play a crucial role in inducing biological effects upon high-dose ionizing radiation. Yet, the miR expression profiles in response to repeated low-dose radiation (LDR) in vivo have not been elucidated. This study investigated the response profiles of 11 miRs with functions involved in metabolism, DNA damage and repair, inflammation, and fibrosis in mouse liver, heart, and testis upon repeated LDR exposure for 4 months. The expression profiles were evaluated using stem-loop quantitative reverse transcription polymerase chain reaction immediately and at 2 months after LDR exposure. The expression profiles varied significantly at both time points. At the organ level, the heart was the most affected, followed by the liver and testis, in which significant miR upregulation related to DNA damage response was found. Metabolism-related miRs decreased in the liver and increased in the testis. The current results showed immediate and long-lasting alterations in the miR expression profiles in response to repeated LDR in different organs.

Leptomeningeal metastasis of pulmonary large-cell neuroendocrine carcinoma: A case report and review of the literature

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare and malignant form of lung cancer with a poor prognosis for patients. The common sites of metastases are the liver, adrenal glands, bone and brain. LCNEC rarely metastasizes to the small intestine, ovaries, tonsils, mandible, vulva or spine. To the best of our knowledge, there have been no reports of leptomeningeal metastasis of LCNEC to date. The present case report describes an unusual case of leptomeningeal metastasis from pulmonary LCNEC alongside a review of the literature. Biopsies of pulmonary lesions and cervical lymph nodes confirmed the diagnosis of LCNEC in a 39-year-old male patient. At 2 months after chemotherapy, the patient began to experience hoarseness, epileptic seizures and blurred vision. Furthermore, the patient presented with radiating pain and numbness in his lower left limb. Imaging findings and cytological examination of cerebral spinal fluid supported the diagnosis of leptomeningeal metastasis. The patients neurological symptoms were markedly alleviated following receipt of radiation and intrathecal chemotherapy. The patient survived for 4.9 months after diagnosis with leptomeningeal metastasis. To the best of our knowledge, the present case report is the first to describe leptomeningeal metastasis from pulmonary LCNEC confirmed by neuroimaging and cerebral spinal fluid cytology. It suggests that leptomeningeal metastasis does occur in this rare disease, and aggressive treatment may result in improved symptoms and possibly survival times.