Purification of proanthocyanidins from nut seeds and study on its bactericidal mechanism against Streptococcus mutans.

AIM: The aim of this study was to purify proanthocyanidins from areca nut seeds (P-AN) and to investigate the bactericidal activity and mechanism of the purified products against S. mutans. METHODS AND RESULTS: UPLC-Q-TOF-MS, FT-IR, MADLI-TOF-MS and thiolysis experiment were used for P-AN chemical analysis. Time-kill analysis and glycolytic pH drop were used to evaluate the activity of S. mutans in vitro. Meanwhile, the investigation of the bacteriostatic mechanism included membrane protein, fluidity, permeability and integrity tests. The results showed that P-AN was a kind of proanthocyanidins mainly composed of B-type proanthocyanidin and their polymers. Moreover, MADLI-TOF-MS and thiolysis experiments demonstrated that the degree of polymerization (DP) of P-AN was 13. The time-kill analysis showed that P-AN had strong bactericidal activity against S. mutans. P-AN at MIC concentrations was able to induce S. mutans death, while complete lethality occurred at 2 MIC. Glycolysis test showed that P-AN significantly inhibited S. mutans acid production (p < 0.01). The morphological changes of S. mutans were observed by SEM and TEM experiments, which indicated that P-AN destroyed the cellular structure of S. mutans. At the same time, significant changes were observed in membrane proteins, fluidity, permeability and integrity. CONCLUSION: P-AN can effectively inhibit the activity of S. mutans. P-AN can reduce the erosion of the tooth surface by the acid of S. mutans. P-AN could break the structure of cell membrane protein of S. mutans. P-AN could destroy the integrity of membrane, resulting in the death of S. mutans.

Groove pancreatitis presenting with upper gastrointestinal obstruction and abnormal renal function: A case report and literature review.

Groove pancreatitis (GP) is a rare type of chronic pancreatitis characterized by fibrotic lesions localized to the groove between the pancreatic head, duodenum, and common bile duct. We present a case of a 59-year-old male alcoholic with vomiting and renal dysfunction found to have duodenal obstruction and low-density pancreatic head lesions on computed tomography concerning for GP. The patient underwent pancreaticoduodenectomy and pathology confirmed the diagnosis postoperatively. The patient recovered well without complications or relapse at follow-up. Although rare, GP should be included in the differential for pancreatic head masses in middle-aged alcoholics and surgical resection may be necessary for symptom relief and exclusion of malignancy.

Blood Oxygen Level-Dependent MR Imaging of Lower Extremities in Peripheral Artery Disease and Its Correlation With Walking Performance.

BACKGROUND: A noninvasive and reliable approach to quantitatively measure muscle perfusion of lower extremity is needed to aid the diagnosis and treatment of peripheral artery disease (PAD). PURPOSE: To verify the reproductivity of using blood oxygen level-dependent (BOLD) imaging to evaluate perfusion in lower extremities, and explore its correlation with walking performance in patients with PAD. STUDY TYPE: Prospective observational study. SUBJECTS: Seventeen patients with lower extremity PAD (mean age: 67 ± 6 years, 15 males) and eight older adults (controls). FIELD STRENGTH/SEQUENCE: Dynamic multi-echo gradient echo T2* weighted imaging at 3T. ASSESSMENT: Perfusion was analyzed in regions of interest according to muscle groups. Perfusion parameters were measured, such as minimum ischemia value (MIV), time to peak (TTP), and gradient during reactive hyperemia (Grad) by two independent users. Walking performance experiments including short physical performance battery (SPPB) and 6-minute walk were tested in patients. STATISTICAL TESTS: BOLD parameters were compared using Mann-Whitney U test and Kruskal-Wallis test. Relations between parameters and walking performance were assessed by Mann-Whitney U test and Spearman's correlation coefficient. RESULTS: Good to perfect agreement was demonstrated for all perfusion parameters of interuser reproducibility, and the interscan reproducibility of MIV, TTP, and Grad was good. The TTP of the patients was longer than that of the controls (87.85 ± 38.85 s vs. 36.54 ± 7.27 s), while the Grad of patients was smaller (0.16 ± 0.12 msec/s vs. 0.24 ± 0.11 msec/s). Among PAD patients, the MIV was significantly lower in the low SPPB subgroup (score 6-8) than in the high SPPB group (score 9-12), and the TTP was negatively correlated with 6-minute walk distance (ρ = -0.549). DATA CONCLUSION: BOLD imaging method had overall good reproducibility for the perfusion assessment of calf muscles. The perfusion parameters were different between PAD patients and controls, and were correlated with lower extremity function. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Small EV-based delivery of CpG ODNs for melanoma postsurgical immunotherapy.

Blocking programmed cell death protein 1 (PD-1) is an effective therapeutic strategy for melanoma. However, patients often develop tumor recurrence postoperatively due to the low response rate to the anti-PD-1 antibody (aPD-1). In this study, we developed an in situ sprayable fibrin gel that contains cytosine-guanine oligodeoxynucleotides (CpG ODNs)-modified ovalbumin (OVA) antigen-expressing bone marrow dendritic cell (DC)-derived small extracellular vesicles (DC-sEVs) and aPD-1. CpG ODNs can activate DCs, which have potent immunostimulatory effects, by stimulating both the maturation and activation of tumor-infiltrating dendritic cells (TIDCs) and DCs in tumor-draining lymph nodes (TDLNs). In addition, DC-sEVs can deliver OVA to the same DCs, leading to the specific expression of tumor antigens by antigen-presenting cells (APCs). In brief, the unique synergistic combination of aPD-1 and colocalized delivery of immune adjuvants and tumor antigens enhances antitumor T-cell immunity, not only in the tumor microenvironment (TME) but also in TDLNs. This effectively attenuates local tumor recurrence and metastasis. Our results suggest that dual activation by CpG ODNs prolongs the survival of mice and decreases the recurrence rate in an incomplete tumor resection model, providing a promising approach to prevent B16-F10-OVA melanoma tumor recurrence and metastasis.

Efficacy and safety of probiotic-supplemented bismuth quadruple therapy for the treatment of Helicobacter pylori infection: a systematic review and meta-analysis.

OBJECTIVE: We performed a meta-analysis to determine whether the addition of probiotics to the bismuth quadruple therapy (BQT) for Helicobacter pylori would improve the incidence of eradication and reduce that of side effects. METHODS: Randomized controlled trials matching the inclusion criteria were collected from PubMed, Embase, Web of Science, and The Cochrane Central Register of Controlled Trials. A Mantel-Haenszel random-effects model was used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs) for the incidences of eradication rate, side effects as a whole, diarrhea, and other side effects. RESULTS: Ten studies were selected for inclusion in the meta-analysis. The pooled RRs for the eradication rates in intention-to-treat and per-protocol analyses of the probiotic group vs. the control group were 1.07 (95% CI: 1.02-1.11) and 1.04 (95% CI: 1.00-1.07), respectively. Probiotic supplementation reduced the incidences of side effects (RR 0.58, 95% CI: 0.37-0.91), diarrhea (RR 0.41, 95% CI: 0.25-0.67), and bitter taste (RR 0.63, 95% CI: 0.40-0.99). CONCLUSIONS: The results of this meta-analysis support the use of probiotics in combination with BQT in the clinical management of patients with H. pylori infection.

Three-Dimensional Fast Spin Echo Pituitary MRI in Treatment-Naïve Cushing's Disease: Reduced Impact of Reader Experience and Increased Diagnostic Accuracy.

BACKGROUND: In patients with Cushing's disease, the preoperative identification of pituitary adenomas is crucial to treatment. However, increasing diagnostic accuracy remains an unresolved issue. PURPOSE: To evaluate the diagnostic accuracy and the impact of readers' experience regarding high-resolution contrast-enhanced magnetic resonance imaging (hrMRI) for identifying pituitary adenomas in comparison with conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI). STUDY TYPE: Retrospective. POPULATION: Sixty-five patients (median age, 39 years; interquartile range [IQR], 28-53 years; 60% females) with treatment-naïve Cushing's disease. FIELD STRENGTH/SEQUENCE: 3-T, seven fast spin echo sequences. ASSESSMENT: The diagnostic accuracies of identifying pituitary adenomas on cMRI, dMRI, combined cMRI and dMRI (cdMRI), and hrMRI were independently evaluated by six readers with three experience levels (high: >20 years, modest: 10-20 years, low: <10 years; two readers for each experience level). Readers were asked to localize the lesion, and measure its diameter on the sequence where identified. The reference standard was postoperative histopathology. The impact of readers' experience and interobserver agreement were assessed. Image quality was assessed using a 5-point Likert scale, including overall image quality, sharpness, and structural conspicuity. STATISTICAL TESTS: McNemar's test, Cochran's test, Wilcoxon signed-rank test, Mann-Whitney U test, and κ statistics for interobserver agreement. A P-value <0.05 was considered statistically significant. RESULTS: For identifying pituitary adenomas (median diameter, 5 mm; IQR, 4-5 mm), hrMRI had significantly higher sensitivity (87.7%-93.8%) than cMRI, dMRI, and cdMRI (52.3%-75.4%) for readers with different experience levels. The interobserver agreement was moderate (κ = 0.461-0.523). The sensitivity for hrMRI was comparable between readers with different experience levels (P = 0.371). All image quality scores on hrMRI were significantly higher than cMRI and dMRI (5.0 vs. 4.0). DATA CONCLUSION: For identifying pituitary adenomas in patients with treatment-naïve Cushing's disease, hrMRI may show high diagnostic accuracy and seems not to be affected by readers' experience. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Revolutionizing cancer treatment: The power of cell-based drug delivery systems.

Intravenous administration of drugs is a widely used cancer therapy approach. However, the efficacy of these drugs is often hindered by various biological barriers, including circulation, accumulation, and penetration, resulting in poor delivery to solid tumors. Recently, cell-based drug delivery platforms have emerged as promising solutions to overcome these limitations. These platforms offer several advantages, including prolonged circulation time, active targeting, controlled release, and excellent biocompatibility. Cell-based delivery systems encompass cell membrane coating, intracellular loading, and extracellular backpacking. These innovative platforms hold the potential to revolutionize cancer diagnosis, monitoring, and treatment, presenting a plethora of opportunities for the advancement and integration of pharmaceuticals, medicine, and materials science. Nevertheless, several technological, ethical, and financial barriers must be addressed to facilitate the translation of these platforms into clinical practice. In this review, we explore the emerging strategies to overcome these challenges, focusing specifically on the functions and advantages of cell-mediated drug delivery in cancer treatment.

Intravenous application of tranexamic acid in intramedullary nailing for the treatment of geriatric intertrochanteric fractures: a systematic review and meta-analysis.

BACKGROUND: Meta-analyses on the use of tranexamic acid (TXA) in intertrochanteric fractures have shown inconsistent results due to variations in inclusion criteria and clinical heterogeneity. To address these limitations, we conducted a rigorous analysis of recent randomized controlled trials (RCTs) with strict inclusion criteria. The aim of this study was to objectively evaluate the effects and safety of intravenous TXA administration in the treatment of geriatric intertrochanteric femoral fractures with intramedullary nailing. METHODS: PubMed, Embase, and the Cochrane Library were searched for RCTs published from the database inception to August 2022. The date of total blood loss (TBL), intra-operative blood loss (IBL), hidden blood loss (HBL), transfusion rate, transfusion units, thromboembolic events, and mortality were extracted. Review Manager 5.3 was used for the analysis. RESULTS: A total of six RCTs involving 689 patients were included. Meta-analyses indicated that TXA can significantly reduce TBL (WMD = -232.82; 95% CI -312.81 to -152.84; p < 0.00001), IBL (WMD = -36.33; 95% CI -51.38 to -21.28; p < 0.00001), HBL (WMD = -189.23; 95% CI -274.92 to -103.54; p < 0.0001), transfusion rate (RR = 0.53; 95% CI 0.33 to 0.85; p = 0.008), and transfusion units (WMD = -0.58; 95% CI -0.75 to -0.41; p < 0.01). No increase in thromboembolic events rate (RR = 0.75; 95% CI 0.38 to 1.50; p = 0.42) and mortality (RR = 1.36; 95% CI 0.61 to 3.04; p = 0.45) was observed. CONCLUSIONS: Our meta-analysis provides robust evidence supporting the efficacy and safety of intravenous TXA administration in treating geriatric intertrochanteric femoral fractures with intramedullary nailing. TXA significantly reduces blood loss and transfusion requirements without increasing the risk of thromboembolic events or mortality.

Burden of dilated perivascular spaces in patients with moyamoya disease and moyamoya syndrome is related to middle cerebral artery stenosis.

Background and objective: The correlation between intracranial large artery disease and cerebral small vessel disease (CSVD) has become a noteworthy issue. Dilated perivascular spaces (dPVS) are an important marker of CSVD, of which cerebral atrophy has been regarded as one of the pathological mechanisms. DPVS has been found to be associated with vascular stenosis in patients with moyamoya disease (MMD), but the underlying mechanism remains unclear. The purpose of our study was to explore the correlation between the middle cerebral artery (MCA) stenosis and dPVS in the centrum semiovale (CSO-dPVS) in patients with MMD/moyamoya syndrome (MMS) and to determine whether brain atrophy plays a mediating role in this relationship. Methods: A total of 177 patients were enrolled in a single-center MMD/MMS cohort. Images of their 354 cerebral hemispheres were divided into three groups according to dPVS burden: mild (dPVS 0-10), moderate (dPVS 11-20), and severe (dPVS > 20). The correlations among cerebral hemisphere volume, MCA stenosis, and CSO-dPVS were analyzed, adjusting for the confounding factors of age, gender, and hypertension. Results: After adjustment for age, gender, and hypertension, the degree of MCA stenosis was independently and positively associated with ipsilateral CSO-dPVS burden (standardized coefficient: ß = 0.247, P < 0.001). A stratified analysis found that the subgroup with a severe CSO-dPVS burden exhibited a significantly higher risk of severe stenosis of the MCA [p < 0.001, OR = 6.258, 95% CI (2.347, 16.685)]. No significant correlation between CSO-dPVS and ipsilateral hemisphere volume was found (p = 0.055). Conclusion: In our MMD/MMS cohort, there was a clear correlation between MCA stenosis and CSO-dPVS burden, which may be a direct effect of large vessel stenosis, without a mediating role of brain atrophy.

Comparison of neuroimaging features of histiocytic neoplasms with central nervous system involvement: a retrospective study of 121 adult patients.

OBJECTIVES: To compare neuroimaging characteristics of three types of histiocytoses, namely Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), with central nervous system (CNS) involvement. METHODS: A total of 121 adult patients with histiocytoses (77 LCH, 37 ECD, and 7 RDD) and CNS involvement were retrospectively included. Histiocytoses were diagnosed based on histopathological findings combined with suggestive clinical and imaging features. Brain and dedicated pituitary MRIs were systematically analyzed for tumorous, vascular, degenerative lesions, sinus, and orbital involvement and for hypothalamic pituitary axis involvement. RESULTS: Endocrine disorders, including diabetes insipidus and central hypogonadism, were more common in LCH patients than in ECD and RDD patients (p < 0.001). In LCH, tumorous lesions were mostly solitary (85.7%), located in the hypothalamic pituitary region (92.9%), and without peritumoral edema (92.9%), while in ECD and RDD, tumorous lesions were often multiple (ECD: 81.3%, RDD: 85.7%), their distribution was more widespread with meninges mostly involved (ECD: 75%, RDD: 71.4%), and they most likely presented with peritumoral edema (ECD: 50%, RDD: 57.1%; all p ≤ 0.020). Vascular involvement was an exclusive imaging characteristic of ECD (17.2%), which was not observed in LCH or RDD; this was also associated with a higher risk of death (p = 0.013, hazard ratio = 11.09). CONCLUSION: The typical characteristic of adult CNS-LCH was endocrine disorders with radiological findings limited to the hypothalamic pituitary axis. The pattern of multiple tumorous lesions with predominant involvement of meninges was the main manifestation of CNS-ECD and CNS-RDD, while vascular involvement was pathognomonic for ECD and associated with poor prognosis. CLINICAL RELEVANCE STATEMENT: Involvement of the hypothalamic-pituitary axis is the typical imaging characteristic of Langerhans cell histiocytosis. Multiple tumorous lesions, predominantly involving but not limited to meninges, occur in most Erdheim-Chester disease and Rosai-Dorfman disease patients. Vascular involvement occurs only in Erdheim-Chester disease patients. KEY POINTS: • The different distribution patterns of brain tumorous lesions can help differentiate among LCH, ECD, and RDD. • Vascular involvement was an exclusive imaging finding of ECD and was associated with high mortality. • Some cases with atypical imaging manifestations were reported to further expand the knowledge on these diseases.

Gas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation.

The immunologically "cold" microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H2S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn2+. Both H2S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

Multidelay MR Arterial Spin Labeling Perfusion Map for the Prediction of Cerebral Hyperperfusion After Carotid Endarterectomy.

BACKGROUND: Multidelay arterial spin labeling (ASL) generates time-resolved perfusion maps, which may provide sufficient and accurate hemodynamic information in carotid stenosis. PURPOSE: To use imaging markers derived from multidelay ASL magnetic resonance imaging (MRI) and to determine the optimal strategy for predicting cerebral hyperperfusion after carotid endarterectomy (CEA). STUDY TYPE: Prospective observational cohort. SUBJECTS: A total of 79 patients who underwent CEA for carotid stenosis. FIELD STRENGTH/SEQUENCE: A 3.0 T/pseudo-continuous ASL with three postlabeling delays of 1.0, 1.57, and 2.46 seconds using fast-spin echo readout. ASSESSMENT: Cerebral perfusion pressure, antegrade, and collateral flow were scored on a four-grade ordinal scale based on preoperative multidelay ASL perfusion maps. Simultaneously, quantitative hemodynamic parameters including cerebral blood flow (CBF), arterial transit time (ATT), relative CBF (rCBF) and relative ATT (rATT; ipsilateral/contralateral values) were calculated. On the CBF ratio map obtained through dividing postoperative by preoperative CBF map, regions of interest were placed covering ipsilateral middle cerebral artery territory. Three neuroradiologists conducted this procedure. Cerebral hyperperfusion was defined as a CBF ratio >2. STATISTICAL TESTS: Weighted κ values, independent sample t test, chi-square test, Mann-Whitney U-test, multivariable logistic regression analysis, receiver-operating characteristic curve analysis, and Delong test. Significance level was P < 0.05. RESULTS: Cerebral hyperperfusion was observed in 15 (19%) patients. Higher blood pressure (odd ratio [OR] = 1.08) and carotid near-occlusion (NO; OR = 7.31) were clinical risk factors for postoperative hyperperfusion. Poor ASL perfusion score (OR = 37.33), decreased CBF (OR = 0.74), prolonged ATT (OR = 1.02), lower rCBF (OR = 0.91), and higher rATT (OR = 1.12) were independent imaging predictors of hyperperfusion. ASL perfusion score exhibited the highest specificity (95.3%), while CBF exhibited the highest sensitivity (93.3%) for the prediction of hyperperfusion. When combined with ASL perfusion score, CBF and ATT, the predictive ability was significantly higher than using blood pressure and NO alone (AUC: 0.98 vs. 0.78). DATA CONCLUSIONS: Multidelay ASL can accurately predict cerebral hyperperfusion after CEA with high sensitivity and specificity. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 5.

High risk factors related to lymph node metastasis in early gastric cancer: A retrospective observational study.

Lymph node metastasis (LNM) is a key factor affecting the prognosis of patients with early gastric cancer. This is a retrospective study, conducted between January 20, 2010 and January 30, 2019 and included 402 patients with early-stage gastric cancer who underwent radical gastrectomy at The Affiliated People Hospital of Ningbo University. Clinical and pathological data including patients' gender, age, tumor location, gross typing, depth of invasion, tumor maximum diameter, type of differentiation, vascular invasion, presence or absence of signet ring cells, and LNM data were collected and analyzed. Univariate analysis identified positive relationships between patient gender, tumor invasion depth, tumor size, presence or absence of vascular involvement, and differentiation type with LNM (P < .05). Multivariate analysis subsequently confirmed tumor size (odds ratio [OR]: 2.38, 95% confidence interval [CI]:1.15-4.92, P = .02), vascular involvement (OR: 4.35, 95% CI: 2.00-9.47, P < .001), and depth of invasion (OR: 6.63, 95% CI: 2.19-20.06, P = .001) as independent risk factors for LNM (P < .05). Tumor size, vascular involvement, and depth of invasion are independent risk factors for LNM in cases of early-stage gastric cancer.

Topical tranexamic acid in intramedullary nailing for the treatment of intertrochanteric fractures in the elderly: A protocol for systematic review and meta-analysis.

BACKGROUND: Numerous studies have demonstrated that the use of tranexamic acid (TXA) intravenously minimizes bleeding, lowers transfusion rates, and does not raise the risk of complications during major orthopedic surgery. Concerning the effectiveness of the topical application, there are, nevertheless, inconsistent findings. We aimed to develop a protocol for systematic review and meta-analysis on the benefits and safety of topical TXA in intramedullary nailing for the treatment of intertrochanteric fractures in the elderly. METHODS: PubMed, Embase, and the Cochrane Library will all be searched for randomized controlled trials published from the database inception to October 15, 2022. The primary outcomes will be intraoperative blood loss, hidden blood loss, total blood loss, transfusion rate, transfusion units, operative time, thromboembolic events, and mortality. The risk of bias will be evaluated using the Cochrane risk of bias assessment tool. Review Manager 5.3 will be used for the analysis. RESULTS: The effects and safety of topical TXA in intramedullary nailing for the treatment of intertrochanteric fractures in the elderly will be quantified in this study. CONCLUSIONS: The study's findings will assist doctors in determining if topical TXA use is secure and efficient.

CtDNA's prognostic value in patients with early-stage colorectal cancer after surgery: A meta-analysis and systematic review.

BACKGROUND: Circulating tumor DNA (ctDNA) positivity has been shown to suggest the presence of minimally residual tumor cells in numerous investigations. We aimed to assess the prognostic value of ctDNA positivity for recurrence-free survival in patients with early-stage colorectal cancer after radical surgery and following adjuvant chemotherapy. METHODS: We systematically reviewed studies published in English until August 15, 2022, concerning ctDNA and tumor-node-metastasis I to III colorectal cancer after surgery, and quantified the correlation between ctDNA positivity and early-stage (tumor-node-metastasis stage I-III) colorectal cancer using meta-analysis methods. RESULTS: In total, the meta-analysis comprised 1713 patients from 6 studies. Patients with ctDNA-positive colorectal cancer after surgery had a significantly higher risk of recurrence than patients with ctDNA-negative colorectal cancer (hazard ratio 4.64, 95% confidence interval 2.17-9.92, z = 3.96; P < .001). After adjuvant chemotherapy, patients who were ctDNA-positive had a significantly higher risk of recurrence than those who were ctDNA-negative (hazard ratio 7.27, 95% confidence interval 4.50-11.75, z = 8.1; P < .001). CONCLUSIONS: CtDNA positivity may potentially be a predictor for early-stage colorectal tumor recurrence following surgery and adjuvant chemotherapy.

Cell-Based Drug Delivery Systems Participate in the Cancer Immunity Cycle for Improved Cancer Immunotherapy.

Immunotherapy aims to activate the cancer patient's immune system for cancer therapy. The whole process of the immune system against cancer referred to as the "cancer immunity cycle", gives insight into how drugs can be designed to affect every step of the anticancer immune response. Cancer immunotherapy such as immune checkpoint inhibitor (ICI) therapy, cancer vaccines, as well as small molecule modulators has been applied to fight various cancers. However, the effect of immunotherapy in clinical applications is still unsatisfactory due to the limited response rate and immune-related adverse events. Mounting evidence suggests that cell-based drug delivery systems (DDSs) with low immunogenicity, superior targeting, and prolonged circulation have great potential to improve the efficacy of cancer immunotherapy. Therefore, with the rapid development of cell-based DDSs, understanding their important roles in various stages of the cancer immunity cycle guides the better design of cell-based cancer immunotherapy. Herein, an overview of how cell-based DDSs participate in cancer immunotherapy at various stages is presented and an outlook on possible challenges of clinical translation and application in future development.

Study protocol of Branch Atheromatous Disease-related stroke (BAD-study): a multicenter prospective cohort study.

BACKGROUND: As a meaningful subtype of ischemic stroke in Asians, Branch atheromatous disease (BAD)-related stroke is associated with high early neurological deterioration (END) and disability, but is understudied and without recommended therapy. The mechanism of END still remains unclear. Branch atheromatous disease-related stroke study (BAD-study) therefore aims to investigate demographic, clinical and radiological features, and prognosis of BAD-related stroke in Chinese patients. METHODS/DESIGN: BAD-study is a nationwide, multicenter, consecutive, prospective, observational cohort study enrolling patients aged 18-80 years with BAD-related stroke within 72 h after symptom onset. Initial clinical data, laboratory tests, and imaging data are collected via structured case report form, and follow-ups will be performed at 7 days, 30 days, 90 days, 6 months and 12 months after enrollment. The primary outcome is the score on modified Rankin Scale at 90-day follow-up with single-blinded assessment. Secondary outcomes include END within 7 days, and National institute of health stroke scale score, Barthel index, cerebrovascular events, major bleeding complications, and all-cause mortality during 90-day follow-up. Characteristics of penetrating and parent artery will be assessed by high-resolution magnetic resonance imaging combined with other imaging techniques. DISCUSSION: BAD-study can provide demographic, clinical, radiological, and prognostic characteristics of BAD-related stroke, and thereby potentially figure out the vascular mechanism of early neurological deterioration and optimize therapy strategy with the aid of advanced imaging technique. Baseline data and evidence will also be generated for randomized controlled trials on BAD-related stroke in the future.

Surface-anchored tumor microenvironment-responsive protein nanogel-platelet system for cytosolic delivery of therapeutic protein in the post-surgical cancer treatment.

Nanoparticle-anchored platelet systems hold great potential to act as drug carriers in post-surgical cancer treatment due to their intrinsic ability to target the bleeding sites. However, rational design is still needed to further improve its cargo release profiles to meet the cytosolic delivery of therapeutic proteins with intracellular targets. Herein, we developed a tumor microenvironment (TME)-responsive backpack-conjugated platelet system to enhance intracellular protein delivery, thereby significantly inhibiting tumor recurrence after surgery. Specifically, protein nanogels encapsulating GALA and Granzyme B (GrB) are conjugated on the platelet surface via an acid-sensitive benzoic-imine linker through a biorthogonal reaction (GALA-GNGs-P). Taking advantage of wound-tropism of platelets, GALA-GNGs-P could actively accumulate at the surgical trauma and release nanogels in response to acidic TME for promoting deep penetration. Following cellular uptake, the pore-forming peptide GALA helps nanogels escape from lysosome. Subsequently, high glutathione (GSH) concentration in tumor cytoplasm facilitates GrB release from NGs, leading to intense cell apoptosis. GALA-GNGs-P shows remarkable tumor-targeting capability, high cellular uptake, and outstanding lysosomal escaping ability, which can significantly inhibit tumor recurrence in mice models with incomplete tumor resection. Our findings indicate that platelets bioengineered with TME-responsive protein nanogels provide an option to intracellularly deliver therapeutic proteins for the post-surgical treatment of cancer. STATEMENT OF SIGNIFICANCE: Platelet-based drug delivery systems (DDSs) have gained considerable achievements in post-surgical cancer treatment. However, there is no research exploring their potential in realizing the controllable release of cargoes in the acidic tumor microenvironment (TME). Herein, we developed a TME-responsive bioengineered platelet delivery platform (GALA-GNGs-P) for achieving controllable and effective protein intracellular delivery to overcome post-surgical tumor recurrence. Our surface-anchored nanogel-platelet system has the following advantages: (i) improving the loading efficiency of therapeutic proteins, (ii) affecting no physiological function of platelets, (iii) realizing on-demand cargo release in the acidic TME, and (iv) helping proteins escape from endosomal entrapment. Our findings further explored the prospect of cellular backpack system and realized the controllable release of cargoes in the acidic TME.

Stroke incidence and cognitive outcomes of intracranial atherosclerotic stenosis: study protocol for a multicenter, prospective, observational cohort study.

Background: Intracranial atherosclerotic stenosis (ICAS) is one of the leading causes of stroke worldwide. Current diagnostic evaluations and treatments remain insufficient to assess the vulnerability of intracranial plaques and reduce the recurrence of stroke in symptomatic ICAS. On the other hand, asymptomatic ICAS is associated with an increased risk of cognitive impairment. The pathogenesis of ICAS related cognitive decline is largely unknown. The aim of SICO-ICAS study (stroke incidence and cognitive outcomes of ICAS) is to elucidate the pathophysiology of stroke and cognitive impairment in ICAS population, comprehensively evaluating the complex interactions among life-course exposure, genomic variation, vascular risk factors, cerebrovascular burden and coexisting neurodegeneration. Methods: SICO-ICAS is a multicenter, prospective, observational cohort study. We aim to recruit 3,000 patients with symptomatic or asymptomatic ICAS (>50% or occlusion) who will be followed up for ≥12 months. All participants will undergo pre-designed magnetic resonance imaging packages, blood biomarkers testing, as well as detailed cognitive domains assessment. All participants will undergo clinical visits every 6 months and telephone interviews every 3 months. The primary outcome measurement is ischemic stroke or cognitive impairment within 12 months after enrollment. Discussion: This study will establish a large prospective ICAS cohort, hopefully discover new biomarkers associated with vulnerable intracranial plaques, identify subjects at high risk for incident ischemic stroke or cognitive impairment, and eventually propose a precise diagnostic and treatment strategy for ICAS population. Trial Registration: Chinese Clinical Trials Register ChiCTR2200061938.