Loss of Nrf2 aggravates ionizing radiation-induced intestinal injury by activating the cGAS/STING pathway via Pirin.

Ionizing radiation (IR)-induced intestinal injury remains a major limiting factor in abdominal radiation therapy, and its pathogenesis remains unclear. In this study, mouse models of IR-induced intestinal injury were established, and the effect of IR on nuclear factor erythroid 2-related factor 2 (Nrf2) was determined. More severe IR-induced intestinal damage was observed in Nrf2 knockout (KO) mice than in wild-type mice. Then, the negative regulation of cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling by Nrf2 was examined both in vivo and in vitro after IR. This was accompanied by alterations in the intestinal neutrophil and macrophage populations in mice. Subsequently, the effect of the cGAS/STING pathway on the intestinal toxicity of IR was also investigated. Moreover, the downregulation of cGAS/STING by Nrf2 via its target gene, Pirin, was confirmed using transfection assays. A rescue experiment with Pirin was also conducted using adeno-associated virus in Nrf2 KO mice. Finally, the protective effect of calcitriol against IR-induced intestinal injury, along with increased Nrf2 and Pirin levels and decreased cGAS, pSTING, and interferon-beta levels, were observed. Taken together, our results suggest that Nrf2 alleviates IR-induced intestinal injury through Pirin-mediated inhibition of the innate immunity-related cGAS/STING pathway.

Effects of preoperative valgus deformity in patients undergoing neutrally aligned total knee arthroplasty: A retrospective cohort study with a minimum five-year follow-up.

OBJECTIVES: This study aimed to investigate the relationship between the severity of preoperative valgus deformity and clinical outcomes of neutrally aligned total knee arthroplasty (TKA). PATIENTS AND METHODS: A total of 376 knees with valgus deformity who underwent TKA from January 2006 to March 2014 were retrospectively screened, and 287 knees (242 patients; 32 males, 210 females; mean age: 64.5±8.8 years; range, 35 to 83 years) aligned neutrally after the operation were included. Patients were divided into four groups based on the preoperative hip-knee-ankle (HKA): mild (0°< HKA ≤5°, n=94), moderate (5°< HKA ≤10°, n=74), severe (10°< HKA ≤15°, n=75), and very severe (HKA >15°, n=44) groups. Range of motion (ROM), Knee Society Score (KSS), Visual Analog Scale (VAS) dynamic pain scores, and Forgotten Joint Score (FJS) were evaluated. Mechanical failures were recorded to assess prosthesis survival. A survival rate analysis was performed using Kaplan-Meier survival analysis. RESULTS: The degree of preoperative valgus deformity did not have a significant impact on the postoperative ROM, KSS, VAS dynamic pain scores, or FJS at the last follow-up. There were no significant differences in cumulative survival rates of neutrally aligned TKAs at 10 years between the four groups (p=0.513). CONCLUSION: The severity of preoperative valgus deformity did not affect the clinical outcomes of neutrally aligned TKAs in the minimum five-year follow-up. Additionally, it did not impact the survival rates of neutrally aligned TKAs over 10 years.

The effect of a split-dose intravenous dexamethasone and a single high-dose on postoperative blood glucose after total joint arthroplasty: a randomized double-blind placebo-controlled trial.

BACKGROUND: In patients undergoing total joint arthroplasty (TJA), the administration of dexamethasone may contribute to perioperative blood glucose (BG) disturbances, potentially resulting in complications, even in patients without diabetes. This study aimed to demonstrate the impact of different administration regimens of dexamethasone in postoperative BG levels. METHODS: In this randomized, controlled, double-blind trial, 136 patients without diabetes scheduled for TJA were randomly assigned to three groups: two perioperative saline injections (Group A, placebo); a single preoperative injection of 20 mg dexamethasone and a postoperative saline injection (Group B), and two perioperative injections of 10 mg dexamethasone (Group C). Primary outcomes were the postoperative fasting blood glucose (FBG) levels. Secondary outcome parameters were the postoperative postprandial blood glucose (PBG) levels. Postoperative complications within 90 days were also recorded. Risk factors for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl were investigated. RESULTS: Compared to Group A, there were transient increases in FBG and PBG on postoperative days (PODs) 0 and 1 in Groups B and C. Statistical differences in FBG and PBG among the three groups were nearly absent from POD 1 onward. Both dexamethasone regimens did not increase the risk for postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl. Elevated preoperative HbA1c levels may increase the risk of postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl, respectively. CONCLUSION: Perioperative intravenous high-dose dexamethasone to patients without diabetes has transient effects on increasing BG levels after TJA. However, no differences were found between the split-dose and single high-dose regimens. The elevated preoperative HbA1c, but not the dexamethasone regimens were the risk factor for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl. TRIAL REGISTRATION: Chinese Clinical Trail Registry, ChiCTR2300069473. Registered 17 March 2023, https://www.chictr.org.cn/showproj.html?proj=186760 .

Radiotherapy refusal in breast cancer with breast-conserving surgery.

BACKGROUND: Although radiotherapy after breast-conserving surgery has been the standard treatment for breast cancer, some people still refuse to undergo radiotherapy. The aim of this study is to identify risk factors for refusal of radiotherapy after breast-conserving surgery. METHODS: To investigate the trend of refusing radiotherapy after breast-conserving surgery in patients with breast cancer using the Surveillance, Epidemiology, and End Results database. The patients were divided into radiotherapy group and radiotherapy refusal group. Survival results were compared using a multivariate Cox risk model adjusted for clinicopathological variables. Multivariate logistic regression was used to analyze the influencing factors of patients refusing radiotherapy after breast-conserving surgery and a nomogram model was established. RESULTS: The study included 87,100 women who underwent breast-conserving surgery for breast cancer between 2010 and 2015. There were 84,948 patients (97.5%) in the radiotherapy group and 2152 patients (2.5%) in the radiotherapy refusal group. The proportion of patients who refused radiotherapy after breast-conserving surgery increased from 2.1% in 2010 to 3.1% in 2015. The Kaplan-Meier survival curve showed that radiotherapy can improve overall survival (p < 0.001) and breast cancer specific survival (p < 0.001) in the patients with breast-conserving surgery. The results of multivariate logistic regression showed that age, income, marital status, race, grade, stage, subtype and chemotherapy were independent factors associated with the refusal of radiotherapy. CONCLUSIONS: Postoperative radiotherapy can improve the benefits of breast-conserving surgery. Patients with old age, low income, divorce, white race, advanced stage, and no chemotherapy were more likely to refuse radiotherapy.

Highly expressed miR-210 in the peripheral blood is closely associated with asphyxiated neonates.

Background: In the present study, we aimed to detect microRNA-210 (miR-210) expression in the peripheral blood of neonates with asphyxia and determine the correlation between miR-210 and clinical manifestations and indicators related to pathological changes. Further, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the potential target genes of miR-210 to examine their related diseases and network interactions. Methods: In total, 27 neonates with asphyxia were included in the asphyxia group and 26 healthy neonates were included in the normal group. Quantitative real-time polymerase chain reaction was performed to measure miR-210 expression in the peripheral blood. Furthermore, the correlation between miR-210 expression and asphyxia-related clinical indicators was determined, and the receiver operating characteristic curve analysis of miR-210 was conducted. Moreover, GO and KEGG analyses were conducted to identify the target genes of miR-210. Lastly, the association between miR-210 target genes and autism and epilepsy was elucidated and network interaction analysis was performed to determine the involvement of the target genes of miR-210 in neurological or cardiovascular diseases. Results: miR-210 was highly expressed in the peripheral blood of neonates with asphyxia. Furthermore, the mode of normal delivery, cord potential of hydrogen, and Apgar scores were elevated in these neonates. Additionally, we identified 142 miR-210 target genes, which were associated with both neurodevelopmental and cardiovascular diseases. These genes were associated with the metabolic, cancer, and phosphatidylinositol3-kinase/serine/threonine kinase and mitogen-activated kinase-like protein pathways. Furthermore, 102 miR-210 target genes were associated with autism and epilepsy. Conclusions: High miR-210 expression in the peripheral blood of neonates with asphyxia may be associated with anoxic cerebral injury. The miR-210 target genes are associated with neurodevelopmental and cardiovascular diseases and autism and epilepsy.

A radiomics approach for predicting acute hematologic toxicity in patients with cervical or endometrial cancer undergoing external-beam radiotherapy.

PURPOSE: This study is purposed to establish a predictive model for acute severe hematologic toxicity (HT) during radiotherapy in patients with cervical or endometrial cancer and investigate whether the integration of clinical features and computed tomography (CT) radiomics features of the pelvic bone marrow (BM) could define a more precise model. METHODS: A total of 207 patients with cervical or endometrial cancer from three cohorts were retrospectively included in this study. Forty-one clinical variables and 2226 pelvic BM radiomic features that were extracted from planning CT scans were included in the model construction. Following feature selection, model training was performed on the clinical and radiomics features via machine learning, respectively. The radiomics score, which was the output of the final radiomics model, was integrated with the variables that were selected by the clinical model to construct a combined model. The performance of the models was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: The best-performing prediction model comprised two clinical features (FIGO stage and cycles of postoperative chemotherapy) and radiomics score and achieved an AUC of 0.88 (95% CI, 0.81-0.93) in the training set, 0.80 (95% CI, 0.62-0.92) in the internal-test set and 0.85 (95% CI, 0.71-0.94) in the external-test dataset. CONCLUSION: The proposed model which incorporates radiomics signature and clinical factors outperforms the models based on clinical or radiomics features alone in terms of the AUC. The value of the pelvic BM radiomics in chemoradiotherapy-induced HT is worthy of further investigation.

Prognostic significance of MRI-based late-course tumor volume in locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: To validate tumor volume-based imaging markers for predicting local recurrence-free survival (LRFS) in locoregionally advanced nasopharyngeal carcinoma patients, who underwent induction chemotherapy followed by definitive intensity-modulated radiotherapy. METHODS: We enrolled 145 patients with stage III-IVA nasopharyngeal carcinoma in this retrospective study. Pre-treatment tumor volume (Vpre) and late-course volume (LCV) were measured based on the MRIs scanned before treatment and during the first 3 days in the sixth week of radiotherapy, respectively. The volume regression rate (VRR) was calculated according to Vpre and LCV. Receiver operating characteristic (ROC) curves were used to identify the cut-off best separating patient subgroups in assessing the prognostic value of Vpre, LCV and VRR. The Kaplan-Meier method was used for survival analysis. Prognostic analyses were performed using univariate and multivariate COX proportional hazard models. RESULTS: The LCV was 5.3 ± 0.5 (range 0-42.1) cm3; The VRR was 60.4 ± 2.2% (range 2.9-100.0). The median follow-up period was 36 months (range 6-98 months). The cut-off value of LCV determined by the ROC was 6.8 cm3 for LRFS prediction (sensitivity 68.8%; specificity 79.8%). The combination of LCV and VRR for LRFS prediction (AUC = 0.79, P < 0.001, 95% CI 0.67-0.90), LCV (AUC = 0.74, P = 0.002, 95% CI 0.60-0.88) and Vpre (AUC = 0.71, P = 0.007, 95% CI 0.56-0.85) are better than T category (AUC = 0.64, P = 0.062, 95% CI 0.50-0.79) alone. Patients with LCV ≤ 6.8 cm3 had significantly longer LRFS (P < 0.001), disease-free survival (DFS, P < 0.001) and overall survival (OS, P = 0.005) than those with LCV > 6.8 cm3. Multivariate Cox regression showed LCV was the only independent prognostic factor for local control (HR = 7.80, 95% CI 2.69-22.6, P < 0.001). CONCLUSIONS: LCV is a promising prognostic factor for local control and chemoradiosensitivity in patients with locoregionally advanced NPC. The LCV, and the combination of LCV with VRR are more robust predictors for patient survival than T category.

Low-dose X-ray irradiation combined with FAK inhibitors improves the immune microenvironment and confers sensitivity to radiotherapy in pancreatic cancer.

Radiation therapy offers limited clinical benefits for patients with pancreatic cancer, partly as a result of the predominantly immunosuppressive microenvironment characteristic of this specific type of cancer. A large number of abnormal blood vessels and high-density fibrous matrices in pancreatic cancer will lead to hypoxia within tumor tissue and hinder immune cell infiltration. We used low-dose X-ray irradiation, also known as low-dose radiation therapy (LDRT), to normalize the blood vessels in pancreatic cancer, while simultaneously administering an inhibitor of focal adhesion kinase (FAK) to reduce pancreatic cancer fibrosis. We found that this treatment successfully reduced pancreatic cancer hypoxia, increased immune cell infiltration, and increased sensitivity to radiation therapy for pancreatic cancer.

Hypoxic Cell-Derived Extracellular Vesicles Aggravate Rectal Injury Following Radiotherapy via MiR-122-5p.

Radiation-induced rectal injury is a common side effect of radiotherapy. Hypoxia often occurs after radiotherapy. This study aimed to explore the bystander effect of hypoxia on radiation-induced rectal injury. In vivo, apoptosis increased nearby the highly hypoxic area in the rectal tissues in the mouse models of radiation-induced rectal injury, indicating the potential involvement of hypoxia. In vitro, flow cytometry and Western blotting showed that both hypoxia and hypoxic human intestinal epithelial crypt (HIEC) cell supernatant promoted apoptosis in normoxic HIEC cells. The pro-apoptotic effect of extracellular vesicles (EVs) derived from hypoxic HIEC cell to normoxic HIEC cells was then determined. MiR-122-5p was chosen for further studies through a microRNA (miRNA) microarray assay and apoptosis was alleviated in cells receiving miR-122-5p inhibiting hypoxic EVs. Together, our study demonstrated that the miR-122-5p containing-EVs derived from hypoxic HIEC cells promoted apoptosis in normoxic HIEC cells. Hypoxic EV-derived miR-122-5p plays a critical pathologic role in radiation-induced rectal injury and may be a potential therapeutic target.

Intelligent design of polymer nanogels for full-process sensitized radiotherapy and dual-mode computed tomography/magnetic resonance imaging of tumors.

Rationale: Development of intelligent radiosensitization nanoplatforms for imaging-guided tumor radiotherapy (RT) remains challenging. We report here the construction of an intelligent nanoplatform based on poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with gold (Au) and manganese dioxide (MnO2) nanoparticles (NPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging-guided "full-process" sensitized RT of tumors. Methods: PVCL NGs were synthesized via precipitation polymerization and in situ loaded with Au and MnO2 NPs. The created PVCL-Au-MnO2 NGs were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular oxygen and ·OH production, and cell cycle arrest in vitro, evaluated to disclose their RT sensitization effects of cancer cells and a tumor model, and assessed to validate their dual-mode CT/MR imaging potential, pharmacokinetics, biodistribution, and biosafety in vivo. Results: The formed PVCL-Au-MnO2 NGs with a size of 121.5 nm and good stability can efficiently generate reactive oxygen species through a Fenton-like reaction to result in cell cycle distribution toward highly radiosensitive G2/M phase prior to X-ray irradiation, sensitize the RT of cancer cells under X-ray through the loaded Au NPs to induce the significant DNA damage, and further prevent DNA-repairing process after RT through the continuous production of O2 catalyzed by MnO2 in the hybrid NGs to relieve the tumor hypoxia. Likewise, the in vivo tumor RT can also be guided through dual mode CT/MR imaging due to the Au NPs and Mn(II) transformed from MnO2 NPs. Conclusion: Our study suggests an intelligent PVCL-based theranostic NG platform that can achieve "full-process" sensitized tumor RT under the guidance of dual-mode CT/MR imaging.

Geniposide exerts protective effects on spinal cord injury in rats by inhibiting the IKKs/NF-κB signaling pathway.

BACKGROUND: Spinal cord injury (SCI) is a traumatic condition of the central nervous system , which can cause nerve injury and affect nerve regeneration, thus leading to severe dysfunction of motor and sensory pathways, and unfortunately these effects are irreversible. Inflammatory response constitutes one of the important mechanisms of spinal cord secondary injury. Geniposide (Gen) is reported to possess anti-inflammation and neuronal repair capacities. OBJECTIVES: To investigate the effect and mechanism of Gen on motor function and inflammatory response in SCI rats. METHODS: Sprague-Dawley (SD) rats were randomly grouped, and the SCI model was established by Allen's method. The motor function of rats was evaluated by the Basso, Beattie, and Bresnahan (BBB) scale. The protective effect of Gen on the injured spinal cord tissues was evaluated by measuring the water content, myeloperoxidase (MPO) activity, and levels of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6. Moreover, the protein level of the inflammation-related pathway was detected by spectrometry and Western blot assays. RESULTS: Gen significantly promoted the recovery of SCI rats, decreased the edema of spinal cord tissues, reduced the area of cavity, increased the number of NF-200-positive neurons, as well as increased the number of horseradish peroxidase (HRP) retrograde tracing-positive neurons and regenerated axons with myelin sheath. Additionally, compared with the control group, the neutrophil infiltration, contents of TNF-α, IL-1ß, and IL-6, the activity of inhibitor of nuclear factor κB kinase subunit ß (IKKß) kinase, and protein levels of (nuclear factor κB) NF-κB p65 and phosphorylated inhibitor of NF-κB (p-I-κB) in the Gen experimental group were significantly decreased. CONCLUSION: Gen effectively alleviated inflammatory response after SCI by inhibiting the IKKs/NF-κB signaling pathway and promoted the recovery of motor function and axon regeneration in rats. SIGNIFICANCE: This study can provide novel insights for the early and effective intervention of SCI and confer basic data for the treatment of spinal cord secondary injury.

A deep learning-based auto-segmentation system for organs-at-risk on whole-body computed tomography images for radiation therapy.

BACKGROUND AND PURPOSE: Delineating organs at risk (OARs) on computed tomography (CT) images is an essential step in radiation therapy; however, it is notoriously time-consuming and prone to inter-observer variation. Herein, we report a deep learning-based automatic segmentation (AS) algorithm (WBNet) that can accurately and efficiently delineate all major OARs in the entire body directly on CT scans. MATERIALS AND METHODS: We collected 755 CT scans of the head and neck, thorax, abdomen, and pelvis and manually delineated 50 OARs on the CT images. The CT images with contours were split into training and test sets consisting of 505 and 250 cases, respectively, to develop and validate WBNet. The volumetric Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (95% HD) were calculated to evaluate delineation quality for each OAR. We compared the performance of WBNet with three AS algorithms: one commercial multi-atlas-based automatic segmentation (ABAS) software, and two deep learning-based AS algorithms, namely, AnatomyNet and nnU-Net. We have also evaluated the time saving and dose accuracy of WBNet. RESULTS: WBNet achieved average DSCs of 0.84 and 0.81 on in-house and public datasets, respectively, which outperformed ABAS, AnatomyNet, and nnU-Net. WBNet could reduce the delineation time significantly and perform well in treatment planning, with clinically acceptable dose differences compared with those in manual delineation. CONCLUSION: This study shows the feasibility and benefits of using WBNet in clinical practice.

Nrf2 alleviates radiation-induced rectal injury by inhibiting of necroptosis.

Radiation-induced rectal injury is one of the common side effects of pelvic radiation therapy. This study aimed to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in this process. In vivo, knockout (KO) of Nrf2 led to aggravated radiation-induced histological changes in the rectums. In vitro, interference or overexpression of Nrf2 resulted in enhanced or reduced radiosensitivity in human intestinal epithelial crypts (HIEC) cells, respectively. A potential relationship between Nrf2 and necroptosis was identified using RNA sequencing (RNA-seq) and western blotting (WB), which showed that necroptosis-related proteins were negatively correlated with Nrf2. Upon treatment with necrostatin-1 (Nec-1), the increased radiosensitivity, decreased cell viability, increased γH2AX foci formation, and decreased mitochondrial membrane potential (MMP) in Nrf2-interfered HIEC cells were alleviated. A significant recovery in morphological alterations was also observed in Nrf2 KO mice administered with Nec-1. Taken together, our results highlight the important protective effect of Nrf2 in radiation-induced rectal injury through the inhibition of necroptosis, and the physiological significance of necroptosis in radiation-induced rectal injury.

Upregulation of microRNA-181a-5p increases the sensitivity of HS578T breast cancer cells to cisplatin by inducing vitamin D receptor-mediated cell autophagy.

Breast cancer (BC) is the leading cause of death in females worldwide. Although cisplatin is a strong-effect and broad-spectrum chemotherapy drug, resistance to cisplatin remains a significant factor effecting clinical efficacy. The underlying mechanism of cancer cell resistance to cisplatin is not fully understood. MicroRNAs (miRs/miRNAs), as a regulator, are involved in regulating chemosensitivity to numerous chemotherapeutic drugs. The present study aimed to investigate the function of miR-181a-5p as a potential tumor suppressor in improving the efficiency of cisplatin in BC. The IC50 of cisplatin and miR-181a-5p expression were determined in five BC cell lines, and HS578T was selected as an appropriate cell line for subsequent experiments. The sensitivity of HS578T cells to cisplatin was assessed using cell proliferation, migration and apoptosis assays. Western blotting was performed to detect the expression of vitamin D receptor (VDR) and autophagy in HS578T cells. It was found that the increase in autophagy resulted in increased apoptosis and sensitivity to cisplatin in HS578T cells. miR-181a-5p transfection also inhibited the proliferation and migration ability of HS578T cells and induced apoptosis. Meanwhile, HS578T cells have increased sensitivity to cisplatin. VDR, as a target gene and autophagy regulator of miR-181a-5p, was negatively regulated by miR-181a-5p. Upon the decrease in VDR expression, the autophagy in HS578T cells was increased. These results indicate that the increase in autophagy enhanced the chemosensitivity of cisplatin by inducing apoptosis of HS578T cells and by inhibiting proliferation and migration. The present study showed that miR-181a-5p increased the chemical sensitivity of HS578T cells to cisplatin by inhibiting VDR to promote autophagy. The use of miR-181a-5p/autophagy/VDR-based treatment strategies may be a potential method to overcome cisplatin resistance in BC.

Ultrasound classification-guided minimally invasive rotary cutting in granulomatous lobular mastitis.

BACKGROUND: To summarize the clinical experience of ultrasound-guided minimally invasive surgery for granulomatous lobular mastitis (GLM), and explore the feasibility of this technique for treating GLM. METHODS: This retrospective study reviewed the clinical features and treatment outcome of 30 patients who were diagnosed pathologically as GLM from 2016.3 to 2019.5 in the Department of Breast Surgery, Women's and Children's Hospital, Xiamen University. These patients weretreated with ultrasound-guided Mammotome minimally invasive surgery, and we tried to classified the lesion into four distinct patterns (diffuse abscess mixed type, sheet hypoechoic type, localized abscess type, localized hypoechoic mass type) according to the sonographic findings and clinical symptoms to find out if these patterns correlated with treatment and recurrence rate. RESULTS: After a median follow-up of 12 months on average (4-42 months), 26 cases (86.7%) were cured without acute or chronic complications such as disseminated inflammation and bleeding. Post-operative bleeding occurred in 1 case, and 3 cases (10.00%) relapsed. The ultrasound classification had 0 cases of diffuse abscess mixed type, 17 cases (56.7%) of sheet hypoechoic type, 9 cases (30%) of localized abscess type, and 4 cases (13.3%) of localized hypoechoic mass type. All 3 recurrent cases were sheet hypoechoic type, which were cured after another open surgical resection and showed no recurrence during an average follow-up of 20 months (11-40 months). CONCLUSIONS: In treating GLM patients with minimally invasive rotary cutting, ultrasound classification helps to select suitable patients, especially those with localized abscess and localized hypoechoic mass types with low recurrence rate, which is one of the safe and effective treatment methods.

MiR-122-5p increases radiosensitivity and aggravates radiation-induced rectal injury through CCAR1.

Radiation-induced rectal injury is a major side-effect observed in patients with pelvic malignancies who receive radiotherapy. MicroRNA (miRNA), involved in many cellular biological processes, can be disturbed by ionizing radiation (IR). In this study, we have investigated the function of microRNA-122-5p (miR-122-5p) in radiation-induced rectal injury. MiR-122-5p levels in the serum of rectal cancer patients or in the rectal tissues of C57BL/6 mice before and after IR were detected by quantitative real-time PCR (qRT-PCR). We found that the miR-122-5p levels were significantly up-regulated in patients' serum or in mice rectal tissues after IR. Elevation of miR-122-5p levels sensitized human intestinal epithelial crypt (HIEC) cells to IR both in vitro and in vivo. MiR-122-5p mimic was transfected to HIEC cells and the downstream targets were predicted by bioinformatic analysis. Two putative target sites of miR-122-5p in the 3'UTR of the cell cycle and apoptosis regulator 1 (CCAR1) mRNA were found and verified by luciferase reporter assay. Overexpression of miR-122-5p or silencing CCAR1 combined with IR significantly inhibited cell survival, enhanced radiosensitivity, and increased cell apoptosis compared to that in the negative control group in vitro. In vivo injection of miR-122-5p antagomir after IR significantly alleviated radiation-induced rectal injury in mice. These results suggest that miR-122-5p aggravates radiation-induced rectal injury through targeting CCAR1.

MRI-guided robotic arm drives optogenetic fMRI with concurrent Ca2+ recording.

Optical fiber-mediated optogenetic activation and neuronal Ca2+ recording in combination with fMRI provide a multi-modal fMRI platform. Here, we developed an MRI-guided robotic arm (MgRA) as a flexible positioning system with high precision to real-time assist optical fiber brain intervention for multi-modal animal fMRI. Besides the ex vivo precision evaluation, we present the highly reliable brain activity patterns in the projected basal forebrain regions upon MgRA-driven optogenetic stimulation in the lateral hypothalamus. Also, we show the step-wise optical fiber targeting thalamic nuclei and map the region-specific functional connectivity with whole-brain fMRI accompanied by simultaneous calcium recordings to specify its circuit-specificity. The MgRA also guides the real-time microinjection to specific deep brain nuclei, which is demonstrated by an Mn-enhanced MRI method. The MgRA represents a clear advantage over the standard stereotaxic-based fiber implantation and opens a broad avenue to investigate the circuit-specific functional brain mapping with the multi-modal fMRI platform.

AnatomyNet: Deep learning for fast and fully automated whole-volume segmentation of head and neck anatomy.

PURPOSE: Radiation therapy (RT) is a common treatment option for head and neck (HaN) cancer. An important step involved in RT planning is the delineation of organs-at-risks (OARs) based on HaN computed tomography (CT). However, manually delineating OARs is time-consuming as each slice of CT images needs to be individually examined and a typical CT consists of hundreds of slices. Automating OARs segmentation has the benefit of both reducing the time and improving the quality of RT planning. Existing anatomy autosegmentation algorithms use primarily atlas-based methods, which require sophisticated atlas creation and cannot adequately account for anatomy variations among patients. In this work, we propose an end-to-end, atlas-free three-dimensional (3D) convolutional deep learning framework for fast and fully automated whole-volume HaN anatomy segmentation. METHODS: Our deep learning model, called AnatomyNet, segments OARs from head and neck CT images in an end-to-end fashion, receiving whole-volume HaN CT images as input and generating masks of all OARs of interest in one shot. AnatomyNet is built upon the popular 3D U-net architecture, but extends it in three important ways: (a) a new encoding scheme to allow autosegmentation on whole-volume CT images instead of local patches or subsets of slices, (b) incorporating 3D squeeze-and-excitation residual blocks in encoding layers for better feature representation, and (c) a new loss function combining Dice scores and focal loss to facilitate the training of the neural model. These features are designed to address two main challenges in deep learning-based HaN segmentation: (a) segmenting small anatomies (i.e., optic chiasm and optic nerves) occupying only a few slices, and (b) training with inconsistent data annotations with missing ground truth for some anatomical structures. RESULTS: We collected 261 HaN CT images to train AnatomyNet and used MICCAI Head and Neck Auto Segmentation Challenge 2015 as a benchmark dataset to evaluate the performance of AnatomyNet. The objective is to segment nine anatomies: brain stem, chiasm, mandible, optic nerve left, optic nerve right, parotid gland left, parotid gland right, submandibular gland left, and submandibular gland right. Compared to previous state-of-the-art results from the MICCAI 2015 competition, AnatomyNet increases Dice similarity coefficient by 3.3% on average. AnatomyNet takes about 0.12 s to fully segment a head and neck CT image of dimension 178 × 302 × 225, significantly faster than previous methods. In addition, the model is able to process whole-volume CT images and delineate all OARs in one pass, requiring little pre- or postprocessing. CONCLUSION: Deep learning models offer a feasible solution to the problem of delineating OARs from CT images. We demonstrate that our proposed model can improve segmentation accuracy and simplify the autosegmentation pipeline. With this method, it is possible to delineate OARs of a head and neck CT within a fraction of a second.

FAK alleviates radiation-induced rectal injury by decreasing apoptosis.

Radiation-induced rectal injury is closely related with radiotherapy efficiency. Here, we investigated the effect of focal adhesion kinase (FAK) in radiation-induced rectal injury. Peripheral blood samples of patients with rectal cancer were collected prior to radiotherapy. Differentially expressed genes and copy number variations (CNVs) were analyzed by microarray analysis. The CTCAE v3.0 toxicity grades were used to assess acute rectal injury. The radiosensitivity of human intestinal epithelial crypt (HIEC) cells were assayed by colony formation, mitochondrial membrane potential, flow cytometry and western blotting. The rectums of C57BL/6 mice were X-irradiated locally with a single dose of 15 Gy. The effect of FAK on radiation-induced injury was investigated by hematoxylin-eosin (H&E) staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR). FAK mRNA level was inversely correlated with rectal injury severity in patient samples. A CNV amplification located on chromosome 8 was closely related with FAK. Further functional assays revealed increased levels of γH2AX expression and apoptosis-related proteins in FAK-silenced HIEC cells. The ratio of TUNEL, cl-caspase-3, cyto-c and bax/bcl-2 expression in the rectum mucosa treated with a FAK inhibitor increased significantly. These results demonstrated that FAK reduced radiation-induced rectal injury by decreasing apoptosis.

Phase II Study of Adjuvant Chemoradiotherapy Using Docetaxel/Cisplatin/5-Fluorouracil Before and After Intensity-modulated Radiotherapy With Concurrent Docetaxel in Patients With Completely (R0) Resected Gastric Carcinoma.

OBJECTIVES: The Intergroup 0116 study has demonstrated a significant survival benefit for completely resected (R0) gastric cancer patients treated with a fluorouracil/leucovorin chemoradiotherapy regimen. However, this regimen is also toxic and less effective in terms of distant disease control. Therefore, a more efficacious and safer regimen is urgently needed. METHODS: Patients with R0 resected gastric carcinoma received up to two 21-day cycles of postoperative adjuvant preradiation and postradiation DCF chemotherapy (docetaxel 37.5 mg/m on days 1 and 8, cisplatin 25 mg/m on days 1 to 3, and a continuous infusion of fluorouracil 750 mg/m on days 1 to 5), respectively. Chemoradiotherapy between preradiation and postradiation chemotherapy was initiated on day 43 and consisted of intensity-modulated radiotherapy (45 Gy) plus concurrent docetaxel 20 mg/m weekly for 5 weeks. RESULTS: A total of 55 patients were evaluated and 76% (42) of patients completed the prescribed therapy. With a median follow-up of 61 months, the 3- and 5-year progression-free survival rates were 67% (95% confidence interval [CI], 54%-80%) and 59% (95% CI, 46%-72%), respectively; and the 3- and 5-year overall survival rates were 72% (95% CI, 60%-84%) and 61% (95% CI, 48%-74%), respectively. The most common grade 3 or greater toxicity, during the chemotherapy phase, was neutropenia (24%). Common grade 3/4 toxicities during concurrent chemoradiotherapy were nausea (32%), vomiting (26%), fatigue (15%), and anorexia (19%). CONCLUSIONS: These results demonstrate that this adjuvant regimen is active with an acceptable toxicity profile. A randomized phase 3 trial comparing the Intergroup 0116 chemoradiotherapy regimen with this regimen is underway.