High-Entropy Transition Metal Phosphorus Trichalcogenides for Rapid Sodium Ion Diffusion.

High-entropy strategies are regarded as a powerful means to enhance performance in energy storage fields. The improved properties are invariably ascribed to entropy stabilization or synergistic cocktail effect. Therefore, the manifested properties in such multicomponent materials are usually unpredictable. Elucidating the precise correlations between atomic structures and properties remains a challenge in high-entropy materials (HEMs). Herein, atomic-resolution scanning transmission electron microscopy annular dark field (STEM-ADF) imaging and four dimensions (4D)-STEM are combined to directly visualize atomic-scale structural and electric information in high-entropy FeMnNiVZnPS3. Aperiodic stacking is found in FeMnNiVZnPS3 accompanied by high-density strain soliton boundaries (SSBs). Theoretical calculation suggests that the formation of such structures is attributed to the imbalanced stress of distinct metal-sulfur bonds in FeMnNiVZnPS3. Interestingly, the electric field concentrates along the two sides of SSBs and gradually diminishes toward the two-dimensional (2D) plane to generate a unique electric field gradient, strongly promoting the ion-diffusion rate. Accordingly, high-entropy FeMnNiVZnPS3 demonstrates superior ion-diffusion coefficients of 10-9.7-10-8.3 cm2 s-1 and high-rate performance (311.5 mAh g-1 at 30 A g-1). This work provides an alternative way for the atomic-scale understanding and design of sophisticated HEMs, paving the way for property engineering in multi-component materials.

Simultaneous determination of folic acid photolysis products and oxidized guanine derivatives in plasma by liquid chromatography-tandem mass spectrometry.

Folic acid (FA) is easily photodegraded to yield 6-formylpterin and pterin-6-carboxylic acid, which can generate reactive oxygen species and result in the formation of oxidized guanine derivatives such as 8-hydroxy-2'-deoxyguanosine and 8-hydroxy-guanosine. In this study, we developed a simple, rapid, and sensitive liquid chromatography-tandem mass spectrometry strategy for the simultaneous determination of FA photolysis products and oxidized guanine derivatives in plasma samples. Chromatographic separation was performed on a Waters HSS T3 column (2.1 × 100 mm, 5.0 µm) with gradient elution at a flow rate of 0.25 mL/min. Plasma samples were first pretreated with 1% formic acid, followed by protein precipitation with methanol. The developed method showed good linear relationships between 1 and 2000 ng/mL (r2 > 0.99). The intra- and inter-day precisions ranged from 2.6% to 7.5% and from 2.5% to 6.5%, respectively. Recoveries of the analytes were between 75.4% and 112.4% with the relative standard deviation < 9.1%. Finally, the method was applied to quantify FA photolysis products and oxidized guanine derivatives in rats with light and non-light conditions.

Phase and Composition Engineering of Self-Intercalated 2D Metallic Tantalum Sulfide for Second-Harmonic Generation.

Self-intercalation in two-dimensional (2D) materials is significant, as it offers a versatile approach to modify material properties, enabling the creation of interesting functional materials, which is essential in advancing applications across various fields. Here, we define ic-2D materials as covalently bonded compounds that result from the self-intercalation of a metal into layered 2D compounds. However, precisely growing ic-2D materials with controllable phases and self-intercalation concentrations to fully exploit the applications in the ic-2D family remains a great challenge. Herein, we demonstrated the controlled synthesis of self-intercalated H-phase and T-phase Ta1+xS2 via a temperature-driven chemical vapor deposition (CVD) approach with a viable intercalation concentration spanning from 10% to 58%. Atomic-resolution scanning transmission electron microscopy-annular dark field imaging demonstrated that the self-intercalated Ta atoms occupy the octahedral vacancies located at the van der Waals gap. The nonperiodic Ta atoms break the centrosymmetry structure and Fermi surface properties of intrinsic TaS2. Therefore, ic-2D T-phase Ta1+xS2 consistently exhibit a spontaneous nonlinear optical (NLO) effect regardless of the sample thickness and self-intercalation concentrations. Our results propose an approach to activate the NLO response of centrosymmetric 2D materials, achieving the modulation of a wide range of optoelectronic properties via nonperiodic self-intercalation in the ic-2D family.

Atomically Unraveling Highly Crystalline Self-Intercalated Tantalum Sulfide with Correlated Stacking Registry-Dependent Magnetism.

In self-intercalated two-dimensional (ic-2D) materials, understanding the local chemical environment and the topology of the filling site remains elusive, and the subsequent correlation with the macroscopically manifested physical properties has rarely been investigated. Herein, highly crystalline gram-scale ic-2D Ta1.33S2 crystals were successfully grown by the high-pressure high-temperature method. Employing combined atomic-resolution scanning transmission electron microscopy annular dark field imaging and density functional theory calculations, we systematically unveiled the atomic structures of an atlas of stacking registries in a well-defined √3(a) × âˆš3(a) Ta1.33S2 superlattice. Ferromagnetic order was observed in the AC' stacking registry, and it evolves into an antiferromagnetic state in AA/AB/AB' stacking registries; the AA' stacking registry shows ferrimagnetic ordering. Therefore, we present a novel approach for fabricating large-scale highly crystalline ic-2D crystals and shed light on a powerful means of modulating the magnetic order of ic-2D systems via stacking engineering, i.e., stackingtronics.

CCL2 Potentiates Inflammation Pain and Related Anxiety-Like Behavior Through NMDA Signaling in Anterior Cingulate Cortex.

Previous studies have shown that the C-C motif chemokine ligand 2 (CCL2) is widely expressed in the nervous system and involved in regulating the development of chronic pain and related anxiety-like behaviors, but its precise mechanism is still unclear. This paper provides an in-depth examination of the involvement of CCL2-CCR2 signaling in the anterior cingulate cortex (ACC) in intraplantar injection of complete Freund's adjuvant (CFA) leading to inflammatory pain and its concomitant anxiety-like behaviors by modulation of glutamatergic N-methyl-D-aspartate receptor (NMDAR). Our findings suggest that local bilateral injection of CCR2 antagonist in the ACC inhibits CFA-induced inflammatory pain and anxiety-like behavior. Meanwhile, the expression of CCR2 and CCL2 was significantly increased in ACC after 14 days of intraplantar injection of CFA, and CCR2 was mainly expressed in excitatory neurons. Whole-cell patch-clamp recordings showed that the CCR2 inhibitor RS504393 reduced the frequency of miniature excitatory postsynaptic currents (mEPSC) in ACC, and CCL2 was involved in the regulation of NMDAR-induced current in ACC neurons in the pathological state. In addition, local injection of the NR2B inhibitor of NMDAR subunits, Ro 25-6981, attenuated the effects of CCL2-induced hyperalgesia and anxiety-like behavior in the ACC. In summary, CCL2 acts on CCR2 in ACC excitatory neurons and participates in the regulation of CFA-induced pain and related anxiety-like behaviors through upregulation of NR2B. CCR2 in the ACC neuron may be a potential target for the treatment of chronic inflammatory pain and pain-related anxiety.

Application of FGD-BCEL loss function in segmenting temporal lobes on localized CT images for radiotherapy.

Objectives: The aim of this study was to find a new loss function to automatically segment temporal lobes on localized CT images for radiotherapy with more accuracy and a solution to dealing with the classification of class-imbalanced samples in temporal lobe segmentation. Methods: Localized CT images for radiotherapy of 70 patients with nasopharyngeal carcinoma were selected. Radiation oncologists sketched mask maps. The dataset was randomly divided into the training set (n = 49), the validation set (n = 7), and the test set (n = 14). The training set was expanded by rotation, flipping, zooming, and shearing, and the models were evaluated using Dice similarity coefficient (DSC), Jaccard similarity coefficient (JSC), positive predictive value (PPV), sensitivity (SE), and Hausdorff distance (HD). This study presented an improved loss function, focal generalized Dice-binary cross-entropy loss (FGD-BCEL), and compared it with four other loss functions, Dice loss (DL), generalized Dice loss (GDL), Tversky loss (TL), and focal Tversky loss (FTL), using the U-Net model framework. Results: With the U-Net model based on FGD-BCEL, the DSC, JSC, PPV, SE, and HD were 0.87 ± 0.11, 0.78 ± 0.11, 0.90 ± 0.10, 0.87 ± 0.13, and 4.11 ± 0.75, respectively. Except for the SE, all the other evaluation metric values of the temporal lobes segmented by the FGD-BCEL-based U-Net model were improved compared to the DL, GDL, TL, and FTL loss function-based U-Net models. Moreover, the FGD-BCEL-based U-Net model was morphologically more similar to the mask maps. The over- and under-segmentation was lessened, and it effectively segmented the tiny structures in the upper and lower poles of the temporal lobe with a limited number of samples. Conclusions: For the segmentation of the temporal lobe on localized CT images for radiotherapy, the U-Net model based on the FGD-BCEL can meet the basic clinical requirements and effectively reduce the over- and under-segmentation compared with the U-Net models based on the other four loss functions. However, there still exists some over- and under-segmentation in the results, and further improvement is needed.

Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons.

The C-C motif chemokine ligand 2 (CCL2) has been implicated in chronic pain, but its exact mechanism of peripheral sensitization is unknown. In this study, we aimed to clarify the mechanism of CCL2 regulation of ion channels. Our behavioral experiments revealed that ZD7288, a blocker of Ih current, can inhibit CFA and CCL2-mediated mechanical and thermal nociceptive sensitization. Furthermore, patch clamp studies demonstrated that CFA-induced peripheral sensitization primarily affects the excitability of small-diameter DRG neurons. Further studies revealed that inflammatory pain caused by CFA or incubation of DRG with CCL2 mainly affected Ih currents in small-diameter DRG neurons, which were blocked by co-incubation CCR2 antagonist INCB3344 or adenylate cyclase inhibitor SQ22536. Immunohistochemical staining showed that both intraplantar injection of CFA as well as DRG injection of CCL2 resulted in significant upregulation of CCR2+/HCN2+ expression. In conclusion, we suggest in the inflammatory pain state, CCL2 can act on small-diameter DRG neurons, leading to upregulation of HCN2 expression and consequently Ih, which in turn leads to neuronal hyperexcitability.

New insights into the suppression of inflammation and lipid accumulation by JAZF1.

Atherosclerosis is one of the leading causes of disease and death worldwide. The identification of new therapeutic targets and agents is critical. JAZF1 is expressed in many tissues and is found at particularly high levels in adipose tissue (AT). JAZF1 suppresses inflammation (including IL-1ß, IL-4, IL-6, IL-8, IL-10, TNFα, IFN-γ, IAR-20, COL3A1, laminin, and MCP-1) by reducing NF-κB pathway activation and AT immune cell infiltration. JAZF1 reduces lipid accumulation by regulating the liver X receptor response element (LXRE) of the SREBP-1c promoter, the cAMP-response element (CRE) of HMGCR, and the TR4 axis. LXRE and CRE sites are present in many cytokine and lipid metabolism gene promoters, which suggests that JAZF1 regulates these genes through these sites. NF-κB is the center of the JAZF1-mediated inhibition of the inflammatory response. JAZF1 suppresses NF-κB expression by suppressing TAK1 expression. Interestingly, TAK1 inhibition also decreases lipid accumulation. A dual-targeting strategy of NF-κB and TAK1 could inhibit both inflammation and lipid accumulation. Dual-target compounds (including prodrugs) 1-5 exhibit nanomolar inhibition by targeting NF-κB and TAK1, EGFR, or COX-2. However, the NF-κB suppressing activity of these compounds is relatively low (IC50 > 300 nM). Compounds 6-14 suppress NF-κB expression with IC50 values ranging from 1.8 nM to 38.6 nM. HS-276 is a highly selective, orally bioavailable TAK1 inhibitor. Combined structural modifications of compounds using a prodrug strategy may enhance NF-κB inhibition. This review focused on the role and mechanism of JAZF1 in inflammation and lipid accumulation for the identification of new anti-atherosclerotic targets.

Self-assembly of Au@AgNR along M13 framework: A SERS nanocarrier for bacterial detection and killing.

Self-assembled functional nanomaterials with electromagnetic hot spots are crucial and highly desirable in surface-enhanced Raman scattering (SERS). Due to its versatile biological scaffold, the M13 phage has been employed to produce novel nano-building blocks and devices. In this study, we propose a novel M13 phage-based SERS nanocarrier, that utilizes the pVIII capsid in M13 to conjugate Au@Ag core-shell nanorod (Au@AgNR) with linker carboxy-PEG-thiol (M13-Au@AgNR) and the pIII capsid to specifically target Escherichia coli (E. coli). The M13-Au@AgNR@DTTC (3,3'- diethylthiocarbocyanine iodide) SERS probe was used to detect E. coli in a concentration range of 6 to 6 × 105 cfu/mL, achieving a limit of detection (LOD) of 0.5 cfu/mL. The proposed SERS platform was also tested in real samples, showing good recoveries (92%-114.3%) and a relative standard deviation (RSD) of 1.2%-4.7%. Furthermore, the system demonstrated high antibacterial efficiency against E. coli, approximately 90%, as measured by the standard plate-count method. The investigation provides an effective strategy for in vitro bacteria detection and inactivation.

The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis.

Cholesterol levels are an initiating risk factor for atherosclerosis. Many genes play a central role in cholesterol synthesis, including HMGCR, SQLE, HMGCS1, FDFT1, LSS, MVK, PMK, MVD, FDPS, CYP51, TM7SF2, LBR, MSMO1, NSDHL, HSD17B7, DHCR24, EBP, SC5D, DHCR7, IDI1/2. Especially, HMGCR, SQLE, FDFT1, LSS, FDPS, CYP51, and EBP are promising therapeutic targets for drug development due to many drugs have been approved and entered into clinical research by targeting these genes. However, new targets and drugs still need to be discovered. Interestingly, many small nucleic acid drugs and vaccines were approved for the market, including Inclisiran, Patisiran, Inotersen, Givosiran, Lumasiran, Nusinersen, Volanesorsen, Eteplirsen, Golodirsen, Viltolarsen, Casimersen, Elasomeran, Tozinameran. However, these agents are all linear RNA agents. Circular RNAs (circRNAs) may have longer half-lives, higher stability, lower immunogenicity, lower production costs, and higher delivery efficiency than these agents due to their covalently closed structures. CircRNA agents are developed by several companies, including Orna Therapeutics, Laronde, and CirCode, Therorna. Many studies have shown that circRNAs regulate cholesterol synthesis by regulating HMGCR, SQLE, HMGCS1, ACS, YWHAG, PTEN, DHCR24, SREBP-2, and PMK expression. MiRNAs are essential for circRNA-mediated cholesterol biosynthesis. Notable, the phase II trial for inhibiting miR-122 with nucleic acid drugs has been completed. Suppressing HMGCR, SQLE, and miR-122 with circRNA_ABCA1, circ-PRKCH, circEZH2, circRNA-SCAP, and circFOXO3 are the promising therapeutic target for drug development, specifically the circFOXO3. This review focuses on the role and mechanism of the circRNA/miRNA axis in cholesterol synthesis in the hope of providing knowledge to identify new targets.

Quantitative analysis with multiphase contrast-enhanced computed tomography to evaluate residual tumor activity of hepatocellular carcinoma after DEB-TACE.

Most hepatocellular carcinomas (HCC) treated by transcatheter arterial chemoembolization with drug-eluting beads (DEB-TACE) are characterized by coagulation necrosis; therefore, it is often difficult to distinguish enhancement in the arterial phase that would lead to false negative evaluation. This study aimed to evaluate the specificity and sensitivity of the difference value of multiphase contrast-enhanced computed tomography (CECT) in predicting residual tumor activity in HCC lesions after DEB-TACE. This retrospective diagnostic study analyzed CECT images of 73 HCC lesions in 57 patients 20 to 40 days (average 28 days) after DEB-TACE treatment at our Hospital from January to December 2019. Postoperative pathology or digital subtraction angiography images were used as references. Residual tumor activity after the first intervention was determined based on the presence of tumor staining in digital subtraction angiography or the postoperative pathological discovery of HCC tumor cells. A significant difference was observed between the active and inactive residual groups in ∆ HU difference between CT values of arterial phase and non-contrast scans (AN, P = .000), difference between CT values of venous phase and non-contrast scans (VN, P = .000), difference between CT values of delay phase and non-contrast scans (DN, P = .000), (difference between CT values of venous and arterial phase scans, P = .001), and (difference between CT values of delay and arterial phase scans, P = .005). No statistically significant difference was observed between the delayed and venous phases (difference between CT values of delay and venous phase scans, P = .361). The area under the curve (AUC) of the ROC curve showed that the diagnostic efficacies in difference in CT value of AN (AUC = 0.976), VN (AUC = 0.927), and DN (AUC = 0.924) were higher, and their cutoff values were 4.86, 12.065, 20.19 HU with their sensitivities of 93.3%, 84.4%, 77.8% and specificities of 100%, 96.4%, and 100%, respectively. difference in CT value values of AN, VN, DN, difference between CT values of venous and arterial phase scans and difference between CT values of delay and arterial phase scans can sensitively detect residual tumor activity 20-40 days after DEB-TACE. Thus, more sensitive active residual foci were detected using all 3 enhanced phases rather than only the arterial phase. Quantitative analysis of multiphase CECT can detect residual tumor activity in an early and noninvasive manner, which can provide time for patients to receive early follow-up treatment.

Peripheral BDNF Regulates Somatosensory-Sympathetic Coupling in Brachial Plexus Avulsion-Induced Neuropathic Pain.

Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation.

The correlation of serum musclin with diabetic nephropathy.

OBJECTIVE: Musclin is a recently found myokine involved in the process of glucose metabolism. The purpose of the present investigation is to evaluate the relationship between serum musclin levels and diabetic nephropathy (DN). METHODS: The current investigation included 175 (T2DM) cases and 62 controls. T2DM patients were divided into three subgroups: normoalbuminuria (DN0), microalbuminuria (DN1), and macroalbuminuria (DN2) on the basis of the values of urine albumin to creatinine ratio (ACR). RESULTS: T2DM group displayed higher serum musclin than the controls. Serum musclin were remarkably elevated in DN2 subgroup compared with DN0 and DN1 subgroups. In addition, elevated serum musclin was observed in DN1 subgroup than in the DN0 subgroup. Serum musclin was correlated with an increased risk of having T2DM and DN using a logistic regression model. Linear regression analysis showed that serum musclin was negatively related with gender, and positively related with body mass index, systolic blood pressure, blood urea nitrogen, creatinine, and ACR. CONCLUSION: Serum musclin increases with the progressed stages of DN. Serum musclin is associated with renal function parameters and ACR.

The correlation of triglyceride/high-density lipoprotein cholesterol ratio with muscle mass in type 2 diabetes patients.

OBJECTIVE: Triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio is correlated with metabolic diseases. The prevalence of sarcopenia is significantly higher in type 2 diabetes mellitus (T2DM) patients compared with healthy controls. The purpose of our study is to evaluate the correlation of TG/HDL-C ratio with muscle mass in T2DM patients. METHOD: Our study consists of 1048 T2DM inpatients recruited from the department of endocrinology. Skeletal muscle index (SMI) was detected with a dual energy X-ray absorptiometry method. Low muscle mass was diagnosed using the criteria of SMI less than 7.0 kg/m2 (in male subjects) or 5.4 kg/m2 (in female subjects). RESULT: The prevalence of low muscle mass was 20.9% and 14.5% in male and female groups respectively. SMI was correlated with TG/HDL ratio after adjustment for age, duration of diabetes, diastolic blood pressure (DBP), and HbA1c in male subgroup. In female subgroup, SMI was associated with TG/HDL ratio after adjustment for age and DBP. CONCLUSION: Higher TG/HDL-C ratio is correlated with muscle mass in T2DM patients.

The correlation between serum creatine kinase with low muscle mass in type 2 diabetes patients.

Creatine kinase (CK), the key enzyme in regulating energy metabolism, is demonstrated to be correlated with insulin resistance. Type 2 diabetes mellitus (T2DM) is considered as a risk factor for developing low muscle mass. The purpose of this investigation was to evaluate whether serum CK is associated with low muscle mass in T2DM patients. This cross-sectional study enrolled a consecutive population of 1086 T2DM patients recruited from the inpatients in our department. Dual-energy X-ray absorptiometry was utilized to detect the skeletal muscle index (SMI). In all, 117 males (20.24%) and 72 females (16.51%) showed low muscle mass in T2DM patients. CK was associated with a reduced risk of low muscle mass in male and female T2DM patients. SMI was correlated with age, duration of diabetes, body mass index (BMI), diastolic blood pressure (DBP), triglyceride, high-density lipoprotein cholesterol, and CK in male subjects analyzed using linear regression. Linear regression analysis showed that SMI was correlated with age, BMI, DBP, and CK in female subjects. In addition, CK was correlated with BMI and fasting plasma glucose in male and female T2DM groups. CK is inversely correlated with low muscle mass in T2DM patients.

Association of triglyceride-glucose index and the presence of low muscle mass in type 2 diabetes patients.

Triglyceride-glucose index (TyG index) has been used in healthy individuals as a marker of insulin resistance. Type 2 diabetes mellitus (T2DM) showed an increased risk of developing low muscle mass compared to control subjects. This study is performed to determine the association of TyG index with the presence of low muscle mass in T2DM patients. This study included 1098 T2DM patients who were recruited from the inpatients in Qilu Hospital (Qingdao). Skeletal muscle index (SMI) was measured using dual energy X-ray absorptiometry. Serum triglyceride and fasting plasma glucose were measured and used to calculate TyG index. 119 male subjects (20.2%) had low muscle mass, while 72 female subjects (14.1%) had low muscle mass in T2DM patients. TyG index was correlated with a decreased risk of low muscle mass in both male and female T2DM groups. TyG index was found to be positively correlated with SMI after multivariate adjustment in male subjects. When TyG index was ≤ 9.5, TyG index was positively correlated with SMI. However, when TyG index was > 9.5, there was not a significant association between TyG index and SMI. Moreover, TyG index was not correlated with SMI after multivariate analysis in female subjects. However, TyG index was positively correlated with SMI when TyG index was ≤ 9. When TyG index was > 9, TyG index was negatively correlated with SMI, however, the correlation was not statistically significant. TyG index is inversely correlated with the presence of low muscle mass in T2DM patients.

ALT-803 in the treatment of non-muscle-invasive bladder cancer: Preclinical and clinical evidence and translational potential.

Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%-85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette-Guérin (BCG) is the gold standard for avoiding cystectomy in the treatment of NMIBC. Unfortunately, up to 30% of patients do not respond to BCG treatment, and up to 70% of BCG responders relapse. The United States Food and Drug Administration (FDA) approved valrubicin (1998) and pembrolizumab (2020) for the treatment of BCG-unresponsive (BCGu) NMBIC. However, the complete remission rate for valrubicin and pembrolizumab was only 16% and 40.6%, respectively. ALT-803 (N-803) is an IL-15 superagonist and reduces tumor burden by promoting the proliferation and activation of NK cells and CD8+ T cells. The FDA received (23 May 2022) and accepted to review (28 July 2022) the marketing submission of ALT-803 plus BCG for the treatment of BCGu NMIBC. However, the FDA previously rejected the application for oportuzumab monatox (OM) due to a lack of data comparing it with pembrolizumab on August 20, 2021. Interestingly, the clinical efficacy and safety of ALT-803 were higher than that of pembrolizumab and OM, suggesting that ALT-803 may be approved by FDA. This review aims to further knowledge of the preclinical and clinical evidence of ALT-803 in the treatment of NMIBC and discuss its translational potential.

Association between ALT/AST and Muscle Mass in Patients with Type 2 Diabetes Mellitus.

Objective: The alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio is thought to be related to metabolic disorders and insulin resistance. Type 2 diabetes mellitus (T2DM) is a high-risk population for low muscle mass. This study was performed to evaluate the association between ALT/AST and muscle mass in subjects with T2DM. Method: This cross-sectional study enrolled 1068 subjects (566 males and 502 females) with T2DM. General information, medical history, and blood samples were collected. Skeletal muscle index (SMI) was detected using dual-energy X-ray absorptiometry. Logistic regression analysis was utilized to determine the correlation of ALT/AST and low muscle mass in subjects with T2DM. Multiple linear regression analysis was utilized to evaluate the association between ALT/AST, SMI and other metabolic characteristics. Result: Of all subjects, 115 men (20.3%) and 71 women (14.1%) presented low muscle mass. ALT/AST was related to an increased risk for low muscle mass in both genders. Multiple linear regression analysis displayed that SMI was negatively associated with ALT/AST, age, glycosylated hemoglobin (HbA1c), and high-density lipoprotein cholesterol (HDL) in male group. While in female group, SMI was positively associated with systolic blood pressure (SBP) and negatively associated with ALT/AST and age. Furthermore, ALT/AST was associated with age and BMI in both genders. Conclusion: ALT/AST was negatively associated with muscle mass in subjects with T2DM.

Identifying gene variants underlying the pathogenesis of diabetic retinopathy based on integrated genomic and transcriptomic analysis of clinical extreme phenotypes.

Diabetic retinopathy (DR) is a common complication and the leading cause of blindness in patients with type 2 diabetes. DR has been shown to be closely correlated with blood glucose levels and the duration of diabetes. However, the onset and progression of DR also display clinical heterogeneity. We applied whole-exome sequencing and RNA-seq approaches to study the gene mutation and transcription profiles in three groups of diabetic patients with extreme clinical phenotypes in DR onset, timing, and disease progression, aiming to identify genetic variants that may play roles in the pathogenesis of DR. We identified 23 putatively pathogenic genes, and ingenuity pathway analysis of these mutated genes reveals their functional association with glucose metabolism, diabetic complications, neural system activity, and dysregulated immune responses. In addition, ten potentially protective genes were also proposed. These findings shed light on the mechanisms underlying the pathogenesis of DR and may provide potential targets for developing new strategies to combat DR.

Effect of long-term intensive cholesterol control on the plaque progression in elderly based on CTA cohort study.

OBJECTIVES: To investigate the long-term effects of intensive LDL cholesterol-lowering treatments on lumen stenosis severity, plaque calcification, spotty calcifications, percent calcified plaque volume (PCPV), and Agatston coronary artery calcium score (CACS) based on coronary computed tomography angiography (CCTA) in elderly patients. METHODS: A total of 240 patients over 60 years old (comprising 754 lesions) who underwent serial CCTA were retrospectively enrolled in this 5-year cohort study. Patients were divided into three groups: an intensive lipid-lowering group, a lipid-lowering group, and a control group. The stenosis severity, plaque volume (PV), plaque composition, PCPV, and high-risk plaque (HRP) presence were quantitatively analyzed. The CACS was calculated at baseline and follow-up. RESULTS: All patients were male with an average age of 66.8 ± 5.8 years old. Over time, increases in the percentages of obstructive coronary lesions (p < 0.001) were observed. Compared with those at baseline, the percentage of obstructive lesions remained unchanged (p = 0.077), and the percentage of spotty calcifications significantly decreased (p < 0.05) at the follow-up CCTA scan in the intensive lipid-lowering group. Patients in the intensive lipid-lowering group demonstrated a higher progression in calcified PV, CACS, and PCPV (all p < 0.05), and a significantly greater attenuation in fibrous-fatty and lipid-rich PV (all p < 0.05) than patients in other groups. CONCLUSIONS: The PV and contents increased gradually with time in all groups. Intensive LDL-C lowering was associated with slower progression of stenosis severity and reduction of high-risk plaque features, with increased plaque calcification and higher progression in PCPV. Comprehensive serial plaque evaluations by CCTAs may contribute to further refinement of risk stratification and reasonable lipid-lowering treatment in elderly patients. KEY POINTS: • Intensive LDL-C lowering increased coronary calcification and percent calcified plaque volume progression. • Comprehensive serial plaque evaluations by serial CCTAs may help to refine risk stratification.