LS301 Fluorescence-guided Photodynamic Therapy of brain cancer using PpIX photosensitizer

Incomplete brain tumor removal always causes neurologic deficit, disease recurrence and high mortality. Protoporphyrin IX (PpIX) accumulated in glioma cells with exogenous 5-aminolevulinic acid (5-ALA) serves as contrast agent for fluorescence-guided surgery and as well as acts as a photosensitizer for photodynamic therapy (PDT). However, the accurate tumor delineation using PpIX is limited by autofluorescence and superficial penetration depth. LS301 is a tumor-targeted near-infrared (NIR) contrast agent developed in our lab which allows deeper tumor imaging and avoids autofluorescence. My project aims to investigate whether LS301 can improve PpIX mediated PDT and tumor removal surgery. We have demonstrated co-localization of LS301 and PpIX in DBT and U87-MG glioma cell lines and are currently testing the effect of LS301 on PpIX mediated PDT in vitro. We will also compare LS301-PpIX with PpIX only PDT and tumor removal in mouse models of brain cancer. This study can potentially increase efficacy of PDT and fluorescence-guided brain tumor resection

Risk of depression, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis:a multinational network cohort study

Objectives: Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA.Methods: We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 &lt;40%.Results: A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis.Conclusion: HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation.Trial registration: Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.</p

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study

Background: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. Methods: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I2 value was less than 0·4. Findings: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12–2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22–3·95]), chest pain or angina (1·15 [1·05–1·26]), and hear

Research advances in sinusoidal obstruction syndrome

Sinusoidal obstruction syndrome (SOS) is a sinusoidal or small venous fibrous occlusive disease. This article reviews the research advances in the etiology, pathogenesis, clinical manifestations, auxiliary examinations, and treatment of SOS, and points out that the pathogenesis of SOS remains unknown and there are no specific therapeutic methods. How to identify SOS and provide intervention and treatment as early as possible becomes the hot research topic

Rockburst prediction and prevention in underground space excavation

The technical challenges associated with deep underground space activities have become increasingly significant. Among these challenges, one major concern is the assessment of rockburst risks and the instability of rock masses. Extensive research has been conducted by numerous scholars to mitigate the risks and prevent occurrences of rockburst through various assessment methods. Rockburst incidents commonly occur during the excavation of hard rock in underground environments, posing severe threats to personnel safety, equipment integrity, and operational continuity. Thus, it is crucial to systematically document real cases of rockburst, allowing for a comprehensive understanding of the underlying mechanisms and triggering conditions. This understanding will contribute to the advancement of rockburst prediction and prevention methods. Proper selection of an appropriate rockburst assessment method is a fundamental aspect in underground operations. However, there is a limited number of studies that summarize and compare different prediction and prevention methods of rockburst. This paper aims to address this gap by analyzing global trends using CiteSpace software since 1990. It discusses rockburst classification and characteristics, comprehensively reviews research findings related to rockburst prediction, including empirical, simulation, mathematical modeling, and microseismic monitoring methods. Additionally, the paper presents a compilation of current rockburst prevention measures. Notably, the paper emphasizes the significance of control strategies, which provide key insights into the effective utilization of stored energy within rock. Finally, the paper concludes by suggesting six directions for implementing intelligent management techniques to mitigate hazards during underground operations and reduce the probability of rockburst incidents

SCAMP2 Interacts with Arf6 and Phospholipase D1 and Links Their Function to Exocytotic Fusion Pore Formation in PC12 Cells

SNAP receptor (SNARE)-mediated fusion is regarded as a core event in exocytosis. Exocytosis is supported by other proteins that set up SNARE interactions between secretory vesicle and plasma membranes or facilitate fusion pore formation. Secretory carrier membrane proteins (SCAMPs) are candidate proteins for functioning in these events. In neuroendocrine PC12 cells, SCAMP2 colocalizes on the cell surface with three other proteins required for dense-core vesicle exocytosis: phospholipase D1 (PLD1), the small GTPase Arf6, and Arf6 guanine nucleotide exchange protein ARNO. Arf6 and PLD1 coimmunoprecipitate (coIP) with SCAMP2. These associations have been implicated in exocytosis by observing enhanced coIP of Arf6 with SCAMP2 after cell depolarization and in the presence of guanosine 5′-O-(3-thio)triphosphate and by inhibition of coIP by a SCAMP-derived peptide that inhibits exocytosis. The peptide also suppresses PLD activity associated with exocytosis. Using amperometry to analyze exocytosis, we show that expression of a point mutant of SCAMP2 that exhibits decreased association with Arf6 and of mutant Arf6 deficient in activating PLD1 have the same inhibitory effects on early events in membrane fusion. However, mutant SCAMP2 also uniquely inhibits fusion pore dilation. Thus, SCAMP2 couples Arf6-stimulated PLD activity to exocytosis and links this process to formation of fusion pores