A novel score to predict progression in anterior circulation single subcortical infarction patients.

OBJECTIVE: Progressive infarction (PI) has a negative effect on functional prognosis. Our study aimed to develop and validate a risk score for predicting PI in patients with anterior circulation single subcortical infarction (ACSSI). METHODS: Between January 2020 and October 2022, we retrospectively enrolled 638 eligible patients with ACSSI. Two-thirds of the eligible patients were randomly allocated to the training cohort (n = 425). Another resampling sample was formed through the bootstrap method and was used as the validation group (n = 425). Multivariate logistic regression analysis was used to identify the independent factors associated with PI. Each factor was then point assigned based on ß-coefficient and a risk scoring system was developed. This scoring system was internally validated through 1000-bootstrap resamplings. The C-statistic and Hosmer-Lemeshow test were used to assess model discrimination and calibration. RESULTS: PI occurred in 121 patients, accounting for 19.0% of the total patients. A 7-point NTS score system based on the initial NIHSS score, triglyceride-glucose index, and the number of infarct slices on axial diffusion-weighted imaging was developed. The NTS score showed good discrimination and calibration in the training cohort (C-statistic = 0.686; p value of Hosmer-Lemeshow test = 0.797) and validation cohort (C-statistic = 0.681; p value of Hosmer-Lemeshow test = 0.451). The three risk levels for predicting PI in the training and validation cohorts based on NTS score were as follows: low (0-2, 9.6% vs. 9.3%), intermediate (3-5, 28.2% vs. 26.7%), and high risk (6-7, 60.2% vs. 57.4%). INTERPRETATION: The NTS score is a valid and convenient risk score for predicting PI in ACSSI patients.

TG/HDL-c ratio as a predictor of progressive infarction in patients with anterior circulation single subcortical infarction.

BACKGROUND: The contributors predicting progressive infarction (PI) in patients with anterior circulation single subcortical infarction (ACSSI) and pontine single infarction (PSI) may be unidentical. The role of triglyceride to high-density lipoprotein cholesterol (TG/HDL-c) ratio on PI is unclear. The purpose of our study is to evaluate the correlation between TG/HDL-c ratio and PI in patients with ACSSI or PSI. METHODS: Between January 2020 and October 2022, we retrospectively enrolled 738 patients including 638 ACSSI patients and 100 PSI patients to analyze. Demographic characteristics, clinical information, and laboratory data were collected within 24 h of admission. RESULTS: PI occurred in 143 (19.4%) patients. In univariate analysis, patients with PI had higher initial National Institutes of Health Stroke Scale (NIHSS) scores, higher discharge NIHSS scores, higher levels of fasting glucose, total cholesterol, TG, low-density lipoprotein cholesterol, and TG/HDL-c ratio, but lower levels of creatinine compared to patients with non-PI (p < .05). Furthermore, the results of the subgroup analyses revealed the independent association between TG/HDL-c ratio and PI in ACSSI patients (OR 1.079, 95% CI 1.009-1.153, p = .026) rather than in PSI patients. Additionally, a receiver operating characteristic curve indicated that the optimal predictive cutoff value of the TG/HDL-c ratio was 3.985, and a TG/HDL-c ratio ≥3.985 was more likely to experience PI in ACSSI patients. CONCLUSION: In conclusion, the TG/HDL-c ratio was independently associated with PI in patients with ACSSI.

Activation of RIG-I/MDA5 Signaling and Inhibition of CD47-SIRPα Checkpoint with a Dual siRNA-Assembled Nanoadjuvant for Robust Cancer Immunotherapy.

Antigen-presenting cells (APCs) play a crucial role in the anti-tumor immunity as they are responsible for capturing, processing, and presenting tumor antigens to T cells. However, their activation is often limited by the absence of adjuvants and the suppressive effects of immune checkpoints, such as CD47-SIRPα. Herein, we present a nanoadjuvant that is self-assembled from long RNA building blocks generated through rolling circle transcription (RCT) reaction and further modified with cationic liposomes. Owing to the high load of densely packed RNA, this nanoadjuvant could robustly activate RIG-I/MDA5 signaling in APCs, leading to the maturation of dendritic cells (DCs) and the polarization of tumor-associated macrophages (TAMs) toward an anti-tumor M1-like phenotype. In addition, with a well-designed template, the generated long RNA from RCT reaction includes two kinds of siRNA targeting both CD47 in tumor cells and SIRPα in APCs. This dual gene silencing results in efficient inhibition of the CD47-SIRPα checkpoint. Collectively, the robust activation of RIG-I/MDA5 signaling and efficient inhibition of CD47-SIRPα checkpoint enhance the phagocytic activity of APCs, which in turn promotes the cross-priming of effector T cells and the activation of anti-tumor immune responses. This study therefore provides a simple and robust RNA nanoadjuvant for cancer immunotherapy.

Knockout of Rnf213 Ameliorates Cerebral Ischemic-reperfusion Injury by Inhibiting Neuronal Apoptosis Through the Akt/GSK-3ß/ß-catenin/Bcl-2 Pathway.

Previous studies by us and others have shown that RING finger protein 213 (RNF213) is associated with cerebrovascular disease and systemic vasculopathy. Indeed, Rnf213 mRNA expression is increased in cerebral ischemia reperfusion injury (CIRI). The purpose of the present study was to investigate the role of Rnf213 in CIRI. Using the middle cerebral artery occlusion (MCAO) model, we confirmed that the expression of RNF213 protein was significantly upregulated in neurons in the ischemic penumbra. Rnf213 knockout mice were successfully generated using CRISPR/Cas9 technology. According to TTC staining and Bederson neurological scale, removal of Rnf213 decreased brain infarct volume and improved neurological deficit score, although the restoration of cerebral blood flow after MCAO was similar in WT and Rnf213-/- mice. In addition, the levels of p-Akt, p-GSK-3ß, ß-catenin and Bcl-2 were significantly increased 24 h after MCAO in the ischemic penumbra of the Rnf213-/- mice compared to WT mice, indicating that Rnf213 removal may ameliorate neuronal apoptosis by regulating the Akt/GSK-3ß/ß-catenin/Bcl-2 signaling pathway. Taken together, our study reveals that Rnf213 regulates neuronal apoptosis in CIRI, therefore impacting on brain infarct volume in brain ischemia.

Tumor cell-induced platelet aggregation accelerates hematogenous metastasis of malignant melanoma by triggering macrophage recruitment.

BACKGROUND: Tumor cell-induced platelet aggregation (TCIPA) is not only a recognized mechanism for paraneoplastic thrombocytosis but also a potential breakthrough alternative for a low response to immune checkpoint inhibitors (ICIs) in hematogenous metastasis of malignant melanoma (MM). However, there is no TCIPA-specific model for further investigation of the relationship among TCIPA, the tumor immune microenvironment (TIME), and metastasis. METHODS: We developed a TCIPA metastatic melanoma model with advanced hematogenous metastasis and enhanced TCIPA characteristics. We also investigated the pathway for TCIPA in the TIME. RESULTS: We found that TCIPA triggers the recruitment of tumor-associated macrophages (TAMs) to lung metastases by secreting B16 cell-educated platelet-derived chemokines such as CCL2, SDF-1, and IL-1ß. Larger quantities of TAMs in the TCIPA model were polarized to the M2 type by B16 cell reprocessing, and their surface programmed cell death 1 ligand 1 (PD-L1) expression was upregulated, ultimately assisting B16 cells in escaping host immunity and accelerating MM hematogenous metastasis. CONCLUSIONS: TCIPA accelerates MM lung metastasis via tumor-educated platelets (TEPs), triggering TAM recruitment, promoting TAM polarization (M2), and remodeling the suppressive TIME in lung metastases.

Self-reported and self-facilitated theranostic oxygen nano-economizer for precise and hypoxia alleviation-potentiated photodynamic therapy.

Photodynamic therapy (PDT) has been extensively investigated for cancer treatment by virtue of singlet oxygen-induced oxidative damage to tumors. Nevertheless, the therapeutic efficiency of PDT is still limited by the low singlet oxygen yield attributed to the improper irradiation duration and the tumor hypoxic microenvironment. To tackle these challenges, we elaborately design a theranostic oxygen nano-economizer to self-report the optimal irradiation duration and alleviate tumor hypoxia simultaneously, which is engineered by fluorescent 9,10-anthracenyl bis (benzoic acid) (DPA)-MOF, tetrakis (4-carboxyphenyl) porphyrin (TCPP), triphenyl phosphine (TPP) and redox-responsive lipid-PEG (DSPE-SS-PEG2k). Upon laser irradiation, the fluorescence of DPA-MOF could be quenched, thereby self-reporting the optimal irradiation duration for sufficient PDT. The decoration of DSPE-SS-PEG2k and TPP endows the theranostic oxygen nano-economizer with a tumor-specific response and mitochondrial targeting capability, respectively. Notably, singlet oxygen generated from TCPP reduces oxygen consumption by disrupting the entire oxidative phosphorylation (OXPHOS) pathway in the mitochondria of tumor cells, further improving the level of singlet oxygen in a self-facilitated manner for hypoxia alleviation-potentiated PDT. As expected, such a self-reported and self-facilitated theranostic oxygen nano-economizer exhibits potent antitumor activity in the 4T1 tumor-bearing mouse model. This study offers a theranostic paradigm for precise and hypoxia alleviation-potentiated cancer therapy.

Dyslipidemia is associated with progressive infarction in anterior circulation single subcortical infarction patients.

BACKGROUND: The predictors of progressive infarction (PI) in patients with anterior circulation single subcortical infarction (ACSSI) and pontine single infarction (PSI) may be different. Our study aims to evaluate the association between various lipid markers and PI in patients with ACSSI or PSI. METHODS: A total of 629 patients (546 patients diagnosed as ACSSI and 83 patients diagnosed as PSI) were retrospectively enrolled between January 2020 and October 2022. Seven lipid markers including total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-c), low density lipoprotein cholesterol (LDL-c), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB) and lipoprotein(a) were collected within 24 h after admission. RESULTS: There were 119 patients with PI, accounting for 18.9% of the total. Univariate analysis showed that the levels of TC, TG, LDL-c, and ApoB in total patients with PI were higher than those in patients without PI (P < 0.05), while there were no significant differences in HDL-c, ApoA-I, and lipoprotein(a) (P > 0.05). In branch atheromatous disease patients, TC, TG, and ApoA-I were independently associated with PI after adjusting some confounding factors. Additionally, multivariate logistic regression analysis of the infarct location subgroup demonstrated TG and LDL-c were related to PI in patients with ACSSI (P < 0.05) but not in patients with PSI. Furthermore, receiver operating characteristic curves were established to compare the predictive abilities of TC, TG, LDL-c, and ApoB, and demonstrated TG was a better indicator to predict PI in ACSSI patients compared to other lipid markers. CONCLUSION: TG and LDL-c are associated with progressive infarction in patients with ACSSI, and TG was a superior predictor for PI compared to other lipid markers.

Ratiometric singlet oxygen self-detecting and oxygen self-supplying nanosensor for real-time photodynamic therapy feedback and therapeutic effect enhancement.

Integration of singlet oxygen (1O2) detection that provides necessary therapeutic feedback into nanotheranostics for hypoxic tumor photodynamic therapy (PDT) is desirable but still challenging. Herein, we report a nanosensor (denominated PAPD) by combining dual-channel ratiometric sensing and oxygen-augmenting strategies, which synergistically realizes real-time 1O2 self-detection, O2 self-supply and enhanced phototherapy. PAPD nanosensor is constructed by encapsulating anthracene-based 1O2 sensitive fluorophore (DPA) into porphyrin metal-organic frameworks (PCN-224), decorating gold nanoparticles (AuNPs) as nanoenzymes, and coating polyethylene glycol thiol (PEG-SH) by the Au-S bond. PCN-224 serves as 1O2 reference fluorescence (FL) agent and photosensitizer. Once PCN-224-induced 1O2 is synthesized, the dual-channel ratiometric FL signal of PAPD actualizes sensitive, accurate and dynamic 1O2 visualization and gives real-time therapeutic information correlated with the therapeutic progression. Additionally, the catalase-like activity of PAPD possesses in situ O2 production via intracellular H2O2 decomposition and accelerates 1O2 yields for amplifying the tumor cell killing efficiency. Moreover, the ratiometric 1O2 self-detection affords the capacity to evaluate the O2 self-supplying effect in tumor 4T1 cells. Consequently, the rational-designed nanosensor PAPD provides a paradigm for real-time therapeutic evaluation and precise hypoxic tumor treatment clinically.

Single-atom engineering of hemicyanine and its amphiphilic derivative for optimized near infrared phototheranostics.

Near-infrared (NIR) dyes are widely used in the field of in vivo phototheranostics. Hemicyanine dyes (HDs) have recently received tremendous attention due to their easy synthesis and excellent NIR features. However, HDs can easily form non-fluorescent aggregates and their potential for phototherapy still needs further exploration due to their poor ability to generate reactive oxygen species (ROS). Herein, a series of hemicyanine dyes with different chalcogen atom (O, S, Se) substitutions were constructed to achieve optimized potential for phototheranostics. By replacing O with the heavy atom Se in the xanthene skeleton, CySe-NEt2 showed much more favourable features such as extended NIR absorption/emission wavelength, boosted 1O2 generation rate and higher photothermal effect. In addition, a poly(ethylene glycol) (PEG) group was introduced into the scaffold and yielded a nanotheranostic agent CySe-mPEG5K, which easily formed nanoparticles with appealing features such as excellent photostability, effective prevention of unpleasant H-aggregation, fast/selective tumor accumulation and minimum dark toxicity. Solid tumor growth was significantly suppressed through combined photodynamic therapy (PDT) and photothermal therapy (PTT) guided by NIR fluorescence (NIRF) and photoacoustic (PA) imaging. This study not only presents the first example of selenium-substituted hemicyanine dyes, but also offers a reliable design strategy for the development of potent NIR phototheranostic agents with multi-mode imaging-guided combination therapeutic ability.

Manipulating the Subcellular Localization and Anticancer Effects of Benzophenothiaziniums by Minor Alterations of N-Alkylation.

Cationic, water-soluble benzophenothiaziniums have been recognized as effective type I photosensitizers (PSs) against hypoxic tumor cells. However, the study of the structure-property relationship of this type of PS is still worth further exploration to achieve optimized photodynamic effects and minimize the potential side effects. Herein, we synthesized a series of benzophenothiazine derivatives with minor N-alkyl alteration to study the effects on the structure-property relationships. The cellular uptake, subcellular organelle localization, reactive oxygen species (ROS) generation, and photocytotoxicity performances were systematically investigated. NH2NBS and EtNBS specifically localized in lysosomes and exhibited high toxicity under light with a moderate phototoxicity index (PI) due to the undesirable dark toxicity. However, NMe2NBS with two methyl substitutions accumulated more in mitochondria and displayed an excellent PI value with moderate light toxicity and negligible dark toxicity. Without light irradiation, NH2NBS and EtNBS could induce lysosomal membrane permeabilization (LMP), while NMe2NBS showed no obvious damage to lysosomes. After irradiation, NH2NBS and EtNBS were released from lysosomes and relocated into mitochondria. All compounds could induce mitochondria membrane potential (MMP) loss and nicotinamide adenine dinucleotide phosphate (NADPH) consumption under light to cause cell death. NMe2NBS exhibited remarkable in vivo photodynamic therapy (PDT) efficacy in a xenograft mouse tumor (inhibition rate, 89%) with no obvious side effects. This work provides a valuable methodology to investigate the structure-property relationships of benzophenothiazine dyes, which is of great importance in the practical application of PDT against hypoxia tumor cells.

Preparation of ß-CD-Vitexin Microspheres and their Effects on SW480 Cell Proliferation.

OBJECTIVE: In order to overcome the insolution and low bioavailability of the vitexin in vivo, ß-cyclodextrin-vitexin (ß-CD-vitexin) microspheres were prepared, and their effects on the proliferation of SW480 cells were observed. METHODS: Scanning electron microscopy, ultraviolet spectrum, Fourier transform infrared spectroscopy, and release rate analysis identified the formation of ß-CD-vitexin microspheres. MTT assay detected the effect of ß-CD-vitexin microspheres on tumor cell proliferation at 6, 12, 24, and 48 h. Fluorescence microscopy and flow cytometry were used to observe the effect of ß-CD-vitexin microspheres on the apoptosis of SW480 cells. The mRNA expression of the p53 gene was measured by qPCR. RESULTS: ß-CD-vitexin microspheres were successfully prepared. SW480 cell proliferation was inhibited by 0.1, 0.2, and 0.4 mg/mL of ß-CD-vitexin microspheres in a dose- and time-dependent manner, and the mechanism of proliferation inhibition was related to cell apoptosis caused by the upregulated expression of p53 gene. CONCLUSION: The preparation of ß-CD-vitexin sustained release microspheres is feasible, and ß-CDvitexin microspheres have potential anti-colorectal cancer value.

PLN: Parasitic-Like Network for Barely Supervised Medical Image Segmentation.

It is known that annotations for 3D medical image segmentation tasks are laborious, time-consuming and expensive. Considering the similarities existing in inter-slice and inter-volume, we believe that the delineation way and the model architecture should be tightly coupled. In this paper, by introducing an extremely sparse annotation way of labeling only one slice per 3D image, we investigate a novel barely-supervised segmentation setting with only a few sparsely-labeled images along with a large amount of unlabeled images. To achieve this goal, we present a new parasitic-like network including a registration module (as host) and a semi-supervised segmentation module (as parasite) to deal with inter-slice label propagation and inter-volume segmentation prediction, respectively. Specifically, our parasitism mechanism effectively achieves the collaboration of these two modules through three stages of infection, development and eclosion, providing accurate pseudo-labels for training. Extensive results demonstrate that our framework is capable of achieving high performance on extremely sparse annotation tasks, e.g., we achieve Dice of 84.83% on LA dataset with only 16 labeled slices. The code is available athttps://github.com/ShumengLI/PLN.

Fasting blood glucose as a predictor of progressive infarction in men with acute ischemic stroke.

OBJECTIVE: Blood glucose is related to early neurological deterioration in acute ischemic stroke, but multiple mechanisms are involved in early neurological deterioration, such as progressive infarction. This study aimed to determine whether fasting blood glucose (FBG) is an independent predictor of progressive infarction. METHODS: From April 2017 to December 2020, we retrospectively enrolled 477 patients with acute ischemic stroke within 48 hours of onset. Demographic characteristics, clinical information, neuroimaging characteristics, and laboratory data were collected after admission. RESULTS: We found that 147 (30.8%) patients had progressive infarction. Multiple regression analysis showed that high FBG concentrations (>7.66 mmol/L) were independently associated with progressive infarction. Sex subgroup analysis showed that high FBG concentrations were an independent predictor of progressive infarction in male patients (odds ratio, 2.559; 95% confidence interval, 1.279-5.121). In a receiver operating characteristic curve analysis, FBG concentrations were a predictor of progressive infarction in all cases, especially in male patients. The cutoff value of FBG in all patients and men was 7.155 mmol/L. CONCLUSIONS: FBG is an independent predictor of progressive infarction in patients with acute ischemic stroke within 48 hours of onset, especially in men. Patients with FBG concentrations ≥7.155 mmol/L are more likely to develop progressive infarction.

A lesion extending three or more slices as a predictor of progressive infarction in anterior circulation small subcortical infarction.

Progressive infarction (PI) is common in small subcortical infarction and may lead to a poor outcome. The purpose of our study is to identify neuroimaging predictors for PI. From April 2017 to December 2020, we enrolled 86 patients with an anterior circulation subcortical infarction within 48 h after onset. Progressive infarction was defined by an increase of ≥ one point in motor power or ≥ two points in the total National Institute of Health Stroke Scale score within 7 days after admission and further confirmed by diffusion-weighted imaging (DWI). To identify predictors, demographic characteristics, clinical information, laboratory date, and neuroimaging characteristics were evaluated. The infarct size and infarct slice number were measured by DWI. We found that thirty-one patients (36%) had PI. In a univariate analysis, the patients with PI had higher levels of triglyceride, lower levels of blood urea nitrogen and prothrombin time, and a higher frequency of infarct slice number ≥ three compared to the patients without PI. After logistic regression stepwise adjustment for all considered relevant confounders, infarct slice number ≥ three slices proved to be independently associated with PI (OR = 4.781, 95% CI 1.677-13.627; OR = 4.867, 95% CI 1.6-14.864; OR = 3.584, 95% CI 1.034-12.420). Our study showed that a lesion extending ≥ three slices on DWI is an independent predictor for progressive infarction in patients with anterior circulation small subcortical infarction.

Juvenile-onset PSAT1-related neuropathy: A milder phenotype of serine deficiency disorder.

Background: Primary serine deficiency disorders have a broad range of the phenotypic spectrum. As an inborn error of metabolism, individuals with severe phenotype may be easily recognized with Neu-Laxova syndrome. However, late-onset mild phenotypes may be underdiagnosed and will lead to disastrous consequences due to treatment delays. Materials and Methods: Clinical features of patients with serine deficiency disorders were summarized in two unrelated patients. Skin and sural nerve biopsies were conducted on the patients. Whole exome sequencing (WES) was performed in the index patients. Sanger sequencing was used to analyze family cosegregation. Results: Patient 1 was a 19-year-old male presenting with infancy-onset ichthyosis and juvenile-onset neuropathy. Patient 2 was a 17-year-old male manifesting childhood-onset ichthyosis and juvenile-onset neuropathy. Except for nystagmus, no other developmental or neurodegenerative disorders were found in the patients. Electrophysiological studies indicated a severe sensorimotor axonal neuropathy with a possible demyelinating component. High-dose oral L-serine and glycine completely alleviated skin lesions and only slightly improved neuropathy symptoms. Skin biopsies showed typical features consistent with ichthyosis and severe loss of unmyelinated axons. Sural biopsies revealed a severe loss of axons and a few thinly myelinated fibers. WES found the same homozygous variant c.43G > C (p.A15P) in the PSAT1 gene, which was cosegregated in the two families. Conclusions: The skin and nervous system may be the main affected targets in serine deficiency disorders. Our patients show a more simple and mild phenotype of PSAT1-related serine deficiency disorder. The pathological changes and regenerative ability of skin and peripheral nerves determine their response to serine supplements.

An Endoplasmic Reticulum Targeting Type I Photosensitizer for Effective Photodynamic Therapy against Hypoxic Tumor Cells.

Organelle-targeted type I photodynamic therapy (PDT) shows great potential to overcome the hypoxic microenvironment in solid tumors. The endoplasmic reticulum (ER) is an indispensable organelle in cells with important biological functions. When the ER is damaged due to the production of reactive oxygen species (ROS), the accumulation of misfolded proteins will interfere with ER homeostasis, resulting in ER stress. Here, an ER-targeted benzophenothiazine-based photosensitizer NBS-ER was presented. ER targeting modification significantly reduced the dark toxicity and improved phototoxicity index (PI). NBS-ER could effectively produce O2 - ⋅ with near-infrared irradiation, making its phototoxicity under hypoxia close to that under normoxia. Meanwhile, the photoinduced ROS triggered ER stress and induced apoptosis. In addition, NBS-ER possessed excellent photodynamic therapeutic effect in 4T1-tumor-bearing mice.

A ratiometric pH probe for acidification tracking in dysfunctional mitochondria and tumour tissue in vivo.

Cellular dysregulated pH and mitochondrial metabolism are commonly two central factors for solid tumour progression. pH regulation and long-term mitochondrial tracking provide a great opportunity for tumour treatment. pH probes with suitable pKa and satisfactory mitochondria-immobilizing character are demanded for tumour recognition and therapy. Here, we report a ratiometric fluorescent probe, CouDa, for pH imaging in mitochondria and tumour tissue. CouDa displays an obvious blue-shifted emission (about 160 nm) in alkaline environment, with a pKa around 7.4 suitable for monitoring mitochondrial pH change. NMR and MS data confirmed an addition reaction mechanism of OH- upon the positively charged conjugated structure of hemicyanine fluorophore. Mitochondrial immobilization and acidification monitoring were realized by CouDa in cells treated with a mitochondrial uncoupler. Moreover, CouDa could distinguish acidified tumour tissue in living mice. Comparing with its analogue, the pH-sensitivity and mitochondria-immobilizing property are attributed to a hydrophobic long alkyl chain on indolium N atom. This work provides an effective strategy to track nucleophilic substances in dysfunctional mitochondria.

Recent advances in noble metal complex based photodynamic therapy.

Photodynamic therapy (PDT) utilizes light-activated photosensitizers (PSs) to generate toxic species for therapeutics. It has become an emerging solution for cancer treatment because of its specific spatiotemporal selectivity and minimal invasiveness. Noble metal (Ru, Ir and Pt) complexes are of increasing interest as photosensitizers for their excellent photophysical, photochemical, and photobiological properties. In this review, we highlight recent advancements in the development of noble metal complex photosensitizers for PDT during the last 5 years. We will summarize the design strategies of noble metal complexes for efficient and precise PDT, including increasing the light penetration depth, reducing the oxygen-dependent nature and improving target ability. Finally, we summarize recent efforts for the development of noble-based PSs and discuss the limitations of such PSs in clinical application and future perspectives in this field, such as the combination of PDT with other treatment modalities.

Pathological changes of the sural nerve in patients with familial episodic pain syndrome.

BACKGROUND: Familial episodic pain syndrome type 3 (FEPS3) is an inherited disorder characterized by the early-childhood onset of severe episodic pain that primarily affects the distal extremities. As skin biopsy has revealed a reduction in intraepidermal nerve fiber density and degeneration of the unmyelinated axons, it remains unclear whether FEPS3 patients have pathological changes in the peripheral nerve. METHODS: The clinical features of patients with FEPS3 were summarized in a large autosomal dominant family. Sural nerve biopsies were conducted in two patients. Whole exome sequencing (WES) was performed in the index patient. Sanger sequencing was used to analyze family co-segregation. RESULTS: Fourteen members exhibited typical and uniform clinical phenotypes characterized by length-dependent and age-dependent severe episodic pain affecting the distal extremities, which can be relieved with anti-inflammatory medicine. The WES revealed a heterozygous mutation c.665G > A (p.R222H) in the SCN11A gene, which was co-segregated with the clinical phenotype in this family. A sural biopsy in patient V:1, who was experiencing episodic pain at 16 years old, showed normal structure, while the sural nerve in patient IV:1, whose pain attack had completely diminished at 42 years old, displayed a decrease of the density of unmyelinated axons with the axonal degeneration. CONCLUSIONS: The clinical phenotype of FEPS3 showed distinctive characteristics that likely arise from dysfunctional nociceptive neurons that lack detectable pathological alterations in the nerve fibers. Nevertheless, long-term dysfunction of the Nav1.9 channel may cause degeneration of the unmyelinated fibers in FEPS3 patient with pain remission.

Lymphocyte-to-Monocyte Ratio Is Independently Associated with Progressive Infarction in Patients with Acute Ischemic Stroke.

Methods: From April 2017 to December 2020, we retrospectively recruited 477 patients with acute ischemic stroke (within 48 hours after onset). Progressive infarction was defined as an increase of ≥1 point in motor power or ≥2 points on the total National Institutes of Health Stroke Scale (NIHSS) within 7 days after admission and extension of the original infarction were further confirmed by diffusion-weighted imaging. Demographic characteristics, clinical information, and neuroimaging characteristics were evaluated after admission. All blood draws and initial imaging were completed within 24 hours of admission. Results: PI occurred in 147 (30.8%) patients. Univariate analysis comparing the two groups revealed that hypertension, initial NIHSS score, discharge NIHSS score, modified Rankin scale score at 90 days, monocyte level, creatinine level, fasting glucose level, LMR, monocyte-to-high-density lipoprotein ratio (MHR), and lesion location were significantly different (P < 0.05). Multivariate logistic regression analysis showed that the odds ratio of PI increased as the quartile of LMR increased, with the lowest quartile as the reference value. Subgroup analyses showed that a high LMR was an independent predictor of PI only in large artery atherosclerosis (LAA) patients. The receiver operating characteristic (ROC) curve was drawn to estimate the predictive value of LMR for PI. For all cases, the area under the curve was 0.583 (95% CI 0.526-0.641), and the best predictive cutoff value was 3.506, with a sensitivity of 53.1% and a specificity of 63.9%. In patients with LAA, the area under the curve was 0.585 (95% CI 0.505-0.665), and the best predictive cutoff value was 3.944, with a sensitivity of 48.7% and a specificity of 72.8%. Conclusions: LMR was an independent predictor for progressive infarction in patients with acute ischemic stroke, especially in LAA cerebral infarction patients.