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.

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 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.

'Hot cross bun' sign with leptomeningeal metastases of breast cancer: a case report and review of the literature.

BACKGROUND: The 'hot cross bun' (HCB) sign refers to a cruciform-shaped hyperintensity within the pons found on T2-weighted magnetic resonance imaging (MRI). It is commonly associated with atrophy of the pons, cerebellum, and putamen in multiple system atrophy (MSA). In this report, we describe a rare case of the HCB sign in an adult female patient with leptomeningeal metastases of breast cancer without any signs of brain atrophy. CASE PRESENTATION: The patient was a 58-year-old woman diagnosed with grade 2 ductal breast carcinoma, who had undergone a right mastectomy, followed by chemotherapy treatments and chest wall radiotherapy. The tumor had metastasized to the skin, and the patient presented with vomiting, drowsiness, and intermittent episodes of confusion, slurred speech, and involuntary movements. Immunohistochemical staining demonstrated a triple-negative status of the tumor. Axial T1-weighted MRI showed a linear enhancement in the cerebellar sulcus. A diagnosis of leptomeningeal metastases of breast cancer was confirmed by detection of tumor cells in the cerebrospinal fluid. Axial T2-weighted MRI indicated a cruciform hyperintensity in the pons without any atrophy of the pons, cerebellum, or putamen. CONCLUSION: The HCB sign can occur with leptomeningeal metastases of solid tumors, though the underlying mechanisms remain unknown.

Leptomeningeal metastasis from hepatocellular carcinoma with other unusual metastases: a case report.

BACKGROUND: Leptomeningeal metastasis, which results from metastasis of tumors to the arachnoid and pia mater, can lead to the dissemination of tumor cells throughout the subarachnoid space via the cerebral spinal fluid, and frequently with a poor prognosis. The primary tumor in adults is most often breast cancer, lung cancer, or melanoma. Although leptomeningeal metastasis due to cholangiocarcinoma has been reported, to the best of our knowledge there is no cytologically confirmed report of leptomeningeal metastasis from hepatocellular carcinoma. CASE PRESENTATION: We herein report a case of leptomeningeal metastasis from hepatocellular carcinoma in a 53-year-old woman with concomitant systemic metastases to the lung, bone, brain, kidney, adrenal gland, subcutaneous tissues, and abdominal pelvis. The neurological symptoms of the patient were relieved after treatment with methotrexate intra-cerebral spinal fluid chemotherapy concurrent with whole brain radiotherapy. CONCLUSION: To our knowledge this is the first report of leptomeningeal metastasis from hepatocellular carcinoma confirmed by cytology. Treatment with methotrexate intra-cerebral spinal fluid chemotherapy concurrent with whole brain radiotherapy was effective.

Bone marrow metastasis in primary bronchial mucoepidermoid carcinoma: a case report.

Primary bronchial mucoepidermoid carcinoma in the lung is relatively rare. It rarely presents with the highly malignant biological characteristic of bone marrow metastasis. We describe a case of this disease with bone marrow metastasis. A 56-year-old man with the primary manifestation of bone pain and bloodstained sputum had two abnormal shadows on the left inferior lobar bronchus and peripheral tissue of the lower lobe of the left lung, respectively. Computed tomography-guided percutaneous puncture biopsy and bone imaging confirmed the diagnosis of high-grade bronchial mucoepidermoid carcinoma with bone metastasis. However, the patient soon presented with progressive hemoglobin and platelet decline and severe multi-organ hemorrhage. Subsequently, we performed bone marrow aspiration and biopsy, which revealed malignant cells and necrosis. The patient deteriorated rapidly from the disease, and died on the 16th day of admission. We hope that this case report will increase awareness of the possibility of primary high-grade bronchial mucoepidermoid carcinoma metastasizing to the bone marrow, which might be a poor prognostic factor.

Leptomeningeal metastases from a primary central nervous system melanoma: a case report and literature review.

Primary central nervous system (CNS) melanoma is a type of rare and aggressive tumor that can easily spread to the leptomeninges, and in fact, leptomeningeal metastasis is one of the most serious complications in patients with this carcinoma. Prognosis is extremely poor if a CNS melanoma has metastasized, and there are no effective treatments. Here, we present a case of a 37-year-old woman who presented with horizontal diplopia and progressive headache. Magnetic resonance imaging findings were consistent with the diagnosis of melanoma. The results of cytological examination of cerebrospinal fluid (CSF) showed malignant cells characteristic of melanoma. No extracranial lesions were observed. All of the available evidence confirmed a diagnosis of leptomeningeal metastases from a primary CNS melanoma. The patient received aggressive treatment, which consisted of concurrent radiotherapy and weekly intra-CSF methotrexate (MTX) followed by adjuvant monthly intra-CSF MTX. Her survival time was 13 months after diagnosis. This case report suggests that the modality of concurrent radiotherapy and weekly intra-CSF MTX followed by adjuvant monthly intra-CSF MTX may be used as the mainstay of treatment for such patients.

Targeting the neural stem cells in subventricular zone for the treatment of glioblastoma: an update from preclinical evidence to clinical interventions.

BACKGROUND: Glioblastoma is one of the most common and aggressive adult brain tumors. The conventional treatment strategy, surgery combined with chemoradiotherapy, did not change the fact that the recurrence rate was high and the survival rate was low. Over the years, accumulating evidence has shown that the subventricular zone has an important role in the recurrence and treatment resistance of glioblastoma. The human adult subventricular zone contains neural stem cells and glioma stem cells that are probably a part of reason for therapy resistance and recurrence of glioblastoma. MAIN BODY: Over the years, both bench and bedside evidences strongly support the view that the presence of neural stem cells and glioma stem cells in the subventricular zone may be the crucial factor of recurrence of glioblastoma after conventional therapy. It emphasizes the necessity to explore new therapy strategies with the aim to target subventricular zone to eradicate neural stem cells or glioma stem cells. In this review, we summarize the recent preclinical and clinical advances in targeting neural stem cells in the subventricular zone for glioblastoma treatment, and clarify the prospects and challenges in clinical application. CONCLUSIONS: Although there remain unresolved issues, current advances provide us with a lot of evidence that targeting the neural stem cells and glioma stem cells in subventricular zone may have the potential to solve the dilemma of glioblastoma recurrence and treatment resistance.

A phase II study of concurrent involved-field radiotherapy and intrathecal chemotherapy for leptomeningeal metastasis from solid tumors.

BACKGROUND: The role of involved-field radiation therapy (IFRT) and intrathecal chemotherapy (IC) in leptomeningeal metastasis (LM) from solid tumors was gradually underestimated in the era of targeted therapy. This study was aimed to investigate the safety and effectiveness of concurrent IFRT and intrathecal methotrexate (MTX)/cytarabine (Ara-C) for LM, particularly for those who developed LM while receiving targeted therapy. MATERIALS AND METHODS: Enrolled patients were given induction IC first and then concurrent treatment, which consisted of IFRT (40 Gy total; 2 Gy/f) and IC (MTX 15 mg or Ara-C 50 mg, once per week). Primary endpoint was clinical response rate (RR). Secondary endpoints were safety and overall survival (OS). RESULTS: Fifty-three patients received induction intrathecal MTX (n = 27) or Ara-C (n = 26). Forty-two patients completed concurrent therapy. Total RR was 34% (18/53). The improvement rate of neurological symptoms and KPS scores were 72% (38/53) and 66% (35/53) respectively. Adverse events (AEs) rate was 28% (15/53). Eight patients (15%, 8/53) showed grade 3-4 AEs, including myelosuppression (n = 4) and radiculitis (n = 5). Median OS was 6.5 months (95% CI, 5.3-7.7 months). Median survival for 18 patients who had clinical response was 7.9 months (95% CI, 4.4-11.4 months), and 0.8 months (95% CI, 0.08-1.5 months) for 6 patients who had LM progression. The median survival in 22 patients who received prior targeted therapy was 6.3 months (95% CI, 4.5-8.1 months). CONCLUSION: Concurrent IFRT and intrathecal MTX or Ara-C was proved to be a feasible treatment option with an acceptable safety profile for LM from a common tumor entity.

An indispensable tool: Exosomes play a role in therapy for radiation damage.

Radiotherapy is one of the three main treatments for tumors. Almost 70% of tumor patients undergo radiotherapy at different periods. Although radiotherapy can enhance the local control rate of tumors and patients' quality of life, normal tissues often show radiation damage following radiotherapy. In recent years, several studies have shown that exosomes could be biomarkers for diseases and be involved in the treatment of radiation damage. Exosomes are nanoscale vesicles containing complex miRNAs and proteins. They can regulate the inflammatory response, enhance the regeneration effect of damaged tissue, and promote the repair of damaged tissues and cells, extending their survival time. In addition, their functions are achieved by paracrine signaling. In this review, we discuss the potential of exosomes as biomarkers and introduce the impact of exosomes on radiation damage in different organs and the hematopoietic system in detail.

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/RAR alpha 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.

Identification of Cerebrospinal Fluid MicroRNAs Associated With Leptomeningeal Metastasis From Lung Adenocarcinoma.

Background: Leptomeningeal metastasis (LM) has frequently been observed in patients with lung adenocarcinoma. So far, its diagnosis and disease course monitoring are still extremely difficult. Moreover, there is no effective treatment regimen for LM due to a lack knowledge on the molecular mechanism of LM. This study aimed to identify LM-related cerebrospinal fluid (CSF) miRNAs, which have potential value for diagnosing and monitoring LM and exploring the molecular mechanism. Methods: CSF miRNAs were screened and verified by microarray analysis and quantitative real-time PCR (qRT-PCR) in LM patients with lung adenocarcinoma and non-LM controls, and the diagnostic performance of candidate miRNAs was evaluated. Then, candidate miRNAs in matched CSF samples from LM patients at diagnosis, after initial therapy, at relapse, and after salvage therapy, were analyzed to assess the relationship between CSF miRNAs and LM disease course. The effect of candidate miRNAs on proliferation, invasion, and migration of lung adenocarcinoma cell lines was assessed. The targeted genes of the candidate miRNA were predicted by TargetScan, miRDB, and miRTarbase online analysis tools. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the functional categories of predicted target genes. Results: CSF miR-7975, miR-7977, and miR-7641 were screened and verified to be statistically significantly up-regulated in LM patients compared to non-LM controls. The three miRNAs, when combined, exhibited optimal diagnostic performance. Longitudinal data of CSF miR-7975 and miR-7977 correlated well with clinical courses of LM. Overexpression of miR-7977 promoted proliferation, migration, and invasion of lung adenocarcinoma cells. Moreover, 385 targeted genes of miR-7977 were predicted and were involved in various pathways related to cancer metastasis. Conclusions: This study offers insights for future research of CSF miRNAs as robust tools for diagnosing and monitoring LM. It also reveals a novel pathway for exploration of underlying mechanisms of LM.

Intrathecal pemetrexed combined with involved-field radiotherapy as a first-line intra-CSF therapy for leptomeningeal metastases from solid tumors: a phase I/II study.

PURPOSE: A phase I/II study of intrathecal pemetrexed (IP) combined with involved-field radiotherapy (IFRT) was performed to determine feasibility, safety, and antitumor activity for leptomeningeal metastases (LM) from solid tumors. METHODS: Participants first received induction IP administration, followed by concomitant radiotherapy within 3 days. The concomitant regimen consisted of IP (pemetrexed 10 mg, dexamethasone 5 mg, once per week, 4 times in 4 weeks) and IFRT (40 Gy in 20 fractions). Six participants were recruited to assess feasibility in phase I, and then 28 patients were recruited further. All patients were assessed to investigate safety, efficacy, and outcomes. RESULTS: Between April 2018 and December 2018, 34 patients (male: 15; female: 19; median age: 56 years) were enrolled, including non-small-cell lung cancer (21), small-cell lung cancer (5), breast cancer (4), and others (4). Thirty-two patients received concurrent therapy and 25 (74%) patients completed the treatment. Major adverse events (AEs) consisted of myelosuppression, the elevation of hepatic aminotransferases, and radiculitis. Total AEs rate was 53% (18/34), including 6 (18%) patients with grade 3 and 1 (3%) with grade 4 AEs. The response rate was 68% (23/34). The median overall survival was 5.5 (0.3-16.6) months. Median neurological progression-free survival (NPFS) was 3.5 (0.3-15.2) months. Six-month NPFS rate was 47%. One-year survival rate was 21.6%. CONCLUSION: IP at a 10 mg dose on a schedule of 1-2 times per week presented good efficacy and safety in CSF. The concomitant regimen is an efficacious therapeutic option for LM patients with solid tumors. TRIAL REGISTRATION: This study (IPLM) was registered at https://register.clinicaltrials.gov [ClinicalTrials.gov identifier: NCT03507244].

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.

A Pilot Phase 1 Study of Intrathecal Pemetrexed for Refractory Leptomeningeal Metastases From Non-small-cell Lung Cancer.

Objectives: We aim to determine the feasibility, safety, maximally tolerated dose (MTD), recommended dose and potential anti-tumor activity of intrathecal pemetrexed (IP). Materials and Methods: Lung adenocarcinoma patients with recurrent or progressive leptomeningeal metastases (LM) after intrathecal chemotherapy were recruited. IP dose was escalated from 10 mg. A minimum of three patients and a maximum of six were enrolled in each cohort. Schedule protocol was IP twice per week for 2 weeks in induction therapy, followed by once per week for 4 weeks in consolidation therapy. Serial samples of plasma and cerebrospinal fluid (CSF) were obtained for pharmacokinetic studies. Results: Thirteen patients were enrolled between March 2017 and July 2018. EGFR driver oncogene was identified in most of the patients. Severe adverse events (AEs) were encountered in 31% (4/13) of the cases, including myelosuppression, radiculitis, and elevation of hepatic aminotransferases (EHA). Study protocol was revised due to lethal myelosuppression. Following protocol revision, vitamin B12 and folic acid supplementation was given at the beginning of treatment, and myelosuppression was well-controlled. Dose-limiting toxicities (DLT) were myelosuppression, radiculitis, and EHA. Two patients (2/2) developed dose-limiting myelosuppression at 15 mg level. One patient (1/6) experienced dose-limiting radiculitis and EHA at 10 mg level. MTD was 10 mg. Response rate was 31% (4/13) and disease control rate was 54% (7/13). The drug concentration showed a decreasing trend in serial CSF samples following each IP. After IP, the peak plasma concentration was reached at 4 h in two cases, 6 h in two cases, 9 h in one case, and 12 h in one case, respectively. Conclusion: Pemetrexed was appropriate for intrathecal administration. IP at 10 mg dose in combination with vitamin supplementation on the schedule of 1-2 times per week showed controllable toxicity and good efficacy. This regimen paves the way for subsequent clinical trial. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03101579.

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.

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.

Leptomeningeal metastasis from solid tumors: clinical features and its diagnostic implication.

In this study, we examined the characteristics and aimed to increase the knowledge of clinical features of leptomeningeal metastasis (LM). The clinical data, including initial diagnosis and treatment of primary tumor, clinical manifestations, neuroimaging findings, cerebrospinal fluid (CSF) examination, were analyzed. For the patients with adenocarcinoma/breast cancer, the incidence of cranial lesions and cranial nerve paralysis was obviously higher than patients with small cell lung cancer. Whereas, the incidence of involvement of intravertebral canal was obviously lower than that of small cell lung cancer. Patients with adenocarcinoma/breast cancer showed more incidence of leptomeningeal enhancement compared to those with small cell lung cancer. Persistent severe headache was noticed in those with squamous carcinoma, and usually showed absence of abnormally LM-related neuroimaging and CSF cytological findings, which resulted in a challenge in the diagnosis of LM from squamous carcinoma. Patients with different primary tumors showed differential clinical features. Significant differences were observed in clinical features between patients with adenocarcinoma/breast cancer and small cell lung cancer. Our study contributes to the understanding of clinical characteristics of LM, and contributes to improvement of LM diagnosis in clinical practice.

Low-dose irradiation inhibits proliferation of the p53null type human prostate cancer cells through the ATM/p21 pathway.

Low-dose ionizing radiation (LDIR) induces hormesis, exerts an adoptive effect on normal mammalian cells and stimulates cell proliferation; however, this effect is absent in cancer cells. Little is known on the molecular mechanisms underlying this differential response between normal and cancer cells. In the present study, it was demonstrated that the human prostate cancer cell line PC-3 and the normal prostate cell line RWPE-1 exhibited differential biological responses to LDIR. Through cell cycle analyses, it was demonstrated that LDIR inhibited cell growth and arrested the cell cycle at the S and G2/M phases in PC-3 cells, but not in RWPE-1 cells. Using western blotting, it was demonstrated that LDIR at 75 mGy induced the expression of ataxia-telangiectasia mutated (ATM) protein in PC-3 as well as RWPE-1 cells. However, the ATM̸p21 pathway was activated in PC-3, but not in RWPE-1 cells. Although the expression of p53 was not affected by 75 mGy LDIR in RWPE-1 cells, the ATM̸p21 pathway was activated when RWPE-1 cells lost p53 function. In addition, when using ATM inhibitors, the ATM̸p21 pathway was inactivated in both cell lines, and the LDIR-induced cell proliferation inhibition was also abolished. These findings suggested that the ATM/p21 pathway directly participated in the LDIR-induced cell proliferation inhibition in p53null type prostate tumor cells, whereas this mechanism was absent in normal prostate cells. Thus, p53 may affect cell stability following LDIR, and plays a crucial role in regulating the ATM/p21 pathway activated by LDIR.

A comparison between oral chemotherapy combined with radiotherapy and radiotherapy for newly diagnosed glioblastoma: A systematic review and meta-analysis.

The prognosis of glioblastoma (GBM), a major subtype of grade IV glioma, is rather poor nowadays. The efficiency of chemotherapy serving as the adjunct to radiotherapy (RT) for treating GBM is still controversial. In this study, we aim to investigate the overall survival (OS) and progression-free survival (PFS) in patients with newly diagnosed GBM received RT plus chemotherapy or with RT alone.Literatures were searched from the PubMed, Embase, and Cochrane Library between January 2001 and June 2015. Study selection was conducted based on the following criteria: randomized clinical trial (RCT) of adjuvant RT plus chemotherapy versus RT alone; studies comparing OS and/or PFS; and studies including cases medically confirmed of newly diagnosed GBM.Five RCTs (1655 patients) were eligible in this study. The meta-analysis showed a significant improvement in OS of patients treated with RT plus oral chemotherapy compared with that of RT alone (hazard ratio 0.70; 95% confidence interval, 0.56-0.88, P = .002).Adjuvant chemotherapy confers a survival benefit in patients newly diagnosed with GBM.