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Hypoxia within the tumor microenvironment, which leads to excessive ROS and genomic instability, is one of the hallmarks of cancer, contributing to self-renewal capability, metastasis, and radio-chemotherapy resistance. PRL-3 is an oncoprotein involved in various pro-survival signaling pathways, such as Ras/Erk, PI3K/Akt, Src/STAT, mTORC1 and JAK/STAT. However, there is little evidence connecting PRL-3-mediated apoptosis resistance to tumor microenvironmental stress. In this study, by profiling the PRL-3 expression of multiple tumor types retrieved from public databases (TCGA and NCBI GEO), we confirmed the oncogenic function of PRL-3 and found an intriguing connection between PRL-3 expression and tumor hypoxia signature genes. Moreover, by using CoCl2, a hypoxia mimetic and ROS inducer, we discovered that cells stably expressing PRL-3, but not catalytically-inactive mutant PRL-3 C104S, showed significant resistance to CoCl2 -induced apoptosis. This resistance to apoptosis was found to depend on p38 MAPK signaling and was further confirmed in other conditions of microenvironmental stress, including UV, H2O2 and hypoxia. Mechanistically, we proved that PRL-3 is a direct phosphatase of p38 MAPK under stressed conditions. Additionally, in mouse models of tumor metastasis, higher lung metastatic burden and lower p38 MAPK phosphorylation were found in mice seeded with GFP-PRL-3 expressing cells compared with those seeded with GFP-Ctrl cells. Taken together, our study identified a critical role of RPL-3 in tumorigenesis by negatively regulating p38 MAPK activity in order to facilitate tumor cell adaptation to a hypoxic stressed tumor microenvironment and suggests that PRL-3 could serve as a promising novel therapeutic target for cancer patients.

This study aimed to comprehensively examine the genetic and phenotypic aspects of GABRB3-related epilepsy and to explore the potential prospects of personalized medicine. Genetic testing was conducted in all epilepsy patients without acquired factors for epilepsy. Through the collaboration of multicenter in China, we analyzed the genotype–phenotype correlation and antiepileptic therapy of 26 patients with GABRB3-related epilepsy. Thirteen GABRB3 variants were novel, and 25 were de novo. The seizure onset age ranged from 1 to 21 months (median age 3.75 months). Seizure types predominated including focal seizures (92.3%), generalized tonic–clonic seizures (23.1%), and epileptic spasms (15.4%). Clinical features included cluster seizures (80.8%), fever sensitivity (53.8%), and developmental delay (96.2%). Neuroimaging was abnormal in 10 patients, including dysplasia of the cerebral cortex, dysplasia of the frontal and temporal cortex, delayed myelination, and corpus callosum dysplasia. Eleven patients were diagnosed with developmental and epileptic encephalopathy (DEE), four with West syndrome, three with epilepsy of infancy with migrating focal seizures (EIMFS), one with epilepsy with myoclonic-atonic seizures (EMAS), one with Dravet syndrome, and one with febrile seizures plus (FS+). Seizures were controlled in 57.7% of patients by valproate, levetiracetam, or perampanel in the majority. The clinical features of GABRB3-related epilepsy included seizure onset in early infancy, cluster seizures and fever sensitivity. Most patients manifest severe epilepsy phenotypes. Valproate, levetiracetam and perampanel seem to have positive effects on seizure control for patients with GABRB3 variants.

Cancer has risen up to be a major cause of mortality worldwide over the past decades. Despite advancements in cancer screening and diagnostics, a significant number of cancers are still diagnosed at a late stage with poor prognosis. Hence, the discovery of reliable and accurate methods to diagnose cancer early would be of great help in reducing cancer mortality. Extracellular vesicles (EVs) are phospholipid vesicles found in many biofluids and are released by almost all types of cells. In recent years, using EVs as cancer biomarkers has garnered attention as a novel technique of cancer diagnosis. Compared with traditional tissue biopsy, there are many advantages that this novel diagnostic tool presents - it is less invasive, detects early-stage asymptomatic cancers, and allows for monitoring of tumour progression. As such, EV biomarkers have great potential in improving the diagnostic accuracy of cancers and guiding subsequent therapeutic decisions. Efficient isolation and accurate characterization of EVs are essential for reliable outcomes of clinical application. However, these are complicated by the size and biomolecular diversity of EVs. In this review, we present an analysis and evaluation of the current techniques of EV isolation and characterization, as well as discuss the potential EV biomarkers for specific types of cancer. Taken together, EV biomarkers have a lot of potential as a novel method in cancer diagnostics and diagnosis. However, more work is still needed to streamline the purification, characterization and biomarker identification process to ensure optimal outcomes for patients.

Objective We aimed to compare the dosimetric characteristics of 6‐MV flattening filter mode (FF) and flattening filter‐free mode (FFF) volumetric‐modulated arc therapy (VMAT) plans in preoperative radiotherapy for rectal cancer using an Edge linear accelerator. Methods Two‐arc FF‐VMAT and FFF‐VMAT plans were generated for 15 patients with rectal cancer using the Philips Pinnacle treatment planning system (version 9.10). The homogeneity index, conformity index, planning target volume covered by 105% isodose lines, organ‐at‐risk dosimetry characteristics, and monitor units (MUs) were compared between the plans. The results were analyzed using paired t‐tests. Results The conformity index of the FF‐VMAT plan and FFF‐VMAT plan were (0.93 ± 0.01) and (0.92 ± 0.02), and the homogeneity index of the two groups were (0.07 ± 0.03) and (0.08 ± 0.01), the differences were not statistically significant (both P > 0.05). The volume covered by 105% isodose lines of the FFF‐VMAT plan was significantly higher than that of the FF‐VMAT plan. The FFF‐VMAT plan required a higher monitor unit (t = 11.49, P = 0.002) and shorter beam‐on time (t = 5.78, P = 0.001) compared with the FF‐VMAT plan. There were no significant differences in the absolute volume receiving 30 Gy and 40 Gy of the bladder between the plans. The absolute volume receiving 30 Gy and absolute volume receiving 40 Gy of the intestine and colon in the FFF‐VMAT plan increased by 5.5% and 2.1% compared with those in the FF‐VMAT plans that increased by 7.2% and 2.2%, respectively (both P > 0.05). The absolute volume receiving 20 Gy of the left and right femoral head in the FFF‐VMAT plan decreased by 3.7% and 4.9% compared with those in the FF‐VMAT plans (P > 0.05). Conclusion Both FF‐VMAT and FFF‐VMAT plans met the clinical requirements.

Objective. Alveolar echinococcosis (AE) is a zoonosis caused by the larval stage of the metacestode Echinococcosis multilocularis with a tumor-like behavior in the targeted organ, especially in the liver. Surgery with albendazole is first-line modality for AE. Drug discontinuation is usually based upon the parasitic viability shown by the positron emission tomography (PET) scan. However, as a demanding and expensive method, it is not widely practiced in majority of the endemic regions. Further understanding on the cytokine and chemokine response profiles in AE patients may provide an interesting insight for potential markers in viability assessment. Methods. Mice were inoculated with Echinococcus multilocularis intrahepatically to develop the hepatic AE murine model. Oral albendazole administration was then applied for three months after the first inoculation, and peripheral and regional immune cells including type 1 T helper cells (Th), Th2, Th17, regulatory T (Treg) cells, related cytokines, and chemokines were examined. Results. The hepatic AE lesion was confirmed by ultrasound examination resulting in a successful rate of 70%. Among the 17 cytokines and chemokines detected, plasma levels of IL-23 were significantly higher in E. multilocularis-infected mice when compared to the control group; furthermore, more obvious increasing levels were found after albendazole treatment ( p < 0.05 ). All chemokine levels other than eotaxin and MCP-3 were slightly higher in E. multilocularis-infected mice compared to the control group ( p > 0.05 ). Eotaxin levels were significantly decreased in mice with E. multilocularis infection followed by albendazole treatment ( p < 0.05 ). Both IL-17A and IL-23 expressions in hepatic AE lesions were significantly higher and related with disease activity. Conclusion. Albendazole administration influenced the balance of immune response and promotes the secretion of proinflammatory factors which is beneficial to parasite clearance. IL-23 seems to be associated with the successful albendazole treatment in mice with E. multilocularis infection; such a change could be translated into clinical application in the near future.

Magnetic resonance elastography (MRE) is commonly regarded as the imaging-based gold-standard for liver fibrosis staging, comparable to biopsy. While ultrasound-based elastography methods for liver fibrosis staging have been developed, they are confined to a 1D or a 2D region of interest and to a limited depth. 3D Shear Wave Absolute Vibro-Elastography (S-WAVE) is a steady-state, external excitation, volumetric elastography technique that is similar to MRE, but has the additional advantage of multi-frequency excitation. We present a novel ultrasound matrix array implementation of S-WAVE that takes advantage of 3D imaging. We use a matrix array transducer to sample axial multi-frequency steady-state tissue motion over a volume, using a Color Power Angiography sequence. Tissue motion with the frequency components {40,50,60} and {45,55,65} Hz are acquired over a (90° lateral) $\times $ (40° elevational) $\times $ (16 cm depth) sector with an acquisition time of 12 seconds. We compute the elasticity map in 3D using local spatial frequency estimation. We characterize this new approach in tissue phantoms against measurements obtained with transient elastography and MRE. Six healthy volunteers and eight patients with chronic liver disease were imaged. Their MRE and S-WAVE volumes were aligned using T1 to B-mode registration for direct comparison in common regions of interest. S-WAVE and MRE results are correlated with R2 = 0.92, while MRE and TE results are correlated with R2 = 0.71. Our findings show that S-WAVE with matrix array has the potential to deliver a similar assessment of liver fibrosis as MRE in a more accessible, inexpensive way, to a broader set of patients.

Rhabdomyosarcoma (RMS) with regional lymph node involvement has a high rate of distant metastases. Lung is the most common site, accounting for 70% of all metastases. The differential diagnosis of lung lesions due to an infectious aetiology versus metastases is usually evaluated by computed tomography (CT) or magnetic resonance imaging. However, it is rare for patients of RMS to present with infectious nodules or masses in the lung during follow-up. More importantly, infections can mimic the imaging characteristics of metastatic RMS in CT. We report two such cases where children diagnosed with head and neck embryonal RMS with lymph node metastasis, presented with pulmonary masses 0.5 and 4 years after end of treatment, without the typical signs and symptoms suggestive of an infection. Chest CT suggested a provisional diagnosis of metastases and biopsies confirmed infectious aetiology (Mycobacterium tuberculosis, Cryptococcus).

The cervicothoracic junction (CTJ) lesions in children is rare. Surgical treatment for lesions at the cervicothoracic junction is challenging due to the presence of the great vessels and other thor...

Objective:. In order to study the important role and molecular mechanism of Brevinin-2 family antimicrobial peptide Brevinin-2ISb in methicillin-resistant Staphylococcus aureus (MRSA) infection of Caenorhabditis (C.) elegans, and to find the optimal therapeutic concentration of Brevinin-2ISb. Methods:. By using a C. elegans model and MRSA infection modelto study the therapeutic effect of different concentrations of Brevinin-2ISb on C. elegans. Real-time PCR was used for investigating the effect of Brevinin-2ISb on the downstream gene expression of DAF-2/DAF-16 innate immune pathway and the major virulence factor gene expression of MRSA. With protein activity tests to study the inhibitory effect of Brevinin-2ISb on MRSA virulence factor protein activity. Finally, laser confocal imaging was carried out to observe real-time expression and distribution of downstream antimicrobial proteins to further prove the effect of Brevinin-2ISb on the activation of DAF-2/DAF-16 pathway by in vivo imaging. All animal study procedures were approved by the Academic Committee at Xidian University and Xi’an Jiaotong University Animal Care and Use Committee, China (approval No. JGC201207) on July 15, 2017. Results:. Host immunity was largely enhanced by Brevinin-2ISb, and the expression of staphylococcal enterotoxin genes, as well as virulence factors, was suppressed by Brevinin-2ISb. Indeed, the expression of many C. elegans innate immune genes, including lys-7, spp-1, K05D8.5 and C29F3.7, was induced by Brevinin-2ISb. In particular, robust, sustained expression of the antibacterial gene lys-7 was observed after Brevinin-2ISb treatment, resulting in increased protein levels. These effects correlated with a reduction in the MRSA-mediated death of the C. elegans host. Low concentrations of Brevinin-2ISb exhibited very low hemolytic activity, and may play a positive role in host innate immunity. Specifically, activation of the DAF-2/DAF-16 pathway appears to be essential for immune activation in C. elegans treated with Brevinin-2ISb. Based on the evolutionary conservation of innate immune pathways, our results suggest that Brevinin-2ISb not only has strong antibacterial activity, but may also enhance the innate immune response in humans. This study demonstrates that Brevinin-2ISb-related peptides are potential candidates for the development of novel anti-inflammatory or anti-microbial drugs. Conclusion:. Antimicrobial peptide Brevinin-2ISb effectively inhibits MRSA at low concentration. This antimicrobial peptide can prolong the life of MRSA-infected C. elegans, has very low hemolytic activity and inhibits the activity and expression of various MRSA virulence factors. More importantly, Brevinin-2ISb activated the expression of antimicrobial genes downstream of DAF-2/DAF-16, which enhanced the MRSA resistance of C. elegans. This peptide could be used as the basis for developing new drugs to replace antibiotics.

Single-domain antibodies have the characteristics of small molecular weight, strong tissue penetration, and high affinity, and are widely used to construct molecular probes for disease diagnosis and treatment. This article reviews molecular imaging studies including positron emission tomography (PET), single-photon emission computed tomography/computed tomography (CT), PET/CT, and fluorescent imaging of molecular probes composed of single-domain antibodies against eight esophageal squamous cell carcinoma biological targets. These 8 targets are highly expressed on the membrane of esophageal squamous cell carcinoma cells and include epidermal growth factor receptor, human epidermal growth factor receptor 2, human epidermal growth factor receptor 3, hepatocyte growth factor receptor, vascular endothelial growth factor receptor 2, chemokine receptor 4, chemokine receptor 7, and carcinoembryonic antigen. The current problems and solutions are also discussed to provide a reference for future design of molecular imaging probes targeting esophageal squamous cell carcinoma.

Mutant RAS genes play an important role in regulating tumors through lysine residue 104 to impair GEF-induced nucleotide exchange, but the regulatory role of KRAS K104 modification on the KRASG12D mutant remains unclear. Therefore, we simulated the acetylation site on the KRASG12D three-dimensional protein structure, including KRASG12D, KRASG12D/K104A and KRASG12D/K104Q, and determined their trajectories and binding free energy with GEF. KRASG12D/K104Q induced structural changes in the α2- and α3-helices, promoted KRAS instability and hampered GEF binding (ΔΔG = 6.14 kJ/mol). We found decreased binding to the Raf1 RBD by KRASG12D/K104Q and reduced cell growth, invasion and migration. Based on whole-genome cDNA microarray analysis, KRASG12D/K104Q decreased expression of NPIPA2, DUSP1 and IL6 in lung and ovarian cancer cells. This study reports computational and experimental analyses of Lys104 of KRASG12D and GEF, and the findings provide a target for exploration for future treatment.

Background Pleuropulmonary blastomas (PPB) are rare aggressive paediatric lung malignancies and are among the most common DICER1-related disorders: it is estimated that 75–80% of children with a PPB have the DICER1 mutation. DICER1 mutations are responsible for familial tumour susceptibility syndrome with an increased risk of tumours. In approximately 35% of families with children manifesting PPB, further malignancies may be observed. Symptoms of DICER1 syndrome may vary, even within monozygotic twins. Preventive screening of carriers with DICER1 mutations is important and follow-up is undertaken as recommended by the 2016 International PPB Register. Case presentation We present two pairs of monozygotic twins. In one pair of 4-year, 2-month old girls, both with DICER1 mutation, one developed PPB(II) and her identical sibling had acute transient hepatitis. In the other pair of 19-month-old female babies, one had a history of bronchopulmonary hypoplasia and developed PPB(III) without DICER1 mutation, and her identical sibling had allergic asthma. Both patients with PPB were treated with R0 resection and received 12 cycles of postoperative chemotherapy. At the most recent review, the twins had been followed up for six and eight years, respectively, and they all remained healthy. However, the height and weight of the patients with PPB were lower than those of their respective identical sister. Conclusions PPB is rare, especially in monozygotic twins. We emphasise the importance of genetic testing and follow-up in monozygotic twins with PPB. During the follow-up, children surviving PPB should be monitored closely for growth and development disorders which caused by chemotherapy.

Importance Cancer is the main cause of death by disease in children. Children experience the highest incidence of cancer in the first year of life. However, there is no comprehensive registration system for children with tumors in China. Objective To summarize the diagnosis and treatment of infant cancer and analyze the status of standardized diagnosis and management among several treatment centers in Beijing, China, thereby providing evidence to guide further clinical research. Methods From January 1, 2010 to December 31, 2019, patients with newly diagnosed infantile malignant solid tumors were admitted to six large tertiary pediatric solid tumor diagnosis and treatment centers in Beijing. The epidemiology, clinical features, and therapeutic effects of tumors in these patients were analyzed retrospectively. All patients were followed up until March 31, 2020. Results In total, 938 patients were enrolled in this study. There were 530 boys (56.5%) and 408 girls (43.5%); the median age was 6.0 months (range, 0–12.0 months). The three most common tumors were retinoblastoma in 366 patients (39.0%), neuroblastoma in 266 patients (28.4%), hepatoblastoma in 133 patients (14.2%), and central nervous system tumors in 52 patients (5.5%). The estimated 5‐year overall survival rate was 81.3% ± 1.8%, and the 5‐year event‐free survival rate was 71.8% ± 2.9%. The 5‐year overall survival rates of non‐rhabdomyosarcoma soft tissue sarcoma, neuroblastoma, and retinoblastoma were 100%, 88% ± 2.2%, and 86.9% ±2.1%, respectively. The 5‐year event‐free survival rates were 81.1% ± 2.7% for neuroblastoma, 81.6% ± 9.8% for non‐rhabdomyosarcoma soft tissue sarcoma, and 72.7% ± 14.1% for extracranial malignant germ cell tumors. Interpretation The three most common infantile malignant solid tumors were retinoblastoma, neuroblastoma, and hepatoblastoma. Multidisciplinary combined diagnosis and treatment is needed for infantile tumors., Children experience the highest incidence of cancer in the first year of life. We summarized 10‐years data of infantile malignant solid tumors from multiple centers in Beijing, China to provide evidence to support further clinical studies.

Importance Pulmonary inflammatory myofibroblastic tumors (PIMTs) are primary lung tumors in children. Misdiagnosis easily occurs because of the nonspecific clinical manifestations, laboratory examination results, and imaging findings in affected patients. Objective To summarize the clinical characteristics, diagnosis, and prognosis of children with PIMTs. Methods This retrospective analysis included 23 children with PIMTs who received treatment in our hospital from January 2008 to January 2019. The clinical manifestations, laboratory examination results, and computed tomography findings were retrospectively analyzed. Results The population included 13 boys and 10 girls, with a median age at onset of 78 months (range, 10–126 months). Fourteen patients had PIMT lesions in the right lung and nine patients had PIMT lesions in the left lung. The surgical procedures included pulmonary wedge resection, pulmonary lobectomy, and total pneumonectomy. The median operation time was 115 min (range, 45–235 min); the median intraoperative blood loss volume was 30 mL (range, 3–500 mL). During the operation, one patient each had pulmonary hemorrhage, vena cava hemorrhage, and thoracic duct injury. Postoperative complications included pulmonary embolism in one patient and tumor recurrence in two patients; neither of these complications recurred after reoperation. The median follow‐up period was 49 months (range, 2–127 months). Interpretation Children with PIMTs exhibited good prognoses and primarily underwent surgical resection as treatment. Complete preoperative evaluation should be performed in affected patients., Pulmonary inflammatory myofibroblastic tumor (PIMT) is relatively rare in the clinical setting, but it is still common among pulmonary primary tumors in children. The prognosis of PIMT is good, and the main therapy of PIMT is surgical resection, thus complete preoperative evaluation should be performed. New treatment options, such as targeted therapy, may reduce the risk of surgery.

High-performance nanomaterial catalysts for hydrogen evolution reaction via electrochemical water splitting are significant to the development of hydrogen energy. In this work, we report a robust and highly active catalyst fabricated through direct electrochemical deposition of Pt nanodendrites at the surface of activated carbon (Pt NDs). Owing to the large electrochemically active area and the exposed (111) facet of Pt, Pt NDs exhibits outstanding activity towards hydrogen evolution reaction with a low requiring overpotential of 0.027 V at 10 mA/cm2 and Tafel slope of ≈ 22 mV/dec in acidic media. In addition, the hydrogen yield of Pt NDs is 30%–45% larger than that of commercial Pt/C at the same Pt loadings. Moreover, Pt NDs exhibits excellent long-term durability whose hydrogen production efficiency remains unchanged after six-hour hydrogen production, while the efficiency of commercial Pt/C catalyst decayed 9% under the same circumstance. Considering the superiority of catalytic activity and stability, this Pt NDs present great potentiality towards practical hydrogen production application.

Introduction There is a known association between primary mediastinal germ cell tumor (PMGCT) and hematologic malignancy that is not linked to treatment. They are exceptionally rare entities with a low morbidity and a poor prognosis. Case presentation An 11‐year‐old boy presented with an anterior mediastinal mass diagnosed as a malignant germ cell tumor on the basis of an excisional biopsy. He was found to have acute myeloid leukemia (AML) two years after the chemotherapy for his germ cell tumor. The clinical course was very aggressive with a survival time of only 1 week after diagnosis of AML associated with PMGCT. Conclusion AML associated with PMGCT needs to be diagnosed correctly. Relevant examinations should be carried out in patients with PMGCTs during and after chemotherapy, and long‐term follow‐up is still necessary to reduce the risk of morbidity and mortality.

Importance Neuroblastoma is the most common extracranial malignant solid tumor in children. Multidisciplinary care is critical to improving the survival of pediatric patients with neuroblastoma. Objective To systematically summarize the clinical characteristics of children with neuroblastoma and evaluate their prognosis with multidisciplinary care provided in a single center. Methods This retrospective study analyzed the clinical data of 1041 patients with neuroblastoma who were diagnosed, treated, and followed‐up in the Hematology‐Oncology Center of Beijing Children’s Hospital from 2007 to 2019. Results The median age at diagnosis was 34 months; 80.8% of the patients were younger than 5 years of age. Notably, 243 patients (23.3%) were classified as low‐risk, 249 patients (23.9%) were classified as intermediate‐risk, and 549 (52.7%) were classified as high‐risk. Furthermore, 956 patients underwent surgical resections; 986 (94.7%) patients received chemotherapy; and 176 patients with high‐risk neuroblastoma received hematopoietic stem cell transplantation. The 5‐year event‐free survival (EFS) rate was 91.3% and 5‐year overall survival (OS) rate was 97.5% in low‐risk group; in the intermediate‐risk group, these rates were 85.1% and 96.7%, respectively, while they were 37.7% and 48.9% in the high‐risk group (P < 0.001 for both). The 5‐year EFS and OS rates were significantly higher in patients diagnosed between 2015 and 2019 than in patients diagnosed between 2007 and 2014 (P < 0.001). In total, 278 patients (26.7%) exhibited tumor relapse or progression; the median interval until relapse or progression was 14 months. Of the 233 patients who died, 83% died of relapse or progression of neuroblastoma and 4.3% died of therapy‐related complications. Interpretation The 5‐year OS rate was low in high‐risk patients, compared with low‐and intermediate‐risk patients. Multidisciplinary care is critical for improvement of survival in pediatric patients with neuroblastoma. Additional treatment strategies should be sought to improve the prognosis of patients with high‐risk neuroblastoma., A multidisciplinary modality for the diagnosis and treatment of neuroblastoma is the key to improve the survival of children with neuroblastoma.

Objective This study was performed to investigate the age at onset, clinical manifestations, pathological types and features, treatment, and prognosis of pleuropulmonary blastoma (PPB) in children in an attempt to reduce the misdiagnosis rate and achieve early detection and timely intervention. Methods We retrospectively studied the clinical data of 41 pediatric patients with PPB who were treated in our center from March 2002 to November 2018. The data comprised the age at onset, clinical manifestations, characteristics of familial diseases, pathological types, surgical procedures, and prognosis. Results Twenty male and 21 female patients were included, with a 0.95:1.00 male:female ratio. In total, 51.2% of the patients were misdiagnosed as having nonneoplastic lesions at the first presentation. The interval from symptom onset to surgery/chemotherapy ranged from 5 to 210 days. The pathological types were type I (cystic) PPB (n = 5, 11.9%), for which the median age at diagnosis was 21 months (range, 8–24 months); (solid/cystic) II PPB (n = 12, 28.6%), for which the median age at diagnosis was 37 months (range, 22–112 months); and type III (solid) PPB (n = 23, 54.8%), for which the median age at diagnosis was 39 months (range, 19–156 months). The pathologic type was undefined in one patient (2.4%). The patients were mainly treated by surgery and chemotherapy. The 5-year disease-free survival rate was 69.2%. Conclusion The clinical manifestations of PPB are nonspecific, its misdiagnosis rate is high, and it has a poor prognosis. Pediatricians should be aware of the seriousness of PPB. The possibility of PPB should be considered in children with pneumothorax, multiple pulmonary cystic lesions, a family history of pulmonary cysts, a family history of PPB, or space-occupying lesions associated with DICER1 syndromes. The lesion should be closely monitored and surgically removed if necessary. The nature of the lesion should be identified early to minimize the risk of progression of the PPB to worse types because of misdiagnosis and missed diagnosis. Multidisciplinary treatment including surgery, chemotherapy, and/or radiotherapy can be applied to patients with PPB. Type of study Treatment study. Level of evidence Level III.

The biocorrosion of magnesium in the external physiological environment is still difficult to accurately evaluate the degradation behavior in vivo, particularly, in the microenvironment of the patients with hyperglycemia or diabetes. Thus, we explored the synergistic effects of glucose and protein on the biodegradation of pure magnesium, so as to have a deeper understanding the mechanism of the degradation in vivo. The surface morphology and corrosion product composition of pure magnesium were investigated using SEM, EDS, FTIR, XRD and XPS. The effect of glucose and albumin on the degradation rate of pure magnesium was investigated via electrochemical and immersion tests. The adsorption of glucose and albumin on the sample surface was observed using fluorescence microscopy. The results showed that the presence of 2 g/L glucose changed the micromorphology of corrosion products on the magnesium surface by reacting with metal cations, thus inhibiting the corrosion of pure magnesium. Protein formed a barrier layer to protect the magnesium at early stage of immersion. The chelation reaction between protein and magnesium surface might accelerate the degradation at later stage. There may be a critical glucose (albumin) content. Biodegradation of pure magnesium was inhibited at low concentrations and promoted at high concentrations. The synergistic effect of glucose and protein restrained the adsorption of aggressive chloride ions to a certain extent, and thus inhibited the degradation of pure magnesium considerably. Moreover, XPS results indicated that glucose promoted the adsorption of protein on the sample surface., Graphical abstract Image 1, Highlights • The absorbed BSA layer delays the corrosion of pure Mg in the initial stage. • BSA promotes the degradation of Mg owing to the chelation effect subsequently. • The glucose curbs the degradation by impeding the attack of Cl− ions. • Glucose promotes the adsorption of protein due to the formation of glycosamine. • The synergistic effects of glucose and BSA reduces the degradation rate of pure Mg.

The autosomal recessive form of primary microcephaly (MCPH) is a rare disorder characterized by microcephaly with variable degree of intellectual disability. WDR62 has been reported as the second causative gene of MCPH2. West syndrome is a severe epilepsy syndrome composed of the triad of spasms, hypsarrhythmia, and mental retardation. There are limited clinical reports regarding WDR62 mutation and West syndrome. Here we report a boy who was identified with WDR62 mutation and was followed up from age 3 months to 5 months and 14 days. He had the first seizure as the classic epileptic spasm at the age of 3 months. Psychomotor retardation was noted before the seizure occurred. The head circumference was 38.5 cm (SD 2.6) when he was 4 months old, no dysmorphic facial features were observed. He couldn’t support his head steadily or turn over. He was able to laugh when tricked by the parents, but couldn’t track the sound and light. At the early stage, the electroencephalogram showed multifocal discharges, which evolved into hypsarrhythmia one month later, and brain MRI showed developmental malformation of cerebral gyrus. Two heterozygous mutations were identified in WDR62 by whole exome sequencing c.1535G > A, p.R512Q and c.2618dupT, p.K874Qfs*40. The patient was administrated with oral sodium valproate, nitrazepam, intramuscular adrenocorticotropic hormone for 2 weeks, and followed by prednisone, levetiracetam, topiramate and vigabatrin. However, there was no significant improvement on the seizure control after these treatments. According to the genetic report and clinical manifestation, we speculated that the WDR62 compound heterozygous mutation is responsible for the serious clinical phenotype.

Objective Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype-phenotype correlations of a large EIMFS cohort. Methods Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. Results We ascertained 135 patients from 128 unrelated families. Ninety-three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X-linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months. Interpretation We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821-831.

INTRODUCTION Non-specific low back pain (LBP) is an idiopathic musculoskeletal condition that affects 4 out of 5 individuals in their lifetime and is the leading cause of job-related disability in the United States (US). The interest in interactive and dynamic telehealth treatments for LBP continues to grow, and it is important for the medical community to remain up-to-date on the state of the science. LITERATURE SURVEY Relevant studies published from March 2016 until March 2021 were identified through a systematic search of EMBASE, MedLine and Web of Science. The search strategy combined the concepts of back pain, telehealth and mobile applications. METHODOLOGY Titles and abstracts were screened to select full text randomized controlled trials or protocols and methodological quality and risk of bias was assessed using the Cochrane risk-of-bias tool. Data were synthesized narratively. SYNTHESIS We included seven concluded randomized controlled trials and two study protocols reporting mobile health (mHealth) solutions for LBP. Six of the seven concluded trials found a significant improvement in self-reported numerical pain rating scale compared to the control group. A single trial compared a mHealth solution to physical therapy, with the majority of studies comparing interventions to "usual care." Substantial heterogeneity in reporting of sample characteristics was found, indicating a lack of standardization through the field. CONCLUSIONS mHealth solutions may positively impact people with LBP. Larger trials should be encouraged and the field should coalesce around a set of baseline variables for collection and reporting. As many interventions involve patient engagement, future trials should aim to further quantify adherence levels and begin to define telehealth 'doses' associated with better outcomes. This article is protected by copyright. All rights reserved.

RationaleDisruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model.MethodsC57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines.ResultsLungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction.ConclusionIncrease in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic of the Coronavirus disease in late 2019 (COVID-19). Vaccine development efforts have predominantly been aimed at 'Extra-viral' Spike (S) protein as vaccine vehicles, but there are concerns regarding ‘viral immune escape’ since multiple mutations may enable the mutated virus strains to escape from immunity against S protein. The ‘Intra-viral’ Nucleocapsid (N-protein) is relatively conserved among mutant strains of coronaviruses during spread and evolution. Herein, we demonstrate novel vaccine candidates against SARS-CoV-2 by using the whole conserved N-protein or its fragment/peptides. Using ELISA assay, we showed that high titers of specific anti-N antibodies (IgG, IgG1, IgG2a, IgM) were maintained for a reasonably long duration (> 5 months), suggesting that N-protein is an excellent immunogen to stimulate host immune system and robust B-cell activation. We synthesized three peptides located at the conserved regions of N-protein among CoVs. One peptide showed as a good immunogen for vaccination as well. Cytokine arrays on post-vaccination mouse sera showed progressive up-regulation of various cytokines such as IFN-γ and CCL5, suggesting that TH1 associated responses are also stimulated. Furthermore, vaccinated mice exhibited an elevated memory T cells population. Here, we propose an unconventional vaccine strategy targeting the conserved N-protein as an alternative vaccine target for coronaviruses. Moreover, we generated a mouse monoclonal antibody specifically against an epitope shared between SARS-CoV and SARS-CoV-2, and we are currently developing the First-in-Class humanized anti-N-protein antibody to potentially treat patients infected by various CoVs in the future.

Purpose This study aimed to evaluate the clinical impact of hybrid intensity-modulated radiotherapy (IMRT) and hybrid volumetric-modulated arc therapy (VMAT) for early-stage breast cancer, including plan quality and second cancer risk (SCR). Methods Three different plans were designed in full IMRT, hybrid IMRT, and hybrid VMAT for each of eight patients with early-stage breast cancer. Target quality, organs at risk (OARs) sparing, and SCR were compared among the three plans. Results Compared with the hybrid IMRT, full IMRT showed deterioration in terms of D2% of simultaneous integrated boost (SIB), V10 of ipsilateral lung, and excess absolute risk (EAR) to contralateral lung and esophagus. The homogeneity index (HI) of SIB, V5 of ipsilateral lung and combined lung, the Dmax and Dmean of the esophagus, the EAR to contralateral breast and lung, and the EAR to the esophagus with hybrid VMAT dramatically increased by 12.5%, 19.49%, 18.87%, 90.59%, 167.69%, 50.14%, 264.68%, and 160.95%, respectively (p = 0.022; 0.040; 0.044; 0.041; 0.003; 0.020; 0.000; 0.003). The EAR to contralateral breast and contralateral lung by full IMRT was significantly decreased compared with the hybrid VMAT (26.97%, p = 0.033; 50.01%, p = 0.026). Conclusion The results confirmed that hybrid IMRT could achieve better target quality and OARs sparing than full IMRT and hybrid VMAT for early-stage right breast cancer. Hybrid IMRT was the best treatment option, while hybrid VMAT performed the worst among the three plans in terms of SCR to peripheral OARs.

ObjectivesThis study is designed to identify different body mass index (BMI) trajectories of individuals aged 40–70 years and test the effect of distinct BMI trajectories on incident hypertension.DesignThe accelerated longitudinal design was used for this study.MethodsThe study drew data from the third to ninth China Health and Nutrition Surveys (CHNS), and 4697 participants were included between 1991 and 2015. As analysed, three distinct individual BMI trajectories were identified by the latent class growth mixed model (LCGMM). Then, BMI values and BMI slopes were worked out through calculation with LCGMM trajectory parameters and their primary derivatives, respectively. Later, Cox proportional hazard models were applied to examine BMI values and slopes, and find out the relationship between the said predicted data and incident hypertension for different classes.ResultsThree different trajectory classes were identified, that is, low-stable class (n=3711), sharp-increasing class (n=282) and high-stable class (n=704). Compared with the low-stable class, the adjusted HRs (95% CI) were 1.321 (1.119 to 1.559) and 1.504 (1.322 to 1.711) for the sharp-increasing class and the high-stable class, respectively. The HR (95% CI) for BMI values rose from 1.081 (1.030 to 1.135) to 1.221 (1.171 to 1.273) while the HR (95% CI) for BMI slopes dropped from 1.154 (1.100 to 1.211) to 0.983 (0.943 to 1.025). That is, the HR for BMI slopes were higher than that for BMI values for the class aged 40–47 years.ConclusionThese findings suggest that the calibrated BMI trajectories for the period from mid-life to elderly adulthood have a significant effect on the risk of incident hypertension. The period from age 40 to 47 years is critical and has positive implications for the early prevention of hypertension.

BACKGROUND: By regulating complex functional processes, circRNAs are crucial in the development of different cancers. Nevertheless, most circRNAs in papillary thyroid cancer metabolic reprogramming remain unknown. METHODS: The expression of circRNA was assessed by qRT-PCR in papillary thyroid cancer tissues and cell lines. Cell proliferation and glucose intake experiments were performed by certain kit. Transwell assays and wound healing assays were performed to investigate the function of circRNA in metastasis. In addition, a serious of molecular experiments were conducted to determine the exact mechanism of circRAD18. Luciferase reporter and RNA immunoprecipitation assay were conducted to determine the molecular interaction between circRNA and miRNA. RESULTS: We characterized circRAD18 as a significantly upregulated circRNA in papillary thyroid tissues and cell lines and found its downregulation could inhibit the growth and metastasis ability of papillary thyroid cancer. Interestingly, we found that circRAD18 was involved in glucose metabolism reprogramming of papillary thyroid cancer, and its silence could remarkably inhibit cell glucose uptake and lactate production in papillary thyroid cancer cells. Inhibition of circRAD18 could decrease the expression level of PDK1 protein by sponging miR-516b. CONCLUSIONS: This study verified the novel function of the circRAD18-miR-516b-PDK1 axis in papillary thyroid cancer metabolic reprogramming progression, which has potential to be a novel therapeutic target.

The purpose of this study was to test the diagnostic performance of 3-D power Doppler ultrasound (3-D-PD) with the virtual organ computer-aided analysis (VOCAL) technique in the detection of prostate cancers (PCa). A total of 99 male patients referred for needle prostate biopsy owing to elevated serum prostate-specific antigen or abnormal direct rectal examination were prospectively included. The transrectal 3-D-PD-VOCAL quantitative vascularity parameters of vascularization index (VI), flow index and vascularization/flow index (VFI) were obtained before biopsy and compared with histopathologic results. We evaluated the predictive values for the detection of clinically significant PCa in the foci from different zones and the discrimination among various cancer grades. 3-D-PD-VOCAL discriminated malignant from benign foci, with cutoff values of 27.4% for VI, 38.2 for flow index and 8.6 for VFI. All parameters had higher areas under the curve in detecting lesions in the peripheral zone than in the transition zone (p < 0.05). VI and VFI had better diagnostic performance in detecting clinically significant PCa than flow index (p < 0.05). The area under the curve, sensitivity, specificity and accuracy in detecting clinically significant PCa were, for the VI and VFI respectively, 95% and 95%, 86% and 94%, 87% and 76%, and 87% and 85%. 3-D-PD-VOCAL initially demonstrated favorable performance in detecting PCa. Further, larger-sample studies based on prostatectomy specimens are needed to evaluate the exact usefulness of the technique.

Xuebijing injection has been widely applied to treat sepsis. However, its roles in the dynamic change of metabolism in sepsis are still unknown. In our study, Gas chromatography-mass spectrometer (GC-MS) combined with multivariate statistical techniques was used to detect the metabolic change in septic rats with or without XBJ injection treatment. The KEGG pathway analysis was used to further analyze the related metabolic pathways in which the identified metabolites were involved. Based on the fold change, variable important in projection, and P value, we found 11, 33 and 26 differential metabolites in the sepsis group at 2, 6 and 12 hours post CLP, compared with the control group. Besides, we also found 32, 23 and 28 differential metabolites in the XBJ group at 2, 6 and 12 hours post CLP. The related pathways of differential metabolites were glycometabolism at 2h, glycometabolism and amino acid metabolism at 6h and amino acid metabolism at 12h post CLP in the sepsis group compared with the control group. Besides, glycometabolism, amino acid metabolism and lipid metabolism changed markedly after XBJ injection for 2 hours; while only amino acid metabolism changed significantly with the treatment of XBJ injection for 6 and 12 hours, compared with the sepsis group. Further analysis showed 3, 6 and 6 differential metabolites were overlapped in the sepsis group and XBJ group at 2, 6 and 12 hours post CLP. These identified differential metabolites were majorly involved in arginine and proline metabolism, suggesting that XBJ injection is capable of improving metabolic disorders in CLP-induced septic rat to a certain extent.

The Chinese herb couple Fuzi and Ganjiang (FG) has been a classic combination of traditional Chinese medicine that is commonly used clinically in China for nearly 2000 years. Traditional Chinese medicine suggests that FG can treat various ailments, including heart failure, fatigue, gastrointestinal upset, and depression. Neuroinflammation is one of the main pathogenesis of many neurodegenerative diseases in which microglia cells play a critical role in the occurrence and development of neuroinflammation. FG has been clinically proven to have an efficient therapeutic effect on depression and other neurological disorders, but its mechanism remains unknown. Cancer-related fatigue (CRF) is a serious threat to the quality of life of cancer patients and is characterized by both physical and psychological fatigue. Recent studies have found that neuroinflammation is a key inducement leading to the occurrence and development of CRF. Traditional Chinese medicine theory believes that extreme fatigue and depressive symptoms of CRF are related to Yang deficiency, and the application of Yang tonic drugs such as Fuzi and Ganjiang can relieve CRF symptoms, but the underlying mechanisms remain unknown. In order to define whether FG can inhibit CRF depression-like behavior by suppressing neuroinflammation, we conducted a series of experimental studies in vitro and in vivo. According to the UPLC-Q-TOF/MSE results, we speculated that there were 49 compounds in the FG extraction, among which 30 compounds were derived from Fuzi and 19 compounds were derived from Ganjiang. Our research data showed that FG can effectively reduce the production of pro-inflammatory mediators IL-6, TNF-α, ROS, NO, and PGE2 and suppress the expression of iNOS and COX2, which were related to the inhibition of NF-κB/activation of Nrf2/HO-1 signaling pathways. In addition, our research results revealed that FG can improve the depression-like behavior performance of CRF model mice in the tail suspension test, open field test, elevated plus maze test, and forced swimming test, which were associated with the inhibition of the expression of inflammatory mediators iNOS and COX2 in the prefrontal cortex and hippocampus of CRF model mice. Those research results suggested that FG has a satisfactory effect on depression-like behavior of CRF, which was related to the inhibition of neuroinflammation.