Effect of gradient pressure therapy on the prevention of chemotherapy-induced peripheral neuropathy in patients with breast cancer.

PURPOSE: To investigate the effect of gradient pressure therapy on the prevention of chemotherapy-induced peripheral neuropathy (CIPN) and improvement in activities of daily living (ADL) in patients with breast cancer. METHODS: Eighty female patients with breast cancer treated at Tangshan People's Hospital between October 2022 and July 2023 were selected as research participants and divided into control and intervention, with 40 patients in each group. The control group received routine treatment and care, whereas the intervention group received gradient pressure therapy based on routine treatment and care. Incidence of peripheral neuropathy and the degree of impact on ADL between the two groups were compared after the intervention for cycles 2, 4, and 6. RESULTS: There was no significant difference in the general information between the two groups (P > 0.05). After two intervention cycles, there was no significant difference in the incidence of CIPN, various dimensions of Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (CIPNAT), and total scores between the two groups (P > 0.05). After four intervention cycles, the two groups had a statistically significant difference in the incidence of CIPN, sensory dimension, general activity dimension, and total CIPNAT score (P < 0.05). After six intervention cycles, there was a significant difference in the incidence of CIPN, sensory dimension, fine activity dimension, general activity dimension, and total CIPNAT score between the two groups (P < 0.05), while there was no significant difference in the other dimensions (P > 0.05). CONCLUSIONS: Gradient pressure therapy can effectively prevent or alleviate peripheral neuropathy in patients with breast cancer undergoing chemotherapy and improve their ability to perform ADL. Thus, it is safe, effective, and worthy of clinical application. TRIAL REGISTRATION: RMYY-LLKS-2022-054.

Therapeutic effects of compression therapy on taxane-induced peripheral neuropathy incidence, negative emotions, and sleep disorders in patients with breast cancer.

PURPOSE: To explore the effects of compression therapy on chemotherapy-induced peripheral neuropathy (CIPN), anxiety, depression, and sleep disorders in breast cancer patients administered taxanes. METHODS: Eighty patients with breast cancer undergoing chemotherapy at Tangshan People's Hospital between October 2022 and July 2023 were randomly divided into control (n = 40) and intervention (n = 40) groups. The control group received routine care, while intervention group received compression therapy in addition to routine care (30 min before the infusion of chemotherapy drugs, patients wore surgical gloves on their hands that were one size smaller than the appropriate size and elastic socks on their feet until 30 min after the infusion). The incidence of CIPN, anxiety, depression, and sleep scores, were compared between these groups before and after compression therapy during chemotherapy cycles 2, 4, and 6. RESULTS: The general characteristics did not differ significantly between the groups (P > 0.05). The CIPN incidence, anxiety and depression scores, and sleep scores also did not differ significantly between the two groups before and after the intervention period (P > 0.05). After the fourth and sixth cycles of intervention, the incidence of CIPN (≥ 1 and ≥ 2), anxiety and depression scores, and sleep scores were significantly lower in the intervention group than in the control group (P < 0.05). CONCLUSION: Compression therapy can effectively reduce the incidence of CIPN, as well as improve the level of anxiety, depression, and sleep disorders in chemotherapy patients. Therefore, medical personnel should closely observe the physical and psychological changes in patients undergoing chemotherapy and provide corresponding preventive measures. REGISTRATION NUMBER: RMYY-LLKS-2022-054. DATE OF REGISTRATION: September 25, 2022.

Largely Improved Creep Resistance and Thermal-Aging Stability of Eco-Friendly Polypropylene High-Voltage Insulation by Long-Chain Branch-Induced Interfacial Constraints.

Polypropylene (PP)-based composites have attracted numerous attention as a replacement of prevailing cross-linked polyethylene (XLPE) for high-voltage insulation due to their ease of processing, recyclability, and excellent electrical performance. However, the poor resistances against high-temperature creep and thermal aging are obstacles to practical applications of PP-based thermoplastic high-voltage insulation. To address these problems, in this Letter, we synthesized an impact polypropylene copolymer (IPC) containing multifold long-chain branched (LCB) structures in phases, especially the interfaces between the PP matrix and the rubber phase. The results indicated that the structural stability of LCBIPC was significantly enhanced under extreme conditions. In comparison to IPC (without LCB structures), 24.1% less creep strain and 75.2% less unrecoverable deformation are achieved in LCBIPC at 90 °C. In addition, the thermal aging experiments were performed at 135 °C for 48 and 88 days for IPC and LCBIPC, respectively. The results show that the resistance against thermal aging was also enhanced in LCBIPC, which showed a 133% longer thermal aging life compared to IPC. Further results revealed that the interfacial layer between the PP matrix and the rubber phase was constructed in LCBIPC. The two phases are tightly linked by chemical bonds in LCB structures, leading to enforced constraints of the rubber phase at the micro level and better resistance performance against creep and thermal aging at the macro level. Evidently, the reported eco-friendly LCBIPC thermoplastic insulation shows great potential for applications in high-voltage cable insulation.

UBAP2L ensures homeostasis of nuclear pore complexes at the intact nuclear envelope.

Assembly of macromolecular complexes at correct cellular sites is crucial for cell function. Nuclear pore complexes (NPCs) are large cylindrical assemblies with eightfold rotational symmetry, built through hierarchical binding of nucleoporins (Nups) forming distinct subcomplexes. Here, we uncover a role of ubiquitin-associated protein 2-like (UBAP2L) in the assembly and stability of properly organized and functional NPCs at the intact nuclear envelope (NE) in human cells. UBAP2L localizes to the nuclear pores and facilitates the formation of the Y-complex, an essential scaffold component of the NPC, and its localization to the NE. UBAP2L promotes the interaction of the Y-complex with POM121 and Nup153, the critical upstream factors in a well-defined sequential order of Nups assembly onto NE during interphase. Timely localization of the cytoplasmic Nup transport factor fragile X-related protein 1 (FXR1) to the NE and its interaction with the Y-complex are likewise dependent on UBAP2L. Thus, this NPC biogenesis mechanism integrates the cytoplasmic and the nuclear NPC assembly signals and ensures efficient nuclear transport, adaptation to nutrient stress, and cellular proliferative capacity, highlighting the importance of NPC homeostasis at the intact NE.

The Catalytic Mechanism and Activity Modulation of Manganese Superoxide Dismutase / 生物化学与生物物理进展

Manganese superoxide dismutase catalyzes the dismutation of two molecules of superoxide radicals to one molecule of oxygen and one molecule of hydrogen peroxide. The oxidation of superoxide anion to oxygen by Mn3+SOD proceeds at a rate close to diffusion. The reduction of superoxide anion to hydrogen peroxide by Mn2+SOD can be progressed parallelly in either a fast or a slow cycle pathway. In the slow cycle pathway, Mn2+SOD forms a product inhibitory complex with superoxide anion, which is protonated and then slowly releases hydrogen peroxide out. In the fast cycle pathway, superoxide anion is directly converted into product hydrogen peroxide by Mn2+SOD, which facilitates the revival and turnover of the enzyme. We proposed for the first time that temperature is a key factor that regulates MnSOD into the slow- or fast-cycle catalytic pathway. Normally, the Mn2+ rest in the pent-coordinated state with four amino acid residues (His26, His74, His163 and Asp159) and one water (WAT1) in the active center of MnSOD. The sixth coordinate position on Mn (orange arrow) is open for water (WAT2, green) or O2• to coordinate. With the cold contraction in the active site as temperature decreases, WAT2 is closer to Mn, which may spatially interfere with the entrance of O2• into the inner sphere, and avoid O2•/Mn2+ coordination to reduce product inhibition. Low temperature compels the reaction into the faster outer sphere pathway, resulting in a higher gating ratio for the fast-cycle pathway. As the temperature increases in the physiological temperature range, the slow cycle becomes the mainstream of the whole catalytic reaction, so the increasing temperature in the physiological range inhibits the activity of the enzyme. The biphasic enzymatic kinetic properties of manganese superoxide dismutase can be rationalized by a temperature-dependent coordination model of the conserved active center of the enzyme. When the temperature decreases, a water molecule (or OH-) is close to or even coordinates Mn, which can interfere with the formation of product inhibition. So, the enzymatic reaction occurs mainly in the fast cycle pathway at a lower temperature. Finally, we describe the several chemical modifications of the enzyme, indicating that manganese superoxide dismutase can be rapidly regulated in many patterns (allosteric regulation and chemical modification). These regulatory modulations can rapidly and directly change the activation of the enzyme, and then regulate the balance and fluxes of superoxide anion and hydrogen peroxide in cells. We try to provide a new theory to reveal the physiological role of manganese superoxide dismutase and reactive oxygen species.

Establishment of reference intervals for serum sTfR and sTfR/lgSF in apparently healthy adults in Wuhan / 中国输血杂志

【Objective】 To establish reference intervals for serum soluble transferrin receptor (sTfR) and sTfR/log serum ferritin index (sTfR/lgSF) in apparently healthy adults in the Wuhan area, so as to provide reference for clinical diagnosis and treatment of iron deficiency and iron-deficiency anemia. 【Methods】 A total of 273 individuals from the Wuhan Aisa General Hospital, including health examination participants and blood donors, were selected to measure sTfR, other iron metabolism indicators and high sensitivity C-reactive protein(hsCRP). The sTfR/lgSF values were calculated and reference intervals for sTfR and sTfR /lgSF were established using the percentile method (P2.5 to P97.5). Spearman correlation analysis was used to evaluate the relationships between sTfR, sTfR/lgSF, and other iron metabolism indicators, as well as hsCRP. 【Results】 The sTfR levels (M, mg/L) between males and females (1.01 vs 1.07) were not statistically significant (P>0.05), but the sTfR/lgSF levels if males were significantly lower than those in females (0.45 vs 0.62)(P0.05). The reference interval for STfR was (0.72-1.68) mg/L, the sTfR/lgSF reference interval was (0.31-0.88) for males, and (0.37-1.19) for females. Correlation analysis showed no correlation between sTfR, sTfR/lgSF and hsCRP (r=0.043, P>0.05; r=-0.064, P>0.05), while serum ferritin(SF), serum iron(SI), transferrin saturation(TSAT)were correlated with hsCRP (r=0.128, P0.05), while sTfR/lgSF was significantly correlated with and SF (r=-0.685, P<0.01). 【Conclusion】 Preliminary reference intervals for serum sTfR and sTfR/lgSF in apparently healthy adults in the Wuhan has been established. sTfR and sTfR/lgSF are not affected by inflammatory factors and are significant for identifying iron deficiency in anemia patients with elevated serum ferritin caused by inflammation.

Expression changes and clinical significance of IRAK1 and TRAF6 in patients with septic shock / 国际检验医学杂志

Objective To investigate the expression changes and clinical significance of interleukin-1 recep-tor-associated kinase 1(IRAK1)and tumor necrosis factor receptor-associated factor 6(TRAF6)in patients with septic shock.Methods A total of 142 patients with septic shock admitted from November 2020 to No-vember 2022(septic shock group)were selected as the study subjects,and those who came to the hospital for physical examination during the same period were selected as the control group.Patients with septic shock were divided into survival group(100 cases)and death group(42 cases)according to their survival status after 28 days of hospitalization observation and treatment.The expression changes of IRAK1 and TRAF6 in pa-tients with septic shock were monitored at admission and after 2,4 and 6 days of treatment.The dynamic changes of acute physiology and chronic health evaluation Ⅱ(APACHEⅡ)score and sequential organ failure assessment(SOFA)score were recorded.Spearman correlation analysis was used to evaluate the correlation between IRAK1,TRAF6 and APACHE Ⅱ score and SOFA score in septic shock patients.The correlation be-tween IRAK1 and TRAF6 was analyzed by Pearson correlation analysis.Logistic regression was used to ana-lyze the factors influencing survival status of patients with septic shock.The diagnostic value of IRAK1 and TRAF6 in survival of patients with septic shock was analyzed by the receiver operating characteristic curve.Results The relative expression levels of IRAK1 and TRAF6 in septic shock group were significantly lower than those in control group,and APACHE Ⅱ score and SOFA score were significantly higher than those in control group,with statistical significance(P＜0.05).Compared with admission,the relative expression levels of IRAK1 and TRAF6 in 2,4 and 6 days after treatment were significantly increased,while APACHE Ⅱ score and SOFA score were significantly decreased,with statistical significance(P＜0.05).Compared with the death group,the relative expression levels of IRAK1 and TRAF6 in the survival group were higher at each corre-sponding time point,and the APACHE Ⅱ score and SOFA score were lower,with statistical significance(P＜0.05).Correlation analysis showed that IRAK1 and TRAF6 were negatively correlated with APACHE Ⅱscores and SOFA scores in septic shock patients,while IRAK1 and TRAF6 were positively correlated(r=0.688,P＜0.05).IRAK1,TRAF6 and APACHE Ⅱ scores were independent risk factors for survival of septic shock patients(P＜0.05).The AUC of the combined diagnosis of IRAK1 and TRAF6 was significantly larger than that of IRAK1 alone(Z=2.044,P=0.041)and that of TRAF6 alone(Z=2.442,P=0.015).Conclusion The expression of IRAK1 and TRAF6 can evaluate the survival and prognosis of patients with septic shock.

LI Fei's Experience in Treating Facial Paralysis with Acupuncture and Moxibustion / 广州中医药大学学报

This article aims to analyze LI Fei's academic thinking and experience in treating facial paralysis.LI Fei proposes that the diagnosis and treatment of facial paralysis should follow the principle of"identify the cause of the disease when it is occured at first time,followed by exploring the pathogenesis of the disease,then differentiating the syndrome and treating the disease,and recognizing the syndrome and treating the disease",and that the basic treatment principle should be"dispelling wind and unblocking the collaterals,regulating the tendons and meridians".In clinical treatment,"put emphasis on anatomy,treat the disease according to symptoms"is the basic policy;meanwhile,integrating Chinese and western theories,combining the anatomical structure of the expression muscle,dynamically judging the recovery of nerves and muscles,and selecting the corresponding empirical acupoints according to the symptoms.LI Fei emphasizes the integration of theories and summarizes the"triple"methods of differentiation by reasoning,staging and symptoms,and the"triple"theory of treatment by regulating menstruation,tendon and spirit,which is worthy of reference in the clinic.

Application and evaluation of diversified teaching mode in clinical teaching for medical students / 基础医学与临床

Objective To investigate the needs and feedback from clinical medical students on the diversified teaching mode adopted by the Department of Endocrinology in Peking Union Medical College Hospital.Methods Questionnaires were distributed to the medicine students who were in clinical rotation in Peking Union Medical Col-lege,and the teaching status and teaching effect was investigated.Results A total of 95 valid questionnaires were received.The attending physicians and the teaching resident physicians performed well in the daily teaching activi-ties.The medical students believed that outpatient training was necessary in addition to ward rotations.After the ro-tation in the endocrinology department,the self-evaluated score of mastery of endocrinology knowledge had been significantly improved,especially in those who rotated in outpatient clinic,suggesting that outpatient teaching was of great significance.In addition,the establishment of a self-learning platform including clinical cases and videos in endocrinology could be used as an important supplementary means for clinical teaching.Conclusions Outpatient training improves learning outcomes of medical students,so must be kept and further strengthened in the future.Building a database of typical clinical cases and teaching videos can improve the training quality.

Application value of venous excess ultrasound score (VExUS Score) in patients with sepsis complicated acute kidney injury / 中华急诊医学杂志

Objective:To evaluate the effect of venous excess ultrasound score (VExUS Score) in the acute kidney injury(AKI) in Patients with sepsis, so as to reduce the risk of disease and improve the prognosis of patients.Methods:This experiment was a single-center prospective cohort study. Include septic patients with AKI who were admitted to the Department of Emergency Intensive Care Unit of the First Affiliated Hospital of Anhui Medical University from February 2022 to February 2023, Those with inadequate window, inferior vena cava (IVC) thrombus, age<18 years and known case of cirrhosis with portal hypertension were excluded from the study. Patients underwent ultrasound examination with serial determination till AKI resolved or patient is initiated on dialysis.Results:Totally 86 patients were enrolled for the study. The mean age was (60.43±15.48) with 50 (58.1%) males. Mean sequential organ failure assessment (SOFA) score was (6.23±1.87). 38 patients (44.2%) were in AKI stage 1, while 24 patients (27.9%) were in AKI stage 2 and stage 3 each. 52 patients (60.5%) had VExUS grade Ⅲ. Resolution of AKI injury showed significant correlation with improvement in VExUS grade ( p value 0.003). Similarly, there was significant association between changes in VExUS grade and fluid balance ( p value 0.005). There was no correlation between central venous pressure (CVP), left ventricular function, and right ventricular function with change in VExUS grade. Conclusions:The study shows a significant correlation between the VExUS Score and AKI staging, With improvement in kidney function, there is decline in the VExUS grade as well. Moreover VExUS Score might reliably demonstrate venous congestion and aid in the clinical decision to perform fluid removal.

Serological and molecular biological characteristics of hepatitis B vaccinated donors with asymptomatic chronical infection in Shenzhen / 中国输血杂志

【Objective】 To investigate asymptomatic infection of hepatitis B virus(HBV) among hepatitis B vaccinated donors in Shenzhen, and analyze its serological and molecular characteristics. 【Methods】 The HBsAg ELISA positive blood samples of blood donors born after 1992 were collected. HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc were further detected by Roche electrochemiluminescence immunoassay (ECL). BCP/PC and S regions were amplified by Nested-PCRs, HBV DNA quantification were adopted by qPCR simultaneously, and the sequences were also analyzed. 【Results】 A total of 46 632 blood samples of donors(31 612 males and 15 020 females) from December 2020 to January 2022 collected, and 99 samples with HBsAg ELISA positive were screened out. After tested by ECL, Nested-PCRs, and real-time fluorescence PCR, 61 were confirmed HBsAg positive, with the positive rate at 0.13% (61/46 632), including 49 males (0.16%, 49/31 612) and 12 females (0.08%, 12/15 020). The HBsAg positive rate of males was higher than that of females (P<0.05). 50 out of 61 sequences for S region were obtained. By phylogenetic analysis, there were 46 cases of type B (92%, 46/50, 38 males and 8 females), 4 cases of type C (8%, 4/50, 3 males and 1 female). The high frequency mutations observed in S region were N40S (8/46,17.39%), G44E (7/46,15.22%), Q129H/R(6/46,13.04%), Y161F/S(7/46, 15.22%), V179A(4/46,8.70%), S53L(2/4,50%), C69T(2/4,50%) and I126S/T(2/4,50%), including the immune escape mutations Q129R and T/I126A/N/S/T. 【Conclusion】 Hepatitis B vaccination can significantly reduce the positive rate of HBsAg and increase the safety of blood transfusion. The high frequency immune escape mutations have become a potential risk of blood safety, and need to be further explored.

The effects of invisible orthodontic appliances without brackets and labial fixed orthodontic appliances on periodontal status and root resorption in orthodontic patients / 中国医师杂志

Objective:To compare the effects of invisible orthodontic appliances without brackets and labial fixed orthodontic appliances on periodontal status and root resorption in orthodontic patients.Methods:A retrospective study was conducted on 102 orthodontic patients who visited the Affiliated Hospital of Jining Medical University from January 2019 to October 2022. According to different treatment methods, they were divided into group A ( n=52) and group B ( n=50). Group A was treated with invisible orthodontic appliances without brackets, while group B was treated with labial fixed orthodontic appliances. We compared two groups of treatment completion time, root resorption, and periodontal health indicators before and after treatment, including plaque index (PLI), gingival index (GI), gingival sulcus bleeding index (SBI), and levels of inflammatory factors in gingival crevicular fluid, including interleukin-1β (IL-1β) and soluble intercellular adhesion molecule-1 (sICAM-1). Results:The completion time of treatment in the Group A was longer than that in the group B [(34.62±4.28)months vs (28.93±3.11)months] ( P<0.01). After treatment, the incidence of root resorption in the group A was 50.96%, while in the group B it was 78.00%. The group A was significantly lower than the group B ( P<0.05), with no root resorption greater than 3 mm in the group A and 0.50% in the group B. After treatment, the levels of PLI, GI, SBI, and IL-1β and sICAM-1 in gingival crevicular fluid increased in both groups, with the group A being lower than group B [(1.26±0.39)points vs (1.73±0.54)points, (1.33±0.25)points vs (2.06±0.46)points, (1.73±0.40)points vs (2.48±0.50)points, (173.74±25.81)ng/ml vs (196.33±31.52)ng/ml, (42.28±5.16)μg/L vs (56.59±7.38)μg/L] (all P<0.05). Conclusions:Although invisible orthodontic appliances without brackets cannot shorten the completion time of treatment, they have advantages in inhibiting root resorption, improving periodontal health, and reducing inflammatory reactions. Clinically, appropriate appliances can be selected based on the specific situation of patients.

Novel antibacterial drug target against Gram-negative bacteria: lipopolysaccharide transport protein LptDE and its inhibitors / 药学学报

The outer membrane composed predominantly of lipopolysaccharide (LPS) is an essential biological barrier for most Gram-negative (G-) bacteria. Lipopolysaccharide transport protein (Lpt) complex LptDE is responsible for the critical final stage of LPS transport and outer membrane assembly. The structure and function of LptDE are highly conserved in most G- bacteria but absent in mammalian cells, and thus LptDE complex is regarded as an attractive antibacterial target. In recent 10 years, the deciphering of the three-dimensional structure of LptDE protein facilities the drug discovery based on such "non-enzyme" proteins. Murepavadin, a peptidomimetic compound, was reported to be the first compound able to target LptD, enlightening a new class of antibacterial molecules with novel mechanisms of action. This article is devoted to summarize the molecular characteristics, structure-function of LptDE protein complex and review the development of murepavadin and related peptidomimetic compounds, in order to provide references for relevant researches.

Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury.

BACKGROUND: The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive. METHODS: A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors. RESULTS: In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-ß (IFN-ß) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR. CONCLUSIONS: Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-ß-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.

KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation.

Immune cells sense the microenvironment to fine-tune their inflammatory responses. Patients with cryopyrin-associated periodic syndrome (CAPS), caused by mutations in the NLRP3 gene, develop autoinflammation triggered by nonantigenic cues such as from the environment. However, the underlying mechanisms are poorly understood. Here, we uncover that KCNN4, a calcium-activated potassium channel, links PIEZO-mediated mechanotransduction to NLRP3 inflammasome activation. Yoda1, a PIEZO1 agonist, lowered the threshold for NLRP3 inflammasome activation. PIEZO-mediated sensing of stiffness and shear stress increased NLRP3-dependent inflammation. Myeloid-specific deletion of PIEZO1/2 protected mice from gouty arthritis. Mechanistically, activation of PIEZO1 triggers calcium influx, which activates KCNN4 to evoke potassium efflux and promotes NLRP3 inflammasome activation. Activation of PIEZO signaling was sufficient to activate the inflammasome in cells expressing CAPS-causing NLRP3 mutants via KCNN4. Last, pharmacological inhibition of KCNN4 alleviated autoinflammation in cells of patients with CAPS and in mice bearing a CAPS mutation. Thus, PIEZO-dependent mechanical inputs boost inflammation in NLRP3-dependent diseases, including CAPS.

Cinobufotalin prevents bone loss induced by ovariectomy in mice through the BMPs/SMAD and Wnt/ß-catenin signaling pathways.

BACKGROUND: Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength. However, current anti-resorptive drugs carry a risk of various complications. The deep learning-based efficacy prediction system (DLEPS) is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes. This study aimed to explore the protective effect and potential mechanisms of cinobufotalin (CB), a traditional Chinese medicine (TCM), on bone loss. METHODS: DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis. Micro-CT, histological and morphological analysis were applied for the bone protective detection of CB, and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells (hBMMSCs) were also investigated. The underlying mechanism was verified using qRT-PCR, Western blot (WB), immunofluorescence (IF), etc. RESULTS: A safe concentration (0.25 mg/kg in vivo, 0.05 µM in vitro) of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs. Both BMPs/SMAD and Wnt/ß-catenin signaling pathways participated in CB-induced osteogenic differentiation, further regulating the expression of osteogenesis-associated factors, and ultimately promoting osteogenesis. CONCLUSION: Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss, further promoting osteogenic differentiation/function of hBMMSCs, with BMPs/SMAD and Wnt/ß-catenin signaling pathways involved.

Imbalanced lipid homeostasis caused by membrane αKlotho deficiency contributes to the acute kidney injury to chronic kidney disease transition.

After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition.

Safety analysis of pemigatinib leveraging the US Food and Drug administration adverse event reporting system.

Background: Cholangiocarcinoma (CCA) is a highly lethal and aggressive epithelial tumor of the hepatobiliary system. A poor prognosis, propensity for relapse, low chance of cure and survival are some of its hallmarks. Pemigatinib, the first targeted treatment for CCA in the United States, has been demonstrated to have a significant response rate and encouraging survival data in early-phase trials. The adverse events (AEs) of pemigatinib must also be determined. Objective: To understand more deeply the safety of pemigatinib in the real world through data-mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: Disproportionality analysis was employed in a retrospective pharmacovigilance investigation to identify the AEs linked to pemigatinib use as signals. Data were collected between 1 January 2020 to 30 June 2022. Four data-mining methods (proportional reporting odds ratio; proportional reporting ratio; Bayesian confidence propagation neural networks of information components; empirical Bayes geometric means) were used to calculate disproportionality. Results: A total of 203 cases using pemigatinib as the prime-suspect medication were found in our search, which involved 99 preferred terms (PTs). Thirteen signals of pemigatinib-induced AEs in seven System Organ Classes were detected after confirming the four algorithms simultaneously. Nephrolithiasis was an unexpected significant AE not listed on the drug label found in our data-mining. Comparison of the differences between pemigatinib and platinum drugs in terms of 33 PTs revealed that 13 PTs also met the criteria of the four algorithms. Ten of these PTs were identical to those compared with all other drugs, in which (excluding a reduction in phosphorus in blood) other PT signal values were higher than those of all other drugs tested. However, comparison of the differences between pemigatinib and infigratinib in terms of the 33 PTs revealed no significant signals in each algorithm method. Conclusion: Some significant signals were detected between pemigatinib use and AEs. PTs with apparently strong signals and PTs not mentioned in the label should be taken seriously.

T-lymphocytes from focused ultrasound ablation subsequently mediate cellular antitumor immunity after adoptive cell transfer immunotherapy.

Background: Our previous studies found that high-intensity focused ultrasound (HIFU) stimulated tumor-specific T cells in a mouse H22 tumor model, and adoptive transfer of the T cells from HIFU-treated mice could subsequently elicit stronger inhibition on the growth and progression of the implanted tumors. The aim of this study was to investigate the mechanism of T cells from focused ultrasound ablation in HIFU-mediated immunomodulation. Methods: Sixty H22 tumor-bearing mice were treated by either HIFU or sham-HIFU, and 30 naïve syngeneic mice served as controls. All mice were euthanized on day 14 after HIFU and splenic T cell suspensions were obtained in each group. Using an adoptive cell transfer model, a total of 1 × 106 T cells from HIFU treated-mice were intravenously injected into each syngeneic H22 tumor-bearing mouse twice on day 3 and 4, followed by the sacrifice for immunological assessments at 14 days after the adoptive transfer. Results: T cells from HIFU-treated mice could significantly enhance the cytotoxicity of CTLs (p < 0.001), with a significant increase of TNF-α (p < 0.001) and IFN-γ secretion (p < 0.001). Compared to control and sham-HIFU groups, the number of Fas ligand+ and perforin+ tumor-infiltrating lymphocytes (TILs) and apoptotic H22 tumor cells were significantly higher (p < 0.001) in the HIFU group. There were linear correlations between apoptotic tumor cells and Fas ligand+ TILs (r = 0.9145, p < 0.001) and perforin+ TILs (r = 0.9619, p < 0.001). Conclusion: T cells from HIFU-treated mice can subsequently mediate cellular antitumor immunity, which may play an important role in the HIFU-based immunomodulation.