Direct radical functionalization of native sugars.

Naturally occurring (native) sugars and carbohydrates contain numerous hydroxyl groups of similar reactivity1,2. Chemists, therefore, rely typically on laborious, multi-step protecting-group strategies3 to convert these renewable feedstocks into reagents (glycosyl donors) to make glycans. The direct transformation of native sugars to complex saccharides remains a notable challenge. Here we describe a photoinduced approach to achieve site- and stereoselective chemical glycosylation from widely available native sugar building blocks, which through homolytic (one-electron) chemistry bypasses unnecessary hydroxyl group masking and manipulation. This process is reminiscent of nature in its regiocontrolled generation of a transient glycosyl donor, followed by radical-based cross-coupling with electrophiles on activation with light. Through selective anomeric functionalization of mono- and oligosaccharides, this protecting-group-free 'cap and glycosylate' approach offers straightforward access to a wide array of metabolically robust glycosyl compounds. Owing to its biocompatibility, the method was extended to the direct post-translational glycosylation of proteins.

BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α.

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders.

The role of amino acid metabolism alterations in acute ischemic stroke: From mechanism to application.

Acute ischemic stroke (AIS) is the most prevalent type of stroke, and due to its high incidence, disability rate, and mortality rate, it imposes a significant burden on the health care system. Amino acids constitute one of the most crucial metabolic products within the human body, and alterations in their metabolic pathways have been identified in the microenvironment of AIS, thereby influencing the pathogenesis, severity, and prognosis of AIS. The amino acid metabolism characteristics in AIS are complex. On one hand, the dynamic progression of AIS continuously reshapes the amino acid metabolism pattern. Conversely, changes in the amino acid metabolism pattern also exert a double-edged effect on AIS. This interaction is bidirectional, dynamic, heterogeneous, and dose-specific. Therefore, the distinctive metabolic reprogramming features surrounding amino acids during the AIS process are systematically summarized in this paper, aiming to provide potential investigative strategies for the early diagnosis, treatment approaches, and prognostic enhancement of AIS.

Hereditary haemorrhagic telangiectasias with recurrent ischemic stroke hinted by manganese deposition in the basal ganglia: a case report and literature review.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant inherited vascular disorder that can involve multiple organs, thus can be associated with so many clinical departments that proper screening and diagnosis of HHT are needed for providing better management of both patients and their family members. CASE PRESENTATION: We present a 58-year-old female patient with recurrent paradoxical brain embolism due to HHT. She received aspirin therapy and underwent pulmonary arteriovenous malformation embolization, recovering well and discharged 3 days postoperatively. Though ischemic stroke caused by HHT-induced vascular disorders has been reported, our patient presented with both recurrent paradoxical brain embolisms and radiologic findings of bilateral globus pallidus manganese deposition at the same time, a combination rarely reported. We also review the literature on the clinical features and management of HHT for prompt diagnosis of this genetic disease behind paradoxical embolism. CONCLUSIONS: When patients with ischemic stroke, especially recurrent ischemic stroke, have combined arteriovenous malformations (AVMs) in single or multiple organs, or clues for AVMs like manganese deposition in globus pallidus, genetic diseases such as HHT may be the reason for ischemic stroke and shouldn't be missed in the evaluation of embolic sources.

Exploring expression levels of the cGAS-STING pathway genes in peripheral blood mononuclear cells of spinal tuberculosis patients.

BACKGROUND: This study aimed to investigate the differential expression levels of the cGAS-STING pathway in peripheral blood mononuclear cells (PBMCs) of spinal tuberculosis (TB) patients with different progression and its feasibility as a diagnostic marker. METHODS: Peripheral blood and medical records of 25 patients with spinal TB and 10 healthy individuals, were prospectively collected and analyzed. PBMCs and serum were extracted from peripheral blood and the expression levels of the cGAS-STING pathway in PBMCs were measured by real-time PCR (RT-PCR) and serum interferon ß (IFN-ß) expression levels were measured by enzyme-linked immunosorbent assay (ELISA). The expression of Interferon regulatory Factor 3 (IRF3) in PBMCs was measured using western blot. Statistical analysis was performed using the SPSS 26.0 statistical package. RESULTS: The results showed that the expression level of the TANK-binding kinase 1 (TBK1) and IRF3 was significantly higher in PBMCs (P < 0.05), in patients with active lesions than in patients with stable lesions. The serum concentration of IFN-ß was significantly higher in patients with active lesions (P = 0.028). Compared with healthy individuals, the expression level of the cGAS-STING pathway was elevated in PBMCs of TB patients (P < 0.05), and the difference in the expression level of IFN-ß was not statistically significant (P > 0.05), and the serum IFN-ß concentration was elevated (P < 0.05). The calculated AUC values for TBK1 and IRF3 in PBMCs, IFN-ß in serum and erythrocyte sedimentation rate (ESR) to distinguish between patients with active and stable lesions were 0.732, 0.714, 0.839, and 0.714 respectively. CONCLUSIONS: The expression level of TBK1 and IRF3 in PBMCs, and IFN-ß in the serum of patients with spinal TB is positively correlated with disease activity. TBK1 has higher specificity and IFN-ß in serum has higher sensitivity when used to differentiate between patients with active and stable lesions.

Reducing catheter-related bloodstream infections using Lean Six Sigma methodology.

BACKGROUND: Central venous catheters (CVC) are used for dialysis in end-stage renal disease patients, presenting a significant risk for Catheter-Related Bloodstream Infections (CRBSI). While Lean Six Sigma has been effective in reducing CRBSI, its efficacy outside intensive care units (ICU) remains less explored. This study aims to evaluate the effectiveness of Lean Six Sigma in mitigating CRBSI risks among non-ICU hemodialysis patients. METHODS: The study was conducted in a nephrology department, focusing on patients undergoing hemodialysis with temporary CVC from February to December 2021. The Lean Six Sigma method, using Define-Measure-Analyze-Improve-Control (DMAIC) methodology, was implemented in 2022 to reduce CRBSI incidence. The 2021 CRBSI rate served as the benchmark, with a goal to reduce it by the end of 2022. Value-stream mapping, Fishbone Diagrams, and Root Cause Analysis identified potential CRBSI causes. After implementing targeted improvements, CRBSI rates before and after the intervention were compared. RESULTS: The Lean Six Sigma method significantly decreased CRBSI incidence from 12.79 to 2.32 per 1,000 catheter-days following the implementation of targeted interventions ([Formula: see text]=4.60, P = 0.05). This improvement was observed comparing February-December 2021 with January-December 2022. CONCLUSION: The findings demonstrate the effectiveness of the Lean Six Sigma method in non-ICU settings, suggesting broader applicability in hemodialysis patient care.

Using standardized workflows and quantitative data-driven management to reduce time interval from simulation to treatment initiation.

PURPOSE: External beam radiotherapy is a complex process, involving timely coordination among multiple teams. The aim of this study is to report our experience of establishing a standardized workflow and using quantitative data and metrics to manage the time-to-treatment initiation (TTI). METHODS AND MATERIALS: Starting in 2014, we established a standard process in a radiation oncology-specific electronic medical record system (RO-EMR) for patients receiving external beam radiation therapy in our department, aiming to measure the time interval from simulation to treatment initiation, defined as TTI, for radiation oncology. TTI data were stratified according to the following treatment techniques: three-dimensional (3D) conformal therapy, intensity-modulated radiotherapy (IMRT), and stereotactic body radiotherapy (SBRT). Statistical analysis was performed with the Mann-Whitney test for the respective metrics of aggregate data for the initial period 2012- 2015 (PI) and the later period 2016-2019 (PII). RESULT: Over 8 years, the average annual number of treatments for PI and PII were 1760 and 2357 respectively, with 3D, IMRT, and SBRT treatments accounting for 53, 29, 18% and 44, 34, 22%, respectively, of the treatment techniques. The median TTI for 3D, IMRT, and SBRT for PI and PII were 1, 6, 7, and 1, 5, 7 days, respectively, while the 90th percentile TTI for the three techniques in both periods were 5, 9, 11 and 4, 9, 10 days, respectively. From the aggregate data, the TTI was significantly reduced (p = 0.0004, p < 0.0001, p < 0.0001) from PI to PII for the three treatment techniques. CONCLUSION: Establishing a standardized workflow and frequently measuring TTI resulted in shortening the TTI during the early years (in PI) and maintaining the established TTI in the subsequent years (in PII).

Construction of electrochemical immunosensor from MXene/multi-walled carbon nanotubes/gold nanoparticles for specific detection of carcinoembryonic antigen.

With the advancement of nanotechnology, various types of nanomaterials have been integrated into electrochemical immunoelectrodes to enhance their performance. Among these, MXene stands out as a promising candidate due to its high electron transfer capacity and abundant surface chemical groups. However, the improvement in electrode performance is often hindered by the self-restacking and agglomeration of MXene. To address this issue, multi-walled carbon nanotubes (MWCNTs) were selected to form composites with MXene. Subsequently, a label-free immunosensor, BSA/Ab/AuNPs/MXene-MWCNTs-Nafion/ITO, was fabricated for specific detection of carcinoembryonic antigen (CEA), a widely used tumor marker. The results demonstrated that the incorporation of MWCNTs can effectively prevent the self-stacking of MXene. Moreover, the composites enhanced the loading of gold nanoparticles (AuNPs) to connect the antibodies, thereby improving electronic transmission signals and sensitivity. The sensor exhibited excellent analytical performance towards CEA with a wide linear range (0.050 to 200 ng mL-1) and a low limit of detection of 0.015 ng mL-1 (S/N = 3). The possibility of it being applied in clinical trials was verified by using ELISA and differential pulse voltammetry (DPV) assays to detect CEA in serum samples. The recoveries ranged from 95.34 to 102.09% with relative standard deviations (RSDs) below 5.00%. Furthermore, the sensor displayed satisfactory selectivity, repeatability, and stability. We hope the findings highlight promising prospects for advanced immunosensor development and alternative strategies in cancer diagnosis.

Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial.

BACKGROUND: Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population. METHODS: Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m2) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m2), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete. FINDINGS: The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group). INTERPRETATION: To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated. FUNDING: National Cancer Institute and Novartis.

Adaptor protein MyD88 confers the susceptibility to stress via amplifying immune danger signals.

Increasing evidence supports the pathogenic role of neuroinflammation in psychiatric diseases, including major depressive disorder (MDD) and neuropsychiatric symptoms of Coronavirus disease 2019 (COVID-19); however, the precise mechanism and therapeutic strategy are poorly understood. Here, we report that myeloid differentiation factor 88 (MyD88), a pivotal adaptor that bridges toll-like receptors to their downstream signaling by recruiting the signaling complex called 'myddosome', was up-regulated in the medial prefrontal cortex (mPFC) after exposure to chronic social defeat stress (CSDS) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The inducible expression of MyD88 in the mPFC primed neuroinflammation and conferred stress susceptibility via amplifying immune danger signals, such as high-mobility group box 1 and SARS-CoV-2 spike protein. Overexpression of MyD88 aggravated, whereas knockout or pharmacological inhibition of MyD88 ameliorated CSDS-induced depressive-like behavior. Notably, TJ-M2010-5, a novel synthesized targeting inhibitor of MyD88 dimerization, alleviated both CSDS- and SARS-CoV-2 spike protein-induced depressive-like behavior. Taken together, our findings indicate that inhibiting MyD88 signaling represents a promising therapeutic strategy for stress-related mental disorders, such as MDD and COVID-19-related neuropsychiatric symptoms.

Theoretical Insights into the Substitution Effect of Phenanthroline Derivatives on Am(III)/Eu(III) Separation.

Separation of trivalent actinides (An(III)) and lanthanides (Ln(III)) poses a huge challenge in the reprocessing of spent nuclear fuel due to their similar chemical properties. N,N'-Diethyl-N,N'-ditolyl-2,9-diamide-1,10-phenanthroline (Et-Tol-DAPhen) is a potential ligand for the extraction of An(III) from Ln(III), while there are still few reports on the effect of its substituent including electron-withdrawing and electron-donating groups on An(III)/Ln(III) separation. Herein, the interaction of Et-Tol-DAPhen ligands modified by the electron-withdrawing groups (CF3, Br) and electron-donating groups (OH) with Am(III)/Eu(III) ions was investigated using scalar relativistic density functional theory (DFT). The analyses of bond order, quantum theory of atoms in molecules (QTAIM), and molecular orbital (MO) indicate that the substitution groups have a slight effect on the electronic structures of the [M(L-X)(NO3)3] (X = CF3, Br, OH) complexes. However, the thermodynamic results suggest that a ligand with the electron-donating group (L-OH) improves the extraction ability of metal ions, and the ligand modified by the electron-withdrawing group (L-Br) has the best Am(III)/Eu(III) selectivity. This work could render new insights into understanding the effect of electron-withdrawing and electron-donating groups in tuning the selectivity of Et-Tol-DAPhen derivatives and pave the way for designing new ligands modified by substituted groups with better extraction ability and An(III)/Ln(III) selectivity.

Effect of the Deletion of icl1 Gene and icl2 Gene on the Growth Rate of Mycobacterium tuberculosis and the Specific Regulatory Mechanism Involved.

Objective: To explore the effect of the deletion of the icl1 gene and icl2 gene on the growth rate of Mycobacterium tuberculosis (Mtb) and the specific regulatory mechanism involved. Methods: H37Rv was purchased from the Tuberculosis Prevention and Control Institute, and H37Rv was grown in Middlebrook 7H9 broth. Macrophages THP-1 cells were purchased by our researchers from the Cell Bank of the Chinese Academy of Sciences, which were maintained in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 10% fetal bovine serum (FBS), at 37°C and 5% CO2. The experiment was divided into 3 groups: the control group (H37Rv infected with THP-1 cells), the icl1/2 deletion group (H37Rv infected with icl1/2 deleted THP-1 cells) and the icl1/2 complementation group (H37Rv infected with icl1/2 deletion, icl1/2 complementary THP-1 cells). Absorbance was measured with a microplate spectrophotometer and the bacterial growth rate was calculated. The colony-forming units (CFU) obtained from the dilution was used to calculate the total number of CFU per milliliter and the percentage of survival of mycobacteria. The protein levels of isocitrate lyase 1 (ICL1), ICL2, p-mTOR and p-Akt were analyzed by Western blot. The CD4+ level was analyzed by flow cytometry. The mRNA expression levels of CCL20, CXCL2, CXCL8, interferon gamma (IFN-γ), interleukin (IL)-17 and IL-22 were analyzed using the quantitative reverse transcription polymerase chain reaction (RT-qPCR) method. Stably transformed monomeric red fluorescent protein (mRFP)-green fluorescent protein (GFP)-LC3 reporter THP-1 cells were used to monitor the aggregation of LC3B in autophagosomes and autophagolysosomes. Results: The Mtb growth rate and CFU of the icl1/2 deletion group were decreased in comparison with the control group (P < .05). When compared with the icl1/2 deletion group, however, the Mtb growth rate and CFU of the icl1/2 complementation group were associated with increased results (P < .05). The protein levels of ICL1 and ICL2 in the icl1/2 deletion group were significantly decreased compared with the control group (P < .05), which were evidently increased in the icl1/2 complementation group when compared with the icl1/2 deletion group (P < .05). In addition, compared with the control group (25.16 ± 2.18), the level of CD4+ appeared to be increased in the icl1/2 deletion group (62.37 ± 5.46) (P < .05), while it was decreased in the icl1/2 complementation group compared with the icl1/2 deletion group (28.33 ± 1.32) (P < .05). The expression levels of chemokine (C-C motif) ligand 20 (CCL20), chemokine (C-X-C motif) ligand 2 (CXCL2), chemokine (C-X-C motif) ligand 8 (CXCL8), IL-17, IFN-γ, and IL-22 mRNA were increased in the icl1/2 deletion group compared with the control group (P < .05), which were significantly decreased in the icl1/2 complementary group compared with the icl1/2 deletion group (P < .05). A comparison between the control group and the icl1/2 deletion group showed that the latter increased the formation of autophagosomes and autophagolysosomes in H37Rv-infected cells (P < .05). However, compared with the icl1/2 deletion group, the icl1/2 complementation group decreased the formation of autophagosomes and autolysosomes in H37Rv-infected cells (P < .05). Moreover, the expression levels of phosphor-mammalian target of rapamycin (p-mTOR) and p-Akt in the icl1/2 deletion group were significantly reduced compared with the control group (P < .05), and were increased in the icl1/2 complementation group compared with the icl1/2 deletion group (P < .05). Conclusion: Loss of icl1/2 was believed to increase the expression of CD4 and CCL20, CXCL8 as well as CXCL2 in the immune system, which increased autophagy. Furthermore, it exerted potential in inhibiting the growth of intracellular Mtb in macrophages.

Contour similarity and its implication on inverse prostate SBRT treatment planning.

PURPOSE: Success of auto-segmentation is measured by the similarity between auto and manual contours that is often quantified by Dice coefficient (DC). The dosimetric impact of contour variability on inverse planning has been rarely reported. The main aim of this study is to investigate whether automatically generated organs-at-risk (OARs) could be used in inverse prostate stereotactic body radiation therapy (SBRT) planning and whether the dosimetric parameters are still clinically acceptable after radiation oncologists modify the OARs. METHODS AND MATERIALS: Planning computed tomography images from 10 patients treated with SBRT for prostate cancer were selected and automatically segmented by commercially available atlas-based software. The automatically generated OAR contours were compared with the manually drawn contours. Two volumetric modulated arc therapy (VMAT) plans, autoRec-VMAT (where only automatically generated rectums were used in optimization) and autoAll-VMAT (where automatically generated OARs were used in inverse optimization) were generated. Dosimetric parameters based on the manually drawn PTV and OARs were compared with the clinically approved plans. RESULTS: The DCs for the rectum contours varied from 0.55 to 0.74 with a mean value of 0.665. Differences of D95 of the PTV between autoRec-VMAT and manu-VMAT plans varied from 0.03% to -2.85% with a mean value of -0.64%. Differences of D0.03cc of manual rectum between the two plans varied from -0.86% to 9.94% with a mean value of 2.71%. D95 of PTV between autoAll-VMAT and manu-VMAT plans varied from 0.28% to -2.9% with a mean value -0.83%. Differences of D0.03cc of manual rectum between the two plans varied from -0.76% to 6.72% with a mean value of 2.62%. CONCLUSION: Our study implies that it is possible to use unedited automatically generated OARs to perform initial inverse prostate SBRT planning. After radiation oncologists modify/approve the OARs, the plan qualities based on the manually drawn OARs are still clinically acceptable, and a re-optimization may not be needed.

Online verification of breath-hold reproducibility using kV-triggered imaging for liver stereotactic body radiation therapy.

PURPOSE: To introduce a new technique for online breath-hold verification for liver stereotactic body radiation therapy (SBRT) based on kilovoltage-triggered imaging and liver dome positions. MATERIAL AND METHODS: Twenty-five liver SBRT patients treated with deep inspiration breath-hold were included in this IRB-approved study. To verify the breath-hold reproducibility during treatment, a KV-triggered image was acquired at the beginning of each breath-hold. The liver dome position was visually compared with the expected upper/lower liver boundaries created by expanding/contracting the liver contour 5 mm in the superior-inferior direction. If the liver dome was within the boundaries, delivery continued; otherwise, beam was held manually, and the patient was instructed to take another breath-hold until the liver dome fell within boundaries. The liver dome was delineated on each triggered image. The mean distance between the delineated liver dome to the projected planning liver contour was defined as liver dome position error edome . The mean and maximum edome of each patient were compared between no breath-hold verification (all triggered images) and with online breath-hold verification (triggered images without beam-hold). RESULTS: Seven hundred thirteen breath-hold triggered images from 92 fractions were analyzed. For each patient, an average of 1.5 breath-holds (range 0-7 for all patients) resulted in beam-hold, accounting for 5% (0-18%) of all breath-holds; online breath-hold verification reduced the mean edome from 3.1 mm (1.3-6.1 mm) to 2.7 mm (1.2-5.2 mm) and the maximum edome from 8.6 mm (3.0-18.0 mm) to 6.7 mm (3.0-9.0 mm). The percentage of breath-holds with edome >5 mm was reduced from 15% (0-42%) without breath-hold verification to 11% (0-35%) with online breath-hold verification. online breath-hold verification eliminated breath-holds with edome >10 mm, which happened in 3% (0-17%) of all breath-holds. CONCLUSION: It is clinically feasible to monitor the reproducibility of each breath-hold during liver SBRT treatment using triggered images and liver dome. Online breath-hold verification improves the treatment accuracy for liver SBRT.

The dosimetric impact of titanium implants in spinal SBRT using four commercial treatment planning algorithms.

To evaluate the dosimetric impact of titanium implants in spine SBRT using four dose calculation algorithms. Twenty patients with titanium implants in the spine treated with SBRT without density override (DO) were selected. The clinical plan for each patient was created in Pinnacle and subsequently imported into Eclipse (AAA and AcurosXB) and Raystation (CC) for dose evaluation with and without DO to the titanium implant. We renormalized all plans such that 90% of the tumor volume received the prescription dose and subsequently evaluated the following dose metrics: (1) the maximum dose to 0.03 cc (Dmax), dose to 99% (D99%) and 90% (D90%) of the tumor volume; (2) Dmax and volumetric metrics of the spinal cord. For the same algorithm, plans with and without DO had similar dose distributions. Differences in Dmax, D99% and D90% of the tumor were on average <2% with slightly larger variations up to 5.58% in Dmax using AcurosXB. Dmax of the spinal cord for plans calculated with DO increased but the differences were clinically insignificant for all algorithms (mean: 0.36% ± 0.7%). Comparing to the clinical plans, the relative differences for all algorithms had an average of 1.73% (-10.36%-13.21%) for the tumor metrics and -0.93% (-9.87%-10.95%) for Dmax of the spinal cord. A few cases with small tumor and spinal cord volumes, dose differences of >10% in both D99% and Dmax of the tumor, and Dmax of the spinal cord were observed. For all algorithms, the presence of titanium implants in the spine for most patients had minimal impact on dose distributions with and without DO. For the same plan calculated with different algorithms, larger differences in volumetric metrics of >10% could be observed, impacted by dose gradient at the plan normalization volume, tumor volumes, plan complexity, and partial voxel volume interpolation.

Using feasibility dose-volume histograms to reduce intercampus plan quality variability for head-and-neck cancer.

The purpose of this work is to objectively assess variability of intercampus plan quality for head-and-neck (HN) cancer and to test utility of a priori feasibility dose-volume histograms (FDVHs) as planning dose goals. In this study, 109 plans treated from 2017 to 2019 were selected, with 52 from the main campus and 57 from various regional centers. For each patient, the planning computed tomography images and contours were imported into a commercial program to generate FDVHs with a feasibility value (f-value) ranging from 0.0 to 0.5. For 10 selected organs-at-risk (OARs), we used the Dice similarity coefficient (DSC) to quantify the overlaps between FDVH and clinically achieved DVH of each OAR and determined the f-value associated with the maximum DSC (labeled as f-max). Subsequently, 10 HN plans from the regional centers were replanned with planning dose goals guided by FDVHs. The clinical and feasibility-guided auto-planning (FgAP) plans were evaluated using our institutional criteria. Among plans from the main campus and regional centers, the median f-max values were statistically significantly different (p < 0.05) for all OARs except for the left parotid (p = 0.622), oral cavity (p = 0.057), and mandible (p = 0.237). For the 10 FgAP plans, the median values of f-max were 0.21, compared to 0.37 from the clinical plans. With comparable dose coverage to the tumor volumes, the significant differences (p < 0.05) in the median f-max and corresponding dose reduction (shown in parenthesis) for the spinal cord, larynx, supraglottis, trachea, and esophagus were 0.27 (8.5 Gy), 0.3 (7.6 Gy), 0.19 (5.9 Gy), 0.19 (8.9 Gy), and 0.12 (4.0 Gy), respectively. In conclusion, the FDVH prediction is an objective quality assurance tool to evaluate the intercampus plan variability. This tool can also provide guideline in planning dose goals to further improve plan quality.

Transperineal ultrasound is a good alternative for intra-fraction motion monitoring for prostate stereotactic body radiotherapy.

PURPOSES: To report our experience in a prospective study of implementing a transperineal ultrasound system to monitor intra-fractional prostate motion for prostate stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: This IRB-approved prospective study included 23 prostate SBRT patients treated between 04/2016 and 11/2019 at our institution. The prescription doses were 36.25 Gy to the Low-Dose planning target volume (LD-PTV) and 40 Gy to the High-Dose PTV (HD-PTV) in five fractions with 3 mm planning margins. The transperineal ultrasound system was successfully used in 110 of the 115 fractions. For intra-fraction prostate motion, the real-time prostate displacements measured by ultrasound were exported for analysis. The percentage of time prostate movement exceeded a 2 mm threshold was calculated for each fraction of all patients. T-test was used for all statistical comparisons. RESULTS: Ultrasound image quality was adequate for prostate delineation and prostate motion tracking. The setup time for each fraction under ultrasound-guided prostate SBRT was 15.0 ± 4.9 min and the total treatment time per fraction was 31.8 ± 10.5 min. The presence of an ultrasound probe did not compromise the contouring of targets or critical structures. For intra-fraction motion, prostate movement exceeded 2 mm tolerance in 23 of 110 fractions for 11 of 23 patients. For all fractions, the mean percentage of time when the prostate moved more than 2 mm in any direction during each fraction was 7%, ranging from 0% to 62% of a fraction. CONCLUSION: Ultrasound-guided prostate SBRT is a good option for intra-fraction motion monitoring with clinically acceptable efficiency.

Anterior debridement combined with autogenous iliac bone graft fusion for the treatment of lower cervical tuberculosis: a multicenter retrospective study.

BACKGROUND: This study aimed to analyze the clinical efficacy of one-stage anterior debridement of lower cervical tuberculosis using iliac crest bone graft fusion and internal fixation. MATERIALS AND METHODS: A retrospective analysis was performed on 48 patients with lower cervical tuberculosis admitted to multiple medical centers from June 2018 to June 2021. Among them, 36 patients had lesions involving two vertebrae and 12 patients had lesions involving more than three vertebrae. All patients were treated with quadruple antituberculosis drugs for more than 2 weeks before the operation, and then treated with one-stage anterior debridement and autogenous iliac bone graft fusion combined with titanium plate internal fixation. After the operation, antituberculosis drugs were continued for 12-18 months. The patients were followed-up to observe the improvement in clinical symptoms, bone graft fusion, Cobb angle, visual analog score (VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), wound healing, and neurological function. RESULTS: The patients were followed-up for 13-43 months, with an average of 21.46 ± 1.52 months. The clinical symptoms significantly improved after the operation. The bone graft was completely fused in all patients, and the bone fusion time was 3-6 months, with an average of 4.16 ± 0.47 months. At the last follow-up, the Cobb angle, VAS, ESR, and CRP level were significantly lower than those before surgery (P < 0.05). None of the patients had loosening, detachment, or rupture of the internal fixation, and no recurrence occurred. All surgical incisions healed in one stage without infection or sinus formation. The preoperative Frankel neurological function classification was grade B in 7 cases, grade C in 13, grade D in 18, and grade E in 10. At the last follow-up, 8 cases recovered to grade D and 40 recovered to grade E. CONCLUSIONS: For patients with lower cervical tuberculosis, based on oral treatment with quadruple antituberculosis drugs, direct decompression through anterior debridement, followed by autologous iliac bone graft fusion combined with internal fixation can completely remove tuberculosis foci, rebuild the stability of the cervical spine, and obtain good clinical efficacy. Level of evidence Level 3.

NLRP3 inflammasome up-regulates major histocompatibility complex class I expression and promotes inflammatory infiltration in polymyositis.

OBJECTIVE: This study was designed to investigate the role of the nucleotide-binding-domain -and leucine-rich repeat -containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome in the pathogenesis of polymyositis (PM). METHODS: Immunochemistry was performed to analyze the NLRP3, caspase-1 and interleukin-1 beta (IL-1ß) expression in the muscle tissue of PM patients. Rat model of PM and C2C12 cell were used to investigate the potential role of NLRP3 inflammasome in PM. RESULTS: The percentage of CD 68+ macrophages, and the expression levels of NLRP3, caspase-1 and IL-1ß in the muscle tissue were elevated in 27 PM patients. LPS/ATP treatment resulted in activation of NLRP3 inflammasome and secretion of IL-1ß as well as interferons (IFNs) and monocyte chemotactic protein-1 (MCP-1) in the Raw 264.7 macrophages. Meanwhile, LPS/ATP challenged activation of NLRP3 inflammasome induced overexpression of major histocompatibility complex class I (MHC-I), a key molecular of PM in the co-cultured C2C12 cells. The effect was decreased by treatment of NLRP3 inflammasome inhibitor MCC950 or siRNA of NLRP3 inflammasome. These findings suggested certain levels of IL-1ß rather than IFNs up-regulated MHC-I expression in C2C12 cells. IL-1ß blockade using neutralizing IL-1ß monoclonal antibody or siRNA of IL-1ß suppressed MHC-I overexpression. In vivo, NLRP3 inflammasome inhibition by MCC950 reduced the expression of NLRP3, IL-1ß and MHC-I in the muscle tissue of PM modal rats. Also, it attenuated the intensity of muscle inflammation as well as the CRP, CK, and LDH levels in the serum. CONCLUSION: NLRP3/caspase-1/IL-1ß axis may play an important role in the development of PM. Inhibition of NLRP3 activation may hold promise in the treatment of PM.

miR-378a regulates keratinocyte responsiveness to interleukin-17A in psoriasis.

BACKGROUND: Psoriasis is an immune-mediated inflammatory skin disease, in which an interplay between infiltrating immune cells and keratinocytes sustains chronic skin inflammation. Interleukin (IL)-17A is a key inflammatory cytokine in psoriasis and its main cellular targets are keratinocytes. OBJECTIVES: To explore the role of miR-378a in psoriasis. METHODS: Keratinocytes obtained from psoriatic skin and healthy epidermis were separated by magnetic sorting, and the expression of miR-378a was analysed by quantitative polymerase chain reaction. The regulation and function of miR-378a was studied using primary human keratinocytes. The expression of miR-378a was modulated by synthetic mimics, and nuclear factor kappa B (NF-κB) activity and transcriptomic changes were studied. Synthetic miR-378a was delivered to mouse skin in conjunction with induction of psoriasiform skin inflammation by imiquimod. RESULTS: We show that miR-378a is induced by IL-17A in keratinocytes through NF-κB, C/EBP-ß and IκBζ and that it is overexpressed in psoriatic epidermis. In cultured keratinocytes, ectopic expression of miR-378a resulted in the nuclear translocation of p65 and enhanced NF-κB-driven promoter activity even in the absence of inflammatory stimuli. Moreover, miR-378a potentiated the effect of IL-17A on NF-κB nuclear translocation and downstream activation of the NF-κB pathway. Finally, injection of miR-378a into mouse skin augmented psoriasis-like skin inflammation with increased epidermal proliferation and induction of inflammatory mediators. Mechanistically, miR-378a acts as a suppressor of NFKBIA/IκBζ, an important negative regulator of the NF-κB pathway in keratinocytes. CONCLUSIONS: Collectively, our findings identify miR-378a as an amplifier of IL-17A-induced NF-κB signalling in keratinocytes and suggest that increased miR-378a levels contribute to the amplification of IL-17A-driven skin inflammation in psoriasis.