Incorporating knowledge of disease-defining hub genes and regulatory network into a machine learning-based model for predicting treatment response in lupus nephritis after the first renal flare.

BACKGROUND: Identifying candidates responsive to treatment is important in lupus nephritis (LN) at the renal flare (RF) because an effective treatment can lower the risk of progression to end-stage kidney disease. However, machine learning (ML)-based models that address this issue are lacking. METHODS: Transcriptomic profiles based on DNA microarray data were extracted from the GSE32591 and GSE112943 datasets. Comprehensive bioinformatics analyses were performed to identify disease-defining genes (DDGs). Peripheral blood samples (GSE81622, GSE99967, and GSE72326) were used to evaluate the effect of DDGs. Single-sample gene set enrichment analysis (ssGSEA) scores of the DDGs were calculated and correlated with specific immunology genes listed in the nCounter panel. GSE60681 and GSE69438 were used to examine the ability of the DDGs to discriminate LN from other renal diseases. K-means clustering was used to obtain the separate gene sets. The clustering results were extended to data derived using the nCounter technique. The least absolute shrinkage and selection operator (LASSO) algorithm was used to identify genes with high predictive value for treatment response after the first RF in each cluster. LASSO models with tenfold validation were built in GSE200306 and assessed by receiver operating characteristic (ROC) analysis with area under curve (AUC). The models were validated by using an independent dataset (GSE113342). RESULTS: Forty-five hub genes specific to LN were identified. Eight optimal disease-defining clusters (DDCs) were identified in this study. Th1 and Th2 cell differentiation pathway was significantly enriched in DDC-6. LCK in DDC-6, whose expression positively correlated with various subsets of T cell infiltrations, was found to be differentially expressed between responders and non-responders and was ranked high in regulatory network analysis. Based on DDC-6, the prediction model had the best performance (AUC: 0.75; 95% confidence interval: 0.44-1 in the testing set) and high precision (0.83), recall (0.71), and F1 score (0.77) in the validation dataset. CONCLUSIONS: Our study demonstrates that incorporating knowledge of biological phenotypes into the ML model is feasible for evaluating treatment response after the first RF in LN. This knowledge-based incorporation improves the model's transparency and performance. In addition, LCK may serve as a biomarker for T-cell infiltration and a therapeutic target in LN.

Developing a novel DNA methylation risk score for survival and identification of prognostic gene mutations in endometrial cancer: a study based on TCGA data.

BACKGROUND: Few studies have focused on DNA methylation in endometrial cancer. The aim of our study is identify its role in endometrial cancer prognosis. METHODS: A publicly available dataset was retrieved from The Cancer Genome Atlas. For validation of expression alteration due to methylation, RNA sequencing data were obtained from other independent cohorts. MethSurv was used to search for candidate CpG probes, which were then filtered by least absolute shrinkage and selection operator Cox regression and multivariate Cox regression analyses to identify final set of CpG probes for overall survival. A methylation-based risk model was developed and receiver operating characteristic analysis with area under curve was used for evaluation. Patients were divided into high- and low-risk groups using an optimal cut-off point. Comprehensive bioinformatic analyses were conducted to identify hub genes, key transcription factors, and enriched cancer-related pathways. Kaplan-Meier curve was used for survival analysis. RESULTS: A 5-CpG signature score was established. Its predictive value for 5-year overall survival was high, with area under curve of 0.828, 0.835 and 0.816 for the training, testing and entire cohorts. cg27487839 and cg12885678 had strong correlation with their gene expression, XKR6 and PTPRN2, and lower PTPRN2 expression was associated with poorer survival in both The Cancer Genome Atlas and the validation datasets. Low-risk group was associated with significantly better survival. Low-risk group harboured more mutations in hub genes and key transcription factors, and mutations in SP1 and MECP2 represented favourable outcome. CONCLUSION: We developed a methylation-based prognostic stratification system for endometrial cancer. Low-risk group was associated with better survival and harboured more mutations in the key regulatory genes.

Gene-associated methylation status of ST14 as a predictor of survival and hormone receptor positivity in breast Cancer.

BACKGROUND: Genomic profiles of specific gene sets have been established to guide personalized treatment and prognosis for patients with breast cancer (BC). However, epigenomic information has not yet been applied in a clinical setting. ST14 encodes matriptase, a proteinase that is widely expressed in BC with reported prognostic value. METHODS: In this present study, we evaluated the effect of ST14 DNA methylation (DNAm) on overall survival (OS) of patients with BC as a representative example to promote the use of the epigenome in clinical decisions. We analyzed publicly available genomic and epigenomic data from 1361 BC patients. Methylation was characterized by the ß-value from CpG probes based on sequencing with the Illumina Human 450 K platform. RESULTS: A high mean DNAm (ß > 0.6779) across 34 CpG probes for ST14, as the gene-associated methylation (GAM) pattern, was associated with a longer OS after adjusting age, stage, histology and molecular features in Cox model (p value < 0.001). A high GAM status was also associated with a higher XBP1 expression level and higher proportion of hormone-positive BC (p value < 0.001). Pathway analysis revealed that altered GAM was related to matrisome-associated pathway. CONCLUSIONS: Here we show the potential role of ST14 DNAm in BC prognosis and warrant further study.

Flexible nanopillars to regulate cell adhesion and movement.

Flexible polymer nanopillar substrates were used to systematically demonstrate cell alignment and migration guided by the directional formation of focal adhesions. The polymer nanopillar substrates were constructed to various height specifications to provide an extensive variation of flexibility; a rectangular arrangement created spatial confinement between adjacent nanopillars, providing less spacing in the horizontal and vertical directions. Three polymer nanopillar substrates with the diameter of 400 nm and the heights of 400, 800, and 1200 nm were fabricated. Super-resolution localization imaging and protein pair-distance analysis of vinculin proteins revealed that Chinese hamster ovary (CHO) cells formed mature focal adhesions on 1200 nm high nanopillar substrates by bending adjacent nanopillars to link dot-like adhesions. The spacing confinement of the adjacent nanopillars enhanced the orthogonal directionality of the formation tendency of the mature focal adhesions. The directional formation of the mature focal adhesions also facilitated the organization of actin filaments in the horizontal and vertical directions. Moreover, 78% of the CHO cells were aligned in these two directions, in conformity with the flexibility and nanotopographical cues of the nanopillars. Biased cell migration was observed on the 1200 nm high nanopillar substrates.

Dual-color dynamic tracking of GM-CSF receptors/JAK2 kinases signaling activation using temporal focusing multiphoton fluorescence excitation and astigmatic imaging.

The dual-color dynamic particle tracking approach that uses temporal focusing multiphoton fluorescence excitation and two-channel astigmatic imaging is utilized to track molecular trajectories in three dimensions to explore molecular interactions. Images of two fluorophores were obtained to extract their positions by optical sectioning excitation using a fast temporal focusing multiphoton excitation microscope (TFMPEM) and by the simultaneous collection of data in two channels. The presented pair of cylindrical lenses, which was used to adjust the astigmatism effect with the minimum shifting of the imaging plane, was more feasible and flexible than single cylindrical lens for aligning two separate detection channels in astigmatic imaging. The lateral and axial positioning resolutions were observed to be approximately 9-13 nm and 23-30 nm respectively, for the two fluorescence channels. The dynamic movement and binding behavior of clusters of GM-CSF receptors and JAK2 kinases in HeLa cells in the presence of GM-CSF ligands were observed. Therefore, the proposed dual-color tracking strategy is useful for the dynamic study of molecular interactions in living specimens with a fast frame rate, less photobleaching, better penetration depth, and minimum optical trapping force.

Hepatobiliary cystadenocarcinoma without mesenchymal stroma in a female patient: a case report.

BACKGROUND: Hepatobiliary cystadenocarcinoma is a rare epithelial malignant neoplasm of the liver or extrahepatic bile ducts. Early diagnosis of hepatobiliary cystadenocarcinoma is difficult because of its asymptomatic features and rarity. Moreover, the molecular pathogenesis of hepatobiliary cystadenocarcinoma remains unclear. Herein, we described a case of hepatobiliary cystadenocarcinoma in female with chronic hepatitis B and repeated hepatolithiasis. CASE PRESENTATION: A 65-year-old woman with medical history of latent hepatitis B virus infection, repeated choledocholisthiasis, and cholecystitis was admitted due to a heterogeneous cystic mass (5.6 cm × 4 cm) shown on abdominal ultrasonography during regular physical checkup. The patient complained about irregular bowel movements with intermittent diarrhea for two months before presentation. Computed tomography (CT) disclosed a multiloculated cystic lesion in the left hepatic lobe with the presence of intraductal stones and dilatation of intrahepatic ducts. Histological results obtained from left lobectomy specimens showed hepatobiliary cystadenocarcinoma without accompanied mesenchymal stroma. CONCLUSION: Notably, hepatobiliary cystadenocarcinoma without mesenchymal stroma seldom occurs in women and is usually associated with poor prognosis. We present the rare findings in this patient and suggest that chronic inflammatory insults in the intrahepatic bile ducts might shed light on the cystadenocarcinogenesis.

Deterministic nuclear reprogramming of mammalian nuclei to a totipotency-like state by Amphibian meiotic oocytes for stem cell therapy in humans.

The ultimate aim of nuclear reprogramming is to provide stem cells or differentiated cells from unrelated cell types as a cell source for regenerative medicine. A popular route towards this is transcription factor induction, and an alternative way is an original procedure of transplanting a single somatic cell nucleus to an unfertilized egg. A third route is to transplant hundreds of cell nuclei into the germinal vesicle (GV) of a non-dividing Amphibian meiotic oocyte, which leads to the activation of silent genes in 24 h and robustly induces a totipotency-like state in almost all transplanted cells. We apply this third route for potential therapeutic use and describe a procedure by which the differentiated states of cells can be reversed so that totipotency and pluripotency gene expression are regained. Differentiated cells are exposed to GV extracts and are reprogrammed to form embryoid bodies, which shows the maintenance of stemness and could be induced to follow new directions of differentiation. We conclude that much of the reprogramming effect of eggs is already present in meiotic oocytes and does not require cell division or selection of dividing cells. Reprogrammed cells by oocytes could serve as replacements for defective adult cells in humans.

MiR-34a functions as a tumor suppressor in oral cancer through the inhibition of the Axl/Akt/GSK-3ß pathway.

Background/purpose: Oral cancer is a prevalent malignancy affecting men globally. This study aimed to investigate the regulatory role of miR-34a in oral cancer cells through the Axl/Akt/glycogen synthase kinase-3ß (GSK-3ß) pathway and its impact on cellular malignancy. Materials and methods: We examined the effects of miR-34a overexpression on the malignancy of oral cancer cells. Multiple oral cancer cell lines were assessed to determine the correlation between endogenous miR-34a and Axl levels. Transfection experiments with miR-34a were conducted to analyze its influence on Axl mRNA and protein expression. Luciferase reporter assays were performed to investigate miR-34a's modulation of Axl gene transcription. Manipulation of miR-34a expression was utilized to demonstrate its regulatory effects on oral cancer cells through the Axl/Akt/GSK-3ß pathway. Results: Overexpression of miR-34a significantly suppressed the malignancy of oral cancer cells. We observed an inverse correlation between endogenous miR-34a and Axl levels across multiple oral cancer cell lines. Transfection of miR-34a resulted in decreased Axl mRNA and protein expression, and luciferase reporter assays confirmed miR-34a-mediated modulation of Axl gene transcription. The study revealed regulatory effects of miR-34a on oral cancer cells through the Axl/Akt/GSK-3ß pathway, leading to alterations in downstream target genes involved in cellular proliferation and tumorigenesis. Conclusion: Our findings highlight the significance of the miR-34a/Axl/Akt/GSK-3ß signaling axis in modulating the malignancy of oral cancer cells. Targeting miR-34a may hold therapeutic potential in oral cancer treatment, as manipulating its expression can attenuate the aggressive behavior of oral cancer cells via the Axl/Akt/GSK-3ß pathway.

The lower trapezius musculocutaneous flap for head and neck reconstruction: two decades of clinical experience.

BACKGROUND: Microsurgical free flap has gained the popularity over pedicle flap nowadays in the reconstruction of head and neck. However, pedicled flaps remain a promising alternative and have a remarkable position in selected patients. This review study aimed to determine the reliability and versatility of the lower trapezius musculocutaneous flap for reconstructing complex defects in the head and neck. METHODS: Between 1993 and 2012, 22 male and 10 female patients underwent a total of 32 lower trapezius flap reconstructions for complex defects that included neoplasm extirpation (n = 21), radionecrosis (n = 6), dehisced laminectomy (n = 2), pressure sore (n = 2), and necrotizing fasciitis (n = 1). The most common site of defect was the perioral region, followed by the neck, posterior skull, back, temporal region, shoulder, and the upper arm. Flap design was based on the defect size and location, as well as the ability to close the donor site primarily and to preserve muscle function. Outcome has been evaluated by the hospital course, postoperative morbidity, mortality, resultant cosmetics, and function at donor and recipient sites. RESULTS: Stable wound coverage with total flap survival was achieved in 30 (93.75%) patients, 2 patients had partial flap necrosis which required flap reinsertion and skin graft coverage. All donor sites were closed primarily. Seroma developed in 2 (6.25%) patients, which were solved by needle aspiration. All muscle function was preserved. Eight patients died of their primary disease. CONCLUSIONS: For selected patients who have advanced stage cancer, surgical sequelae after free flap surgery, unable to tolerate microsurgery, or special defect location, pedicled lower trapezius musculocutaneous flap provides efficient and effective reconstruction for complex defects especially in the head and neck.

Bioinformatic Analyses of Peripheral Blood Transcriptome Identify Altered Neutrophil-Related Pathway and Different Transcriptomic Profiles for Acute Pancreatitis in Patients with and without Chylomicronemia Syndrome.

Acute pancreatitis (AP) is a serious inflammatory condition of the pancreas that can be associated with chylomicronemia syndrome (CS). Currently, no study has explored the differences between non-CS-associated AP and CS-associated AP in terms of gene expression. Transcriptomic profiles of blood samples from patients with AP were retrieved from GSE194331 (non-CS-associated) and GSE149607 (CS-associated). GSE31568 was used to examine the linkage between non-CS-associated AP and the expression of micro RNAs (miRNAs). Differentially expressed genes (DEGs) were identified, a gene regulatory network was constructed, and hub genes were defined. Subsequently, single-sample gene set enrichment analysis (ssGSEA) scores of hub genes were calculated to represent their regulatory-level activity. A total of 1851 shared DEGs were identified between non-CS-associated and CS-associated AP. Neutrophils were significantly enriched in both conditions. In non-CS-associated AP, miRNAs including hsa-miR-21, hsa-miR-146a, and hsa-miR-106a demonstrated a lower expression level as compared with the healthy control. Furthermore, the expression patterns and regulatory activities were largely opposite between non-CS-associated and CS-associated AP, with significantly lower estimated neutrophils in the latter case. In summary, we found that the regulation of neutrophils was altered in AP. There was a different gene expression pattern and lower estimated neutrophil infiltration in CS-associated AP. Whether these findings are clinically significant requires further investigation.

Novel Inflammasome-Based Risk Score for Predicting Survival and Efficacy to Immunotherapy in Early-Stage Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICI) for early-stage non-small cell lung cancer (NSCLC) have been approved to improve outcomes and reduce recurrence. Biomarkers for patient selection are needed. In this paper, we proposed an inflammasome-based risk score (IRS) system for prognosis and prediction of ICI response for early-stage NSCLC. Cox regression analysis was used to identify significant genes (from 141 core inflammasome genes) for overall survival (OS) in a microarray discovery cohort (n = 467). IRS was established and independently validated by other datasets (n = 1320). We evaluated the inflammasome signaling steps based on five gene sets, which were IL1B-, CASP-1-, IL18-, GSDMD-, and inflammasome-regulated genes. Gene set enrichment analysis, the Kaplan-Meier curve, receiver operator characteristic with area under curve (AUC) analysis, and advanced bioinformatic tools were used to confirm the ability of IRS in prognosis and classification of patients into ICI responders and non-responders. A 30-gene IRS was developed, and it indicated good risk stratification at 10-year OS (AUC = 0.726). Patients were stratified into high- and low-risk groups based on optimal cutoff points, and high-risk IRS had significantly poorer OS and relapse-free survival. In addition, the high-risk group was characterized by an inflamed immunophenotype and higher proportion of ICI responders. Furthermore, expression of SLAMF8 was the key gene in IRS and indicated good correlation with biomarkers associated with immunotherapy. It could serve as a therapeutic target in the clinical setting of immunotherapy.

Significant muscle loss after stereotactic body radiotherapy predicts worse survival in patients with hepatocellular carcinoma.

The relationship between sarcopenia and treatment outcomes, especially in patients with hepatocellular carcinoma (HCC) undergoing stereotactic body radiotherapy (SBRT) has not been well-explored. This study aimed to investigate the effects of sarcopenia on the survival and toxicity after SBRT in patients with HCC. We included 137 patients with HCC treated with SBRT between 2008 and 2018. Sarcopenia was defined as a skeletal muscle index (SMI) of < 49 cm2/m2 for men and < 31 cm2/m2 for women using computed tomography images at the mid-level of the third lumbar vertebra. The SMI change was presented as the change per 90 days. The Kaplan-Meier method was used for survival estimation, and the Cox regression was used to determine prognosticators. Sarcopenia was present in 67 of 137 eligible patients. With the median follow-up of 14.1 months and 32.7 months in the entire cohort and in those alive, respectively, patients with pre-SBRT sarcopenia or SMI loss ≥ 7% after SBRT had worse overall survival than their counterparts. Significant survival predictors on multivariate analysis were SMI loss ≥ 7% after SBRT [hazard ratio (HR): 1.96, p = 0.013], presence of extrahepatic metastasis (HR: 3.47, p < 0.001), neutrophil-to-lymphocyte ratio (HR: 1.79, p = 0.027), and multiple tumors (HR: 2.19, p = 0.003). Separate Cox models according to the absence and presence of pre-SBRT sarcopenia showed that SMI loss ≥ 7% remained a significant survival predictor in patients with sarcopenia (HR: 3.06, p = 0.017) compared with those without sarcopenia. SMI loss ≥ 7% is also a predictor of the Child-Pugh score increase by ≥ 2 points after SBRT. SMI loss ≥ 7% after SBRT is a significant prognostic factor for worse survival and is associated with liver toxicity compared with pre-SBRT sarcopenia.

Radiomics-Based Predictive Model of Radiation-Induced Liver Disease in Hepatocellular Carcinoma Patients Receiving Stereo-Tactic Body Radiotherapy.

(1) Background: The application of stereotactic body radiation therapy (SBRT) in hepatocellular carcinoma (HCC) limited the risk of the radiation-induced liver disease (RILD) and we aimed to predict the occurrence of RILD more accurately. (2) Methods: 86 HCC patients were enrolled. We identified key predictive factors from clinical, radiomic, and dose-volumetric parameters using a multivariate analysis, sequential forward selection (SFS), and a K-nearest neighbor (KNN) algorithm. We developed a predictive model for RILD based on these factors, using the random forest or logistic regression algorithms. (3) Results: Five key predictive factors in the training set were identified, including the albumin-bilirubin grade, difference average, strength, V5, and V30. After model training, the F1 score, sensitivity, specificity, and accuracy of the final random forest model were 0.857, 100, 93.3, and 94.4% in the test set, respectively. Meanwhile, the logistic regression model yielded an F1 score, sensitivity, specificity, and accuracy of 0.8, 66.7, 100, and 94.4% in the test set, respectively. (4) Conclusions: Based on clinical, radiomic, and dose-volumetric factors, our models achieved satisfactory performance on the prediction of the occurrence of SBRT-related RILD in HCC patients. Before undergoing SBRT, the proposed models may detect patients at high risk of RILD, allowing to assist in treatment strategies accordingly.

Dynamic Changes in Neutrophil-to-Lymphocyte Ratio are Associated with Survival and Liver Toxicity Following Stereotactic Body Radiotherapy for Hepatocellular Carcinoma.

PURPOSE: Immune response to antitumor therapies has been correlated with oncologic outcomes. This study aimed to determine whether dynamic changes in immune parameters could predict survival outcomes and assess their relationship with liver toxicity in hepatocellular carcinoma (HCC) patients treated with stereotactic body radiation therapy (SBRT). METHODS: Data on pre- and post-SBRT (within 3 months) peripheral blood cell counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were retrospectively collected. Kinetic changes in these immune parameters and delta-NLR (dNLR) and delta-PLR (dPLR) in response to SBRT were evaluated. Overall survival (OS) and progression-free survival (PFS) were compared based on baseline NLR/PLR and dNLR/dPLR. Additionally, the association of these dynamic measures with liver toxicity was determined. RESULTS: The study included 93 patients with a median 10.7-month follow-up. Significant increases in NLR (p<0.001) and PLR (p=0.003) were observed after SBRT. In the multivariable analysis, elevated pre-SBRT NLR (p<0.001) and dNLR (p=0.011) were predictive of worse OS. dNLR was not associated with PFS. Neither PLR nor dPLR was predictive of survival outcomes. Patients with Child-Turcotte-Pugh class B had higher dNLR and greater risk of liver toxicity than class A counterparts. Receiver operating characteristic curve analysis found that dNLR ≥1.9 was an optimal cut-off value for determining liver toxicity risk (35.1% vs 7.5%, p=0.002). CONCLUSION: Baseline NLR and dNLR can complementarily predict OS in HCC patients treated with SBRT. Elevated dNLR is associated with worse OS and development of liver toxicity, possibly through their relationship with baseline liver function. Dynamic changes in NLR should be monitored in HCC care.

Clinical outcome and pathologic correlation of stereotactic body radiation therapy as a bridge to transplantation for advanced hepatocellular carcinoma: a case series.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an emerging modality for hepatocellular carcinoma (HCC). However, there is scant information about its safety and effectiveness in the neoadjuvant setting prior to liver transplantation (LT). We present the clinical outcome and pathologic assessment of SBRT followed by LT for patients with advanced HCC. METHODS: This retrospective study included HCC patients treated with neoadjuvant SBRT prior to LT between 2009 and 2018. Radiographic response and adverse effects, including radiation-induced liver disease (RILD), were evaluated. Pathologic response was assessed by the percentage of tumor necrosis relative to the total tumor volume. Overall survival (OS) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method. RESULTS: Fourteen patients underwent SBRT for a total of 25 HCC lesions, followed by LT. The median tumor size was 4.45 cm in diameter, and the median prescribed dose was 45 Gy in 5 fractions. SBRT provided significant AFP reduction, 100% infield control, and a 62.5% response rate. The maximum detected toxicity included grade 3 thrombocytopenia and two grade 3-4 hyperbilirubinemia. One patient developed non-classic RILD. Patients were bridged to LT with a median time of 8.4 months after SBRT, and 23.1% of them achieved a complete pathologic response. The median OS and RFS were 37.8 and 18.3 months from the time of LT, respectively. CONCLUSIONS: SBRT provides favorable tumor control and acceptable adverse effects for patients awaiting LT. Further prospective studies to test SBRT as a bridging therapy for LT are feasible.

Radiosensitivity index emerges as a potential biomarker for combined radiotherapy and immunotherapy.

In the era of immunotherapy, there lacks of a reliable genomic predictor to identify optimal patient populations in combined radiotherapy and immunotherapy (CRI). The purpose of this study is to investigate whether genomic scores defining radiosensitivity are associated with immune response. Genomic data from Merged Microarray-Acquired dataset (MMD) were established and the Cancer Genome Atlas (TCGA) were obtained. Based on rank-based regression model including 10 genes, radiosensitivity index (RSI) was calculated. A total of 12832 primary tumours across 11 major cancer types were analysed for the association with DNA repair, cellular stemness, macrophage polarisation, and immune subtypes. Additional 585 metastatic tissues were extracted from MET500. RSI was stratified into RSI-Low and RSI-High by a cutpoint of 0.46. Proteomic differential analysis was used to identify significant proteins according to RSI categories. Gene Set Variance Analysis (GSVA) was applied to measure the genomic pathway activity (18 genes for T-cell inflamed activity). Kaplan-Meier analysis was performed for survival analysis. RSI was significantly associated with homologous DNA repair, cancer stemness and immune-related molecular features. Lower RSI was associated with higher fraction of M1 macrophage. Differential proteomic analysis identified significantly higher TAP2 expression in RSI-Low colorectal tumours. In the TCGA cohort, dominant interferon-γ (IFN-γ) response was characterised by low RSI and predicted better response to programmed cell death 1 (PD-1) blockade. In conclusion, in addition to radiation response, our study identified RSI to be associated with various immune-related features and predicted response to PD-1 blockade, thus, highlighting its potential as a candidate biomarker for CRI.

Pretreatment Neutrophil-to-Lymphocyte Ratio Predicts Survival and Liver Toxicity in Patients With Hepatocellular Carcinoma Treated With Stereotactic Ablative Radiation Therapy.

PURPOSE: The objective of this study was to determine whether pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict survival outcomes and liver toxicity in hepatocellular carcinoma (HCC) patients treated with stereotactic ablative radiation therapy (SABR). METHODS AND MATERIALS: In this retrospective study we collected pretreatment NLR of HCC patients treated with SABR between December 2007 and August 2018 and determined its association with overall survival (OS), progression-free survival, and radiation-related liver toxicity defined as an increase in the Child-Turcotte-Pugh score by ≥2 within 3 months after SABR in the absence of disease progression. RESULTS: A total of 153 patients with a median follow-up of 13.3 months were included. Receiver operating characteristic curve analysis found that an NLR ≥2.4 was optimum (area under the curve, 0.762; 95% confidence interval [CI], 0.682-0.841, P < .001) for predicting poor 1-year OS (38.2% vs 83.6%, P < .001). Multivariable analysis demonstrated that NLR was significantly associated with OS, both as a continuous (P = .006) and a binary variable (NLR set at 2.4; P = .003). Multiple tumors (P = .003), macrovascular invasion (P = .024), extrahepatic spread (P = .002), and albumin-bilirubin score (P = .020) were also significant predictors of OS. Elevated NLR independently prognosticated poor progression-free survival (P = .016). Liver toxicity was seen in 22 evaluable patients (15.4%). Receiver operating characteristic curve analysis found NLR ≥4.0 was optimum at predicting liver toxicity (31.4% vs 10.2%, P = .005). A higher NLR (P = .049) and albumin-bilirubin score (P = .002) were independent risk factors for liver toxicity. CONCLUSIONS: NLR is an objective and ubiquitous inflammatory marker that can predict OS and liver toxicity in HCC patients undergoing SABR. NLR could be a useful biomarker for patient risk stratification and therapeutic decision-making.

Fighter Pilots With Nasopharyngeal Carcinoma Successfully Returning to Flight After Radiotherapy: A Case Series.

For nasopharyngeal carcinoma (NPC), radiotherapy is the primary treatment. However, complications occur after radiation to the nasopharynx, which could potentially affect the flying safety. Four fighter pilots with NPC were reported. With early to locally advanced NPC, they received radiotherapy with or without concurrent chemotherapy. The prescribed radiation dose was 70 Gy to the primary tumor over the nasopharynx. Before treatment, all patients presented with various degrees of hearing loss on pure tone audiometry (main frequencies of 20-45 dB at 3-4.5 kHz for affected ears). After the full course of radiotherapy, tumor regression was noticed during months to years of follow-ups. The follow-up audiometry evaluation showed gradually recovered hearing function (average improvement of 5 dB at pretreatment frequencies) in all pilots. They then returned back to the flight line on annual waiver points. Here, we conclude that fighter pilots with NPC could successfully return to the flight line after radiotherapy. However, detailed physical examinations and confirmation of adaptation to flying condition are warranted.

Preparation of aluminum sludge composite gel spheres and adsorption of U(IV) from aqueous solution.

A novel three-dimensional aluminum sludge/polyvinyl alcohol/sodium alginate(AS/PA/SA) gel spheres were designed and prepared for uranium(VI) adsorption, and it overcomes the shortcomings of poor recycling of powdery aluminum sludge adsorbent and poor stability of sodium alginate. Experiments show that the P-S-AS has a good pH range for removal of uranium (4-5). Fitting experimental data with pseudo-first-order kinetic model and pseudo-second-order kinetic model shows that the adsorption of U(VI) by P-S-AS is a chemical action. The fit of the Langmuir isotherm model and Freundlich isotherm model to the experimental data found that the P-S-AS adsorbed U(VI) to a single layer. Thermodynamic analysis shows that the adsorption occurs spontaneously, and an increase in temperature is favorable for the adsorption of uranium by the P-S-AS. Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS) analysis of the P-S-AS before and after adsorption showed that the main adsorption mechanism was the complexation reaction between functional groups and U(VI), the bonding reaction between metal oxides and U(VI).

The intracellular seven amino acid motif EEGEVFL is required for matriptase vesicle sorting and translocation to the basolateral plasma membrane.

Matriptase plays important roles in epithelial integrity and function, which depend on its sorting to the basolateral surface of cells, where matriptase zymogen is converted to an active enzyme in order to act on its substrates. After activation, matriptase undergoes HAI-1-mediated inhibition, internalization, transcytosis, and secretion from the apical surface into the lumen. Matriptase is a mosaic protein with several distinct protein domains and motifs, which are a reflection of matriptase's complex cellular itinerary, life cycle, and the tight control of its enzymatic activity. While the molecular determinants for various matriptase regulatory events have been identified, the motif(s) required for translocation of human matriptase to the basolateral plasma membrane is unknown. The motif previously identified in rat matriptase is not conserved between the rodent and the primate. We, here, revisit the question for human matriptase through the use of a fusion protein containing a green fluorescent protein linked to the matriptase N-terminal fragment ending at Gly-149. A conserved seven amino acid motif EEGEVFL, which is similar to the monoleucine C-terminal to an acidic cluster motif involved in the basolateral targeting for some growth factors, has been shown to be required for matriptase translocation to the basolateral plasma membrane of polarized MDCK cells. Furthermore, time-lapse video microscopy showed that the motif appears to be required for entry into the correct transport vesicles, by which matriptase can undergo rapid trafficking and translocate to the plasma membrane. Our study reveals that the EEGEVFL motif is necessary, but may not be sufficient, for matriptase basolateral membrane targeting and serves as the basis for further research on its pathophysiological roles.