Proposals for the delineation of neck clinical target volume for definitive Radiation therapy in patients with oral/ oropharyngeal squamous cell cancer based on lymph node distribution.

PURPOSE/OBJECTIVE(S): To establish the distribution pattern of cervical lymph node metastasis (LNM) and propose optimized clinical target volume (CTV) boundaries specific to oral/ oropharyngeal squamous cell cancer (OSCC/OPSCC). MATERIALS/METHODS: 531 patients with pathologically confirmed OSCC/OPSCC were enrolled from January 2013 to June 2022. Patients were stratified into two groups based on the minimal distance from the lesion's edge to the body's midline: ≤1 cm or > 1 cm. The geometric center of cervical metastatic LN was marked on a template CT. LN distribution probability maps were established. The relationships between the LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to OSCC/OPSCC. RESULTS: A total of 1962 positive LNs were enrolled. Compared with the > 1 cm group, the ≤ 1 cm group has following feature tendencies: male smokers, younger, median organs, large gross lesion, infiltrative growth pattern, contralateral LNM. The most frequently involved level of LNM was ipsilateral II, but ipsilateral Ib had the highest involvement rate in the > 1 cm OSCC group. In addition, tongue cancer had a higher incidence of LN extranodal extension (ENE), which mainly distributes in ipsilateral level II. The skip metastasis was prone to from level III to Vb (3.5 %) in LN(+)/ENE (-), and level Ib to VIa (3.7 %) in LN(+)/ENE (+). Accordingly, we proposed the following modifications: 1. only including lateral and posterior margin of submandibular gland within 5 mm; 2. retracting posterior boundary of level II to front edge of levator scapula muscle, and descending the upper boundary to transverse process of C2 vertebra only for OSCC; 3. including posterior third of thyroglossal muscle or anterior edge of sternocleidomastoid muscle; 4. sparing level Va in case of only level II involvement; 5. including upper area of the thyroid cartilage plate in case of level Ib LN(+)/ENE (+); 6. sparing level VIIa is considered. CONCLUSION: This is the first description of LN topographic spread patterns for OSCC/OPSCC. Modified CTV for prophylactic irradiation was proposed to spare the organs at risk and minimize adverse effects.

Re-analysis of single-cell transcriptomics reveals a critical role of macrophage-like smooth muscle cells in advanced atherosclerotic plaque.

Aims: Smooth muscle cell (SMC) remodeling poses a critical feature in the development and progression of atherosclerosis. Although fate mapping and in silicon approaches have expanded SMC phenotypes in atherosclerosis, it still remains elusive about the contributions of individual SMC phenotypes and molecular dynamics to advanced atherosclerotic plaque. Methods: Using single-cell transcriptome, we investigated cellular compositions of human carotid plaque laden with atherosclerotic core, followed by in vivo experiments utilizing SMC-lineage tracing technology, bulk RNA sequencing (RNA-seq) and both in vivo and in vitro validation of the underlying molecular mechanism. Results: 5 functionally distinct SMC subtypes were uncovered based on transcriptional features (described as contractile, fibroblast-like, osteogenic, synthetic and macrophage-like) within the niche. A proinflammatory, macrophage-like SMC subtype displaying an intermediary phenotype between SMC and macrophage, exhibits prominent potential in destabilizing plaque. At the molecular level, we explored cluster-specific master regulons by algorithm, and identified interferon regulatory factor-8 (IRF8) as a potential stimulator of SMC-to-macrophage transdifferentiation via activating nuclear factor-κB (NF-κB) signaling. Conclusions: Our study illustrates a comprehensive cell atlas and molecular landscape of advanced atherosclerotic lesion, which might renovate current understanding of SMC biology in atherosclerosis.

Comprehensive scRNA-seq Model Reveals Artery Endothelial Cell Heterogeneity and Metabolic Preference in Human Vascular Disease.

Vascular disease is one of the major causes of death worldwide. Endothelial cells are important components of the vascular structure. A better understanding of the endothelial cell changes in the development of vascular disease may provide new targets for clinical treatment strategies. Single-cell RNA sequencing can serve as a powerful tool to explore transcription patterns, as well as cell type identity. Our current study is based on comprehensive scRNA-seq data of several types of human vascular disease datasets with deep-learning-based algorithm. A gene set scoring system, created based on cell clustering, may help to identify the relative stage of the development of vascular disease. Metabolic preference patterns were estimated using a graphic neural network model. Overall, our study may provide potential treatment targets for retaining normal endothelial function under pathological situations.

The Clinical Characteristics of Heart Rate Variability After Stroke: A Systematic Review.

The autonomic nervous system dysfunction has been reported in up to 76% of stroke patients 7 days after an acute stroke. Heart rate variability (HRV) is one of the important indicators reflecting the balance of sympathetic and parasympathetic nerves. Therefore, we performed a systematic literature review of existing literature on the association between heart rate variability and the different types of stroke. We included studies published in the last 32 years (1990 to 2022). The electronic databases MEDLINE and PubMed were searched. We selected the research that met the inclusion or exclusion criteria. A narrative synthesis was performed. This review aimed to summarize evidence regarding the potential mechanism of heart rate variability among patients after stroke. In addition, the association of clinical characteristics of heart rate variability and stroke has been depicted. The review further discussed the relationship between post-stroke infection and heart rate variability, which could assist in curbing clinical infection in patients with stroke. HRVas a noninvasive clinical monitoring tool can quantitatively assess the changes in autonomic nervous system activity and further predict the outcome of stroke. HRV could play an important role in guiding the clinical practice for autonomic nervous system disorder after stroke.

Eosinophil dynamics during chemo-radiotherapy correlate to clinical outcome in stage â ¡-â £a nasopharyngeal carcinoma patients: Results from a large cohort study.

BACKGROUND AND PURPOSE: We investigated the dynamics of eosinophil depletion during definitive concurrent chemo-radiotherapy (CCRT) and their association with the prognosis of stage Ⅱ-Ⅳa nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: Fuzzy C-means algorithm (FCMA) assessed longitudinal trends in circulating eosinophil counts (CECs) of 1225 patients throughout the period of radical radiotherapy. The prognostic impact on patients' survival was evaluated with Kaplan-Meier analysis and Cox proportional risk model was used to determine the hazard ratio for adverse prognostic effects in grades of eosinophil depletion. The interactive effect of pre-treatment CECs and CCRT on outcomes was evaluated using HRs within the framework of Cox regression models. RESULTS: Three grades of eosinophil depletion, as defined by the interaction between dynamic types of CECs in the period of treatment and the value of CECs at the termination of treatment, significantly stratified the poor prognosis in terms of progression-free survival (PFS), overall survival (OS), and distant metastasis-free survival (DMFS) [1.57-fold (P = 0.001), 1.69-fold (P = 0.007), and 1.51-fold (P = 0.019) for G1, 2.4-fold (P < 0.001), 2.76-fold (P < 0.001), and 2.31-fold (P < 0.001) for G2, as compared with G0]. Furthermore, high levels of pre-treatment CECs acted as the strongest protective factor against severe depletion grade (G0 vs. G2, HR = 0.20, P = 0.005; G1 vs. G2, HR = 0.14, P < 0.001). However, compared with radiotherapy alone, the benefit from CCRT was attenuated in patients with high pre-treatment CECs. CONCLUSIONS: CECs reduction after treatment in patients with NPC may be helpful in the clinical setting to aid in assessing the prognosis for standard treatment of NPC.

Radiation-induced eosinophil increase ratio predicts patient outcomes in non-small celllung cancer.

Background and purpose: Radiotherapy (RT) is a double-edged sword in regulating immune responses. This study aimed to investigate the impact of thoracic RT on circulating eosinophils and its association with patient outcomes in non-small cell lung cancer (NSCLC). Materials and methods: This retrospective study included 240 patients with advanced NSCLC treated with definitive thoracic RT from January 2012 to January 2020. Statistics included Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS), multivariate Cox analyses to identify significant variables, and Spearman's correlation to qualify the relationship between dose-volume histogram (DVH) parameters and EIR. Results: Absolute eosinophil counts (AECs) showed an increasing trend during RT and an obvious peak in the 1st month after RT. Thresholds of eosinophil increase ratio (EIR) at the 1st month after RT for both OS and PFS were 1.43. Patients with high EIR above 1.43 experienced particularly favorable clinical outcomes (five-year OS: 21% versus 10%, P<0.0001; five-year PFS: 10% versus 8%, P=0.014), but may not derive PFS benefit from the addition of chemotherapy to RT. The higher a patient's EIR, the larger the potential benefit in the absence of chemotherapy. DVH parameters including heart mean dose and heart V10 were negatively associated with EIR. None of these DVH parameters was correlated with the clinical outcomes. Conclusion: EIR may serve as a potential biomarker to predict OS and PFS in NSCLC patients treated with RT. These findings require prospective studies to evaluate the role of such prognostic marker to identify patients at risk to tailor interventions.

Reduced-dose radiation in human papillomavirus-associated oropharyngeal carcinoma can improve outcome: a systematic review and meta-analysis.

Background: Despite its effectiveness, the standard course of chemoradiation for the treatment of human papillomavirus (HPV)-related oropharyngeal carcinoma (OPC) results in considerable treatment-related adverse effects. Studies proved that HPV-positive OPC is very sensitive to radiotherapy. Using de-escalation therapy as a new strategy is critical to maintaining positive outcomes while alleviating side effects. However, some studies hold that reduced dose causes insufficient effect on tumor killing. We conducted this systematic review and meta-analysis of survival and adverse reactions in patients with HPV-related OPC by retrospective analysis and evaluated the therapeutic effect of reducing the radiation dose. Methods: Data were double-selected and extracted by searching seven electronic databases, Original studies in all language treated HPV-associated OPC with reduced-dose and standard-dose therapies were included. Overall survival (OS), progression-free survival (PFS), and incidence rates of adverse events were obtained by pooling analyses. Statistical analyses were performed using RStudio Version 1.1.383 (RStudio, Boston, MA, USA) via the Meta-Analysis R Package (metafor). Heterogeneity was evaluated using the I2 statistic and the Cochran Q test. We used Stata (version 15.0) for forest graph. Results: Thirteen studies were included in this meta-analysis, involving a dose range of 66-70 Gy for the standard treatment regimen and <66 Gy for the reduced-dose group. There was no significant difference in the age of the patients in the standard and the reduced treatment groups (60.9±5.9 vs. 58.6±2.4 years). Nine studies were included as standard cohort and thirteen studies were enrolled as reduced-dose cohort. The 2- and 3-year overall survival rates in the reduced-dose group (95.66% and 91.51%, respectively) were superior to those in the standard-dose group (88.36% and 87.46%, respectively). There was no significant difference in PFS between the two groups. A systematic review of articles on dose reduction and the standard dose was also conducted. The most common complication in reduced-dose radiation was oral mucositis (36.4%), followed by decreased white blood cell (WBC) count (30.5%) and dry mouth (29.1%). Conclusions: Reducing the radiation dose in patients with HPV-related OPC substantially alleviates the treatment toxicities and optimizes the quality of life of patients while at the same time maintaining favorable oncologic outcomes.

Ultrasound-guided high intensity focused ultrasound ablation for uterine fibroids: long-term outcomes and factors affecting local recurrence.

OBJECTIVE: To assess the long-term outcomes and the factors affecting local recurrence of uterine fibroids after ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation. MATERIALS AND METHODS: 629 patients with a solitary uterine fibroid smaller than 10 cm in diameter treated with USgHIFU at our institutes between January 2011 and December 2016 were retrospectively analyzed. The patients were requested to take pre-HIFU and one day post-HIFU MRI. The patients were asked to return to the hospital every 3 months until January 2020, for imaging evaluation and to check on improvement in symptoms. RESULTS: Five hundred and thirty-six patients completed follow-up according to our protocol. The median follow-up time was 69 (interquartile range: 48 to 89) months. Among them, local recurrence was detected in 110 patients. 18 (16.4%) patients required additional treatment between 12 and 24 months after USgHIFU treatment, 59 (53.6%) patients required additional treatment 24 months after USgHIFU. Therefore, in total, 77 patients required additional treatment, of which 32 received USgHIFU and 45 underwent myomectomy. The median non-perfused volume (NPV) ratio in patients with recurrence was 73%, compared to 89% among patients without recurrence. Multivariate analysis showed that NPV ratio, maximum fibroid diameter and fibroid enhancement type were the independent factors affecting the recurrence of fibroids after USgHIFU treatment. CONCLUSIONS: Achievement of NPV ratio higher than 70% has led to acceptable re-intervention rate during the follow-up period after USgHIFU. NPV ratio, maximum fibroid diameter, and fibroid enhancement type were the independent factors affecting the recurrence of fibroids after USgHIFU treatment.

Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition.

In this study, we first established the doxorubicin-induced cardiotoxicity (DIC) model with C57BL/6 mice and confirmed cardiac dysfunction with transthoracic echocardiography examination. RNA-sequencing was then performed to explore the potential mechanisms and transcriptional changes in the process. The metabolic pathway, biosynthesis of polyunsaturated fatty acid was significantly altered in DOX-treated murine heart, and Acot1 was one of the leading-edge core genes. We then investigated the role of Acot1 to ferroptosis that was reported recently to be related to DIC. The induction of ferroptosis in the DOX-treated heart was confirmed by transmission electron microscopy, and the inhibition of ferroptosis using Fer-1 effectively prevented the cardiac injury as well as the ultrastructure changes of cardiomyocyte mitochondrial. Both in vitro and in vivo experiments proved the downregulation of Acot1 in DIC, which can be partially prevented with Fer-1 treatment. Overexpression of Acot1 in cell lines showed noteworthy protection to ferroptosis, while the knock-down of Acot1 sensitized cardiomyocytes to ferroptosis by DIC. Finally, the heart tissue of αMHC-Acot1 transgenic mice presented altered free fatty acid composition, indicating that the benefit of Acot1 in the inhibition of ferroptosis lies biochemically and relates to its enzymatic function in lipid metabolism in DIC. The current study highlights the importance of ferroptosis in DIC and points out the potential protective role of Acot1 in the process. The beneficial role of Acot1 may be related to its biochemical function by shaping the lipid composition. In all, Acot1 may become a potential treating target in preventing DIC by anti-ferroptosis.

Trimetazidine Inhibits Renal Tubular Epithelial Cells to Mesenchymal Transition in Diabetic Rats via Upregulation of Sirt1.

Trimetazidine (TMZ), as a metabolic regulator, is effective in treatment of coronary atherosclerotic heart disease with rare side effects in the clinic for long years. Interestingly, studies have shown that TMZ protects against several acute kidney injuries (AKI). However, the effect of TMZ on chronic kidney diseases (CKD) remains unknown. This study aimed to investigate the role of TMZ in diabetic nephropathy (DN) and its potential mechanisms. A rat model of DN was established in male Sprague-Dawley rats by streptozotocin (STZ) intraperitoneal injection. Experimental rats were separated into three groups: control, DN and DN + TMZ treatment. Metabolic parameters, pathological features and renal function markers were evaluated after 20 weeks of diabetes induction. In vitro experiments, the effect of TMZ on high fat and high glucose (HFG) induced or TGFß1-induced epithelial-to-mesenchymal transition (EMT) was examined in HK-2 cells. Our results showed that TMZ could maintain renal function without affecting hemodynamic and plasma metabolic levels in diabetic rats. The effect was associated with a reversion of pathological progression of DN, especially for tubulointerstitial fibrosis. EMT is an important contributor to renal fibrosis. In this study, we investigated the role of TMZ in the process of EMT in DN. Mechanistically; TMZ attenuated HFG-induced EMT by relieving oxidative stress via deacetylation forkhead box O1 (FoxO1) in a Sirt1-dependent pathway. And it suppressed TGFß1-induced EMT by deacetylating Smd4 in a Sirt1-dependent manner. Moreover, our study found that TMZ upregulated Sirt1 expression by increasing the expression of nicotinamide phosphoribosyl transferase (Nampt), which is a rate limiting enzyme for nicotinamide adenine dinucleotide (NAD+) generation by salvage pathway. And the increased NAD+ promoted Sirt1 expression. In conclusion, TMZ can prevent renal dysfunction and pathogenesis of tubulointerstitial fibrosis in DN, partly by inhibition of EMT via FoxO1/ROS pathway and TGFß/Smad pathway in a Nampt/NAD+/Sirt1 dependent manner.

Adverse effect analysis of high-intensity focused ultrasound in the treatment of benign uterine diseases.

OBJECTIVE: To retrospectively analyze the adverse effects of high-intensity focused ultrasound (HIFU) in management of benign uterine diseases. MATERIALS AND METHODS: From 2011 to 2017, 27,053 patients with benign uterine diseases were treated with HIFU in 19 centers in China. Among them, 17,402 patients had uterine fibroids, 8434 had adenomyosis, 876 had caesarean scar pregnancies, and 341 had placenta accreta. RESULTS: The median age, height, weight, BMI of the patients was 42 years, 158 mm, 56 kg, 22.5 kg/cm2, respectively. After HIFU treatment, 13,170 adverse events were observed. Based on society of interventional radiology classification system, these adverse events were classified as Class A (47.5030%), Class B (0.7947%), Class C (0.3327%), and Class D (0.0518%). The rate of major adverse effects (Class C&D) was 0.3844%. Major adverse effects include skin burn, leg pain, vaginal discharge or bleeding, urinary retention, acute cystitis, intrauterine infection, bowel injury, acute renal failure, deep vein thrombosis, pubic symphysis injury, post-HIFU thrombocytopenia, sciatic nerve injury, and hydronephrosis. In 2011, the annual rate of major adverse effects was 0.9565%; the incidence decreased to 0.2852% in 2017. No significant difference was observed in the rates of major adverse effects between patients with uterine fibroids, adenomyosis and placenta accreta. CONCLUSIONS: Based on the results with low rate of major adverse effects from multiple centers, we concluded that HIFU is safe in treating patients with benign uterine diseases. With development of this technique and more experience on the part of the physicians, the rates of the major adverse effects will be further lowered.

Establishment of a scoring system for predicting the difficulty level of high-intensity focussed ultrasound ablation of uterine fibroids.

PURPOSE: To establish a scoring system that predicts the difficulty level of high-intensity focussed ultrasound (HIFU) ablation of uterine fibroids. MATERIALS AND METHODS: Four hundred and twenty-two patients with fibroids were enrolled. The energy efficiency factor (EEF) and sonication time were set as dependent variables, with factors possibly affecting EEF and sonication time including age, body mass index (BMI), the volume of fibroids, the location of the uterus, the type of fibroids, the signal intensity on the T2-weighted imaging (T2WI), the enhancement type, the thickness of the rectus abdominis and the subcutaneous fat layer, the distance from the anterior/posterior surface of the fibroid to the skin, and the abdominal wall scars were set as predictors for building optimal scaling regression models. RESULTS: The volume of the fibroids, the location of the uterus, the signal intensity on T2WI, enhancement type, rectus abdominis thickness, subcutaneous fat thickness, and distance from the anterior surface of fibroid to the skin were related to EEF. Signal intensity on T2WI, the volume of fibroids, distance from the posterior surface of fibroid to the skin, and enhancement type were related to sonication time. Models that can predict the difficulty level of HIFU for fibroids have been established: for EEF, y ' = 0.338X '1 - 0.231X '2+0.156X '3+0.167X '4 ; for sonication time, y = 0.227X1+0.321X2+0.157X3+0.194X4. CONCLUSIONS: A scoring system for predicting the difficulty level of HIFU treatment for uterine fibroids has been established and it can be used to help select patients and to predict the sonication time for a given fibroid.

High intensity focused ultrasound treatment of adenomyosis: The relationship between the features of magnetic resonance imaging on T2 weighted images and the therapeutic efficacy.

OBJECTIVES: To investigate the relationship between the features of magnetic resonance imaging (MRI) on T2 weighted images (T2WI) and the therapeutic efficacy of high intensity focused ultrasound (HIFU) on adenomyosis. MATERIALS AND METHODS: From January 2011 to November 2015, four hundred and twenty-eight patients with symptomatic adenomyosis were treated with HIFU. Based on the signal intensity and the number of hyperintense foci in the adenomyotic lesions on T2WI, the patients were classified into groups. The day after HIFU ablation patients underwent contrast-enhanced MRI and a comparison was made of non-perfused volume (NPV) ratio, energy efficiency factor (EEF), treatment time, sonication time, and adverse effects. RESULTS: No significant difference in terms of HIFU treatment settings and results was observed between the group of patients with hypointense adenomyotic lesions and the group with isointense adenomyotic lesions (P>0.05). However, the sonication time and EEF were significantly higher in the group with multiple hyperintense foci compared to the group with few hyperintense foci. The NPV ratio achieved in the lesions with multiple hyperintenese foci was significantly lower than that in the lesions with few hyperintense foci (P<0.05). No significant difference was observed in the rate of adverse effects between the two groups. CONCLUSIONS: Based on our results, the response of the adenomyotic lesions to HIFU treatment is not related to the signal intensity of adenomyotic lesions on T2WI. However, the number of the high signal intensity foci in the adenomyotic lesions on T2WI can be considered as a predictive factor to help select patients for HIFU treatment.

Rhodol-based far-red fluorescent probe for the detection of cysteine and homocysteine over glutathione.

The simultaneous discrimination of cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) is of great importance due to their roles in biology and close link to many diseases, especially via the development of a far-red fluorescent probe that could be used for rapid, selective, and sensitive detection of all three. Herein, we report the characterization of a far-red fluorescent probe with turn-on fluorescence properties and visible color changes that could be used for the detection of cysteine and homocysteine over glutathione. In this study we found that the sensor could discriminate cysteine and homocysteine over glutathione within 20 min. Function of this probe was based on the conjugate addition-cyclization reaction and showed a low detection limit to cysteine and homocysteine. Upon the addition of cysteine and homocysteine, the absorption band at 592 nm rose gradually and fluorescence was detected at 645 nm. The color changed from colorless to blue and fluorescence changed from absent to strong red fluorescence, which could be differentiated by the naked eye. All these unique features make this probe particularly potentially favorable for use in cysteine/homocysteine sensing and bioimaging applications. Copyright © 2016 John Wiley & Sons, Ltd.