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Chuan Tian,1,2,* Haifeng Ying,3,* Rongyuan Zhuang,4 Xiaowei Zhang,5 Hongmin Lu,6 Hui Wang,7 Shuowen Wang,8 Qi Li,1 Chungang Wang,9 Xun Cai1 1Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 2Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, People’s Republic of China; 3Department of Traditional Chinese Medicine, Ruijin Hospital, Medical College, Shanghai Jiaotong University, Shanghai 200025, People’s Republic of China; 4Department of Oncology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 5Department of Medical Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 6Department of Oncology, Renji Hospital, Medical College, Shanghai Jiaotong University, Shanghai 200127, People’s Republic of China; 7Department of Oncology, Shanghai Tenth People’s Hospital, Shanghai Tongji University, Shanghai 200072, People’s Republic of China; 8Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 9Department of Radiotherapy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China *These authors contributed equally to this work Purpose: The relationship between the pharmacokinetics of irinotecan and outcomes of advanced colorectal cancer is unclear, and few studies have examined individualized irinotecan-based chemotherapy depending on plasma 7-ethyl-10-hydroxy camptothecin (SN-38) levels and dihydropyrimidine dehydrogenase (DPD) activity, particularly for the UGT1A1*6 or UGT1A1*28 heterozygous type. Methods: This study retrospectively explored the relationship among plasma SN-38 level 1.5 hours after critical enzyme for irinotecan (CPT-11) administration (CSN-38 1.5h), plasma SN-38 level 49 hours after CPT-11 administration (CSN-38 49h), DPD activity, and clinical outcomes for the UGT1A1*6 and UGT1A1*28 heterozygous types. Results: CSN-38 1.5h and CSN-38 49h of the UGT1A1*6 or UGT1A1*28 heterozygous type were close to those of UGT1A1*6 and UGT1A1*28 wild-types; some of those with relatively high CSN-38 1.5h levels obtained better median progression-free survival (mPFS), whereas others with higher CSN-38 49h concentrations showed a relatively high incidence of adverse reactions possibly because of the decreased activity of DPD. Conclusion: Increasing the dosage of CPT-11 according to CSN-38 1.5h may improve the efficacy in patients with lower CSN-38 1.5h levels. For cases with comparably low DPD activity, advisable primary and subsequent dose adjustment of 5-fluorouracil based on plasma 5-fluorouracil levels may be a practical strategy for reducing the occurrence of adverse reactions for personalized treatment of the UGT1A1*6 or UGT1A1*28 heterozygous type. Keywords: irinotecan, pharmacokinetics, enzyme activity, uridine diphosphate glucuronosyltransferase 1A1, colorectal cancer

Background: Many studies have reported that the interaction and dose-response effects of betel quid chewing, tobacco smoking and alcohol drinking habits are important risk factors for oral cancer and precancerous lesions or conditions. These results are useful for comparing statistics, but may not be informative for personal disease-related information. Methods: This study used data from a community screening program to evaluate the dose-response effects of daily frequency and duration from oral habits in Taiwan. The receiver operating characteristic (ROC) curves were further used to compare exposure measurements on indicating the occurrence of lesions/conditions. Results: Our results showed that the highest prevalence was found in leukoplakia (11.1%) and followed by oral submucous fibrosis (OSF, 4.4%). Betel quid chewing habit was found to have dose-response effects on leukoplakia and OSF, cigarette smoking habit only has the dose-response effect on leukoplakia, and alcohol drinking was not associated with both oral precancers. The daily frequency of chewing habit is a better indicator than other dose-response measurements for the occurrence of precancers. In addition, the cut-off points of two to five counts per day have about 60-82% of sensitivities and 79-88% of specificities. Conclusions: The cut-off points from ROC curves can provide an informative message to people with oral habits and their chances of developing diseases. High daily frequency of chewing can lead to excessive irritation to oral mucosa. Although the tobacco is never added to chewing quid in Taiwan, intensive irritation may play an important role in developing oral precancers in Taiwan. [ABSTRACT FROM AUTHOR]

Houttuynia cordata (Saururaceae) injection (HCI) was widely used to treat disease in China. At present, there were about 40 factories producing HCI, but a good quality standard for its quality control was lacking. In this study, an optimized and validated gas chromatography-mass spectrum (GC-MS) method was applied for the fingerprint analysis of 340 batches of HCI from 34 Chinese pharmaceutical factories. The results showed that HCI from the same factory had very similar GC-MS fingerprints, and evident difference existed among different factories. The representative fingerprints from 20 factories whose intra-factory correlation coefficients were over 0.90 and inter-factory correlation coefficients were over 0.75 were used to calculate the mean fingerprint of all samples. Spectral correlative chromatogram (SCC) was adopted to identify common component in different samples. Fifteen main 'common components' were obtained. The mean fingerprint containing those 15 components was suggested to be used as characteristic fingerprint for the rapid identification of HCI and evaluation of the consistency of HCI from factory to factory and from batch to batch. [ABSTRACT FROM AUTHOR]

This study investigated the association between food insecurity and Taiwanese children's ambulatory medical care use for treating eighteen disease types linked to endocrine and metabolic disorders, nutrition, immunity, infections, asthma, mental health, injury, and poisoning. We used longitudinal data in the Taiwan National Health Insurance scheme (NHI) for 764,526 elementary children, and employed approximate NHI data to construct three indicators imputed to food insecurity: low birth weight status, economic status (poverty versus non-poverty), and time of year (summer break time versus semester time). We compared ambulatory care for these diseases between children with low birth weight and those not, and between children living in poverty and those not. A difference-in-differences method was adopted to examine the potential for a publicly- funded lunch program to reduce the harmful health effects of food insecurity on poor children. We found that children in poverty were significantly more likely to have ambulatory visits linked with diabetes, inherited disorders of metabolism, iron deficiency anemias, ill-defined symptoms concerning nutrition, metabolism and development, as well as mental disorders. Children with low birth weight also had a significantly higher likelihood of using care for other endocrine disorders and nutritional deficiencies, in addition to the above diseases. The study failed to find any significant effect of the semester school lunch program on alleviating the harmful health effects of food insecurity for poor children, suggesting that a more intensive food program or other program approaches might be required to help poor children overcome food insecurity and its related health outcomes. [ABSTRACT FROM AUTHOR]

Background: The advantages of proton therapy can be further enhanced with online magnetic resonance imaging (MRI) guidance. One of the challenges in the realization of MRI-guided proton therapy (MRPT) is accurately calculating the radiation dose in the presence of magnetic fields., Purpose: This study aims to develop an efficient and accurate proton dose calculation algorithm adapted to the presence of magnetic fields., Methods: An analytical-numerical radiation dose calculation algorithm, Proton and Ion Dose Engine (PRIDE), was developed. The algorithm combines the pencil beam algorithm (PBA) with a novel iterative voxel-based ray-tracing algorithm. The new ray-tracing method uses fewer assumptions and ensures broader applicability for proton beam trajectory prediction in magnetic fields, and has been compared to Wolf's method and Schellhammer's method. The accuracy of PRIDE algorithm was validated on three phantoms and two practical plans (one single-field water plan and one prostate tumor plan) in different magnetic field strengths up to 3.0 T. The validation was performed by comparing the results against the Monte Carlo (MC) simulations, using the global gamma index criteria of 2%/2 mm and 3%/3 mm with a 10% threshold., Results: PRIDE showed good agreement with MC in homogeneous and slab heterogeneous phantom, achieving gamma passing rates (%GPs) above 99% for 2%/2 mm criteria when magnetic field strength is not greater than 1.5 T. Although the agreement decreased for scenarios involving high proton energy (240 MeV) and strong magnetic field (3.0 T), the 2%/2 mm %GPs still remained above 98%. In lateral heterogeneous phantom, the accuracy of PRIDE decreased due to the PBA's limitation. For the two practical plans in different magnetic fields, %GPs exceeded 98% and 99% for 2%/2 mm and 3%/3 mm criteria, respectively., Conclusions: PRIDE can perform efficient and accurate proton dose calculation in magnetic fields up to 3.0 T, and is expected to work as a useful tool for proton dose calculation in MRPT., (© 2024 American Association of Physicists in Medicine.)

Background: The accuracy of proton therapy and preclinical proton irradiation experiments is susceptible to proton range uncertainties, which partly stem from the inaccurate conversion between CT numbers and relative stopping power (RSP). Proton computed tomography (PCT) can reduce these uncertainties by directly acquiring RSP maps., Purpose: This study aims to develop a novel PCT imaging system based on scintillator-based proton range detection for accurate RSP reconstruction., Methods: The proposed PCT system consists of a pencil-beam brass collimator with a 1 mm aperture, an object stage capable of translation and 360° rotation, a plastic scintillator for dose-to-light conversion, and a complementary metal oxide semiconductor (CMOS) camera for light distribution acquisition. A calibration procedure based on Monte Carlo (MC) simulation was implemented to convert the obtained light ranges into water equivalent ranges. The water equivalent path lengths (WEPLs) of the imaged object were determined by calculating the differences in proton ranges obtained with and without the object in the beam path. To validate the WEPL calculation, measurements of WEPLs for eight tissue-equivalent inserts were conducted. PCT imaging was performed on a custom-designed phantom and a mouse, utilizing both 60 and 360 projections. The filtered back projection (FBP) algorithm was employed to reconstruct the RSP from WEPLs. Image quality was assessed based on the reconstructed RSP maps and compared to reference and simulation-based reconstructions., Results: The differences between the calibrated and reference ranges of 110-150 MeV proton beams were within 0.18 mm. The WEPLs of eight tissue-equivalent inserts were measured with accuracies better than 1%. Phantom experiments exhibited good agreement with reference and simulation-based reconstructions, demonstrating average RSP errors of 1.26%, 1.38%, and 0.38% for images reconstructed with 60 projections, 60 projections after penalized weighted least-squares algorithm denoising, and 360 projections, respectively. Mouse experiments provided clear observations of mouse contours and major tissue types. MC simulation estimated an imaging dose of 3.44 cGy for decent RSP reconstruction., Conclusions: The proposed PCT imaging system enables RSP map acquisition with high accuracy and has the potential to improve dose calculation accuracy in proton therapy and preclinical proton irradiation experiments., (© 2024 American Association of Physicists in Medicine.)

Background: Observational studies have indicated a potential association between autoimmune diseases and the occurrence of Osteoarthritis (OA), with an increased risk of mortality among affected patients. However, whether a causal relationship exists between the two remains unknown., Methods: In the Mendelian randomization (MR) study, we accessed exposure Genome-wide association study (GWAS) data from both the MRC Integrative Epidemiology Unit (MRC-IEU) and the FinnGen consortium. GWAS data for OA were obtained from MRC-IEU. We employed univariable, multivariable, and reverse MR analyses to explore potential associations between autoimmune disorders and OA. Additionally, a two-step mediation MR analysis was performed to investigate indirect factors possibly influencing the relationship between autoimmune disorders and OA. Afterward, we conducted an observational analysis to further explore the relationship between autoimmune disease and occurrence as well as of OA using a real-world database (the MIMIC-IV database). Based on public gene expression sequencing data, we further explored the potential shared pathogenesis between autoimmune diseases and OA., Results: In our univariable MR study, we identified five autoimmune diseases that are associated with OA. These include Celiac disease (OR = 1.061, 95% CI = 1.018-1.105, p  = 0.005), Crohn's disease (OR = 1.235, 95% CI = 1.149-1.327, p  = 9.44E-09), Ankylosing spondylitis (OR = 2.63, 95% CI = 1.21-5.717, p  = 0.015), RA (OR = 1.082, 95% CI = 1.034-1.133, p  = 0.001), and Ulcerative colitis (OR = 1.175, 95% CI = 1.068-1.294, p  = 0.001). In the mediation effect analysis, it was found that there is no correlation between cytokines and autoimmune diseases and OA. Based on transcriptome data analysis, it was found that metabolism-related pathways play a key role in the co-morbidity of autoimmune diseases and OA., Conclusion: Our findings revealed that genes associated with Celiac disease, Crohn's disease, Ankylosing spondylitis, RA, and Ulcerative colitis were independently linked to the development of OA. Furthermore, we conducted an analysis of potential pathogenic genes between these diseases and OA, offering a novel approach for the simultaneous treatment of multiple conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dan, Lu, Zhou, Wang and Wang.)

Ulcerative colitis (UC) is associated with changed dietary habits and mainly linked with the gut microbiota dysbiosis, necroptosis of epithelial cells, and mucosal ulcerations. Liver dysfunction and abnormal level of liver metabolism indices were identified in UC patients, suggesting a close interaction between gut and liver disorders. Methionine-choline deficient diet (MCD) has been shown to induce persistent alterations of gut microbiota and metabolome during hepatitis. In this study we further explored the disease phenotypes in UC patients and investigated whether MCD functioned as a trigger for UC susceptibility. After assessing 88 serum specimens from UC patients, we found significant liver dysfunction and dyslipidemia including abnormal ALT, AST, TG, TC, LDL-c and HDL-c. Liver dysfunction and dyslipidemia were confirmed in DSS-induced colitis mice. We fed mice with MCD for 14 days to cause mild liver damage, and then treated with DSS for 7 days. We found that MCD intake significantly exacerbated the pathogenesis of mucosal inflammation in DSS-induced acute, progressive, and chronic colitis, referring to promotion of mucosal ulcers, colon shortening, diarrhea, inflammatory immune cell infiltration, cytokines release, and abnormal activation of inflammatory macrophages in colon and liver specimens. Intraperitoneal injection of clodronate liposomes to globally delete macrophages dramatically compromised the pathogenesis of MCD-triggering colitis. In addition, MCD intake markedly changed the production pattern of short-chain fatty acids (SCFAs) in murine stools, colons, and livers. We demonstrated that MCD-induced colitis pathogenesis largely depended on the gut microbes and the disease phenotypes could be transmissible through fecal microbiota transplantation (FMT). In conclusion, this study supports the concept that intake of MCD predisposes to experimental colitis and enhances its pathogenesis via modulating gut microbes and macrophages in mice., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Magnetic sense, or termed magnetoreception, has evolved in a broad range of taxa within the animal kingdom to facilitate orientation and navigation. MagRs, highly conserved A-type iron-sulfur proteins, are widely distributed across all phyla and play essential roles in both magnetoreception and iron-sulfur cluster biogenesis. However, the evolutionary origins and functional diversification of MagRs from their prokaryotic ancestor remain unclear. In this study, MagR sequences from 131 species, ranging from bacteria to humans, were selected for analysis, with 23 representative sequences covering species from prokaryotes to Mollusca, Arthropoda, Osteichthyes, Reptilia, Aves, and mammals chosen for protein expression and purification. Biochemical studies revealed a gradual increase in total iron content in MagRs during evolution. Three types of MagRs were identified, each with distinct iron and/or iron-sulfur cluster binding capacity and protein stability, indicating continuous expansion of the functional roles of MagRs during speciation and evolution. This evolutionary biochemical study provides valuable insights into how evolution shapes the physical and chemical properties of biological molecules such as MagRs and how these properties influence the evolutionary trajectories of MagRs.

Objective: To evaluate the diagnostic efficacy and practicality of the Jaundice color card (JCard) as a screening tool for neonatal jaundice. Methods: Following the standards for reporting of diagnostic accuracy studies (STARD) statement, a multicenter prospective study was conducted in 9 hospitals in China from October 2019 to September 2021. A total of 845 newborns who were admitted to the hospital or outpatient department for liver function testing due to their own diseases. The inclusion criteria were a gestational age of ≥35 weeks, a birth weight of ≥2 000 g, and an age of ≤28 days. The neonate's parents used the JCard to measure jaundice at the neonate's cheek. Within 2 hours of the JCard measurement, transcutaneous bilirubin (TcB) was measured with a JH20-1B device and total serum bilirubin (TSB) was detected. The Pearson's correlation analysis, Bland-Altman plots and the receiver operating characteristic (ROC) curve were used for statistic analysis. Results: Out of the 854 newborns, 445 were male and 409 were female; 46 were born at 35-36 weeks of gestational age and 808 were born at ≥37 weeks of gestational age. Additionally, 432 cases were aged 0-3 days, 236 cases were aged 4-7 days, and 186 cases were aged 8-28 days. The TSB level was (227.4±89.6) μmol/L, with a range of 23.7-717.0 μmol/L. The JCard level was (221.4±77.0) μmol/L and the TcB level was (252.5±76.0) μmol/L. Both the JCard and TcB values showed good correlation ( r =0.77 and 0.80, respectively) and agreements (96.0% (820/854) and 95.2% (813/854) of samples fell within the 95% limits of agreement, respectively) with TSB. The JCard value of 12 had a sensitivity of 0.93 and specificity of 0.75 for identifying a TSB ≥205.2 μmol/L, and a sensitivity of 1.00 and specificity of 0.35 for identifying a TSB ≥342.0 μmol/L. The TcB value of 205.2 μmol/L had a sensitivity of 0.97 and specificity of 0.60 for identifying TSB levels of 205.2 μmol/L, and a sensitivity of 1.00 and specificity of 0.26 for identifying TSB levels of 342.0 μmol/L. The areas under the ROC curve (AUC) of JCard for identifying TSB levels of 153.9, 205.2, 256.5, and 342.0 μmol/L were 0.96, 0.92, 0.83, and 0.83, respectively. The AUC of TcB were 0.94, 0.91, 0.86, and 0.87, respectively. There were both no significant differences between the AUC of JCard and TcB in identifying TSB levels of 153.9 and 205.2 μmol/L (both P> 0.05). However, the AUC of JCard were both lower than those of TcB in identifying TSB levels of 256.5 and 342.0 μmol/L (both P <0.05). Conclusions: JCard can be used to classify different levels of bilirubin, but its diagnostic efficacy decreases with increasing bilirubin levels. When TSB level are ≤205.2 μmol/L, its diagnostic efficacy is equivalent to that of the JH20-1B. To prevent the misdiagnosis of severe jaundice, it is recommended that parents use a low JCard score, such as 12, to identify severe hyperbilirubinemia (TSB ≥342.0 μmol/L).

Purpose: Beam delivery latency in respiratory-gated particle therapy systems is a crucial issue to dose delivery accuracy. The aim of this study is to develop a multi-channel signal acquisition platform for investigating gating latencies occurring within RPM respiratory gating system (Varian, USA) and ProBeam proton treatment system (Varian, USA) individually., Methods: The multi-channel signal acquisition platform consisted of several electronic components, including a string position sensor for target motion detection, a photodiode for proton beam sensing, an interfacing board for accessing the trigger signal between the respiratory gating system and the proton treatment system, a signal acquisition device for sampling and synchronizing signals from the aforementioned components, and a laptop for controlling the signal acquisition device and data storage. RPM system latencies were determined by comparing the expected gating phases extracted from the motion signal with the trigger signal's state turning points. ProBeam system latencies were assessed by comparing the state turning points of the trigger signal with the beam signal. The total beam delivery latencies were calculated as the sum of delays in the respiratory gating system and the cyclotron proton treatment system. During latency measurements, simulated sinusoidal motion were applied at different amplitudes and periods for complete beam delivery latency evaluation under different breathing patterns. Each breathing pattern was repeated 30 times for statistical analysis., Results: The measured gating ON/OFF latencies in the RPM system were found to be 104.20 ± 13.64 ms and 113.60 ± 14.98 ms, respectively. The measured gating ON/OFF delays in the ProBeam system were 108.29 ± 0.85 ms and 1.20 ± 0.04 ms, respectively. The total beam ON/OFF latencies were determined to be 212.50 ± 13.64 ms and 114.80 ± 14.98 ms., Conclusion: With the developed multi-channel signal acquisition platform, it was able to investigate the gating lags happened in both the respiratory gating system and the proton treatment system. The resolution of the platform is enough to distinguish the delays at the millisecond time level. Both the respiratory gating system and the proton treatment system made contributions to gating latency. Both systems contributed nearly equally to the total beam ON latency, with approximately 100 ms. In contrast, the respiratory gating system was the dominant contributor to the total beam OFF latency., (© 2024 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Objective . Conventional transarterial chemoembolization (cTACE) is a common treatment for hepatocellular carcinoma (HCC), often with unsatisfactory local controls. Combining cTACE with radiotherapy shows a promise for unresectable large HCC, with proton therapy preserving healthy liver tissue. However, the proton therapy benefits are subject to the accuracy of tissue relative stopping power (RSP) prediction. The RSP values are typically derived from computed tomography (CT) images using stoichiometric calibration. Lipiodol deposition significantly increases CT numbers in liver regions of post-cTACE. Hence, it is necessary to evaluate the accuracy of RSP in liver regions of post-cTACE. Approach . Liver, water, and iodinated oil samples were prepared. Some liver samples contained iodinated oil. The water equivalent path length (WEPL) of sample was measured through the pullbacks of spread-out Bragg peak (SOBP) depth-dose profiles scanned in a water tank with and without sample in the beam path. Measured RSP values were compared to estimated RSP values derived from the CT number based on the stoichiometric calibration method. Main results . The measured RSP of water was 0.991, confirming measurement system calibration. After removing the RSP contribution from container walls, the pure iodinated oil and liver samples had RSP values of 1.12 and 1.06, while the liver samples mixed with varying oil volumes (5 ml, 10 ml, 15 ml) showed RSP values of 1.05, 1.05 and 1.06. Using the stoichiometric calibration method, pure iodinated oil and liver samples had RSP values of 2.79 and 1.06. Liver samples mixed with iodinated oil (5 ml, 10 ml, 15 ml) had calculated RSP values of 1.21, 1.34, and 1.46. The RSP discrepancy reached 149.1% for pure iodinated oil. Significance. Iodinated oil notably raises CT numbers in liver tissue. However, there is almost no effect on its RSP value. Proton treatment of post-cTACE HCC patients can therefore be overshooting if no proper measures are taken against this specific effect., (© 2024 Institute of Physics and Engineering in Medicine.)

Background: Our study investigated the role of FAM53B in regulating macrophage M2 polarization and its potential mechanisms in promoting pancreatic ductal adenocarcinoma (PDAC) metastasis., Aim: To further investigate the role of FAM53B in regulating macrophage M2 polarization and its potential mechanism in promoting PDAC metastasis. Our goal is to determine how FAM53B affects macrophage M2 polarization and to define its underlying mechanism in PDAC metastasis., Methods: Cell culture and various experiments, including protein analysis, immunohistochemistry, and animal model experiments, were conducted. We compared FAM53B expression between PDAC tissues and healthy tissues and assessed the correlation of FAM53B expression with clinical features. Our study analyzed the role of FAM53B in macrophage M2 polarization in vitro by examining the expression of relevant markers. Finally, we used a murine model to study the role of FAM53B in PDAC metastasis and analyzed the potential underlying mechanisms., Results: Our research showed that there was a significant increase in FAM53B levels in PDAC tissues, which was linked to adverse tumor features. Experimental findings indicated that FAM53B can enhance macrophage M2 polarization, leading to increased anti-inflammatory factor release. The results from the mouse model further supported the role of FAM53B in PDAC metastasis, as blocking FAM53B prevented tumor cell invasion and metastasis., Conclusion: FAM53B promotes PDAC metastasis by regulating macrophage M2 polarization. This discovery could lead to the development of new strategies for treating PDAC. For example, interfering with the FAM53B signaling pathway may prevent cancer spread. Our research findings also provide important information for expanding our understanding of PDAC pathogenesis., Competing Interests: Conflict-of-interest statement: The authors declare having no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Acute lung injury (ALI) is an acute and progressive hypoxic respiratory failure that could progress to acute respiratory distress syndrome (ARDS) with a high mortality rate, thus immediate medical attention and supportive care are necessary. The pathophysiology of ALI is characterized by the disruption of the alveolar-capillary barrier and activation of neutrophils, leading to lung tissue damage. The receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising target for the treatment of multiple inflammatory diseases, but the role of RIPK1 in the ALI remains poorly understood. In this study, we aimed to figure out the pathological role of RIPK1 in ALI, especially in the pulmonary immune microenvironment involving neutrophils and endothelial cells. In vivo experiments showed that RIPK1 inhibitor protected against lipopolysaccharide (LPS)-induced lung injury in mouse models, with reduced neutrophils and monocytes infiltration in the lungs. Further studies demonstrated that, besides the inhibitory action on necroptosis, RIPK1 inhibitor directly suppressed reactive oxygen species (ROS) generation and inflammatory cytokines secretion from neutrophils. Furthermore, RIPK1 inhibition maintains the barrier function in TNF-α-primed vascular endothelial cells and prevents their activation induced by the supernatant from LPS-stimulated neutrophils. Mechanistically, the aforementioned effects of RIPK1 inhibitor are associated with the NF-κB signaling pathway, which is partially independent of necroptosis inhibition. These results provide new evidence that RIPK1 inhibitor directly regulates the function of neutrophils and endothelial cells, as well as interferes with the interactions between these two cell types, therefore contributing to a better understanding of RIPK1 in ALI and providing a potential avenue for future therapeutic interventions., (© 2024. The Author(s).)

Background: Non-surgical methods such as percutaneous drainage are crucial for the treatment of patients with severe acute pancreatitis (SAP). However, there is still an ongoing debate regarding the optimal timing for abdominal paracentesis catheter placement and drainage., Aim: To explore the influence of different timing for abdominal paracentesis catheter placement and drainage in SAP complicated by intra-abdominal fluid accumulation., Methods: Using a retrospective approach, 184 cases of SAP complicated by intra-abdominal fluid accumulation were enrolled and categorized into three groups based on the timing of catheter placement: group A (catheter placement within 2 d of symptom onset, n = 89), group B (catheter placement between days 3 and 5 after symptom onset, n = 55), and group C (catheter placement between days 6 and 7 after symptom onset, n = 40). The differences in progression rate, mortality rate, and the number of cases with organ dysfunction were compared among the three groups., Results: The progression rate of group A was significantly lower than those in groups B and groups C (2.25% vs 21.82% and 32.50%, P < 0.05). Further, the proportion of patients with at least one organ dysfunction in group A was significantly lower than those in groups B and groups C (41.57% vs 70.91% and 75.00%, P < 0.05). The mortality rates in group A, group B, and group C were similar ( P > 0.05). At postoperative day 3, the levels of C-reactive protein (55.41 ± 19.32 mg/L vs 82.25 ± 20.41 mg/L and 88.65 ± 19.14 mg/L, P < 0.05), procalcitonin (1.36 ± 0.51 ng/mL vs 3.20 ± 0.97 ng/mL and 3.41 ± 0.98 ng/mL, P < 0.05), tumor necrosis factor-alpha (15.12 ± 6.63 pg/L vs 22.26 ± 9.96 pg/L and 23.39 ± 9.12 pg/L, P < 0.05), interleukin-6 (332.14 ± 90.16 ng/L vs 412.20 ± 88.50 ng/L and 420.08 ± 87.65ng/L, P < 0.05), interleukin-8 (415.54 ± 68.43 ng/L vs 505.80 ± 66.90 ng/L and 510.43 ± 68.23ng/L, P < 0.05) and serum amyloid A (270.06 ± 78.49 mg/L vs 344.41 ± 81.96 mg/L and 350.60 ± 80.42 mg/L, P < 0.05) were significantly lower in group A compared to those in groups B and group C. The length of hospital stay in group A was significantly lower than those in groups B and group C (24.50 ± 4.16 d vs 35.54 ± 6.62 d and 38.89 ± 7.10 d, P < 0.05). The hospitalization expenses in group A were also significantly lower than those in groups B and groups C [2.70 (1.20, 3.55) ten-thousand-yuan vs 5.50 (2.98, 7.12) ten-thousand-yuan and 6.00 (3.10, 8.05) ten-thousand-yuan, P < 0.05). The incidence of complications in group A was markedly lower than that in group C (5.62% vs 25.00%, P < 0.05), and similar to group B ( P > 0.05)., Conclusion: Percutaneous catheter drainage for the treatment of SAP complicated by intra-abdominal fluid accumulation is most effective when performed within 2 d of onset., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Previous studies have observed relationships between immune cells and systemic lupus erythematosus (SLE), but their causal links remain undetermined. Based on the public available genome-wide association studies (GWAS) summary statistics, we conducted two-sample Mendelian randomization (MR) to evaluate the associations between 731 immune phenotypes and SLE pairs. Pairwise pleiotropy analysis was performed to identify pleiotropic genes for significant immunophenotype-SLE pairs. A comprehensive gene function analysis was undertaken to explore the mechanisms of immune cells in SLE. By using the instrumental variables extracted from GWAS data, we observed that increased levels of five immune phenotypes were causally associated with SLE risk (FDR < 0.05), that were CD20 on IgD + CD38 - naïve, BAFF-R on IgD + CD38 dim , CD39 + secreting Treg AC, CD14 - CD16 + monocyte AC, and HLA DR on CD14 + monocyte. Pairwise gene-based analyses identified a total of 38 pleiotropic genes for 5 significant pairs identified and gene set enrichment analysis revealed the involvement of the identified pleiotropic genes in complex pathways (i.e., systemic lupus erythematosus, an integral component of luminal side of endoplasmic reticulum membrane, C-type lectin receptor signaling pathway and regulation of hormone secretion). This study demonstrates that the immune response influences the progression of SLE in a complex pattern. These findings greatly improve our understanding of the interaction between immune response and SLE risk and also aid in the design of therapeutic strategies from an immunological perspective., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Insect olfactory receptors (iORs) with atypical 7-transmembrane domains, unlike Chordata olfactory receptors, are not in the GPCR protein family. iORs selectively bind to volatile ligands in the environment and affect essential insect behaviors. In this study, we constructed a new platform (iORbase, https://www.iorbase.com) for the structural and functional analysis of iORs based on a combined algorithm for gene annotation and protein structure prediction. Moreover, it provides the option to calculate the binding affinities and binding residues between iORs and pheromone molecules by virtual screening of docking. Furthermore, iORbase supports the automatic structural and functional prediction of user-submitted iORs or pheromones. iORbase contains the well-analyzed results of approximately 6 000 iORs and their 3D protein structures identified from 59 insect species and 2 077 insect pheromones from the literature, as well as approximately 12 million pairs of simulated interactions between functional iORs and pheromones. We also built 4 online modules, iORPDB, iInteraction, iModelTM, and iOdorTool to easily retrieve and visualize the 3D structures and interactions. iORbase can help greatly improve the experimental efficiency and success rate, identify new insecticide targets, or develop electronic nose technology. This study will shed light on the olfactory recognition mechanism and evolutionary characteristics from the perspectives of omics and macroevolution., (© 2022 The Authors. Insect Science published by John Wiley & Sons Australia, Ltd on behalf of Institute of Zoology, Chinese Academy of Sciences.)

Background: Large cell lung carcinoma (LCLC) is an exceptionally aggressive disease with a poor prognosis. At present, little is known about the molecular pathology of LCLC., Methods: Ultra-deep sequencing of cancer-related genes and exome sequencing were used to detect the LCLC mutational in 118 tumor-normal pairs. The cell function test was employed to confirm the potential carcinogenic mutation of PI3K pathway., Results: The mutation pattern is determined by the predominance of A > C mutations. Genes with a significant non-silent mutation frequency (FDR) < 0.05) include TP53 (47.5%), EGFR (13.6%) and PTEN (12.1%). Moreover, PI3K signaling (including EGFR, FGRG4, ITGA1, ITGA5, and ITGA2B) is the most mutated pathway, influencing 61.9% (73/118) of the LCLC samples. The cell function test confirmed that the potential carcinogenic mutation of PI3K pathway had a more malignant cell function phenotype. Multivariate analysis further revealed that patients with the PI3K signaling pathway mutations have a poor prognosis (P = 0.007)., Conclusions: These results initially identified frequent mutation of PI3K signaling pathways in LCLC and indicate potential targets for the treatment of this fatal type of LCLC., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Comparative analysis of primate genomes within a phylogenetic context is essential for understanding the evolution of human genetic architecture and primate diversity. We present such a study of 50 primate species spanning 38 genera and 14 families, including 27 genomes first reported here, with many from previously less well represented groups, the New World monkeys and the Strepsirrhini. Our analyses reveal heterogeneous rates of genomic rearrangement and gene evolution across primate lineages. Thousands of genes under positive selection in different lineages play roles in the nervous, skeletal, and digestive systems and may have contributed to primate innovations and adaptations. Our study reveals that many key genomic innovations occurred in the Simiiformes ancestral node and may have had an impact on the adaptive radiation of the Simiiformes and human evolution.

Objective . In the traditional beam-blocker based cone beam CT (CBCT) scatter correction, the scatter measured in the region shaded by lead strips was multiplied by a correction factor to directly represent the scatter in the unblocked region. The correction factor optimization is a tedious process and lacks an objective stop criterion. To skip the optimization process, an indirect scatter estimation method was developed and validated in phantom imaging. Approach. A beam-blocker made of lead strips was mounted between the x-ray source and object for scatter estimation. The primary signal between lead strips in the blocked region was first calculated by subtracting the measured scatter, and then used to calculate the scatter signal in the unblocked region corresponding to the same attenuation path. The calculated scatter signal was smoothed via local filtration and used to correct the measured projection in the unblocked region. Finally, the CBCT was reconstructed via Feldkamp-Davis-Kress algorithm. A Catphan and a head phantom were used to verify the performance of the proposed method in both full- and half-blocker scenarios, and with and without a bow-tie filter. Main Results . For scans without the bow-tie filter, the CT number error was reduced to 3.97±2.27 and 5.51±3.90 HU in the full- and half-blocker scenarios, respectively, for the Catphan, and to 4.01±2.18 and 7.97 ± 4.05 HU for the head phantom. When the bow-tie filter was applied, the CT number error was reduced to 2.29±1.42 and 6.72±0.77 HU in the full- and half-blocker scenarios, respectively, for the Catphan, and 2.35±1.25 and 4.96 ± 1.89 HU for the head phantom. Significance . The proposed method effectively avoids the influence of the inserted beam blocker itself on the scatter intensity estimation, and proves a more practical and robust way for the beam-blocker based scatter correction in CBCT scanning., (© 2023 Institute of Physics and Engineering in Medicine.)

Some patients with therapy-related myeloid neoplasms (t-MN) may have unsuspected inherited cancer predisposition syndrome (CPS). We propose a set of clinical criteria to identify t-MN patients with high risk of CPS (HR-CPS). Among 225 t-MN patients with an antecedent non-myeloid malignancy, our clinical criteria identified 52 (23%) HR-CPS patients. Germline whole-exome sequencing identified pathogenic or likely pathogenic variants in 10 of 27 HR-CPS patients compared to 0 of 9 low-risk CPS patients (37% vs. 0%, p = 0.04). These simple clinical criteria identify t-MN patients most likely to benefit from genetic testing for inherited CPS., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Oral squamous cell carcinoma (OSCC) is a common malignancy in the world. Recently, scientists have focused on therapeutic strategies to determine the regulation of tumors and design molecules for specific targets. Some studies have demonstrated the clinical significance of human leukocyte antigen G (HLA-G) in malignancy and NLR family pyrin domain-containing 3 (NLRP3) inflammasome in promoting tumorigenesis in OSCC. This is the first study to investigate whether aberrant epidermal growth factor receptor (EGFR) induces HLA-G expression through NLRP3 inflammasome-mediated IL-1β secretion in OSCC. Our results showed that the upregulation of NLRP3 inflammasome leads to abundant HLA-G in the cytoplasm and cell membrane of FaDu cells. In addition, we also generated anti-HLA-G chimeric antigen receptor (CAR)-T cells and provided evidence for their effects in EGFR-mutated and overexpressed oral cancer. Our results may be integrated with OSCC patient data to translate basic research into clinical significance and may lead to novel EGFR-aberrant OSCC treatment., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Objective. Proton therapy after breast-conserving surgery (BCS) can substantially reduce the dose to lung and cardiac structures. However, these dosimetric benefits are subject to beam range uncertainty in patient. The conversion of the CT-Hounsfield unit (HU) into relative stopping power (RSP) is the primary contribution to range uncertainty. Hence, an accurate HU-RSP conversion is essential. Approach. Real tissue samples, including muscle and adipose, were prepared. The water equivalent path length (WEPL) of these samples was measured under homogeneous conditions using a 12-diode detector array of our time-resolved in vivo range verification system (IRVS). The HU-RSP conversion was improved using the measured WEPL and HU for adipose tissue. The measured WEPL values were compared with the treatment planning calculation results based on the stoichiometric CT-HU calibration technique. The effect was investigated for both with and without adipose tissue in HU-RSP conversion. Main results. The IRVS was calibrated based on the solid water phantom. The relative differences in WEPL (RSP) between measurements and calculations for muscle, adipose, and water was -1.19% (-0.75%), -4.25%(-4%), and -0.23%(-0.07%), respectively. Based on the improved HU-RSP conversion, the relative differences in WEPL was reduced to -0.97%(-0.62%), -1.50%(-1.46%), and -0.22% (0.00%), respectively. Significance. The WEPL deviation of adipose tissue is larger than the testing limit of 3.5% for beam range robustness in current clinical practice. However, the improved HU-RSP conversion reduced this deviation. The main component of breast tissue is adipose. Hence, the proton treatment of BCS can be undershooting if no proper measures are taken against this specific uncertainty., (© 2022 Institute of Physics and Engineering in Medicine.)

Background: With uncontrolled inflammatory progression, acute pancreatitis (AP) can progress to severe acute pancreatitis (SAP). Inflammation and parenchymal cell death are key pathologic responses of AP. Toll-like receptor 4 (TLR4) plays a pro-inflammatory role in AP. Myeloid differentiation primary response protein 88 (MyD88) is the most essential utilized adaptor of TLR4, but its role in AP remains unclear. We investigated the potential role of MyD88 in the pathogenesis of AP., Methods: An AP model was induced by administering either cerulein or L-arginine to wild-type or MyD88-deficient mice. Additionally, receptor-interacting protein kinase 1 (RIP1) inhibitor necrostatin-1 (Nec-1) was administered to the MyD88 -/- mice. The severity of AP was determined by measuring serum amylase and lipase activities, quantifying pancreatic myeloperoxidase (MPO) activity, and histological examination. The effects of MyD88 deletion on cell death and the inflammatory response were determined by measuring apoptosis, necrosis, and inflammatory cytokines. Western blot was used to assess the necrotic mediators, RIP1 and RIP3., Results: The deletion of MyD88 resulted in more severe acute experimental pancreatitis as assessed by increased amylase and lipase activities, increased pancreatic MPO activity, a reduced anti-inflammatory response, reduced apoptosis, and increased necrosis. Additionally, Nec-1 treatment significantly reduced necrosis in the MyD88 -/- mice., Conclusions: The deletion of MyD88 inhibited the TLR4/MyD88-dependent pathway mediated protective immune defense response and enhanced TLR4/MyD88-independent TRIF pathway-mediated pancreatic necrosis, which in turn aggravated the severity of AP. The critical role of MyD88 in immune defense response and cell death indicates that MyD88 represents a potential therapeutic target in the management of AP., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5134/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Introduction: Unscheduled machine downtime can cause treatment interruptions and adversely impact patient treatment outcomes. Conventional Quality Assurance (QA) programs of a proton Pencil Beam Scanning (PBS) system ensure its operational performance by keeping the beam parameters within clinical tolerances but often do not reveal the underlying issues of the device prior to a machine malfunction event. In this study, we propose a Predictive Maintenance (PdM) approach that leverages an advanced analytical tool built on a deep neural network to detect treatment delivery machine issues early., Methods: Beam delivery log file data from daily QA performed at the Burr Proton Center of Massachusetts General Hospital were collected. A novel PdM framework consisting of long short-term memory-based autoencoder (LSTM-AE) modeling of the proton PBS delivery system and a Mahalanobis distance-based error metric evaluation was constructed to detect rare anomalous machine events. These included QA beam pauses, clinical operational issues, and treatment interruptions. The model was trained in an unsupervised fashion on the QA data of normal sessions so that the model learned characteristics of normal machine operation. The anomaly is quantified as the multivariate deviation between the model predicted data and the measured data of the day using Mahalanobis distance (M-Score). Two-layer and three-layer Long short-term memory-based stacked autoencoder (LSTM-SAE) models were optimized for exploring model performance improvement. Model validation was performed with two clinical datasets and was analyzed using the area under the precision-recall curve (AUPRC) and the area under the receiver operating characteristic (AUROC)., Results: LSTM-SAE models showed strong performance in predicting QA beam pauses for both clinical validation datasets. Despite severe skew in the dataset, the model achieved AUPRC of 0.60 and 0.82 and AUROC of 0.75 and 0.92 in the respective 2018 and 2020 datasets. Moreover, these amount to 2.8-fold and 10.7-fold enhancement compared to the respective baseline event rates. In addition, in terms of treatment interruption events, model prediction enabled 3.88-fold and 51.2-fold detection improvement, while the detection improvement for clinical operational issues was 1.04-fold and 1.37-fold, respectively, in the 2018 and 2020 datasets., Conclusion: Our novel deep LSTM-SAE-based framework allows for highly discriminative prediction of anomalous machine events and demonstrates great promise for enabling PdM for proton PBS beam delivery., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Acute lung injury (ALI) is a common and devastating clinical disorder featured by excessive inflammatory responses. Stimulator of interferon genes (STING) is an indispensable molecule for regulating inflammation and immune response in multiple diseases, but the role of STING in the ALI pathogenesis is not well elucidated. In this study, we explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (15, 30 mg/kg, i.p.) before LPS inhalation to induce ALI. We showed that LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 pretreatment dose-dependently suppressed the expression of STING, decreased the production of inflammatory cytokines including TNF-α, IL-6, IL-12, and IL-1β, and restrained the expression of chemokines and adhesion molecule vascular cell adhesion protein-1 (VCAM-1) in the lung tissues. Consistently, in vitro experiments conducted in TNF-α-stimulated HMEC-1cells (common and classic vascular endothelial cells) revealed that human STING inhibitor H-151 or STING siRNA downregulated the expression levels of adhesion molecule and chemokines in HMEC-1cells, accompanied by decreased adhesive ability and chemotaxis of immunocytes upon TNF-α stimulation. We further revealed that STING inhibitor H-151 or STING knockdown significantly decreased the phosphorylation of transcription factor STAT1, which subsequently influenced its binding to chemokine CCL2 and adhesive molecule VCAM-1 gene promoter. Collectively, STING inhibitor can alleviate LPS-induced ALI in mice by preventing vascular endothelial cells-mediated immune cell chemotaxis and adhesion, suggesting that STING may be a promising therapeutic target for the treatment of ALI., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Aims: Sonic hedgehog subtype medulloblastoma is featured with overactivation of hedgehog pathway and can be targeted by SMO-specific inhibitors. However, the resistance is frequently developed leading to treatment failure of SMO inhibitors. W535L mutation of SMO (SMO W535L ) is thought to be an oncogenic driver for Sonic hedgehog subtype MB and confer resistance to SMO inhibitors. The regulation network of SMO W535L remains to be explored in comparison with wild-type SMO (SMO WT )., Methods: In this study, we profiled transcriptomes, methylomes, and interactomes of MB cells expression SMOWT or SMOW535L in the treatment of DMSO or SMO inhibitor, respectively., Results: Analysis of transcriptomic data indicated that SMO inhibitor disrupted processes of endocytosis and cilium organization in MB cells with SMO WT , which are necessary for SMO activation. In MB cells with SMO W535L , however, SMO inhibitor did not affect the two processes-related genes, implying resistance of SMO W535L toward SMO inhibitor. Moreover, we noticed that SMO inhibitor significantly inhibited metabolism-related pathways. Our metabolic analysis indicated that nicotinate and nicotinamide metabolism, glycerolipid metabolism, beta-alanine metabolism, and synthesis and degradation of ketone bodies might be involved in SMO W535L function maintenance. Interactomic analysis revealed casein kinase II (CK2) as an important SMO-associated protein. Finally, we linked CK2 and AKT together and found combination of inhibitors targeting CK2 and AKT showed synergetic effects to inhibit the growth of MB cells with SMO constitutive activation mutation., Conclusions: Taken together, our work described SMO-related transcriptomes, metabolomes, and interactomes under different SMO status and treatment conditions, identifying CK2 and AKT as therapeutic targets for SHH-subtype MB cells with SMO inhibitor resistance., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Invasive growth of glioblastoma makes residual tumor unremovable by surgery and leads to disease relapse. Temozolomide is widely used first-line chemotherapy drug to treat glioma patients, but development of temozolomide resistance is almost inevitable. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is found to be related to temozolomide response of gliomas. However, whether inducing ferroptosis could affect invasive growth of glioblastoma cells and which ferroptosis-related regulators were involved in temozolomide resistance are still unclear. In this study, we treated glioblastoma cells with RSL3, a ferroptosis inducer, in vitro (cell lines) and in vivo (subcutaneous and orthotopic animal models). The treated glioblastoma cells with wild-type or mutant IDH1 were subjected to RNA sequencing for transcriptomic profiling. We then analyze data from our RNA sequencing and public TCGA glioma database to identify ferroptosis-related biomarkers for prediction of prognosis and temozolomide resistance in gliomas. Analysis of transcriptome data from RSL3-treated glioblastoma cells suggested that RSL3 could inhibit glioblastoma cell growth and suppress expression of genes involved in cell cycle. RSL3 effectively reduced mobility of glioblastoma cells through downregulation of critical genes involved in epithelial-mesenchymal transition. Moreover, RSL3 in combination with temozolomide showed suppressive efficacy on glioblastoma cell growth, providing a promising therapeutic strategy for glioblastoma treatment. Although temozolomide attenuated invasion of glioblastoma cells with mutant IDH1 more than those with wild-type IDH1, the combination of RSL3 and temozolomide similarly impaired invasive ability of glioblastoma cells in spite of IDH1 status. Finally, we noticed that both ferritin heavy chain 1 and ferritin light chain predicted unfavorable prognosis of glioma patients and were significantly correlated with mRNA levels of methylguanine methyltransferase as well as temozolomide resistance. Altogether, our study provided rationale for combination of RSL3 with temozolomide to suppress glioblastoma cells and revealed ferritin heavy chain 1 and ferritin light chain as biomarkers to predict prognosis and temozolomide resistance of glioma patients., (© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Background and Objectives: The immunogenicity of vaccines is known to be attenuated in patients with end-stage kidney disease due to uremia. Patients on dialysis were excluded from coronavirus disease 2019 (COVID-19) vaccine trials; thus, the effectiveness of vaccines for this population is unclear. The aim of this study was to explore whether Asian dialysis patients can effectively produce an immune response after being vaccinated with the first dose of the ChAdOx1 nCoV-19 vaccine., Design Setting, Participants, and Measurements: In this prospective cohort study, we included Asian hemodialysis patients who received the ChAdOx1 nCoV-19 vaccine. At 3 weeks after the first dose of vaccination, we assessed the humoral immune response by measuring anti-SARS-CoV-2 S antibody titers. The primary outcome was the seropositive rate following vaccination, defined as an antibody titer greater than or equal to 0.8 U/ml. Factors associated with seropositivity were explored in multivariate logistic regression analyses., Results: In total, 434 participants were included. The mean age was 64 years, the mean dialysis vintage was 6 years, and 61% of the participants were men. At a mean time of 22 days from vaccination, 56% of the participants were seropositive. The vast majority (88%) had low antibody titers (< 15 U/ml). The multivariate logistic regression analyses showed that older age (every increase of 10 years, odds ratio [OR] 0.80, 95% CI 0.65-0.98, p = 0.03) was negatively associated with seropositivity and that higher Kt/V (every increase of 0.1, OR 1.14, 95% CI 1.01-1.28, p = 0.03) and higher serum albumin level (every increase of 0.1 g/dl, OR 1.09, 95% CI 1.02-1.18, p = 0.02) were positively associated with seropositivity., Conclusions: In Asian hemodialysis patients, the seropositive rate was low, and most had low antibody titers after the first dose of the ChAdOx1 nCoV-19 vaccine. Younger age, better dialysis adequacy, and higher albumin levels were associated with seropositivity., (© 2022 International Society for Hemodialysis.)

Objective To explore the association between lipid profiles and left ventricular hypertrophy in a Chinese general population. Methods We conducted a retrospective observational study to investigate the relationship between lipid markers [including triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL-cholesterol, apolipoprotein A-I, apolipoprotein B, lipoprotein[a], and composite lipid profiles] and left ventricular hypertrophy. A total of 309,400 participants of two populations (one from Beijing and another from nationwide) who underwent physical examinations at different health management centers between 2009 and 2018 in China were included in the cross-sectional study. 7,475 participants who had multiple physical examinations and initially did not have left ventricular hypertrophy constituted a longitudinal cohort to analyze the association between lipid markers and the new-onset of left ventricular hypertrophy. Left ventricular hypertrophy was measured by echocardiography and defined as an end-diastolic thickness of the interventricular septum or left ventricle posterior wall > 11 mm. The Logistic regression model was used in the cross-sectional study. Cox model and Cox model with restricted cubic splines were used in the longitudinal cohort. Results In the cross-sectional study, for participants in the highest tertile of each lipid marker compared to the respective lowest, triglycerides [odds ratio ( OR ): 1.250, 95% CI : 1.060 to 1.474], HDL-cholesterol ( OR : 0.780, 95% CI : 0.662 to 0.918), and lipoprotein(a) ( OR : 1.311, 95% CI : 1.115 to 1.541) had an association with left ventricular hypertrophy. In the longitudinal cohort, for participants in the highest tertile of each lipid marker at the baseline compared to the respective lowest, triglycerides [hazard ratio ( HR ): 3.277, 95% CI : 1.720 to 6.244], HDL-cholesterol ( HR : 0.516, 95% CI : 0.283 to 0.940), non-HDL-cholesterol ( HR : 2.309, 95% CI : 1.296 to 4.112), apolipoprotein B ( HR : 2.244, 95% CI : 1.251 to 4.032) showed an association with new-onset left ventricular hypertrophy. In the Cox model with forward stepwise selection, triglycerides were the only lipid markers entered into the final model. Conclusion Lipids levels, especially triglycerides, are associated with left ventricular hypertrophy. Controlling triglycerides level potentiate to be a strategy in harnessing cardiac remodeling but deserve to be further investigated.

Circular RNAs (circRNAs) have been increasingly linked to cancer progression. However, the detailed biological functions of circRNAs in prostate cancer (PCa) remain unclear. Using high-throughput circRNA sequencing, we previously identified 18 urine extracellular vesicle circRNAs that were increased in patients with PCa compared with those with benign prostatic hyperplasia. Spearman correlation analysis of the expression levels of the 18 circRNAs between the tumor tissue and matched urine extracellular vesicles in 30 PCa patients showed that circSCAF8 had the highest R 2 (R 2  = 0.635, P < 0.001). The Cox proportional hazards regression model was used to estimate the effect of circSCAF8 on progression-free survival. The in vitro and in vivo functional experiments were implemented to investigate the effects of circSCAF8 on the phenotype of PCa. We found that the knockdown of circSCAF8 in PCa cells suppressed the proliferation, migration, and invasion ability, while overexpression of circSCAF8 had the opposite effects. Similar results were observed in vivo. In a cohort of 85 patients who had undergone radical prostatectomy, circSCAF8 expression in PCa tissues was a powerful predictor of progression-free survival (HR = 2.14, P = 0.022). Mechanistically, circSCAF8 can function by binding to both miR-140-3p and miR-335 to regulate LIF expression and activate the LIF-STAT3 pathway that leads to the growth and metastasis of PCa. Collectively, our findings demonstrate that circSCAF8 contributes to PCa progression through the circSCAF8-miR-140-3p/miR-335-LIF pathway., (© 2022. The Author(s).)

Although the tumorigenic potential of glioma stem cells (GSCs) is associated with multiple molecular alterations, the gene amplification status of GSCs has not been elucidated. Overexpression of HomeoboxA5 (HOXA5) is associated with increased glioma malignancy. In this study, we identify the gene amplification and protein overexpression of HOXA5 in GSCs and its function in regulating GSC maintenance and the downstream transcriptional effector, to explore the significance of HOXA5 amplification/overexpression for GSC identification and prognostic determination. The HOXA5 gene is significantly amplified in glioblastoma (GBM) and is an independent prognostic factor for predicting worse patient outcomes. Specifically, HOXA5 gene amplification and the resultant protein overexpression are correlated with increased proportions of GSCs and enhanced self-renewal/invasiveness of these cells. Disruption of HOXA5 expression impairs GSC survival and GBM tumor propagation. Mechanistically, HOXA5 directly binds to the promoter region of protein tyrosine phosphatase receptor type Z1 (PTPRZ1), thereby upregulating this gene for GSC maintenance. Suppression of PTPRZ1 largely compromises the pro-tumoral effect of HOXA5 on GSCs. In summary, HOXA5 amplification serves as a genetic biomarker for predicting worse GBM outcome, by enhancing PTPRZ1-mediated GSC survival., (Copyright © 2022. Published by Elsevier B.V.)

Background: The severity of acute pancreatitis in pregnancy (APIP) is correlated with higher risks of maternal and fetal death., Aim: To develop a nomogram that could predict moderately severe and severe acute pancreatitis in pregnancy (MSIP)., Methods: Patients with APIP admitted to West China Hospital between January 2012 and December 2018 were included in this study. They were divided into mild acute pancreatitis in pregnancy (MAIP) and MSIP. Characteristic parameters and laboratory results were collected. The training set and test set were randomly divided at a ratio of 7:3. Least absolute shrinkage and selection operator regression was used to select potential prognostic factors. A nomogram was developed by logistic regression. A random forest model was used to validate the stability of the prediction factors. Receiver operating characteristic curves and calibration curves were used to evaluate the model's predictive performance., Results: A total of 190 patients were included in this study. A total of 134 patients (70.5%) and 56 patients (29.5%) were classified as having MAIP and MSIP, respectively. Four independent predictors (lactate dehydrogenase, triglyceride, cholesterol, and albumin levels) were identified for MSIP. A nomogram prediction model based on these factors was established. The model had areas under the curve of 0.865 and 0.853 in the training and validation sets, respectively. The calibration curves showed that the nomogram has a good consistency., Conclusion: A nomogram including lactate dehydrogenase, triglyceride, cholesterol, and albumin levels as independent predictors was built with good performance for MSIP prediction., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: This study aims to develop a deep learning method that skips the time-consuming inverse optimization process for automatic generation of machine-deliverable intensity-modulated radiation therapy (IMRT) plans., Methods: Ninety cervical cancer clinical IMRT plans were collected to train a two-stage convolution neural network, of which 66 plans were assigned for training, 11 for validation, and 13 for test. The neural network took patients' computed tomography (CT) anatomy as the input and predicted the fluence map for each radiation beam. The predicted fluence maps were then imported into a treatment planning system and converted to multileaf collimators motion sequences. The automatic plan was evaluated against its corresponding clinical plan, and its machine deliverability was validated by patient-specific IMRT quality assurance (QA)., Results: There were no significant differences in dose parameters between automatic and clinical plans for all 13 test patients, indicating a good prediction of fluence maps and a decent quality of automatic plans. The average dice similarity coefficient of isodose volumes encompassed by 0%-100% isodose lines ranged from 0.94 to 1. In patient-specific IMRT QA, the mean gamma passing rate of automatic plans achieved 99.5% under 3%/3 mm criteria, and 97.3% under 2%/2 mm criteria, with a low dose threshold of 10%., Conclusions: The proposed deep learning framework can produce machine-deliverable IMRT plans with quality similar to the clinical plans in the test set. It skips the inverse plan optimization process and provides an effective and efficient method to accelerate treatment planning process., (© 2022 American Association of Physicists in Medicine.)

Major immunotherapy challenges include a limited number of predictive biomarkers and the unusual imaging features post-therapy, such as pseudo-progression, which denote immune infiltrate-mediated tumor enlargement. Such phenomena confound clinical decision-making, since the cancer may eventually regress, and the patient should stay on treatment. We prospectively evaluated serial, blood-derived cell-free DNA (cfDNA) (baseline and 2-3 weeks post-immune checkpoint inhibitors [ICIs]) for variant allele frequency (VAF) and blood tumor mutation burden (bTMB) changes (next-generation sequencing) (N = 84 evaluable patients, diverse cancers). Low vs. high cfDNA-derived average adjusted ΔVAF (calculated by a machine-learning model) was an independent predictor of higher clinical benefit rate (stable disease ≥6 months/complete/partial response) (69.2% vs. 22.5%), and longer median progression-free (10.1 vs. 2.25 months) and overall survival (not reached vs. 6.1 months) (all P < .001, multivariate). bTMB changes did not correlate with outcomes. Therefore, early dynamic changes in cfDNA-derived VAF were a powerful predictor of pan-cancer immunotherapy outcomes., Competing Interests: SK serves as a consultant for Foundation Medicine, receives speaker fees from Roche and research grants from ACT Genomics, Sysmex, Konica Minolta, and OmniSeq. JJA and LK have no disclosures. BL, SWC, DBF, DQ, RH, JH, PG, and HML are employed by Ambry Genetics, and NK, TI, and MK are employed by Konica Minolta, Inc., when they are working on this project. RK receives research funding from Genentech, Incyte, Merck, Serono, Pfizer, Sequenom, Foundation Medicine, Grifols, and Guardant, as well as consultant fees from Loxo, X Biotech, NeoMed, and Actuate Therapeutics; speaker fees from Roche; and an ownership interest in IDbyDNA and Curematch, Inc., and is a Board member of CureMatch and CureMetrix, Inc., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Platelet-derived growth subunit A (PDGFA) plays critical roles in development of glioblastoma (GBM) with substantial evidence from TCGA database analyses and in vivo mouse models. So far, only platelet-derived growth receptor α (PDGFRA) has been identified as receptor for PDGFA. However, PDGFA and PDGFRA are categorized into different molecular subtypes of GBM in TCGA&#95;GBM database. Our data herein further showed that activity or expression deficiency of PDGFRA did not effectively block PDGFA activity. Therefore, PDGFRA might be not necessary for PDGFA function.To profile proteins involved in PDGFA function, we performed co-immunoprecipitation (Co-IP) and Mass Spectrum (MS) and delineated the network of PDGFA-associated proteins for the first time. Unexpectedly, the data showed that EPHA2 could be temporally activated by PDGFA even without activation of PDGFRA and AKT. Furthermore, MS, Co-IP, in vitro binding thermodynamics, and proximity ligation assay consistently proved the interaction of EPHA2 and PDGFA. In addition, we observed that high expression of EPHA2 leaded to upregulation of PDGF signaling targets in TCGA&#95;GBM database and clinical GBM samples. Co-upregulation of PDGFRA and EPHA2 leaded to worse patient prognosis and poorer therapeutic effects than other contexts, which might arise from expression elevation of genes related with malignant molecular subtypes and invasive growth. Due to PDGFA-induced EPHA2 activation, blocking PDGFRA by inhibitor could not effectively suppress proliferation of GBM cells, but simultaneous inhibition of both EPHA2 and PDGFRA showed synergetic inhibitory effects on GBM cells in vitro and in vivo. Taken together, our study provided new insights on PDGFA function and revealed EPHA2 as a potential receptor of PDGFA. EPHA2 might contribute to PDGFA signaling transduction in combination with PDGFRA and mediate the resistance of GBM cells to PDGFRA inhibitor. Therefore, combination of inhibitors targeting PDGFRA and EHA2 represented a promising therapeutic strategy for GBM treatment., (© 2021. The Author(s).)

Systemic sclerosis (SSc) is a life-threatening chronic connective tissue disease with the characteristics of skin fibrosis, vascular injury, and inflammatory infiltrations. Though inhibition of phosphodiesterase 4 (PDE4) has been turned out to be an effective strategy in suppressing inflammation through promoting the accumulation of intracellular cyclic adenosine monophosphate (cAMP), little is known about the functional modes of inhibiting PDE4 by apremilast on the process of SSc. The present research aimed to investigate the therapeutic effects and underlying mechanism of apremilast on SSc. Herein, we found that apremilast could markedly ameliorate the pathological manifestations of SSc, including skin dermal thickness, deposition of collagens, and increased expression of α-SMA. Further study demonstrated that apremilast suppressed the recruitment and activation of macrophages and T cells, along with the secretion of inflammatory cytokines, which accounted for the effects of apremilast on modulating the pro-fibrotic processes. Interestingly, apremilast could dose-dependently inhibit the activation of M1 and T cells in vitro through promoting the phosphorylation of CREB. In summary, our research suggested that inhibiting PDE4 by apremilast might provide a novel therapeutic option for clinical treatment of SSc patients., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Primary lung cancer is one of the most common malignant tumors in China. Approximately 60% of lung cancer patients have distant metastasis at the initial diagnosis, so it is necessary to find new tumor markers for early diagnosis and individualized treatment. Tumor markers contribute to the early diagnosis of lung cancer and play important roles in early detection and treatment, as well as in precision medicine, efficacy monitoring, and prognosis prediction. The pathological diagnosis of lung cancer in small biopsy specimens determines whether there are tumor cells in the biopsy and tumor type. Because biopsy is traumatic and the compliance of patients with multiple biopsies is poor, liquid biopsy has become a hot research direction. Liquid biopsies are advantageous because they are nontraumatic, easy to obtain, reflect the overall state of the tumor, and allow for real-time monitoring. At present, liquid biopsies mainly include circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. This review introduces the research progress and clinical application prospect of liquid biopsy technology for lung cancer., (© 2022. The Author(s).)

There are numerous antibodies used for cancer therapy in clinic, but they are essentially less efficacy than expected. None of them has tumor-specific and broad-spectral properties. PIWIL2-like (PL2L) protein 60 (PL2L60) is a product of alienated activation of PIWIL2 gene, and has been found to be specifically and widely expressed in various types of cancers, including hematopoietic and solid ones. Current study aims to investigate whether a monoclonal antibody (mAb) to PL2L60 has both tumor-specific and broad-spectral properties, which can be used universally to treat various types of cancers. The expression of PL2L60 protein in the cell surface and cytoplasm were determined in a panel of human and mouse tumor cell lines by flow cytometry, immunofluorescent microscopy and Western Blotting. The apoptosis and the cell cycle arrest of the tumor cells treated with mAb KAO3 were evaluated by flow cytometry. The tumorigenesis of the mAb KAO3-pretreated tumor cells was determined by tumor incidence and tumor size, and the efficacy of mAb KAO3 treatment on tumor growth in tumors-bearing mice were kinetically evaluated. Complement-dependent cytotoxicity (CDC) assay was used to determine the capacity of mAb KAO3 to kill tumor cells. Treatment of human or mouse tumor cells from hematopoietic or solid tumors with mAb KAO3 at the time of inoculation efficiently inhibited tumorigenesis in the severe combined immunodeficient (SCID) mice. Moreover, injection of mAb KAO3 into established tumors significantly inhibited their growth, and prolonged survival of the tumor-bearing mice, including lymphoma, breast cancer, lung cancer and cervical cancer. The efficacy of mAb KAO3 treatment is likely associated with its binding to PL2L60 expressed on tumor cell surface, which may lead to cancer cell death through blocking cell cycling and/or activation of complement. In conclusion, we have identified a tumor-specific mAb to PL2L60 (KAO3), which may be used potentially to treat all the types of human cancers including from both hematopoietic and solid ones., Competing Interests: JXG is a founder and partially supported by Shanghai Evac Biotechnology Inc., (AJCR Copyright © 2022.)

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck. The primary clinical manifestations are nasal congestion, blood-stained nasal discharge, headache, and hearing loss. It occurs frequently in Southeast Asia, North Africa, and especially in southern China. Radiotherapy is the main treatment, and currently, imaging examinations used for the diagnosis, treatment, and prognosis of NPC include computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and PET-MRI. These methods play an important role in target delineation, radiotherapy planning design, dose evaluation, and outcome prediction. However, the anatomical and metabolic information obtained at the macro level of images may not meet the increasing accuracy required for radiotherapy. As a technology used for mining deep image information, radiomics can provide further information for the diagnosis and treatment of NPC and promote individualized precision radiotherapy in the future. This paper reviews the application of radiomics in the diagnosis and treatment of nasopharyngeal carcinoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Gong, Qiu, Han, Lu and Yin.)

Rationale: Around 10%-20% patients with glioblastoma (GBM) are diagnosed with more than one tumor lesions or multifocal GBM (mGBM). However, the understanding on genetic, DNA methylomic, and transcriptomic characteristics of mGBM is still limited. Methods: In this study, we collected nine tumor foci from three mGBM patients followed by whole genome sequencing, whole genome bisulfite sequencing, RNA sequencing, and immunohistochemistry. The data were further examined using public GBM databases and GBM cell line. Results: Analysis on genetic data confirmed common features of GBM, including gain of chr.7 and loss of chr.10, loss of critical tumor suppressors, high frequency of PDGFA and EGFR amplification. Through profiling DNA methylome of individual tumor foci, we found that promoter methylation status of genes involved in detection of chemical stimulus, immune response, and Hippo/YAP1 pathway was significantly changed in mGBM. Although both CNV and promoter methylation alteration were involved in heterogeneity of different tumor foci from same patients, more CNV events than promoter hypomethylation events were shared by different tumor foci, implying CNV were relatively earlier than promoter methylation alteration during evolution of different tumor foci from same mGBM. Moreover, different tumor foci from same mGBM assumed different molecular subtypes and mesenchymal subtype was prevalent in mGBM, which might explain the worse prognosis of mGBM than single GBM. Interestingly, we noticed that LIF and CCL2 was tightly correlated with mesenchymal subtype tumor focus in mGBM and predicted poor survival of GBM patients. Treatment with LIF and CCL2 produced mesenchymal-like transcriptome in GBM cells. Conclusions: Together, our work herein comprehensively profiled multi-omics features of mGBM and emphasized that components of extracellular microenvironment, such as LIF and CCL2, contributed to the evolution and prognosis of tumor foci in mGBM patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)