Accumulation and bio-oxidation of arsenite mediated by thermoacidophilic Cyanidiales: innate potential biomaterials toward arsenic remediation.

Addressing geogenic and anthropogenic arsenic (As) pollution is critical for environmental health. This study explored arsenite [As(III)] removal using Cyanidiales, particularly Cyanidium caldarium (Cc) and Galdieria partita (Gp), under acidic to neutral pH, and determined As(III) detoxification mechanisms in relation to As speciation and protein secondary structure in Cyanidiales. Regarding As(III) sorption amounts, Cc outperformed Gp, reaching 83.2 mg g-1 of removal at pH 5.0. Wherein, 23.5 % of sorbed As on Cc presented as arsenate [As(V)] complexation with polysaccharides, alongside other predominant species including As(III)-cysteine (41.2 %) and As(III)-polysaccharides (35.3 %) complexes. This suggested that As(III) was directly transported into cells, rather than As(V). Coupled with the formation of As(III)-cysteine complexes within cells, these mechanisms may be key to efficiently accumulating As(III) in Cyanidiales during the 6-h incubation. These results highlight the potential of Cyanidiales for sustainable As(III) remediation and provide new insights into managing As(III) toxicity.

Association between body mass index and glymphatic function using diffusion tensor image-along the perivascular space (DTI-ALPS) in patients with Parkinson's disease.

Background: Obesity is considered a risk factor for the development of several neurodegenerative diseases, including Parkinson's disease (PD). Recent studies have revealed that glymphatic function is compromised in PD patients. This study aims to investigate the impact of different body mass index (BMI) statuses on glymphatic system function in PD patients using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. Methods: This study used a cross-sectional study design. A total of 145 PD patients were retrospectively enrolled in Parkinson's Progression Markers Initiative (PPMI) from 2010-2013. Eligibility criteria included diagnosis of PD based on PPMI criteria. Diffusion tensor image (DTI) scans (diffusion gradient =64, b-value =1,000 s/mm2, slice thickness =2 mm) were acquired, and the analysis along the perivascular space (ALPS) index of each subject was calculated. The patient cohort was categorized into three groups based on BMI: normal weight (N=49), overweight (N=69), and obese (N=27). The difference in ALPS index among groups was performed by one-way analysis of variance (ANOVA). Partial correlation analysis was used to observe the relationship between ALPS index, BMI status, and demographics. Spearman's rank correlation coefficient and multivariable linear regression analyses were used to identify factors associated with ALPS index. Results: PD patients with higher BMI exhibited a reduced ALPS index (normal weight > overweight > obese), and the ALPS index for patients with obesity was statistically significantly lower than that for patients with normal weight (P<0.001). After adjusting for age, sex, years of education, handedness, and disease duration, a significant negative correlation between the ALPS index and BMI was observed in the PD patients (R=-0.275, P<0.001). Furthermore, a negative correlation between the ALPS index and the severity of motor symptoms was identified in the subgroup of overweight (R=-0.318, P=0.01), rather than in the normal weight and obese groups. Conclusions: High BMI has a negative impact on the glymphatic function in PD patients, suggesting that weight control may have clinical relevance in the management of PD patients.

A novel endoscopic nasopharyngectomy by low-temperature plasma radiofrequency ablation in localized recurrent nasopharyngeal carcinoma.

OBJECTIVE: Endoscopic nasopharyngectomy (ENPG) with en bloc resection has been well accepted in resectable localized recurrent nasopharyngeal carcinoma (rNPC), but it is a difficult technique to master for most otorhinolaryngology head and neck surgeons. Ablation surgery is a new and simplified method to remove tumors. We designed a novel method using low-temperature plasma radiofrequency ablation (LPRA) and evaluated the survival benefit. METHODS: A total of 56 localized rNPC patients were explained in detail and retrospectively analyzed. The surgery method was ablated from the resection margin to the center of the tumor. The postmetastatic overall survival (OS), local relapse-free survival (LRFS) rate, progression-free survival (PFS) and distant metastasis-free survival (DMFS) were analyzed using the Kaplan-Meier method and compared by the log-rank test. RESULTS: All surgeries were successfully performed without any severe postoperative complications or deaths. The median operation time of ablation and harvested NSFF respectively were 29 min (range, 15-100 min) and 101 min (range, 30-180 min). The average number of hospital days postoperation was 3 days (range, 2-5 days). All cases (100.0%) had radical ablation with negative resection margins. The nasopharyngeal defects were completely re-epithelialized in 54 (96.4%) patients. As of the data cutoff (September 3, 2023), the median follow-up time was 44.3 months (range, 17.1-52.7 months, 95% CI: 40.4-48.2). The 3-year OS, LRFS, PFS and DMFS of the entire cohort were 92.9% (95% CI: 0.862-0.996), 89.3% (95% CI: 0.813-0.973), 87.5% (95% CI: 0.789-0.961), and 92.9% (95% CI: 0.862-0.996), respectively. Cycles of radiotherapy were independent risk factors for OS (p = 0.003; HR, 32.041; 95% CI: 3.365-305.064), LRFS (p = 0.002; HR, 10.762; 95% CI: 2.440-47.459), PFS (p = 0.004; HR, 7.457; 95% CI: 1.925-28.877), and DMFS (p = 0.002; HR, 34.776; 95% CI: 3.806-317.799). CONCLUSION: Radical endoscopic nasopharyngectomy by using low-temperature plasma radiofrequency ablation is a novel, safe and simplified method to master and disseminate for treating resectable rNPC. However, further data and longer follow-up time are needed to prove its efficacy.

Efficacy of sequential chemoradiotherapy combined with toripalimab in de novo metastatic nasopharyngeal carcinoma: A phase II trial.

Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3 months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3 months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3 months after radiotherapy is 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>104 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC.

Camrelizumab plus famitinib in patients with recurrent or metastatic nasopharyngeal carcinoma treated with PD-1 blockade: data from a multicohort phase 2 study.

Background: Treatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens. Methods: This multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381. Findings: Between October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6-55.4) and the DCR was 77.8% (90% CI, 56.1-92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0-not reach), and the median PFS was 7.2 months (90% CI, 4.4-13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3-4 major epistaxis, and they were cured by nasal packing and vascular embolization. Interpretation: Camrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings. Funding: Jiangsu Hengrui Pharmaceutical Co., Ltd.

Fosaprepitant Weekly vs Every 3 Weeks for the Prevention of Concurrent Chemoradiotherapy-Induced Nausea and Vomiting: A Pilot Randomized Clinical Trial.

Importance: Unlike substantial evidence in the prevention of chemotherapy-induced nausea and vomiting (CINV), research in the prevention of nausea and vomiting caused by concurrent chemoradiotherapy (CCRT) is currently lacking. Objective: To compare the efficacy and safety of fosaprepitant weekly vs every 3 weeks for the prevention of nausea and emesis caused by CCRT among patients with nasopharyngeal carcinoma. Design, Setting, and Participants: This pilot randomized clinical trial was conducted at a single cancer center from November 24, 2020, to July 26, 2021, among patients with nasopharyngeal carcinoma who had achieved CINV control after 2 to 3 cycles of induction chemotherapy. Efficacy analyses were performed in the intention-to-treat population. Data were analyzed on November 4, 2022. Interventions: Eligible patients were randomly assigned (1:1) to receive fosaprepitant either weekly or every 3 weeks. Main Outcomes and Measures: The primary end point was the proportion of patients with sustained complete response (defined as no emesis and no rescue therapy) during CCRT. Secondary end points were sustained no emesis, no nausea, no significant nausea, mean time to first emetic episode, quality of life, and 1-year progression-free survival (PFS). Results: A total of 100 patients (mean [SD] age, 46.6 [10.9] years; 83 [83.0%] male) who had achieved CINV control after induction chemotherapy were randomly assigned to receive fosaprepitant weekly (50 patients) or every 3 weeks (50 patients). There was no significantly significant difference in cumulative risk of emesis or rescue therapy in the group that received weekly fosaprepitant compared with those who received fosaprepitant every 3 weeks (subhazard ratio, 0.66 [95% CI, 0.43-1.02]; P = .06). The proportion of patients with sustained no emesis (38% vs 14%; P = .003) or no significant nausea (92% vs 72%; P = .002) was significantly higher in the group that received fosaprepitant weekly vs those who received fosaprepitant every 3 weeks. Treatments were well tolerated. Patients in the weekly group had improved scores for multiple quality-of-life measures. There was no significant difference in survival outcomes between groups (91.8% vs 93.7%; P = .99). In the mean brainstem dose subgroups, a possible treatment interaction effect was observed in sustained complete response (mean brainstem dose ≥36 Gy: hazard ratio [HR], 0.32 [95% CI, 0.15-0.69]; mean brainstem dose <36 Gy: HR, 0.95 [95% CI, 0.55-1.63]) and sustained no emesis (mean brainstem dose ≥36 Gy: HR, 0.21 [95% CI, 0.08-0.53]; mean brainstem dose <36 Gy: HR, 0.73 [95% CI, 0.41-1.28]). Conclusions and Relevance: In this pilot randomized clinical trial, there was no statistically significant difference in the complete response primary end point, but patients receiving weekly fosaprepitant were less likely to experience emesis compared with those who received fosaprepitant every 3 weeks, especially in the subgroup with a mean brainstem dose of 36 Gy or more. Weekly fosaprepitant was well tolerated and improved quality of life of patients without compromising survival. Trial Registration: ClinicalTrials.gov Identifier: NCT04636632.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

BACKGROUND: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. METHODS: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. FINDINGS: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). INTERPRETATION: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. FUNDING: Institut National du Cancer and Ligue Nationale Contre le Cancer.

Distinct resting-state functional connectivity patterns of Anterior Insula affected by smoking in mild cognitive impairment.

Smoking is a modifiable risk factor for Alzheimer's disease (AD). The insula plays a vital role in both smoking and cognition. However, the smoking effects on insula-related networks in cognitively normal controls (CN) and mild cognitive impairment (MCI) patients remain unknown. We identified 129 CN (85 non-smokers and 44 smokers) and 83 MCI (54 non-smokers and 29 smokers). Each underwent neuropsychological assessment and MRI (structural and resting-state functional). Seed-based functional analyses in the anterior and posterior insula were performed to calculate the functional connectivity (FC) with voxels in the whole brain. Mixed-effect analyses were performed to explore the interactive effects on smoking and cognitive status. Associations between FC and neuropsychological scales were assessed. Mixed-effect analyses revealed the FC differences between the right anterior insula (RAI) with the left middle temporal gyrus (LMTG) and that with the right inferior parietal lobule (RIPL) (p < 0.01, cluster level < 0.05, two-tailed, gaussian random field correction). The FC of RAI in both LMTG and RIPL sees a significant decrease in MCI smokers (p < 0.01). Smoking affects insula FC differently between MCI and CN, and could decrease the insula FC in MCI patients. Our study provides evidence of neural mechanisms between smoking and AD.

Clinical features and 1-year outcomes of chronic bronchitis in participants with normal spirometry: results from the ECOPD study in China.

BACKGROUND: Evidence regarding clinical features and outcomes of individuals with non-obstructive chronic bronchitis (NOCB) remains scarce, especially in never-smokers. We aimed to investigate the clinical features and 1-year outcomes of individuals with NOCB in the Chinese population. METHODS: We obtained data on participants in the Early Chronic Obstructive Pulmonary Disease Study who had normal spirometry (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ≥0.70). NOCB was defined as chronic cough and sputum production for at least 3 months for two consecutive years or more at baseline in participants with normal spirometry. We assessed the differences in demographics, risk factors, lung function, impulse oscillometry, CT imaging and frequency of acute respiratory events between participants with and without NOCB. RESULTS: NOCB was present in 13.1% (149/1140) of participants with normal spirometry at baseline. Compared with participants without NOCB, those with NOCB had a higher proportion of men and participants with smoke exposure, occupational exposure, family history of respiratory diseases and worse respiratory symptoms (all p<0.05), but there was no significant difference in lung function. Never-smokers with NOCB had higher rates of emphysema than those without NOCB, but airway resistance was similar. Ever-smokers with NOCB had greater airway resistance than those without NOCB, but emphysema rates were similar. During 1-year follow-up, participants with NOCB had a significantly increased risk of acute respiratory events compared with participants who did not have NOCB, after adjustment for confounders (risk ratio 2.10, 95% CI 1.32 to 3.33; p=0.002). These results were robust in never-smokers and ever-smokers. CONCLUSIONS: Never-smokers and ever-smokers with NOCB had more chronic obstructive pulmonary disease-related risk factors, evidence of airway disease and greater risk of acute respiratory events than those without NOCB. Our findings support expanding the criteria defining pre-COPD to include NOCB.

Increased iron deposition in nucleus accumbens associated with disease progression and chronicity in migraine.

BACKGROUND: Migraine is one of the world's most prevalent and disabling diseases. Despite huge advances in neuroimaging research, more valuable neuroimaging markers are still urgently needed to provide important insights into the brain mechanisms that underlie migraine symptoms. We therefore aim to investigate the regional iron deposition in subcortical nuclei of migraineurs as compared to controls and its association with migraine-related pathophysiological assessments. METHODS: A total of 200 migraineurs (56 chronic migraine [CM], 144 episodic migraine [EM]) and 41 matched controls were recruited. All subjects underwent MRI and clinical variables including frequency/duration of migraine, intensity of migraine, 6-item Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS), and Pittsburgh Sleep Quality Index (PSQI) were recorded. Quantitative susceptibility mapping was employed to quantify the regional iron content in subcortical regions. Associations between clinical variables and regional iron deposition were studied as well. RESULTS: Increased iron deposition in the putamen, caudate, and nucleus accumbens (NAC) was observed in migraineurs more than controls. Meanwhile, patients with CM had a significantly higher volume of iron deposits compared to EM in multiple subcortical nuclei, especially in NAC. Volume of iron in NAC can be used to distinguish patients with CM from EM with a sensitivity of 85.45% and specificity of 71.53%. As the most valuable neuroimaging markers in all of the subcortical nuclei, higher iron deposition in NAC was significantly associated with disease progression, and higher HIT-6, MIDAS, and PSQI. CONCLUSIONS: These findings provide evidence that iron deposition in NAC may be a biomarker for migraine chronicity and migraine-related dysfunctions, thus may help to understand the underlying vascular and neural mechanisms of migraine. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT04939922.

Impaired exercise capacity in individuals with non-obstructive small airway dysfunction.

Background: Whether individuals with non-obstructive spirometry-defined small airway dysfunction (SAD) have impaired exercise capacity is unclear, particularly in never-smokers. This study clarifies the degree of impaired exercise capacity and its potential cause in individuals with non-obstructive SAD. Methods: This community-based, multiyear cross-sectional study analyzed data collected in Guangdong, China from 2012-2019 by the National Science and Technology Support Plan Program. Measurements of exercise capacity [peak work rate and peak oxygen uptake ( V ˙ O 2peak )] in participants with non-obstructive spirometry-defined SAD (n=157) were compared with those in controls (n=85) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) I patients (n=239). Subgroup analyses were performed by smoking status. Results: The risk of impaired exercise capacity was significantly higher in participants with non-obstructive SAD [ V ˙ O 2peak <84%predicted, adjusted odds ratio (aOR) =2.53; 95% confidence interval (CI): 1.42-4.52] than in controls but was not significantly different from that in GOLD I patients. Results were consistent within subgroups of smoking status (ever-smokers: non-obstructive SAD vs. controls, aOR =2.44; 95% CI: 1.08-5.51; never-smokers: non-obstructive SAD vs. controls, aOR =2.38, 95% CI: 1.02-5.58). Participants with non-obstructive SAD had a significantly lower peak work rate (ß=-10.5; 95% CI: -16.3 to -4.7) and V ˙ O 2peak (%predicted, ß=-4.0; 95% CI: -7.7 to -0.2) and tended to have higher ventilatory equivalents for carbon dioxide at the ventilatory threshold ( V ˙ E / V ˙ CO 2AT , ß=1.1; 95% CI: -0.1 to 2.3) when compared with controls. Both peak work rate and V ˙ O 2peak were negatively correlated with V ˙ E / V ˙ CO 2AT . Conclusions: Although not meeting the current criteria for chronic obstructive pulmonary disease, individuals with non-obstructive SAD have impaired exercise capacity that may be associated with ventilatory inefficiency regardless of smoking status.

Monitoring Substantia Nigra Degeneration Using Free Water Imaging across Prodromal and Clinical Parkinson's Disease.

BACKGROUND: Substantia nigra (SN) free water has been suggested as a good surrogate marker in Parkinson's disease (PD). However, its usefulness for diagnosing prodromal PD (pPD) and monitoring disease progression warrants further validation. OBJECTIVE: The aim was to investigate SN free water values across prodromal and clinical stages of PD. METHODS: Four groups were enrolled in this study: 48 healthy controls (HC), 43 pPD patients, 50 de novo PD (dnPD) patients, and 49 medicated PD (mPD) patients. Based on diffusion tensor images, free water maps were calculated, and SN free water values were extracted from the anterior SN (ASN) and posterior SN (PSN). The SN free water values were compared among the four groups, and associations between free water and clinical symptoms were explored. The distinguishing power of PSN free water was evaluated using the receiver operating characteristic curve analysis. Follow-up was performed for 14 pPD patients. RESULTS: PSN free water in the pPD group was significantly higher than that in the HC group and significantly lower than that in the dnPD group. Surprisingly, the mPD group showed decreased PSN free water compared to the dnPD group. There was a positive correlation between motor symptoms and PSN free water in the pPD and dnPD groups. Longitudinal analysis showed a significant increase in PSN free water in pPD patients over time. CONCLUSIONS: The PSN free water increased from prodromal to early clinical stages, but the trend might be reversed in late disease stages. This biphasic trend should be considered when applying this marker in future studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genetic impacts on nigral iron deposition in Parkinson's disease: A preliminary quantitative susceptibility mapping study.

BACKGROUND: Dysfunction of iron metabolism, especially in substantia nigra (SN), is widely acknowledged in Parkinson's disease (PD), but the genetic influence on iron deposition remains largely unknown. Thus, in this study, we aimed to investigate potential genetic impacts on iron deposition in PD. METHODS: Seventy-four subjects, including 38 patients with PD and 36 age-matched normal controls, participated in this study. Imaging genetic association analysis was used to identify the specific influence of single nucleotide polymorphism (SNP) on iron-related quantitative traits (QT). Genetic effects on iron deposition at the disease level, SNP level, and their interactive effect were highlighted. RESULTS: Four strong SNP-QT associations were detected: rs602201-susceptibility of bilateral SN, rs198440-susceptibility of left SN, and rs7895403-susceptibility of left caudate head. Detailed analyses showed that: (1) significant iron deposition was exclusively found in bilateral SN in PD; (2) altered polymorphisms of the A allele/A- genotype of rs602201 and G allele/G- genotype of rs198440 and rs7895403 were more frequently observed in PD; (3) for rs602201, among all subjects, A- genotype carriers showed significantly increased iron content than TT genotype in bilateral SN; for rs198440 and rs7895403, G- carriers showed increased iron content than AA genotype in left SN and left caudate head, respectively; and (4) rs602201 exhibited significant SNP-by-disease interaction in bilateral SN. CONCLUSIONS: This study shows that rs602201 and rs198440 have a stimulative impact on nigral iron deposition in PD, which provides improved understanding of iron-related pathogenesis in PD, and specifically, that vulnerability to iron deposition in SN is genetic-based.

Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance.

It is critical to understand factors associated with nasopharyngeal carcinoma (NPC) metastasis. To track the evolutionary route of metastasis, here we perform an integrative genomic analysis of 163 matched blood and primary, regional lymph node metastasis and distant metastasis tumour samples, combined with single-cell RNA-seq on 11 samples from two patients. The mutation burden, gene mutation frequency, mutation signature, and copy number frequency are similar between metastatic tumours and primary and regional lymph node tumours. There are two distinct evolutionary routes of metastasis, including metastases evolved from regional lymph nodes (lymphatic route, 61.5%, 8/13) and from primary tumours (hematogenous route, 38.5%, 5/13). The hematogenous route is characterised by higher IFN-γ response gene expression and a higher fraction of exhausted CD8+ T cells. Based on a radiomics model, we find that the hematogenous group has significantly better progression-free survival and PD-1 immunotherapy response, while the lymphatic group has a better response to locoregional radiotherapy.

Camrelizumab Plus Apatinib in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma: An Open-Label, Single-Arm, Phase II Study.

PURPOSE: Immune checkpoint inhibitors combined with antiangiogenic therapy reportedly have potential synergistic antitumor activity. We investigated the activity and safety of this regimen for recurrent/metastatic nasopharyngeal carcinoma (NPC). METHODS: This single-arm, Simon two-stage study enrolled patients with recurrent/metastatic NPC who were refractory to at least first-line systemic therapy and treatment-naive to immune checkpoint inhibitors. The patients received camrelizumab 200 mg once every 3 weeks and apatinib 250 mg once per day. The primary end point was the objective response rate. Key secondary end points included disease control rate, progression-free survival, duration of response, overall survival, and safety. RESULTS: Between October 14, 2020, and December 23, 2021, 58 patients were enrolled, and all were included in the efficacy and safety analysis set. The objective response rate was 65.5% (95% CI, 51.9 to 77.5), and the disease control rate was 86.2% (95% CI, 74.6 to 93.9). The median duration of response was not reached, and the median progression-free survival was 10.4 months (95% CI, 7.2 to 13.6), with a median follow-up duration of 12.4 months (range, 2.1-19.9 months). Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 34 (58.6%) patients, with the most common being hypertension (19.0%), nasopharyngeal necrosis (15.5%), headache (12.1%), AST elevation (10.3%), and creatine phosphokinase elevation (10.3%). Sixteen (27.6%) patients discontinued apatinib treatment before progression because of unbearable TRAEs, and the most common complication was nasopharyngeal necrosis (9/16; 56.3%). Recurrent nasopharyngeal lesions (odds ratio, 5.94 [95% CI, 1.45 to 24.24]) and reirradiation (odds ratio, 5.33 [95% CI, 1.15 to 24.79]) were significantly positively correlated with nasopharyngeal necrosis. CONCLUSION: Camrelizumab plus apatinib had promising antitumor activity in patients with refractory recurrent/metastatic NPC who failed first-line therapy. Moderate to severe TRAEs were experienced by 58.6%, including nasopharyngeal necrosis associated with local recurrence and a history of reirradiation.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Early detection of the initial stages of LED light-triggered non-alcoholic fatty liver disease by wax physisorption kinetics-Fourier transform infrared imaging.

Light-emitting diodes (LEDs), particularly in the blue waveform range, are regarded as a major source of circadian rhythm dysregulation. A circadian rhythm dysregulation induced by blue LEDs is associated with non-alcoholic fatty liver disease (NAFLD). Hepatocellular accumulation of lipids is a key event in the early stages of NAFLD. Kupffer cells (KCs) have been reported to be lost in the early onset of NAFLD followed by an inflammatory reaction that alters the liver response to lipid overload. This study focused on the detection of the initial stages (subpathological stages) of LED light-triggered NAFLD. Mice were exposed to either blue or white LED irradiation for 44 weeks. Synchrotron radiation-based Fourier-transform infrared microspectroscopy (SR-FTIRM) and wax physisorption kinetic-Fourier transform infrared (WPK-FTIR) imaging were used to evaluate the ratio of lipid to protein and the glycosylation of glycoprotein, respectively. Immunohistopathological studies on KCs and circadian-related proteins were performed. Although liver biopsy showed normal pathology, an SR-FTIRM study revealed a high hepatic lipid-to-protein ratio after receiving LED illumination. The results of WPK-FTIR demonstrated that a high inflammation index was found in the high irradiance of the blue LED illumnation group. These groups showed a decrease in KC number and an increase in Bmal1 and Reverbα circadian protein expression. These findings provide explanations for the reduction of KCs without subsequent inflammation. A significant reduction of Per2 and Cry1 expression is correlated with the findings of WPK-FTIR imaging. WPK-FTIR is a sensitive method for detecting initiative stages of NAFLD induced by long-term blue LED illumination.

White Matter Tract Injury by MRI in CADASIL Patients is Associated With Iron Accumulation.

BACKGROUND: Widespread white matter (WM) injury is a hallmark feature of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, controversies about the mechanism of WM tract injury exist persistently. Excessive iron accumulation, frequently reported in CADASIL patients, might cause WM tract injury. PURPOSE: To test the association between iron accumulation and WM tract injury in CADASIL patients. STUDY TYPE: Retrospective. POPULATION: A total of 35 CADASIL patients (age = 50.4 ± 6.4, 62.9% female) and 48 healthy controls (age = 55.7 ± 8.0, 68.8% female). FIELD STRENGTH/SEQUENCE: Diffusion-weighted spin-echo echo-planar sequence; enhanced susceptibility-weighted angiography (ESWAN) gradient echo sequence on a 3 T scanner. ASSESSMENT: The phase images acquired by ESWAN were used to calculate quantitative susceptibility mapping (QSM). Iron accumulation was evaluated in deep gray matters using QSM. WM tract injury was quantified by diffusion metrics based on WM major tracts skeleton. We compared iron deposition between groups and analyzed the correlation between WM tract injury and iron deposition in regions showing significant differences from healthy controls. Exploratory analysis was carried out to investigate whether WM tract injury mediated the relationship between iron deposition and cognitive impairment evaluated by Mini-Mental State Examination (MMSE). STATISTICAL TESTS: General linear model (GLM), partial correlation, stepwise linear regression and mediation analysis were used. The threshold of statistical significance was set as p < 0.05. RESULTS: Compared with healthy controls, CADASIL patients had significantly increased iron deposition in the caudate and putamen. Aberrant iron deposition in these two regions was significantly associated with decreased WM fractional anisotropy (FA) (caudate, r = -0.373； putamen, r = - 0.421), and increased radial diffusivity (RD) (caudate, r = 0.372; putamen, r = 0.386). Furthermore, WM tract injury mediated the relationship between iron deposition and cognitive impairment. DATA CONCLUSION: Patients with CADASIL show increased iron deposition in the caudate and putamen that is correlated to WM tract injury, which may in turn mediate the association with cognitive impairment. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

An innovative diagnosis in gastrointestinal neuroendocrine neoplasms using Wax-Physisorption-Kinetics-based FTIR Imaging.

Neuroendocrine neoplasm (NEN) is a common gastrointestinal (GI) tract tumor divided into the neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC) according to mitosis and Ki-67 index. However, the objective discordance between interobserver may cause unsuitable diagnosis and misleading treatment. Nowadays, aberrant glycosylation of glycoconjugates inducing further populations of elongated complex oligosaccharide covalent attached to glycoconjugates anchored in the cell membrane by neo-synthesis of cancer-associated alteration of carbohydrate determinants were observed during cancer development. This study aimed to demonstrate the wax physisorption kinetics coupled with Fourier transform infrared (WPK-FTIR) imaging between NET and NEC in the rectum, colon, and stomach by utilizing two wax reagents (beeswax and paraplast) as glycan adsorbents for physical binding glycans of glycoconjugates based on dipole-induced dipole interaction. Results showed greater physisorption with beeswax than that of paraplast, suggesting highly populated elongated glycans of glycoconjugates adhering onto the tumor surfaces of NETs than that of adjacent benign mucosa in the rectum and colon. Besides, the WPK results of gastric NEN tissue sections showed a higher infrared absorbance ratio of beeswax-remnant to paraplast-remnant remains onto the tissue sections referring to a higher population of elongated glycans in gastric NET as compared with that of gastric NEC. Based on our findings, different anatomical locations could share similar phenomena with minor variance. In conclusion, WPK-FTIR imaging may have the potential to be employed as an alternative diagnostic method in GI NENs in the future.

The Effects of Charged Amino Acid Side-Chain Length on Diagonal Cross-Strand Interactions between Carboxylate- and Ammonium-Containing Residues in a ß-Hairpin.

The ß-sheet is one of the common protein secondary structures, and the aberrant aggregation of ß-sheets is implicated in various neurodegenerative diseases. Cross-strand interactions are an important determinant of ß-sheet stability. Accordingly, both diagonal and lateral cross-strand interactions have been studied. Surprisingly, diagonal cross-strand ion-pairing interactions have yet to be investigated. Herein, we present a systematic study on the effects of charged amino acid side-chain length on a diagonal ion-pairing interaction between carboxylate- and ammonium-containing residues in a ß-hairpin. To this end, 2D-NMR was used to investigate the conformation of the peptides. The fraction folded population and the folding free energy were derived from the chemical shift data. The fraction folded population for these peptides with potential diagonal ion pairs was mostly lower compared to the corresponding peptide with a potential lateral ion pair. The diagonal ion-pairing interaction energy was derived using double mutant cycle analysis. The Asp2-Dab9 (Asp: one methylene; Dab: two methylenes) interaction was the most stabilizing (-0.79 ± 0.14 kcal/mol), most likely representing an optimal balance between the entropic penalty to enable the ion-pairing interaction and the number of side-chain conformations that can accommodate the interaction. These results should be useful for designing ß-sheet containing molecular entities for various applications.