Multi-phase FZA lensless imaging via diffusion model.

Lensless imaging shifts the burden of imaging from bulky and expensive hardware to computing, which enables new architectures for portable cameras. However, the twin image effect caused by the missing phase information in the light wave is a key factor limiting the quality of lensless imaging. Conventional single-phase encoding methods and independent reconstruction of separate channels pose challenges in removing twin images and preserving the color fidelity of the reconstructed image. In order to achieve high-quality lensless imaging, the multiphase lensless imaging via diffusion model (MLDM) is proposed. A multi-phase FZA encoder integrated on a single mask plate is used to expand the data channel of a single-shot image. The information association between the color image pixel channel and the encoded phase channel is established by extracting prior information of the data distribution based on multi-channel encoding. Finally, the reconstruction quality is improved through the use of the iterative reconstruction method. The results show that the proposed MLDM method effectively removes the influence of twin images and produces high-quality reconstructed images compared with traditional methods, and the results reconstructed using MLDM have higher structural similarity and peak signal-to-noise ratio.

The impact of bone marrow irradiation dose on acute haematologic toxicity in cervical cancer patients treated with concurrent chemoradiotherapy.

OBJECTIVE: To evaluate the impact of bone marrow (BM) irradiation dose on acute haematologic toxicity (HT) in concurrent chemoradiotherapy for cervical cancer. METHODS: Sixty-nine patients with cervical cancer treated with curative or postoperative adjuvant therapy received weekly cisplatin concurrent chemotherapy (CCT) and intensity-modulated radiation therapy (IMRT). The whole pelvic bone marrow (PBM) was delineated and divided into three subsites: ilium (IL), lower pelvis (LP), and lumbosacral spine (LS). Associations between clinical variables, dose volume of BM, including PBM, IL, LP, and LS in the form of x-Vy (volume receiving y Gy for x), and blood cell count nadir were tested using linear regression models. Receiver operating characteristic (ROC) curve analysis was further used to analyse the cutoff values of the variables with p < 0.05 in the multivariate analysis. RESULTS: In 69 patients, the haemoglobin nadir was positive correlated with baseline haemoglobin (p < 0.001), negative correlated with relative LP-V10 (p = 0.005), relative LP-V25 (p = 0.002), relative LP-V50 (p = 0.007), relative LP-mean (p = 0.003), absolute LP-V15 (p = 0.049), absolute LP-V25 (p = 0.004) and absolute LP-V30 (p = 0.009). The platelet nadir was positive correlated with baseline platelets (p = 0.048) and negative correlated with relative LP-V40 (p = 0.028), but there was no significant variable in absolute radiation volume by multivariate analysis. No variables related to the neutrophil nadir were found, and the 69 patients were divided into group A (43 cases) receiving 3-4 cycles of CCT and group B (26 cases) receiving 5-6 cycles of CCT. In group A, the relative IL-V15 (p = 0.014), the relative IL-V50 (p = 0.010) and the absolute LP-V50 (p = 0.011) were negative correlated with the neutrophil nadir. No significant variable was found in group B. No significant variables related to the lymphocyte nadir were found, and the neutrophil-to-lymphocyte ratio (NLR) was analysed. Age (p < 0.05), relative LP-V15 (p = 0.037) and absolute PBM-mean (p < 0.001) were found to be negative related to NLR. CONCLUSION: The dosimetric parameters of relative irradiated volume of BM have more statistically significant datas on acute HT than absolute irradiated volume. The nadir of haemoglobin and platelets and the vertice of NLR were more affected by the irradiation dose to LP, while neutrophils were more affected by the dose to IL. Acute HT was negative related to both low-dose irradiation (V10-30) and high-dose irradiation (V40, V50). For more than 4 cycles of CCT, the effect of BM irradiation on the neutrophils nadir was masked by chemotherapy.

Going deeper and further: a range and depth extension for the deep-sea feather star Paratelecrinuscubensis (Carpenter, 1881) (Comatulida, Atelecrinidae), first record from the Western Pacific.

A specimen belonging to the deep-sea feather-star family Atelecrinidae was collected in April 2018 at the Kocebu Guyot at 1294 m deep. Based on its morphological characters, the specimen was identified as Paratelecrinuscubensis (Carpenter, 1881). This species of feather star is restricted to the deep sea and was known only from 12 records from the Bahamas and Cuba at depths of 567-892 m. The data represent the first record from the Western Pacific Ocean and the deepest record known, extending the depth where this feather star has been found to beyond 1000 m. The morphological characteristics of the Kocebu Guyot specimen were essentially identical to the morphology of the neotype, with a slight difference in the dorsal spine at the end of the cirri. The phylogenetic analysis based on the mitochondrial cytochrome c oxidase subunit I (COI), 16S rRNA genes, 28S rRNA genes, and 18S rRNA genes reveal a close relationship of P.cubensis with P.wyvilli. Results of our molecular phylogenetic analysis are consistent with our morphological identifications. Our find extends the known geographical distribution of the feather star P.cubensis to the Western Pacific Ocean and provide insights into deep-sea biodiversity in the Kocebu Guyot.

Altered DNA Methylation and Gene Expression Profiles in Radiation-Induced Heart Fibrosis of Sprague-Dawley Rats.

Radiation-induced heart disease (RIHD) is a serious side effect of radiotherapy for thoracic tumors. Advanced myocardial fibrosis in the late phase of RIHD can lead to myocardial remodeling, heart function impairing and heart failure, resulting in serious clinical consequences, and its pathogenesis remains vague. DNA methylation is one of the important epigenetic mechanisms which often occurs in response to environmental stimuli and is crucial in regulating gene expression. We hypothesized DNA methylation may contribute to pathogenesis in radiation-induced heart fibrosis (RIHF) and altered DNA methylation patterns probably influenced the genes expression in RIHF. In present study, we found genome-wide differences in DNA methylation status and RNA expression were demonstrated and we screened out 44 genes whose altered expression maybe were regulated by CpG island methylation within the gene promoter in RIHF of Sprague-Dawley rat by employing gene expression arrays and human CpG island microarrays. Gene expression and CpG island methylation levels of several candidate genes were further validated. Our investigation provided a new dimension to reveal the specific mechanisms of RIHF and explore the potential therapeutic targets for it.

Characteristics of homologous recombination repair pathway genes mutation in ovarian cancers.

Background: Few studies have investigated the characteristics of non-BRCA homologous recombination repair (HRR) pathway somatic mutations, and the impact of these mutations on efficacy of treatment in ovarian cancer patients is not clear. Therefore, we conducted this study to analyze the frequency and spectrum of somatic mutations in HRR pathway genes in patients with ovarian cancer and to examine the relationships between somatic mutations in HRR pathway genes and their effects on the efficacy of platinum-based chemotherapy. Methods: We performed targeted sequencing of 688 genes related to the occurrence, development, treatment, and prognosis of solid tumors. Somatic mutations were identified by paired analysis of tumor tissue and germline DNA in blood cells. Results: A total of 38 patients with ovarian cancer were included in the study, and 35 (92.1%) patients were diagnosed with high-grade serous carcinoma. All patients exhibited somatic mutations in the tumor tissue samples. The commonly mutated genes were TP53 (73.7%), BRCA2 (55.3%), NF1 (52.6%), BRCA1 (47.4%), and CDH1 (47.4%). Overall, 71.1% of the patients exhibited mutation in at least one HRR pathway gene. The most frequently altered HRR genes were BRCA2 (55.3%), followed by BRCA1 (47.4%), ATM (44.7%), BARD1 (42.1%), and CHEK1 (36.8%). The median progression-free survival (PFS) in patients with HRR pathway mutation was 36.0 months compared with 13.6 months in patients with no HRR pathway mutation (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.08-0.77; p = 0.016). Patients harboring BRCA1/2 and/or CDK12 mutations displayed a longer PFS (median, 36.0 months) compared with patients with no BRCA1/2 or CDK12 mutation (median, 13.6 months; HR, 0.21; 95% CI, 0.07-0.61; p = 0.004). In multivariate analysis Cox proportional hazards models, after adjustment for tumor stage at diagnosis and histology of initial diagnosis, patients with HRR pathway mutation had a longer PFS than patients with HRR wild-type genes (p = 0.006). Conclusions: HRR pathway somatic mutations are common in Chinese patients with ovarian cancer. HRR pathway somatic mutations were associated with improved sensitivity to platinum-based chemotherapy. Large-scale prospective studies are needed to verify our findings.

Persistent response of an ovarian cancer patient after a short-term single-agent immunotherapy: a case report.

Epithelial ovarian cancer is extremely difficult to treat due to its high recurrence rate and acquired tolerance to chemotherapy. Immune checkpoint inhibitors (ICIs) are expected to be promising solutions for treatment failure. However, the low response rate to a single ICI agent was demonstrated in approximately all published clinical trials. Surprisingly patients with complete response were also noticed as an anecdote. Proper indicators of treatment response were urgently required. Programmed death- ligand 1 expression levels in the tumor tissues provide relatively limited discrimination. Tumor mutation burden (TMB) serves as a more reliable parameter. Here we presented an ovarian cancer case with multiple gene mutations and high TMB, who benefited from a short-term treatment of pembrolizumab and experienced a long-lasting complete response of 2 years till now. The patient was irradiated in the pelvic before pembrolizumab. Our study demonstrated that ICIs might provide survival benefits for ovarian cancer with high TMB and that pelvic radiation might have synergistical effects with immunotherapy.

A Retrospective Cohort Study Evaluates Clinical Value of Anlotinib in Persistent, Metastatic, or Recurrent Cervical Cancer After Failure of First-Line Therapy.

BACKGROUND: Anlotinib is an oral anti-angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, fibroblast growth factor receptors, etc., and its clinical value in cervical cancer is rarely reported. We designed a retrospective study to evaluate the efficacy and safety of anlotinib in patients with persistent, metastatic, or recurrent cervical cancer who have failed first-line therapy, and compare the efficacy of anlotinib with that of apatinib which targets only VEGFR2 and has shown efficacy in recent studies. METHODS: Fifty-two patients with persistent, metastatic, or recurrent cervical cancer who failed first-line therapy and administrated anlotinib or apatinib as monotherapy or combination with chemo-, radio- or immunotherapy were included in this study. Among the 52 patients, 20 patients who received anlotinib from January 2019 to August 2020 were defined as anlotinib group, whereas 32 patients who received apatinib from our previous study were selected as apatinib group. The safety, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were reviewed and recorded. RESULTS: The ORR and DCR in patients receiving anlotinib were 25% and 80%, respectively. The median PFS and OS in anlotinib group were significantly longer than those in apatinib group, respectively (PFS: 5 months vs 3 months, p=0.015; OS: 10 months vs 5 months, p=0.008). Moreover, the patients treated with anlotinib had better survival with a significantly lower cumulative incidence of cancer-related death than those treated with apatinib (HR=0.31, 95% CI: 0.13-0.77, p=0.012). The most common adverse effects in the patients treated with anlotinib were hypertension (20%), fatigue (20%), and nausea (15%). No drug-related death occurred. CONCLUSION: Anlotinib showed beneficial efficacy and safety and can be a treatment option for patients with persistent, metastatic, or recurrent cervical cancer who have failed the first-line therapy.

Effectiveness and prognostic factors of apatinib treatment in patients with recurrent or advanced cervical carcinoma: A retrospective study.

BACKGROUND: Apatinib is an oral anti-angiogenic drug, its efficacy and prognosis in cervical carcinoma are unclear. This study evaluates the effectiveness and prognostic factors of apatinib in the treatment of recurrent or advanced cervical carcinoma. METHODS: Patients with recurrent or advanced cervical cancer, who agreed to take apatinib, were recruited into this single-center and retrospective study, and administrated apatinib with or without combination of chemo- or radio-therapy until progressive disease (PD) or unacceptable toxicity. RESULTS: From March 2017 to February 2019, 53 patients were reviewed. Among them, 2 (3.77%) patients occurred complete response, 16 (30.19%) patients showed partial response, 27 (50.95%) patients had stable disease, and 8 (15.09%) patients had PD. The objective response rate and disease control rate (DCR) of these patients were 33.96% and 84.91%, respectively. The DCR of patients younger than 50, nonsquamous carcinoma, first-line apatinib therapy, combined radiotherapy, lesions within radiation field, surgical history, and Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 were significantly higher than other patients (p < 0.05). The median progression-free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.43-7.57) and 8.0 months (95% CI: 6.52-9.48), respectively. The univariable and multivariable analysis showed that the patients with an ECOG performance status score of 2 and further line therapy were associated with poor prognosis in both PFS and OS (PFS: HR =8.35, p = 0.000; HR =6.66, p = 0.001; OS: HR = 7.40, p = 0.000; HR = 3.24, p = 0.039), respectively. The most common adverse effects (AEs) were hand-foot syndrome (35.58%), hypertension (18.87%) and fatigue (15.09%). No grade 3 AEs and drug-related death occurred. CONCLUSION: The efficacy and prognosis of patients who are in good general condition and first-line apatinib combination therapy may be better than other patients. But further phase III clinical trials should be taken to prove this hypothesis.

Meningeal metastasis of a malignant peritoneal mesothelioma: A case report and literature review.

Malignant peritoneal mesothelioma is a very rare tumor originating from the peritoneal serous mesothelium. Meningeal metastasis of malignant peritoneal is even more rare. Here, we reported a case of a 60-year-old female patient with a history of exposure to asbestos for 10 years who presented with massive peritoneal effusion followed by disorder of consciousness and symptoms of cranial nerve injury. The patient was diagnosed as peritoneal mesothelioma with meningeal metastasis through neurological symptoms, cytological finding of cerebrospinal fluid combined with cranial magnetic resonance imaging (MRI). The patient received systemic chemotherapy and total craniospinal irradiation. The follow up visits showed that the survival time of patient after diagnosis of meningeal metastasis from peritoneal mesothelioma was 5 months. To our knowledge, this is the first case of menigeal metastasis of peritoneal mesothelioma. We hope this particular case may be helpful in providing some experience to the treatment of peritoneal mesothelioma with meningeal metastasis.

Effects of different doses of X-ray irradiation on cell apoptosis, cell cycle, DNA damage repair and glycolysis in HeLa cells.

The present study examined the radiation biological response of cancer cells to different fractional irradiation doses and investigates the optimal fractional irradiation dose with improved biological effects. Radiobiological studies were performed at the molecular and cellular levels to provide insights into DNA damage and repair, and the apoptosis mechanism of cells that were exposed to different doses of X-ray irradiation (0, 2, 4, 6, 8, 10, 12.5, 15 and 20 Gy). Evidence of increased reactive oxygen species (ROS), DNA double strand breaks (DSB), cellular apoptosis, G2/M phase proportion and inhibition of cell proliferation were observed following irradiation. Differences in the ROS amount and apoptotic percentages of cells between the 2 and 4 Gy groups were insignificant. Compared with 0 Gy, the expression of the apoptosis suppression protein B-cell lymphoma-2 was decreased following at increased irradiation doses. However, apoptosis-associated protein Bcl-2-associated X (Bax), caspase-9 and BH3 interacting domain death agonist (Bid) were elevated following irradiation, compared with the control group (0 Gy). Furthermore, the expression levels of Bax in the 6, 8, 10 and 12.5 Gy groups were significantly increased, compared with the other groups. Caspase-9 expression with 2, 4, 6 and 8 Gy were increased compared with other groups, and the Bid levels with 6 and 8 Gy were also increased compared with other groups. G2/M phase arrest was associated with the increase of checkpoint kinase 1 and reduction of cyclin dependent kinase 1. DNA damage repair was associated with the protein Ku70 in the 2, 8, 10, 12.5, 15 and 20 Gy groups were less than other group. Compared with other group, Ku80 levels were reduced in the 6 and 8 Gy groups, and Rad51 levels were reduced in the 2, 8 and 10 Gy groups. The expression of hypoxia inducible factor-1α, c-Myc and glucose transporter 1 (GLUT1) demonstrated an increasing trend following irradiation in a dose-dependent manner, but the expression of pyruvate kinase M2, in the 2-10 Gy irradiation groups, and GLUT1, in the 12.5, 15 and 20 Gy irradiation groups, were reduced, compared with the other groups. Considering the DNA damage repair and apoptosis mechanisms at molecular and cellular levels, it was concluded that 2, 6, 8 and 10 Gy may be the optimal fractional dose that can promote cell apoptosis, and inhibit DNA damage repair and glycolysis.

α7­nAchR agonist GTS­21 reduces radiation­induced lung injury.

Radiation­induced lung injury (RILI) is a major complication of thoracic radiotherapy that starts as exudative inflammation and proceeds to lung fibrosis, and additional studies are required to develop methods to ameliorate RILI. The aim of this study was to explore whether the nicotinic acetylcholine receptor subtype­7 (α7­nAChR) agonist GTS­21 has a protective effect against RILI. C57BL6 mice were irradiated with 12 Gy to induce a mouse model of RILI. Some of the mice received an i.p. injection of 4 mg/kg GTS­21 for three days with or without radiation treatment. Mice were sacrificed at 1, 3, 7, 14 and 21 days and at 3 and 6 months after irradiation. The results showed that GTS­21 treatment significantly relieved RILI by decreasing TNF­α, IL­1ß and IL­6 production in serum via inhibition of NF­κB activation and downregulation of TLR­4 and HMGB1 expression in the lungs. In addition, we found that GTS­21 may regulate the MMP/TIMP balance in RILI. Finally, we found that GTS­21 inhibited NOX­1 and NOX­2 expression, which subsequently reduced ROS levels and Hif­1α expression in RILI. However, GTS­21 showed little effect on lung tissue without radiation exposure. The results above were also validated in RAW264.7 macrophages. Our results showed that activation of the cholinergic anti­inflammatory pathway via the α7­nAChR agonist GTS­21 reduced RILI. The protective effect of GTS­21 against RILI is partly attributed to inhibition of the HMGB1/TLR4/NF­κB pathway and ROS production. Thus, activation of the α7­nAChR pathway may lead to new possibilities in the therapeutic management of RILI.

Ovarian cancer initially presenting with supra-clavicular lymph node metastasis: A case report.

Supra-clavicular lymph node metastasis from ovarian cancer is rare. The present study reports the unique case of a 43-years-old patient who initially presented with left supra-clavicular lymph node metastasis, and was nulliparous. According to fine-needle aspiration cytology of the metastatic left supra-clavicular lymph nodes and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) scan, the patient was diagnosed with poorly differentiated serous carcinoma of ovarian cancer, stage IV. Following two cycles of platinum-based chemotherapy, PET/CT showed that the patient had achieved a complete response. Next, cytoreductive surgery was performed and the postoperative histological findings showed that the patient had achieved a complete pathological response. According to NCCN Clinical Practice Guidelines in Oncology, the patient was stage IV and four cycles of chemotherapy were provided, with no recurrence observed during 3 years of follow-up. This case indicates that patients who initially present with distant metastatic lymph nodes and are nulliparous might have a better prognosis and avoid overtreatment.

The effect of the TLR9 ligand CpG-oligodeoxynucleotide on the protective immune response to radiation-induced lung fibrosis in mice.

CpG-oligodeoxynucleotide (CpG-ODN) is not only reported to protect against airway hyper responsiveness but is also known as a potent vaccine adjuvant for anti-tumor therapy. Little is known about the effect of CpG-ODN in mice with radiation-induced lung fibrosis (RILF), a common late stage form of tissue damage that occurs after thorax radiotherapy (RT). Here, we evaluated the immunomodulatory effects of CpG-ODN on the development of RILF. Mice were divided into four groups: (1) RT, single dose of 12Gy to the whole thorax; (2) CpG, only intraperitoneal injection of CpG-ODN for total 5 weeks; (3) RT+CpG, irradiation plus CpG-ODN treatment before and after irradiation for total 5 weeks; and (4) control (CTL): No RT or CpG-ODN treatment. In this study, we found that CpG-ODN treatment attenuated lung fibrosis and collagen deposition by increasing the number of M1 macrophagocytes, levels of Type-2 cytokines and TGF-ß. CpG-ODN administration up-regulated the expression of TLR9 and STAT1 phosphorylation and reversed the expression of Type-2 immune response key transcription factor GATA-3. Activation of the JAK-STAT1 signaling pathway further enhanced M1 macrophage differentiation and Type-1 cytokine production. This study reveals the mitigating effect of early exposure to CpG-ODN on lung injury caused by irradiation in mice. The potential mechanism of action may be related to enhancement of Type-1 immunity. In conclusion, CpG-ODN may be a potential therapeutic target to treat RILF.

MicroRNA-320 regulates the radiosensitivity of cervical cancer cells C33AR by targeting ß-catenin.

Cervical cancer is the second most common malignancy in women worldwide and always has recurrence owing to radioresistance. MicroRNA (miRNA or miR) has been identified to relate to the sensitivity of cancer radiotherapy. Here, we investigated the potential of miRNA-320 as a biomarker for radiosensitivity by targeting ß-catenin in cervical cancer. A radioresistant cervical cancer cell line, C33AR, was established, and the radioresistance of C33AR cells was confirmed by a colony-formation assay. The expression of miRNA-320 was detected by reverse transcription-quantitative polymerase chain reaction, and compared between C33A and C33AR. ß-catenin, the target of miRNA-320, was determined at the protein level by western blotting after transfecting the inhibitor of miRNA-320. The expression of miRNA-320 was markedly decreased in C33AR cells, which appeared to be more radioresistant, compared with its parental cell line C33A. Target prediction suggested that miRNA-320 negatively regulated the expression of ß-catenin. Knockdown of ß-catenin increased C33AR radiosensitivity, which revealed that the inhibition of ß-catenin could rescue the miRNA-320-mediated cell radioresistance. On the other hand, overexpressing miRNA-320 increased C33AR radiosensitivity. In conclusion, miRNA-320 regulated the radiosensitivity of C33AR cells by targeting ß-catenin. This finding provides evidence that miRNA-320 may be a potential biomarker of radiosensitivity in cervical cancer.

Radiation-induced lung fibrosis in a tumor-bearing mouse model is associated with enhanced Type-2 immunity.

Lung fibrosis may be associated with Type-2 polarized inflammation. Herein, we aim to investigate whether radiation can initiate a Type-2 immune response and contribute to the progression of pulmonary fibrosis in tumor-bearing animals. We developed a tumor-bearing mouse model with Lewis lung cancer to receive either radiation therapy alone or radiation combined with Th1 immunomodulator unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotide (CpG-ODN). The Type-2 immune phenotype in tumors and the histological grade of lung fibrosis were evaluated in mice sacrificed three weeks after irradiation. Mouse lung tissues were analyzed for hydroxyproline and the expression of Type-1/Type-2 key transcription factors (T-bet/GATA-3). The concentration of Type-1/Type-2 cytokines in serum was measured by cytometric bead array. Lung fibrosis was observed to be more serious in tumor-bearing mice than in normal mice post-irradiation. The fibrosis score in irradiated tumor-bearing mice on Day 21 was 4.33 ± 0.82, which was higher than that of normal mice (2.00 ± 0.63; P < 0.05). Hydroxyproline and GATA-3 expression were increased in the lung tissues of tumor-bearing mice following irradiation. CpG-ODN attenuated fibrosis by markedly decreasing GATA-3 expression. Serum IL-13 and IL-5 were elevated, whereas INF-γ and IL-12 expression were decreased in irradiated tumor-bearing mice. These changes were reversed after CpG-ODN treatment. Thus, Type-2 immunity in tumors appeared to affect the outcome of radiation damage and might be of interest for future studies on developing approaches in which Type-1-related immunotherapy and radiotherapy are used in combination.

ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer.

Evidences suggest that tumor microenvironment may play an important role in cancer drug resistance. Sphingosine kinase 2 (SphK2) is proposed to be the key regulator of sphingolipid signaling. This study is aimed to investigate whether the combination of molecular targeting therapy using a specific inhibitor of SphK2 (ABC294640), with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can enhance the apoptosis of non-small cell lung cancer (NSCLC) cells. Our results revealed that NSCLC cells' sensitivity to TRAIL is correlated with the level of SphK2. Compared with TRAIL alone, the combination therapy enhanced the apoptosis induced by TRAIL, and knockdown of SphK2 by siRNA presented a similar effect. Combination therapy with ABC294640 increased the activity of caspase-3/8 and up-regulated the expression of death receptors (DR). Additional investigations revealed that translocation of DR4/5 to the cell membrane surface was promoted by adding ABC294640. However, expression of anti-apoptosis proteins such as Bcl(-)2 and IAPs was not significantly modified by this SphK2 inhibitor. Overall, this work demonstrates that SphK2 may contribute to the apoptosis resistance in NSCLC, thus indicating a new therapeutic target for resistant NSCLC cells.

The miR-15 family enhances the radiosensitivity of breast cancer cells by targeting G2 checkpoints.

Enhancing radiosensitivity is an important area of investigation for improving breast cancer therapy outcomes. The aim of this study was to assess the role of the miR-15 family in the radiosensitivity of breast cancer cells. MicroRNAs (miRNAs) encoded by the miR-15 cluster are known to induce G1 arrest and apoptosis by targeting G1 checkpoints and the anti-apoptotic B cell lymphoma 2 (BCL-2) gene. However, the effect of the miR-15 family on G2/M arrest and radiosensitivity remains poorly understood. In the current study, cells transfected with miR-15a/15b/16 mimic or inhibitor were irradiated and examined by: clonogenic assays, phosphorylated H2AX assay, flow cytometry, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), real-time PCR and Western blot. Real-time PCR was also used to monitor time-dependent changes of miR-15a/15b/16 expression after irradiation. A putative target site for miR-15a/15b/16 within the Chk1 and Wee1 3' UTRs was confirmed using luciferase reporter assays. Additionally, siRNA was used to validate the effect of Chk1 and Wee1 on radiosensitivity in breast cancer cells. In our study, we investigated the effects of radiation on the miR-15 family and found a time-dependent change in the expression of miR-15a/15b/16 in breast cancer cells postirradiation, as well as an increase in miR-15 family-mediated sensitization of breast cancer cells to radiation. The increase in radiosensitivity induced by the miR-15 family was associated with persistent unrepaired DNA damage, abrogation of radiation-induced G2 arrest and suppressed cell proliferation, and appear to involve both the checkpoint kinase 1 (Chk1) and Wee1. In addition, we found that inhibition of the miR-15 family could not induce cell resistance to radiation. These findings suggest that the expression of the miR-15 family contributes to increased radiosensitivity of breast cancer cells by influencing G2/M checkpoint proteins.

Downregulation of high mobility group box 1 modulates telomere homeostasis and increases the radiosensitivity of human breast cancer cells.

The functions of the high mobility group box 1 (HMGB1) in tumor cells include replenishing telomeric DNA and maintaining cell immortality. There is a negative correlation between human telomerase reverse transcriptase (hTERT) and radiosensitivity in tumor cells. Our aim was to elucidate the relationship among HMGB1, telomere homeostasis and radiosensitivity in MCF-7 cells. In this study, we established stably transfected control (MCF-7-NC) and HMGB1 knockdown (MCF-7-shHMGB1) cell lines. The expression of HMGB1 mRNA and the relative telomere length were examined by real-time PCR. Radiosensitivity was detected by clonogenic assay. The protein expressions were determined by western blot analysis. The telomerase activity was detected by PCR-ELISA. Proliferation ability was examined by CCK-8 assay. Cell cycle and apoptosis were examined by flow cytometry. DNA damage foci were detected by immunofluorescence. ShRNA-mediated downregulation of HMGB1 expression increased the radiosensitivity of MCF-7 cells, and reduced the accumulation of hTERT and cyclin D1. Moreover, knockdown of HMGB1 in MCF-7 cells inhibited telomerase activity and cell proliferation, while increasing the extent of apoptosis. Downregulation of HMGB1 modulated telomere homeostasis by changing the level of telomere-binding proteins, such as TPP1 (PTOP), TRF1 and TRF2. This downregulation also inhibited the ATM and ATR signaling pathways. The current data demonstrate that knockdown of HMGB1 breaks telomere homeostasis, enhances radiosensitivity, and suppresses the repair of DNA damage in human breast cancer cells. These results suggested that HMGB1 might be a potential radiotherapy target in human breast cancer.

Results on efficacy and safety of cancer treatment with or without tumor necrosis factor-related apoptosis-inducing ligand-related agents: A meta-analysis.

This meta-analysis aimed to evaluate the currently available evidence on the efficacy and safety of cancer treatment with or without tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-related agents. We conducted a systematic search through Medline, Cochrane Library and EMBASE electronic databases and manually searched the Journal of Clinical Oncology to identify randomized controlled trials (RCTs) conducted between 1995 and 2013 comparing the efficacy and safety results of cancer treatment with and without TRAIL-related agents. The methodological quality of the included RCTs was assessed by the Cochrane Risk of Bias assessment tool. The outcome measurements included objective response rate (ORR), clinical benefit rate (CBR)/disease control rate (DCR) and adverse events (AEs). The relevant data were analyzed using Review Manager 5.2 software. Grading of Recommendations Assessment Development and Evaluation was used to assess the quality of evidence and grade of recommendation. Four RCTs, including a total of 596 patients, were ultimately selected and analyzed. There were no statistically significant differences among the 4 RCTs regarding ORR [relative risk (RR)=0.92, 95% confidence interval (CI): 0.73-1.15, P=0.45], CBR/DCR (RR=0.92, 95% CI: 0.81-1.05, P=0.21), progression-free survival [hazard ratio (HR)=0.89, 95% CI: 0.75-1.05, P=0.16], overall survival (HR=0.90, 95% CI: 0.74-1.09, P=0.27), number of patients with any AEs (RR=0.99, 95% CI: 0.96-1.03, P=0.77), number of patients with any severe AEs (RR=0.95, 95% CI: 0.78-1.55, P=0.58), number of patients with ≥grade 3 AEs (RR=1.13, 95% CI: 0.93-1.38, P=0.22) and number of fatal AEs (RR=1.14, 95% CI: 0.71-1.81, P=0.59). The quality of evidence was considered to be moderate and the recommendation grades were weak. In conclusion, the benefits of TRAIL-related agents in the treatment of cancer patients remain uncertain and further clinical trials are required.