Radiotherapy combined with PD-1/PD-L1 inhibitors in NSCLC brain metastases treatment: The mechanisms, advances, opportunities, and challenges.

At present, whole-brain radiation therapy/stereotactic radiosurgery is one of the main local treatments for brain metastasis of non-small-cell lung cancer (NSCLC). Currently, it has been proved that radiotherapy (RT) can regulate the immune response, and small-sample studies have shown that patients with NSCLC brain metastases (BMs) can benefit from RT combined with immunotherapy (IO). However, the efficacy and safety of the combination treatment have not been deeply elaborated. Notably, as a challenge that is still being explored, the timing of RT combined with IO is likely to be an important factor affecting efficacy and prognosis. This article reviews the current application and challenges of RT combined with IO from the perspectives of molecular mechanism, combination timing, safety, and efficacy. The purpose is to provide information on clinical evidence-based medicine of combination between RT with IO. For further investigation, we also discuss the major challenges and prospects of RT combined with IO in NSCLC BMs.

Effectiveness of Tuina Therapy Combined With Yijinjing Exercise in the Treatment of Nonspecific Chronic Neck Pain: A Randomized Clinical Trial.

Importance: Both tuina therapy and yijinjing exercise were beneficial to patients with nonspecific chronic neck pain, but the evidence for this combination is limited. Objective: To investigate the effectiveness of tuina therapy combined with yijinjing exercise compared with tuina therapy alone for patients with nonspecific chronic neck pain. Design, Setting, and Participants: A 12-week, open-label, analyst-blinded randomized clinical trial (8-week intervention plus 4-week observational follow-up) was conducted from September 7, 2020, to October 25, 2021. A total of 102 participants with nonspecific chronic neck pain were recruited, and data were analyzed from December 10, 2021, to March 26, 2022. Interventions: Participants in the tuina group or tuina combined with yijinjing group received 3 sessions of tuina therapy per week for 8 weeks, for a total of 24 sessions. Participants in the tuina combined with yijinjing group practiced yijinjing 3 times a week for 8 weeks, including an instructor-guided exercise at the hospital and 2 self-practice exercises at home. Main Outcomes and Measures: The primary outcome was change in visual analog scale (VAS) score from baseline to week 8. Secondary outcomes included Neck Disability Index scores, Self-rating Anxiety Scale scores, tissue hardness, and active range of motion. Results: This randomized clinical trial recruited 102 patients (mean [SD] age, 36.5 [4.9] years; 69 [67.6%] female) who were randomized to 2 groups. All 102 patients (100%) completed all the outcome measurements. The mean difference in VAS scores from baseline at week 8 for the tuina combined with yijinjing group was -5.4 (95% CI, -5.8 to -5.1). At week 8, the difference in VAS score was -1.2 (95% CI, -1.6 to -0.8; P < .001) between the tuina group and the tuina combined with yijinjing group. The effectiveness of tuina combined with yijinjing in treating nonspecific chronic neck pain remained at the 12-week follow-up. Conclusions and Relevance: In this randomized clinical trial, for patients with nonspecific chronic neck pain, tuina combined with yijinjing was more effective than tuina therapy alone in terms of pain, functional recovery, and anxiety at week 8, and effectiveness remained at week 12. A combination of tuina and yijinjing should be considered in the management of nonspecific chronic neck pain. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000036805.

A carrier free photodynamic oxidizer for enhanced tumor therapy by redox homeostasis disruption.

Abnormal tumor microenvironments play important roles in cancer progression. In general, tumor cells are capable of upregulating glutathione (GSH) levels to maintain aberrant redox homeostasis and cause resistance to oxidative damage. Herein, we develop a photodynamic oxidizer to disrupt the redox homeostasis of tumor cells for enhanced photodynamic tumor therapy. Based on pyropheophorbide-a (Pyro) and naphthazarin (Nap), a carrier free photodynamic oxidizer (named PyroNap) is prepared by the self-assembly technique through hydrophobic interactions. It is confirmed that nanosized PyroNap has high drug contents as well as favorable dispersity and stability. Besides, the photodynamic property of Pyro has obviously improved after self-assembly into the nanomedicine of PyroNap, which facilitates the production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). More importantly, the Nap induced GSH decrease could disrupt the redox homeostasis of tumor cells to further improve the PDT efficacy on tumor suppression. Consequently, after intravenous administration, PyroNap was able to significantly inhibit tumor growth and cause minimal side effects. This study might shed light on developing translational nanomedicine for tumor precision therapy.

Correlation Study of Galectin-3 in Patients with an Ascending Aortic Aneurysm and Ventricular Remodeling Before and After Surgical Correction.

OBJECTIVE: The present study aims to observe the changes in galectin-3 (Gal-3) expression levels in patients with an ascending aortic aneurysm and ventricular remodeling and analyze Gal-3's correlation with ventricular remodeling. METHODS: A total of 102 patients with an ascending aortic aneurysm were included as the research subjects. Gal-3 expression levels in the peripheral blood of the patients were detected by an enzyme-linked immunosorbent assay before the operation and then three and six months after. The left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), interventricular septal thickness, and left ventricular posterior wall thickness were recorded, and the left ventricular mass index (LVMI) was calculated. Changes in Gal-3 expression levels, LVMI, LVEF, and LVEDD were observed before and after surgery, and these changes were then analyzed. RESULTS: There were significant differences in Gal-3 expression levels, LVMI, and LVEDD before surgery and three months after (P < 0.001) but no significant difference in LVEF (P = 0.887). There were significant differences in Gal-3 expression levels, LVMI, LVEDD, and LVEF (P < 0.05) three and six months after surgery. Before surgery and three and six months after surgery, Gal-3 was positively correlated with LVMI and LVEDD (R = 0.697, R = 0.571, and R = 0.454, respectively), and a receiver operating characteristic curve found that Gal-3 was able to predict ventricular remodeling, with an area under the curve value of 0.721. CONCLUSION: Gal-3 expression levels are correlated with ascending aortic aneurysms combined with ventricular remodeling, which provides a reference value for predicting ventricular remodeling.

Severe bleeding following off-pump coronary artery bypass grafting: predictive factors and risk model.

BACKGROUND: Severe bleeding following cardiac surgery remains a troublesome complication, but to date, there is a lack of comprehensive predictive models for the risk of severe bleeding following off-pump coronary artery bypass grafting (OPCABG). This study aims to analyze relevant indicators of severe bleeding after isolated OPCABG and establish a corresponding risk assessment model. METHODS: The clinical data of 584 patients who underwent OPCABG from January 2018 to April 2020 were retrospectively analyzed. We gathered the preoperative baseline data and postoperative data immediately after intensive care unit admission and used multifactor logistic regression to screen the potential predictors of severe bleeding, upon which we established a predictive model. Using the consistency index and calibration curve, decision curve, and clinical impact curve analysis, we evaluated the performance of the model. RESULTS: This study is the first to establish a risk assessment and prediction model for severe bleeding following isolated OPCABG. Eight independent risk factors were identified: male sex, aspirin/clopidogrel withdrawal time, platelet count, fibrinogen level, C-reactive protein, serum creatinine, and total bilirubin. Among the 483 patients in the training group, 138 patients (28.6%) had severe bleeding; among the 101 patients in the verification group, 25 patients (24.8%) had severe bleeding. Receiver operating characteristic (ROC) curve analysis for the internal training group revealed a convincing performance with a concordance index (C-index) of 0.859, while the area under the ROC curve for the external validation data was 0.807. Decision curve analysis showed that the model was useful for both groups. CONCLUSIONS: Although there are some limitations, the model can effectively predict the probability of severe bleeding following isolated OPCABG and is therefore worthy of further exploration and verification.

[Complex mechanisms of chronic pain in knee osteoarthritis identified by neuroimaging technology].

Chronic pain of knee osteoarthritis (KOA) greatly affects the quality of life and functional activities of patients. It is important to clarify the underlying mechanisms of KOA pain and the analgesic effect of different therapies. Neuroimaging technology has been widely used in the basic and clinical research of pain. In the recent years, neuroimaging technology has played an important role in the basic and clinical research of KOA pain. Increasing evidence demonstrates that chronic pain in KOA includes both nociceptive and neuropathic pain. The neuropathic mechanism involved in KOA pain is complex, which may be caused by peripheral or central sensitization. In this paper, we review the regional changes of brain pathophysiology caused by KOA pain based on magnetic resonance imaging (MRI), electroencephalogram (EEG), magnetoencephalogram (MEG), near-infrared spectroscopy (NIRS) and other neuroimaging techniques. We also discuss the central analgesic mechanism of different KOA therapies, with a focus on the latest achievements in the evaluation and prediction of pain. We hope to provide new thoughts for the treatment of KOA pain, especially in the early and middle stages of KOA.

The Short-Term Patency Rate of a Saphenous Vein Bridge Using the No-Touch Technique in off-Pump Coronary Artery Bypass Grafting in Vein Harvesting.

OBJECTIVE: This study aimed to examine the short-term effect of the no-touch technique on the patency rate of a great saphenous vein (GSV) bridge used during off-pump coronary artery bypass grafting (OPCABG). METHODS: Between June 2018 and September 2020, 140 patients undergoing OPCABG, with grafts obtained from the GSV using the "no-touch" technique or the left internal mammary artery (LIMA), were enrolled in this study. The early clinical results and short-term patency rate of the OPCABG were evaluated at a three-month follow-up by comparing the patency rate of the LIMA bridge and the GSV bridge obtained by the no-touch technique. This study also analyzed the impacts of the postoperative complications of the lower limbs and the distribution area of diseased vessels on the patency rate of a GSV bridge obtained by the no-touch technique at an early stage. RESULTS: No perioperative death or adverse cardiovascular or cerebrovascular events occurred in the 140 patients undergoing OPCABG. The difference in the early patency rate between the GSV bridge obtained by the no-touch technique and the LIMA bridge was not statistically significant (95.9% vs 97.1%, p = 0.501). There was no significant difference in the patency rate between an end-to-side anastomosed venous bridge and a LIMA bridge (95.0% [248/261] vs 97.1% [136/140], p = 0.314). The overall patency rate of a no-touch vein bridge in the right coronary artery region was lower than it was in the left coronary artery region (93.8% [165/176] vs 97.9% [183/187], p = 0.049). CONCLUSION: The no-touch technique may improve the early patency rate of a GSV bridge, and its effect is similar to that of a LIMA bridge.

Using Thromboelastography to Predict Blood Loss After Off-Pump Coronary Artery Bypass Grafting.

OBJECTIVE: This study aims to investigate the value of thromboelastography (TEG) in predicting blood loss, and its relationship with blood transfusion demand, during the perioperative period in off-pump coronary artery bypass grafting (OPCABG). METHODS: The data of 398 patients undergoing OPCABG were retrospectively analyzed. Blood was drawn before anesthesia induction (T1) and at 10 minutes after heparin neutralization (T2) for further TEG detection. The patients were divided into two groups based on the results at T2: a TEG normal group and a TEG abnormal group. Logistic regression analysis was used to predict the related factors contributing to the significant increase in perioperative blood loss (more than 20% of the estimated blood volume). RESULTS: There were 277 (69.6%) patients in the TEG normal group and 121 (30.4%) in the TEG abnormal group. Compared with the TEG normal group, the volume of blood loss, red blood cell count, and volume of plasma transfusion in the TEG abnormal group significantly increased within 24 hours after surgery. The results of the logistic regression analysis identified the use of clopidogrel, platelet count at T2, fibrinogen level at T2, and abnormality in TEG value as independent predictors for the significant increase in perioperative blood loss (P < 0.001). CONCLUSION: The abnormality in TEG value after heparin neutralization is correlated with massive hemorrhage and blood transfusion during the perioperative period in OPCABG. TEG detection can assist in clinical treatment and reduce the volume of blood lost in a hemorrhage and the volume of blood required in a transfusion during OPCABG.

Identification of the significant pathways of Banxia Houpu decoction in the treatment of depression based on network pharmacology.

Banxia Houpu decoction (BXHPD) has been used to treat depression in clinical practice for centuries. However, the pharmacological mechanisms of BXHPD still remain unclear. Network Pharmacology (NP) approach was used to explore the potential molecular mechanisms of BXHPD in treating depression. Potential active compounds of BXHPD were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform Database. STRING database was used to build a interaction network between the active compounds and target genes associated with depression. The topological features of nodes were visualized and calculated. Significant pathways and biological functions were identified using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. A total of 44 active compounds were obtained from BXHPD, and 121 potential target genes were considered to be therapeutically relevant. Pathway analysis indicated that MAPK signaling pathway, ErbB signaling pathway, HIF-1 signaling pathway and PI3K-Akt pathway were significant pathways in depression. They were mainly involved in promoting nerve growth and nutrition and alleviating neuroinflammatory conditions. The result provided some potential ways for modern medicine in the treatment of depression.

HIV protease inhibitors in pulmonary hypertension: rationale and design of a pilot trial in idiopathic pulmonary arterial hypertension.

We propose an exploratory clinical study, the first of its kind to our knowledge, to determine the safety and potential clinical benefit of the combination of the HIV protease inhibitors (HIV-PIs) saquinavir and ritonavir (SQV+RIT) in patients with idiopathic pulmonary arterial hypertension (IPAH). This study is based on evidence that (1) HIV-PIs can improve pulmonary hemodynamics in experimental models; (2) both Toll-like receptor 4 and high-mobility group box 1 (HMGB1) participate in the pathogenesis of experimental pulmonary hypertension; and (3) a high-throughput screen for inhibitors of HMGB1-induced macrophage activation yielded HIV-PIs as potent inhibitors of HMGB1-induced cytokine production. In this proposed open-label, pre-post study, micro, low, and standard doses of SQV+RIT will be given to IPAH patients for 14 days. Patients will receive follow-up for the next 14 days. The primary outcome to be evaluated is change in HMGB1 level from baseline at 14 days. The secondary outcome is changes in tumor necrosis factor α, interleukin 1ß, interleukin 6, C-reactive protein, pulmonary arterial pressure based on echocardiography parameters and New York Heart Association/World Health Organization functional class, and Brog dyspnea scale index from baseline at 14 days. Other secondary measurements will include N-terminal pro-brain natriuretic peptide, atrial natriuretic peptide, and 6-minute walk distance. We propose that SQV+RIT treatment will improve inflammatory disorders and pulmonary hemodynamics in IPAH patients. If the data support a potentially useful therapeutic effect and suggest that SQV+RIT is safe in IPAH patients, the study will warrant further investigation. (ClinicalTrials.gov identifier: NCT02023450.).

[Single plane Simpson's method for measurement of right ventricular volume by X-ray ventriculography].

OBJECTIVE: To study the validity of single plane Simpson's method with conventional X-ray ventriculography for estimation of right ventricular (RV) volume. METHODS: Fifteen human RV casts were obtained from 15 subjects who died from non-cardiac causes within 24 hours after death. These casts were photographed respectively and their volumes were calculated by using the single plane Simpson's method based on a new half-circle model. The actual RV cast volumes were determined by water displacement method. RESULTS: The actual RV volume was (64.23 +/- 24.51) ml and the calculated volume was (58.04 +/- 24.45) ml. The calculated RV volume underestimated the actual volume by (6.19 +/- 12.38) ml, but there was no significant difference between the actual and the calculated RV volume (P > 0.05). There was a significant correlation between the actual cast volume and the calculated volume (r = 0.983, P < 0.01). The regression equation was: RV actual volume = 1.074 x (RV calculated volume). CONCLUSION: RV volume calculated by single plane Simpson's method with conventional X-ray ventriculography is accurate and deserves further study.