The global nitrogen regulator GlnR is a direct transcriptional repressor of the key gluconeogenic gene pckA in actinomycetes.

In most actinomycetes, GlnR governs both nitrogen and non-nitrogen metabolisms (e.g., carbon, phosphate, and secondary metabolisms). Although GlnR has been recognized as a global regulator, its regulatory role in central carbon metabolism [e.g., glycolysis, gluconeogenesis, and the tricarboxylic acid (TCA) cycle] is largely unknown. In this study, we characterized GlnR as a direct transcriptional repressor of the pckA gene that encodes phosphoenolpyruvate carboxykinase, catalyzing the conversion of the TCA cycle intermediate oxaloacetate to phosphoenolpyruvate, a key step in gluconeogenesis. Through the transcriptomic and quantitative real-time PCR analyses, we first showed that the pckA transcription was upregulated in the glnR null mutant of Amycolatopsis mediterranei. Next, we proved that the pckA gene was essential for A. mediterranei gluconeogenesis when the TCA cycle intermediate was used as a sole carbon source. Furthermore, with the employment of the electrophoretic mobility shift assay and DNase I footprinting assay, we revealed that GlnR was able to specifically bind to the pckA promoter region from both A. mediterranei and two other representative actinomycetes (Streptomyces coelicolor and Mycobacterium smegmatis). Therefore, our data suggest that GlnR may repress pckA transcription in actinomycetes, which highlights the global regulatory role of GlnR in both nitrogen and central carbon metabolisms in response to environmental nutrient stresses. IMPORTANCE: The GlnR regulator of actinomycetes controls nitrogen metabolism genes and many other genes involved in carbon, phosphate, and secondary metabolisms. Currently, the known GlnR-regulated genes in carbon metabolism are involved in the transport of carbon sources, the assimilation of short-chain fatty acid, and the 2-methylcitrate cycle, although little is known about the relationship between GlnR and the TCA cycle and gluconeogenesis. Here, based on the biochemical and genetic results, we identified GlnR as a direct transcriptional repressor of pckA, the gene that encodes phosphoenolpyruvate carboxykinase, a key enzyme for gluconeogenesis, thus highlighting that GlnR plays a central and complex role for dynamic orchestration of cellular carbon, nitrogen, and phosphate fluxes and bioactive secondary metabolites in actinomycetes to adapt to changing surroundings.

Pneumonitis Risk After Chemoradiotherapy With and Without Immunotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Chemoradiotherapy (CRT) combined with immune checkpoint inhibitors (ICIs) is the standard of care for patients with unresectable and locally advanced non-small cell lung cancer. This study aimed to determine whether the addition of ICIs to CRT is associated with an increased risk of pneumonitis. METHODS AND MATERIALS: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for eligible studies published between January 1, 2015, and July 31, 2023. The outcome of interest was the incidence rate of pneumonitis. A random-effects model was used for statistical analysis. RESULTS: A total of 185 studies with 24,527 patients were included. The pooled rate of grade ≥2 pneumonitis for CRT plus ICIs was significantly higher than that for CRT alone (29.6%; 95% CI, 25.7%-33.6% vs 20.2%; 95% CI, 17.7%-22.8%; P < .0001) but not that of grade ≥3 (5.7%; 95% CI, 4.8%-6.6% vs 5.6%; 95% CI, 4.7%-6.5%; P = .64) or grade 5 (0.1%; 95% CI, 0.0%-0.2% vs 0.3%; 95% CI, 0.1%-0.4%; P = .68). The results from the subgroup analyses of prospective studies, retrospective studies, Asian and non-Asian studies, concurrent CRT (cCRT), and durvalumab consolidation were comparable to the overall results. However, CRT or cCRT plus PD-1 inhibitors not only significantly increased the incidence of grade ≥2 but also that of grade ≥3 pneumonitis compared to CRT alone or cCRT plus PD-L1 inhibitors. CONCLUSIONS: Compared with CRT alone, durvalumab consolidation after CRT appears to be associated with a higher incidence of moderate pneumonitis and CRT plus PD-1 inhibitors with an increased risk of severe pneumonitis. Nevertheless, these findings are based on observational studies and need to be validated in future large head-to-head studies.

Protection against myocardial ischemia/reperfusion injury in mice by 3-caffeoylquinic acid isomers isolated from Saxifraga tangutica.

The development of ischemic heart disease (IHD) involves a variety of pathophysiological responses, such as mitochondrial dysfunction. Many compounds with antioxidant activity isolated from natural products have been shown to have significant effects on the prevention and treatment of cardiovascular diseases. However, little is known about the palliative effects of 3-caffeoylquinic acid isomers isolated from Saxifraga tangutica (S. tangutica) on myocardial ischemia/reperfusion injury (MIRI). Three isomers of 3-caffeoylquinic acid were isolated from S. tangutica and identified as neochlorogenic acid (Fr2-4-1-1, 18.5 mg), chlorogenic acid (Fr2-5-1-1, 81.7 mg) and cryptochlorogenic acid (Fr2-5-2-1, 15.0 mg) using medium-pressure liquid chromatography-high-pressure two-dimensional liquid chromatography. An in vitro DPPH assay showed that cryptochlorogenic acid (CCGA), neochlorogenic acid (NCGA) and chlorogenic acid (CGA) (in order of activity from strongest to weakest) possessed superior antioxidant activity. Langendorff's in vitro model was utilized to explore the protective effects of 3 caffeoylquinic acid isomers against MIRI. The ex vivo MIRI assay demonstrated that CCGA significantly improved hemodynamic function (P < 0.05), hemodynamic function-related indices (LVDP, RPP, +dP/dt and -dP/dt), and cell morphology in I/R myocardium tissues. In addition, the results of western blot analysis showed that mitochondrial biogenesis was significantly increased in I/R myocardial tissues after treatment with CCGA. In contrast, the activities of CGA and NCGA were lower. This is the first demonstration of efficient preparative isolation of 3-caffeoylquinic acid isomers (CGA, NCGA and CCGA) from S. tangutica. CCGA may be a promising approach for the treatment of cardiac I/R injury, especially for the regulation of mitochondrial biogenesis after MIRI.

Impact of Preparative Isolation of C-Glycosylflavones Derived from Dianthus superbus on In Vitro Glucose Metabolism.

Dianthus superbus L. has been extensively studied for its potential medicinal properties in traditional Chinese medicine and is often consumed as a tea by traditional folk. It has the potential to be exploited in the treatment of inflammation, immunological disorders, and diabetic nephropathy. Based on previous studies, this study continued the separation of another subfraction of Dianthus superbus and established reversed-phase/reversed-phase and reversed-phase/hydrophilic (RPLC) two-dimensional (2D) high-performance liquid chromatography (HPLC) modes, quickly separating two C-glycosylflavones, among which 2″-O-rhamnosyllutonarin was a new compound and isomer with 6‴-O-rhamnosyllutonarin. This is the first study to investigate the effects of 2″-O-rhamnosyllutonarin and 6‴-O-rhamnosyllutonarin on cellular glucose metabolism in vitro. First, molecular docking was used to examine the effects of 2″-O-rhamnosyllutonarin and 6″-O-rhamnosyllutonarin on AKT and AMPK; these two compounds exhibited relatively high activity. Following this, based on the HepG2 cell model of insulin resistance, it was proved that both of the 2″-O-rhamnosyllutonarin and 6‴-O-rhamnosyllutonarin demonstrated substantial efficacy in ameliorating insulin resistance and were found to be non-toxic. Simultaneously, it is expected that the methods developed in this study will provide a basis for future studies concerning the separation and pharmacological effects of C-glycosyl flavonoids.

Median arcuate ligament syndrome complicated with gallbladder stones: A case report.

BACKGROUND: Median arcuate ligament syndrome (MALS) is a rare disease caused by compression of the celiac trunk artery by the median arcuate ligament (MAL). It can cause symptoms of postprandial abdominal pain, weight loss, and nausea and vomiting. CASE SUMMARY: A 55-year-old woman was admitted due to abdominal pain, nausea and vomiting. On admission, the patient presented with epigastric pain that worsened after eating, without signs of peritoneal irritation. Computed tomography angiography of the upper abdomen showed compression of the proximal segment of the abdominal trunk, local luminal stenosis with angular "fishhook" changes, which changed significantly during forceful inspiration and expiration; gallbladder stones; and multiple cysts in the liver. Abdominal duplex ultrasonography showed that peak systolic velocity was 352 cm/s. After diagnosis of MALS was confirmed, an arch ligament release procedure was performed. MALS has no specific symptoms and can be misdiagnosed as other abdominal diseases. Awareness of MALS should be improved to avoid misdiagnosis. The commonly used treatment option is MAL release and resection of the peripheral ganglion of the celiac trunk artery. CONCLUSION: The diagnosis and treatment of MALS must be individualized, and MAL release is effective and provides immediate symptomatic relief.

Predictive value of Dmax and %ΔSUVmax of 18F-FDG PET/CT for the prognosis of patients with diffuse large B-cell lymphoma.

PURPOSE: To investigate the prognosis value of a combined model based on 18F-fluoro-deoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) baseline and interim parameters in patients with diffuse large B-cell lymphoma (DLBCL). METHODS: We retrospectively analyzed the PET metabolic parameters and clinical data of 154 DLBCL patients between December 2015 and October 2020. All of these patients underwent 18F-FDG PET/CT scan before treatment and after three or four courses of chemotherapy. The optimal cut-off values for quantitative variables were determined by the receiver operating characteristic (ROC) curve. The baseline and interim PET/CT parameters, which respectively included maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax) and total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), and clinical characteristics were analyzed by chi-squared test, Kaplan-Meier survival curve, and Cox regression analysis. RESULTS: Of 154 patients, 35 exhibited disease progression or recurrence. ROC analysis revealed that baseline 18F-FDG PET/CT metabolic parameters, including maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax), along with interim 18F-FDG PET/CT metabolic parameters such as total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), were predictive of relapse or progression in DLBCL patients (P < 0.05). The chi-squared test showed that TMTV0, STMTV0, Dmax, SUVmax1, TMTV1, TTLG1, %ΔSUVmax, Deauville score, IPI, Ann Arbor stage, and LDH were associated with patient prognosis (P < 0.05). Multivariate Cox regression analysis showed that Dmax (P = 0.021) and %ΔSUVmax (P = 0.030) were independent predictors of prognosis in DLBCL patients. There were statistically significant differences in PFS among the three groups with high, intermediate, and low risk according to the combination model (P < 0.001). The combination model presented higher predictive efficacy than single indicators. CONCLUSION: The combined model of baseline parameter Dmax and intermediate parameter %ΔSUVmax of 18F-FDG PET/CT improved the predictive efficacy of PFS and contributed to the risk stratification of patients, providing a reference for clinical individualization and precision treatment.

Comparison of post-chemoradiotherapy pneumonitis between Asian and non-Asian patients with locally advanced non-small cell lung cancer: a systematic review and meta-analysis.

Background: Pneumonitis is a common complication for patients with locally advanced non-small cell lung cancer undergoing definitive chemoradiotherapy (CRT). It remains unclear whether there is ethnic difference in the incidence of post-CRT pneumonitis. Methods: PubMed, Embase, Cochrane Library, and Web of Science were searched for eligible studies from January 1, 2000 to April 30, 2023. The outcomes of interest were incidence rates of pneumonitis. The random-effect model was used for statistical analysis. This meta-analysis was registered with PROSPERO (CRD42023416490). Findings: A total of 248 studies involving 28,267 patients were included. Among studies of CRT without immunotherapy, the pooled rates of pneumonitis for Asian patients were significantly higher than that for non-Asian patients (all grade: 66.8%, 95% CI: 59.2%-73.9% vs. 28.1%, 95% CI: 20.4%-36.4%; P < 0.0001; grade ≥2: 25.1%, 95% CI: 22.9%-27.3% vs. 14.9%, 95% CI: 12.0%-18.0%; P < 0.0001; grade ≥3: 6.5%, 95% CI: 5.6%-7.3% vs. 4.6%, 95% CI: 3.4%-5.9%; P = 0.015; grade 5: 0.6%, 95% CI: 0.3%-0.9% vs. 0.1%, 95% CI: 0.0%-0.2%; P < 0.0001). Regarding studies of CRT plus immunotherapy, Asian patients had higher rates of all-grade (74.8%, 95% CI: 63.7%-84.5% vs. 34.3%, 95% CI: 28.7%-40.2%; P < 0.0001) and grade ≥2 (34.0%, 95% CI: 30.7%-37.3% vs. 24.6%, 95% CI: 19.9%-29.3%; P = 0.001) pneumonitis than non-Asian patients, but with no significant differences in the rates of grade ≥3 and grade 5 pneumonitis. Results from subgroup analyses were generally similar to that from the all studies. In addition, the pooled median/mean of lung volume receiving ≥20 Gy and mean lung dose were relatively low in Asian studies compared to that in non-Asian studies. Interpretation: Asian patients are likely to have a higher incidence of pneumonitis than non-Asian patients, which appears to be due to the poor tolerance of lung to radiation. Nevertheless, these findings are based on observational studies and with significant heterogeneity, and need to be validated in future large prospective studies focusing on the subject. Funding: None.

First-line treatment with TKI plus brain radiotherapy versus TKI alone in EGFR-mutated non-small cell Lung cancer with brain metastases: a systematic review and meta-analysis.

BACKGROUND: It remains uncertain whether first-line treatment with upfront brain radiotherapy (RT) in combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is superior to EGFR-TKIs alone for EGFR-mutated non-small cell lung cancer with newly diagnosed brain metastases (BMs). Therefore, we performed a meta-analysis to address this issue. METHODS: We searched PubMed, Embase, Cochrane Library, and Web of Science databases for eligible studies published until February 28, 2023. The primary outcomes of interest were overall survival (OS) and intracranial progression-free survival (iPFS), reported as hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Twenty-four retrospective studies with 3184 patients were included. First- or second-generation EGFR-TKIs were used in each study. Upfront brain RT plus EGFR-TKIs significantly prolonged OS (HR = 0.75, 95% CI: 0.64-0.88) and iPFS (HR = 0.61, 95% CI: 0.52-0.72) compared to EGFR-TKIs alone. There were no significant differences in OS and iPFS benefits from the combination therapy between asymptomatic and symptomatic patients, patients with exon 19 and 21 mutations, patients with 1-3 and > 3 BMs, and males and females, respectively (HRs interaction, P > 0.05 for each subgroup comparison). CONCLUSIONS: First-line treatment with upfront brain RT plus EGFR-TKIs is likely to be more effective than EGFR-TKIs alone. The benefits of combination therapy did not appear to be significantly affected by BM-related symptoms, EGFR mutation subtype, number of BMs, or sex.

An exploratory study of unexplained concentration of 18F-PSMA-1007 in the bladder for prostate cancer PET/CT imaging.

18F-PSMA-1007 PET/CT imaging is increasingly used for the diagnosis, staging, and efficacy assessment of patients with prostate cancer. Compared with other PSMA tracers, 18F-PSMA-1007 is mainly cleared by the liver and bile and has lower urinary clearance, thus allowing a better assessment of the lesions around the bladder. However, there were some patients who showed an obvious concentration of the 18F-PSMA-1007 in the bladder, which may affect the observation of peripheral lesions, but the mechanism of this change is unknown. The aim of this study was to explore the cause of bladder 18F-PSMA-1007 concentration by assessing the clinical and imaging characteristics of 18F-PSMA-1007 PET/CT scans. A total of 284 patients were included in this retrospective study, and their clinical characteristics such as age, height, weight, Gleason score, metastases, different treatment methods, the level of liver and kidney function, PSA level, and imaging characteristics such as 18F-PSMA-1007 injected activity, the interval between injection to scan, physiological distribution (parotid gland, kidney, liver, spleen, intestine, obturator internus), pathological distribution (prostate lesions, metastases) were collected, and were compared after subgrouping using bladder urine SUVmax. This study showed that the distribution of bladder 18F-PSMA-1007 was not correlated with the above clinical and imaging characteristics, so further studies are needed to find the explanations, and thus to improve the disease assessment of this type of prostate cancer patients.

Prediction nomogram based on 18F-FDG PET/CT and clinical parameters for patients with diffuse large B-cell lymphoma.

The objective of this study was to develop a nomogram including parameters assessed by 18F-FDG PET/CT and clinical parameters for patients with diffuse large B-cell lymphoma (DLBCL) to predict progression-free survival (PFS). A total of 181 patients with pathologically diagnosed DLBCL at Sichuan Cancer Hospital and Institute from March 2015 to December 2020 were enrolled in this retrospective study. The area under the receiver operating characteristic (ROC) curve (AUC) was used to calculate the optimal cutoff values of the semiquantitative parameters (SUVmax, TLG, MTV, and Dmax) for PFS. A nomogram was constructed according to multivariate Cox proportional hazards regression. The predictive and discriminatory capacities of the nomogram were then measured using the concordance index (C-index), calibration plots, and Kaplan-Meier curves. The predictive and discriminatory capacities of the nomogram and the International Prognostic Index of the National Comprehensive Cancer Network (NCCN-IPI) were compared via the C-index and AUC. Multivariate analysis demonstrated that male gender and pretreatment Ann Arbor stage III-IV, non-GCB, elevated lactate dehydrogenase (LDH), number of extranodal organ involvement (Neo)>1, MTV≥152.8 cm3, and Dmax ≥53.9 cm were associated with unfavorable PFS (all p<0.05). The nomogram, including gender, Ann Arbor stage, pathology type, Neo, LDH levels, MTV, and Dmax, showed good prediction accuracy, with a C-index of 0.760 (95% CI: 0.727-0.793), which was higher than that of NCCN-IPI (0.710; 95% CI: 0.669-751). The calibration plots for 2-year demonstrated good consistency between the predicted and observed probabilities for survival time. We established a nomogram including MTV, Dmax, and several clinical parameters to predict the PFS of patients with DLBCL, and the nomogram showed better predictability and higher accuracy than NCCN-IPI.

An Integrated Strategy for Investigating Antioxidants from Ribes himalense Royle ex Decne and Their Potential Target Proteins.

Natural products have been used extensively around the world for many years as therapeutic, prophylactic, and health-promotive agents. Ribes himalense Royle ex Decne, a plant used in traditional Tibetan medicine, has been demonstrated to have significant antioxidant and anti-inflammatory properties. However, the material basis of its medicinal effects has not been sufficiently explored. In this study, we established an integrated strategy by online HPLC-1,1-diphenyl-2-picrylhydrazyl, medium-pressure liquid chromatography, and HPLC to achieve online detection and separation of antioxidants in Ribes himalense extracts. Finally, four antioxidants with quercetin as the parent nucleus were obtained, namely, Quercetin-3-O-ß-D-glucopyranoside-7-O-α-L-rhamnopyranoside, Quercetin-3-O-ß-D-xylopyranosyl(1-2)-ß-D-glucopyranoside, Quercetin-3-O-ß-D-glucopyranoside, and Quercetin-3-O-ß-D-galactoside. Until now, the four antioxidants in Ribes himalense have not been reported in other literatures. Meanwhile, the free-radical-scavenging ability of them was evaluated by DPPH assay, and potential antioxidant target proteins were explored using molecular docking. In conclusion, this research provides insights into the active compounds in Ribes himalense which will facilitate the advancement of deeper studies on it. Moreover, such an integrated chromatographic strategy could be a strong driver for more efficient and scientific use of other natural products in the food and pharmaceutical industries.

Survival and prognostic factors in patients with synchronous multiple primary esophageal squamous cell carcinoma receiving definitive radiotherapy: A propensity score-matched analysis.

Purpose: To compare the lesion characteristics and radiotherapy efficacy of patients with single and multiple esophageal squamous cell carcinoma (ESCC), to evaluate the effect of multiple lesions on ESCC, and establish a nomogram survival prediction model for patients with synchronous multiple primary esophageal squamous cell carcinoma (SMPESCC) who received definitive radiotherapy. Materials and methods: The study enrolled 1,034 patients with ESCC who underwent definitive radiotherapy between 2010 and 2020. The efficacy of radiotherapy was compared between 101 patients with SMPESCC and 933 patients with single ESCC. Propensity score matching was used to control for potential confounders. For patients with SMPESCC, a nomogram prediction model was established based on the Cox regression model. Results: The median OS was 30.00 (95% CI = 25.08-34.92) months for the single lesion group and 19.00 (95% CI = 15.51-22.48) months for the multiple cancer group respectively. Multivariate COX regression analysis showed that multiple cancer was an independent prognostic factor for ESCC patients (HR=1.89, 95%CI=1.49-2.38, P<0.001). Cox multivariate analysis of SMPESCC patients showed that T stage (P =0.002), chemotherapy (P =0.006), and lesion spacing (P =0.004) were independent prognostic factors associated with OS. The nomogram was established by combining T stage, chemotherapy, and lesion spacing, and Harrell's C index was 0.711 after internal cross-validation. The calibration curve and decision curve analysis confirmed that the nomogram survival prediction model had a good predictive value for individual survival. Conclusions: The survival rate of single esophageal cancer is significantly better than that of multiple lesions. Patients with SMPESCC exhibit worse survival than patients with single ESCC. Multiple lesions have a significant impact on the survival of patients with ESCC. The nomogram model established for SMPESCC patients can well predict the individual survival of patients.

Comparison of initial learning algorithms for long short-term memory method on real-time respiratory signal prediction.

Aim: This study aimed to examine the effect of the weight initializers on the respiratory signal prediction performance using the long short-term memory (LSTM) model. Methods: Respiratory signals collected with the CyberKnife Synchrony device during 304 breathing motion traces were used in this study. The effectiveness of four weight initializers (Glorot, He, Orthogonal, and Narrow-normal) on the prediction performance of the LSTM model was investigated. The prediction performance was evaluated by the normalized root mean square error (NRMSE) between the ground truth and predicted respiratory signal. Results: Among the four initializers, the He initializer showed the best performance. The mean NRMSE with 385-ms ahead time using the He initializer was superior by 7.5%, 8.3%, and 11.3% as compared to that using the Glorot, Orthogonal, and Narrow-normal initializer, respectively. The confidence interval of NRMSE using Glorot, He, Orthogonal, and Narrow-normal initializer were [0.099, 0.175], [0.097, 0.147], [0.101, 0.176], and [0.107, 0.178], respectively. Conclusions: The experiment results in this study indicated that He could be a valuable initializer in the LSTM model for the respiratory signal prediction.

Prognostic factors for pulmonary carcinoid with positive lymph node after surgical resection: a SEER database study.

BACKGROUND: Prognostic factors and role with chemotherapy (CT) and radiotherapy (RT) remain unclear for patients of pulmonary carcinoid (PC) with positive lymph node after surgery. METHODS: PC patients who underwent surgery and with positive lymph node between 2000 and 2016 were identified from the SEER database. Univariate and multivariate cox regression analysis were used to identify independent risk factors for overall survival (OS). RESULTS: A total of 552 patients were identified. Multivariate analysis indicated that age (≤ 70/ > 70) (HR = 0.32, 95% CI 0.21-0.50; P < 0.001), histologic type (typical carcinoid [TC]/atypical carcinoid [AC]) (HR = 0.53, 95% CI 0.36-0.78, P = 0.001), number of positive lymph nodes (n ≥ 3/n = 1-2) (HR = 1.91, 95% CI 1.26-2.90; P = 0.002), and treatment mode (surgery + RT/surgery alone) (HR = 1.75, 95% CI 1.09-2.81; P 0.02) were independent prognostic factors for OS. In subgroup analysis according to histological type, prognostic factors were similar between AC and TC, except surgery + RT being negative prognostic factor for TC but AC. No significant difference in OS was observed between the surgery alone and surgery + CT in any subgroup of patients. CONCLUSIONS: Age > 70, histological type of AC, positive lymph nodes ≥ 3, and surgery + RT were likely to be negative prognostic factors for OS. Addition CT to surgery did not appear to provide additional OS benefit.

Performance of 18 F-FAPI PET/CT in assessing glioblastoma before radiotherapy: a pilot study.

BACKGROUND: We aimed to determine the performance of 18 F-FAPI PET/CT used for preprocedural assessment of glioblastoma before radiotherapy. METHODS: Twelve glioblastoma patients having undergone incomplete surgical resection or biopsy were examined with 18 F-FAPI PET/CT and MRI scanning before radiotherapy. All patients had confirmed tumor residues according to findings of histopathological and/or long-term clinical and radiological follow-ups. Lesion characterization data, including SUVmax and tumor-to-background ratio (TBR) on PET/CT were attained. PET/CT and MRI findings were compared in terms of number of lesions. The correlation between immunohistochemistry, molecular expression, and PET/CT parameters was also evaluated. RESULTS: 18 F-FAPI PET/CT detected 16 FAPI-avid out of 23 lesions in 12 patients described on MRI. MRI was statistically different from 18 F-FAPI PET/CT for lesion detection according to the exact McNemar statistical test (P = 0.0156). The SUVmax and TBR of the glioblastomas was 7.08 ± 3.55 and 19.95 ± 13.22, respectively. The sensitivity and positive predictive value (PPV) of 18 F-FAPI PET were 69.6% and 100%, respectively. Neither the Ki-67 index nor the molecular expression was correlated with the FAPI-PET/CT parameters. CONCLUSION: 18 F-FAPI PET/CT detects glioblastomas at a lower rate than MRI. However, the 100% PPV of the examination may make it useful for differentiating controversial lesions detected on MRI. The 18 F-FAPI-avid lesions are displayed more clearly probably due to a higher TBR. 18 F-FAPI PET/CT imaging might find application in glioblastoma biopsy and radiotherapy planning.

Neoadjuvant immunotherapy and neoadjuvant chemotherapy in resectable non-small cell lung cancer: A systematic review and single-arm meta-analysis.

Background: It remains uncertain whether neoadjuvant immune checkpoint inhibitor (nICI) is superior to neoadjuvant chemotherapy (nCT) in resectable non-small cell lung cancer. In addition, there are outstanding questions for nICI such as the ideal treatment mode and predictors. Methods: PubMed, Embase, Cochrane Library, Web of Science, and scientific meetings were searched for eligible single-arm or multi-arm trials until 31 December 2021. The primary outcomes of interest were major pathological response (MPR) and pathological complete response (pCR). The random-effect model was used for statistical analysis. Results: Twenty-four trials of nICI (n = 1,043) and 29 trials of nCT (n = 2,337) were identified. nICI combination therapy was associated with higher MPR (63.2%, 95% CI: 54.2%-72.1%) and pCR (35.3%, 95% CI: 27.4%-43.3%) rates compared to nCT (16.2%, 95% CI: 7.5%-25.0%, P < 0.001 and 5.5%, 95% CI: 3.5%-7.5%, P < 0.001) and nICI monotherapy (23.3%, 95% CI: 12.7%-33.8%, P < 0.001, and 6.5%, 95% CI: 1.7%-11.2%, P < 0.001). As for safety, nICI monotherapy had the best tolerability; nICI combination showed a similar surgical resection rate and higher R0 resection rate compared to nCT. PD-1 inhibitor and high PD-L1 expression (≥1% or ≥50%) were correlated with higher MPR and pCR rates compared to PD-L1 inhibitor and PD-L1 expression <1%. Conclusions: nICI combination therapy is associated with higher MPR and pCR rates compared to nCT and nICI monotherapy. PD-1 inhibitor seems to be superior to PD-L1 inhibitor. PD-L1 status appears to be predictive of MPR and pCR for patients receiving nICI. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=278661, CRD42021278661.

Preparative isolation of antioxidative furanocoumarins from Dracocephalum heterophyllum and their potential action target.

Traditional Tibetan medicine has extensively documented the health benefits of Dracocephalum heterophyllum. However, there are few reports on the chemical composition of furanocoumarins, probably because of their complicated isolation and purification procedures. In this study, four antioxidative furanocoumarins were isolated from Dracocephalum heterophyllum by medium- and high-pressure liquid chromatography in combination with on-line high-performance liquid chromatography-1,1-diphenyl-2-picrylhydrazyl recognition. Crude samples were sequentially pretreated by medium-pressure liquid chromatography using silica gel, MCI GEL CHP20P, and diol as stationary phases, whereas on-line high-performance liquid chromatography-1,1-diphenyl-2-picrylhydrazyl system was used to recognize antioxidant peaks in target fractions. Thereafter, the antioxidative peaks were separated and purified through high-pressure liquid chromatography to obtain four furanocoumarins with purities greater than 95%; namely isodemethylfuropinarine, demethylfuropinarine, alloimperatorin, and alloisoimperatorin. Finally, the antioxidant capacity of the isolated furanocoumarins was determined using in vitro experiments (1,1-diphenyl-2-picrylhydrazyl assays, molecular docking, and cellular validation) and it was concluded that nuclear factor erythroid 2-related factor 2 protein is a potential target of these compounds for their antioxidation effects. Thus, the proposed methodology exhibits excellent efficacy for the preparative isolation of high-purity antioxidative furanocoumarins from extracts of Dracocephalum heterophyllum and it can be efficiently utilized for isolating antioxidants from other natural products.

Integrated chromatographic approach for the discovery of gingerol antioxidants from Dracocephalum heterophyllum and their potential targets.

As a traditional Tibetan medicine, Dracocephalum heterophyllum has many benefits, but due to the complicated procedures of separation and purification of its chemical constituents, there are few reports on gingerols. In this study, four antioxidative gingerols were isolated from Dracocephalum heterophyllum by an integrated chromatographic approach. Antioxidant activity was then determined by in vitro experiments and its potential targets of action were investigated. First, the extract was pretreated using silica gel, MCI GEL®CHP20P, and diol and spherical medium pressure columns, while the antioxidant peaks were identified using an online HPLC-1,1-diphenyl-2-picrylhydrazyl system. Then, the antioxidant peaks were directionally separated and purified by high pressure liquid chromatography to obtain four gingerols with a purity higher than 95%, namely 5-methoxy-6-gingerol, 6-shogaol, 6-paradol, and diacetoxy-6-gingerdiol. Finally, 1,1-diphenyl-2-picrylhydrazyl assays and cellular antioxidant experiments were carried out, and molecular docking was used to explore potential antioxidant targets. The isolated gingerols upregulated the activity of antioxidant enzymes, including superoxide dismutase (SOD), heme oxygenase-1 (HO-1) and NADPH oxidase 2 (NOX2), while they had little effect on the activity of nadph:quinone oxidoreductase-1 (NQO1). This method can efficiently prepare and isolate antioxidative gingerols from Dracocephalum heterophyllum, and it can be extended to isolate antioxidants from other natural products.

The Isolation and Preparation of Samwinol from Dracocephalum heterophyllum and Prevention on Aß25-35-Induced Neuroinflammation in PC-12 Cells.

Dracocephalum heterophyllum (D. heterophyllum) is a traditional Chinese Tibetan medicine that has been used for the treatment of lymphitis, hepatitis, and bronchitis. However, only a few selected chemical components are currently obtained from D. heterophyllum, which limits its further pharmacological applications. In this study, we have obtained samwinol from D. heterophyllum by medium- and high-pressure liquid chromatography separation for the first time. Thereafter, we investigated the protective actions of samwinol against amyloid beta protein fragment 25-35 (Aß25-35) induced neurotoxicity in cultured rat pheochromocytoma PC-12 cells and explored its underlying mechanisms of action. The results indicated that samwinol could increase cell viability and inhibit the production of reactive oxygen species (ROS) and mitochondria-derived ROS, as assessed by MTT assay, Giemsa staining, and flow cytometry assay. Through Western blot analysis, it was found that samwinol substantially inhibited the phosphorylation of ERK(1/2) and promoted the expression of HO-1 and Nrf2. The data obtained from molecular docking were also consistent with the above conclusions. All of these results showed that samwinol from D. heterophyllum can display significant anti-neuroinflammatory and antioxidant activities in vitro, which are associated with the suppression of ERK/AKT phosphorylation and the activation of the Nrf2/HO-1 signaling pathway. In the future, additional in-depth mechanism studies will be carried out to provide more evidence for the potential of samwinol in the treatment of Alzheimer's disease.

Neoadjuvant immune checkpoint inhibitor in combination with chemotherapy or chemoradiotherapy in resectable esophageal cancer: A systematic review and meta-analysis.

Background: Neoadjuvant immune checkpoint inhibitor in combination with chemotherapy (nICT) or chemoradiotherapy (nICRT) has been tested in resectable esophageal cancer. Nevertheless, efficacy and safety for this new strategy have not been clearly demonstrated. Patients and methods: PubMed, Embase, Cochrane Library, Web of Science, and scientific meetings were searched for eligible trials until June 30, 2022. The primary outcome of interest was pathological complete response (pCR). The random-effect model was used for statistical analysis. Results: Twenty-seven trials with 809 patients were identified. The estimated rates of pCR for nICRT and nICT were comparable (32.7%, 95% CI: 20.3%-45.1% vs 26.3%, 95% CI: 19.8%-32.8%; P = 0.37). As for safety, surgical resection rate, R0 resection rate, surgical delay rate, and surgical mortality rate were similar between nICRT and nICT, while more grade ≥3 treatment-related adverse events were observed for nICRT (52.6%, 95% CI: 30.7%-74.5% vs 19.9%, 95% CI: 8.8%-31.0%; P = 0.01). In subgroup analysis, nICRT achieved higher pCR rate compared to nICT (56.2%, 95% CI: 41.0%-71.3% vs 27.2%, 95% CI: 20.2%-34.1%; P < 0.001) for squamous cell carcinoma (SCC) but adenocarcinoma. In patients receiving nICT, PD-L1 expression CPS ≥1 showed higher pCR rate compared to CPS <1 (51.3%, 95% CI: 41.4%-61.2% vs 26.6%, 95% CI: 8.6%-44.5%; P = 0.02); regimen of paclitaxel plus carboplatin/cisplatin (PC/TP) and 3-4 cycles of nICT did not lead to an significantly improved pCR rate compared to other chemotherapy regimens and 2 cycles of nICT, respectively, despite without increased toxicity. Conclusion: Both nICT and nICRT achieved promising pCR rates with acceptable tolerability, and nICRT was likely to have more antitumor efficacy compared to nICT for patients with SCC. PD-L1 status seemed to be predictive of pCR in patients receiving nICT; pCR rate did not appear to be greatly affected by CT regimen and increasing cycles of nICT.