Kiwi-Inspired Rational Nanoarchitecture with Intensified and Discrete Magneto-Fluorescent Functionalities for Ultrasensitive Point-of-Care Immunoassay.

Fluorescent lateral flow immunoassays (FLFIA) is a well-established rapid detection technique for quantitative analysis. However, achieving accurate analysis of biomarkers at the pg mL-1 level using FLFIA still poses challenges. Herein, an ultrasensitive FLFIA platform is reported utilizing a kiwi-type magneto-fluorescent silica nanohybrid (designated as MFS) that serves as both a target-enrichment substrate and an optical signal enhancement label. The spatially-layered architecture comprises a Fe3O4 core, an endocarp-fibers like dendritic mesoporous silica, seed-like quantum dots, and a kiwi-flesh like silica matrix. The MFS demonstrates heightened fluorescence brightness, swift magnetic response, excellent size uniformity, and dispersibility in water. Through liquid-phase capturing and fluorescence-enhanced signal amplification, as well as magnetic-enrichment sample amplification and magnetic-separation noise reduction, the MFS-based FLFIA is successfully applied to the detection of cardiac troponin I that achieved a limit of detection at 8.4 pg mL-1, tens of times lower than those of previously published fluorescent and colorimetric lateral flow immunoassays. This work offers insights into the strategic design of magneto-fluorescent synergetic signal amplification on LFIA platform and underscores their prospects in high-sensitive rapid and on-site diagnosis of biomarkers.

Orexin Neurons to Sublaterodorsal Tegmental Nucleus Pathway Prevents Sleep Onset REM Sleep-Like Behavior by Relieving the REM Sleep Pressure.

Proper timing of vigilance states serves fundamental brain functions. Although disturbance of sleep onset rapid eye movement (SOREM) sleep is frequently reported after orexin deficiency, their causal relationship still remains elusive. Here, we further study a specific subgroup of orexin neurons with convergent projection to the REM sleep promoting sublaterodorsal tegmental nucleus (OXSLD neurons). Intriguingly, although OXSLD and other projection-labeled orexin neurons exhibit similar activity dynamics during REM sleep, only the activation level of OXSLD neurons exhibits a significant positive correlation with the post-inter-REM sleep interval duration, revealing an essential role for the orexin-sublaterodorsal tegmental nucleus (SLD) neural pathway in relieving REM sleep pressure. Monosynaptic tracing reveals that multiple inputs may help shape this REM sleep-related dynamics of OXSLD neurons. Genetic ablation further shows that the homeostatic architecture of sleep/wakefulness cycles, especially avoidance of SOREM sleep-like transition, is dependent on this activity. A positive correlation between the SOREM sleep occurrence probability and depression states of narcoleptic patients further demonstrates the possible significance of the orexin-SLD pathway on REM sleep homeostasis.

Association between adding salt in food and dementia in European descent: A mendelian randomization study.

BACKGROUND: High salt intake has been proposed as a risk factor for dementia. However, causal relationship between salt intake and dementia remains uncertain. PURPOSE: The aim of this study was to employ a mendelian randomization (MR) design to investigate the causal impact of salt intake on the risk of dementia. METHODS: Genome-wide association study (GWAS) data of exposures and outcomes (any dementia, cognitive performance, different types of dementia, Alzheimer's disease [AD], and Parkinson's disease) were obtained from the IEU database. MR estimates were generated though inverse-variance weighted model. MR-Egger, weighted median, and MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) method also used in our study. Sensitivity analyses included Cochran's Q test, MR-Egger intercept, MR-PRESSO global test and outlier test, leave-one-out analysis, and funnel plot assessment. RESULTS: Our MR analysis provided evidence of a causal association between high salt added to food and dementia (odds ratio [OR] = 1.73, 95% confidence interval [CI]: 1.21-2.49, and p = .003), dementia in AD (OR = 2.10, 95% CI: 1.15-3.83, and p = .015), and undefined dementia (OR = 2.61, 95% CI: 1.26-5.39, and p = .009). Higher salt added was also associated with increased risk of AD (OR = 1.80, 95% CI: 1.12-2.87, and p = .014) and lower cognitive performance (ß = -.133, 95% CI: -.229 to -.038, and p = .006). CONCLUSION: This study provides evidence suggesting that high salt intake is causally associated with an increased risk of developing dementia, including AD and undefined dementia, highlighting the potential importance of reducing salt consumption as a preventive measure.

The effect of guardrail color on driver behavior based on driving style along mountain curves.

OBJECTIVE: Mountain highways are linearly complex, with extensive curves and high accident injury rates, how to improve driving safety is the key to traffic safety management on mountain highways, and it also meets the need for harmonious and sustainable development of the society. Therefore, this study investigates the effects of different guardrail color configurations on the driving behavior of different styles of drivers when driving on mountainous curves from the perspective of improving road aids - guardrails. METHODS: A virtual reality experiment was designed using a driving simulator and VR technology, and 64 subjects were recruited to participate and complete the experiment. RESULTS: Drivers with non-adaptive driving styles (Reckless, Angry, Anxious) traveled at significantly higher speeds than subjects with adaptive driving styles (Cautious) on mountainous roads; drivers with Cautious styles had better lane-keeping ability when passing through different radii of curves as compared to non-adaptive drivers; and the red and yellow guardrails were more effective in decreasing the speeds at which drivers passed and in increasing the stability of lane-keeping. CONCLUSIONS: The results of the study show that the effectiveness of red and yellow guardrails is better, which provides a reference for the traffic management department to propose a standardized color setting of guardrails in mountainous areas, which is conducive to the development of more precise traffic management measures to reduce the occurrence of traffic accidents.

Ionic Current Saturation Enabled by Cation Gating Effect in Metal-Organic-Framework Membranes.

Ion transport through nanoporous two-dimensional (2D) membranes is predicted to be tunable by controlling the charging status of the membranes' planar surfaces, the behavior of which though remains to be assessed experimentally. Here we investigate ion transport through intrinsically porous membranes made of 2D metal-organic-framework layers. In the presence of certain cations, we observe a linear-to-nonlinear transition of the ionic current in response to the applied electric field, the behavior of which is analogous to the cation gating effect in the biological ion channels. Specifically, the ionic currents saturate at transmembrane voltages exceeding a few hundreds of millivolts, depending on the concentration of the gating cations. This is attributed to the binding of cations at the membranes' surfaces, tuning the charging states there and affecting the entry/exit process of translocating ions. Our work also provides 2D membranes as candidates for building nanofluidic devices with tunable transport properties.

How adult children experience and cope with their parents' diagnosis of multiple myeloma: A qualitative exploration.

PURPOSE: The aim of this study was to understand and explore the caregiving experience of adult children of patients with multiple myeloma (MM) during diagnosis and initial treatment based in Chinese filial piety culture. METHODS: A descriptive phenomenology study was conducted to investigate semi-structured interview responses from the adult children (N = 22) of MM patients within three months after diagnosis. Colaizzi's descriptive analysis framework was employed to analyze data. This study was reported following the COREQ checklist. RESULTS: Four themes and twelve subthemes were identified from the interviews. (1) Commitment to filial piety. Participants subconsciously fulfilled their commitment to filial piety by supporting their parents, obeying their wishes, providing emotional comfort, and protecting them from harm. (2) Experiencing multiple dilemmas. They faced challenges such as difficult treatment decisions, insufficient caregiving preparation, emotional distress, and role conflict. (3) Benefiting from setbacks. The caregiving experience allowed participants to cherish the present more and to establish a new view of life. (4) Adaptive coping. Family supports and self-adaptation are effective coping strategies to achieve their good psychosocial adaptation. CONCLUSIONS: Our study provides a culturally sensitive perspective on the caregiving experience of adult children of patients with MM. This study found that Chinese culture, especially filial piety culture, influenced the experiences and coping strategies of MM caregivers. Healthcare providers should focus on the challenges faced by adult children and develop various strategies to help them cushion the burden and adjust to caregiving roles, such as supportive care programs, meaning-centered psychotherapy, and family-centered medical communication interventions.

Tetrahydrofolate Attenuates Cognitive Impairment after Hemorrhagic Stroke by Promoting Hippocampal Neurogenesis via PTEN Signaling.

Intracerebral hemorrhage (ICH), the most common subtype of hemorrhagic stroke, leads to cognitive impairment and imposes significant psychological burdens on patients. Hippocampal neurogenesis has been shown to play an essential role in cognitive function. Our previous study has shown that tetrahydrofolate (THF) promotes the proliferation of neural stem cells (NSCs). However, the effect of THF on cognition after ICH and the underlying mechanisms remain unclear. Here, we demonstrated that administration of THF could restore cognition after ICH. Using Nestin-GFP mice, we further revealed that THF enhanced the proliferation of hippocampal NSCs and neurogenesis after ICH. Mechanistically, we found that THF could prevent ICH-induced elevated level of PTEN and decreased expressions of phosphorylated AKT and mTOR. Furthermore, conditional deletion of PTEN in NSCs of the hippocampus attenuated the inhibitory effect of ICH on the proliferation of NSCs and abnormal neurogenesis. Taken together, these results provide molecular insights into ICH-induced cognitive impairment and suggest translational clinical therapeutic strategy for hemorrhagic stroke.

An approach based on a combination of toxicological experiments and in silico predictions to investigate the adverse outcome pathway (AOP) of paraquat neuro-immunotoxicity.

Paraquat (PQ) exposure is strongly associated with neurotoxicity. However, research on the neurotoxicity mechanisms of PQ varies in terms of endpoints of toxic assessment, resulting in a great challenge to understand the early neurotoxic effects of PQ. In this study, we developed an adverse outcome pathway (AOP) to investigate PQ-induced neuro-immunotoxicity from an immunological perspective, combining of traditional toxicology methods and computer simulations. In vivo, PQ can microstructurally lead to an early synaptic loss in the brain mice, which is a large degree regarded as a main reason for cognitive impairment to mice behavior. Both in vitro and in vivo demonstrated synapse loss is caused by excessive activation of the complement C1q/C3-CD11b pathway, which mediates microglial phagocytosis dysfunction. Additionally, the interaction between PQ and C1q was validated by molecular simulation docking. Our findings extend the AOP framework related to PQ neurotoxicity from a neuro-immunotoxic perspective, highlighting C1q activation as the initiating event for PQ-induced neuro-immunotoxicity. In addition, downstream complement cascades induce abnormal microglial phagocytosis, resulting in reduced synaptic density and subsequent non-motor dysfunction. These findings deepen our understanding of neurotoxicity and provide a theoretical basis for ecological risk assessment of PQ.

Uterine necrosis following uterine artery embolization as treatment for postpartum hemorrhage: A case report and literature review.

Uterine necrosis is a rare complication of uterine artery embolization for postpartum hemorrhage and most patients end up having a hysterectomy. Here we report a case in which the patient experienced a recurrent fever 28 days after uterine artery embolization as treatment for postpartum hemorrhage and had no response to antibiotics. Magnetic resonance imaging of the pelvis revealed a mass which was approximately 12-cm in size with air bubbles in the uterus, suggesting necrosis with infection. Transvaginal clamping of the uterine mass was performed and necrotic tissue removed under laparoscopic monitoring, which successfully spared the necessity for a hysterectomy. The patient's subsequent progress was favorable. In the present study we review the high-risk factors of uterine necrosis following uterine artery embolization and summarize the key points of early diagnosis. In addition, we propose a strategy to successfully spare the necessity for a hysterectomy without the spread of infection or uterine perforation.

Umbilical cord mesenchymal stem cell-derived exosomes inhibits fibrosis in human endometrial stromal cells via miR-140-3p/FOXP1/Smad axis.

Endometrial fibrosis is the histologic appearance of intrauterine adhesion (IUA). Emerging evidences demonstrated umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-exo) could alleviate endometrial fibrosis. But the specific mechanism is not clear. In this study, we explored the effect of UCMSC-exo on endometrial fibrosis, and investigated the possible role of miR-140-3p/FOXP1/Smad axis in anti-fibrotic properties of UCMSC-exo. UCMSC-exo were isolated and identified. Transforming growth factor-ß (TGF-ß) was used to induce human endometrial stromal cell (HESC) fibrosis. Dual luciferase assay was performed to verify the relationship between miR-140-3p and FOXP1. The expressions of fibrotic markers, SIP1, and p-Smad2/p-Smad3 in HESCs stimulated with UCMSC-exo were detected by western blot. In addition, the effects of miR-140-3p mimic, miR-140-3p inhibitor and FOXP1 over-expression on endometrial fibrosis were assessed. The isolated UCMSC-exo had a typical cup-shaped morphology and could be internalized into HESCs. The expressions of fibrotic markers were significantly increased by TGF-ß, which was reversed by UCMSC-exo. MiR-140-3p in UCMSC-exo ameliorated TGf-ß-induced HESCs fibrosis. FOXP1 was identified as the direct target of miR-140-3p, which could inversely regulate miR-140-3p's function on HESCs fibrosis. Furthermore, we demonstrated that miR-140-3p in UCMSC-exo regulated Smad signal pathway to exert the anti-fibrotic effect in HESCs. The anti-fibrotic effect of UCMSC-derived exosomes against HESC fibrosis was at least partially achieved by miR-140-3p/FOXP1/Smad axis.

Shenshuai Yingyang Jiaonang ameliorates chronic kidney disease-associated muscle atrophy in rats by inhibiting ferroptosis mediated by the HIF-1α/SLC7A11 pathway.

Objective: Shenshuai Yingyang Jiaonang (SSYYJN), a traditional Chinese medicine formula, can ameliorate muscle atrophy associated with chronic kidney disease (CKD). However, its mechanisms of action remain unclear. This study is to investigate the molecular mechanisms involved in the effects of SSYYJN in ameliorating muscle atrophy associated with CKD in rats. Methods: The chemical compounds of SSYYJN were identified by UPLC-Q-Orbitrap HRMS. Considering the dose-response relationship of the identified compounds, male SD rats were randomly divided into Sham, Model, SSYYJN, and α-Keto Acid (KA) groups. Subsequently, we assessed the therapeutic and anti-ferroptotic effects of SSYYJN. Network pharmacology studies were used to predict the molecular mechanism of SSYYJN on ferroptosis and were further verified for accuracy. Results: A total of 42 active compounds were identified from SSYYJN. SSYYJN alleviated muscle atrophy caused by CKD, as evidenced by changes in body weight, serum biochemical indices, mass and histopathology of the skeletal muscle, and the levels of MuRF1. SSYYJN reduced the levels of iron, MDA, and ROS, increased the levels of GSH, NAPDH, and Gpx4. Network pharmacology analysis indicated that SSYYJN exerted anti-ferroptotic effects that were closely related to the HIF-1α signaling pathway. Molecular protein and genetic test results showed that SSYYJN increased HIF-1α protein and increased SLC7A11. Conclusions: SSYYJN attenuates muscle atrophy in CKD by inhibiting ferroptosis through the activation of the HIF-1α/SLC7A11 pathway and might be a promising traditional Chinese medicine for muscle atrophy in CKD.

Clot removAl with or without decompRessive craniectomy under ICP monitoring for supratentorial IntraCerebral Hemorrhage (CARICH): a randomized controlled trial.

BACKGROUND: Decompressive craniectomy, a surgery to remove part of the skull and open the dura mater, maybe an effective treatment for controlling intracranial hypertension. It remains great interest to elucidate whether decompressive craniectomy is beneficial to intracerebral hemorrhage patients who warrant clot removal to prevent intracranial hypertension. METHODS: The trial was a prospective, pragmatic, controlled trial involving adult patients with intracerebral hemorrhage who were undergoing removal of hematoma. Intracerebral hemorrhage patients were randomly assigned at a 1:1 ratioto undergo clot removal with or without decompressive craniectomy under the monitoring of intracranial pressure. The primary outcome was the proportion of unfavorable functional outcome (modified Rankin Scale 3-6) at 3 months. Secondary outcomes included the mortality at 3 months and the occurrence of re-operation. RESULTS: A total of 102 patients were assigned to the clot removal with decompressive craniectomy group and 102 to the clot removal group. Median hematoma volume was 54.0 mL (range 30-80 mL) and median preoperative Glasgow Coma Scale was 10 (range 5-15). At 3 months, 94 patients (92.2%) in clot removal with decompressive craniectomy group and 83 patients (81.4%) in the clot removal group had unfavorable functional outcome (P=0.023). Fourteen patients (13.7%) in the clot removal with decompressive craniectomy group died versus five patients (4.9%) in the clot removal group (P=0.030). The number of patients with re-operation was similar between the clot removal with decompressive craniectomy group and clot removal group (5.9% vs. 3.9%; P=0.517). Postoperative intracranial pressure values were not significantly different between two groups and the mean values were less than 20 mmHg. CONCLUSIONS: Clot removal without decompressive craniectomy decreased the rate of modified Rankin Scale score of 3-6 and mortality in patients with intracerebral hemorrhage, compared with clot removal with decompressive craniectomy.

Homogeneous electrochemical ratiometric biosensor for MircoRNA detection based on UiO-66-NH2 signal probe and waste-free entropy-driven DNA machine.

The construction of efficient methods for highly sensitive and rapid detection of disease markers is essential for the early diagnosis of serious diseases. In this paper, taking advantage of the UiO-66-NH2 signal molecule in combination with a waste-free entropy-driven DNA machine, a novel homogeneous electrochemical ratiometric platform is developed to detect MircoRNA (miRNA). Metal-organic framework materials (UiO-66-NH2 MOF) and ferrocene were utilized as electrochemical signal tags and reference probes, respectively. The target-initiated waste-free three-dimensional (3D) entropy-driven DNA nanomachine is activated in the presence of miRNA, resulting in DNA-labeled-UiO-66-NH2 falling off from the electrode, leading to a decrease in the signal of UiO-66-NH2 at 0.83V. Our strategy can mitigate false positive responses induced by the DNA probes immobilized on electrodes in traditional distance-dependent signal adjustment ratiometric strategies. The proposed ratiometric platform demonstrates superior sensitivity (a detection limit of 9.8 fM), simplified operation, high selectivity, and high repeatability. The ratiometric biosensor is also applied to detect miRNA content in spiked serum samples.

ß-Lapachone, an NQO1 bioactivatable drug, prevents lung tumorigenesis in mice.

Lung cancer is one of the most lethal cancers with high incidence worldwide. The prevention of lung cancer is of great significance to reducing the social harm caused by this disease. An in-depth understanding of the molecular changes underlying precancerous lesions is essential for the targeted chemoprevention against lung cancer. Here, we discovered an increased NQO1 level over time within pulmonary premalignant lesions in both the KrasG12D-driven and nicotine-derived nitrosamine ketone (NNK)-induced mouse models of lung cancer, as well as in KrasG12D-driven and NNK-induced malignant transformed human bronchial epithelial cells (BEAS-2B and 16HBE). This suggests a potential correlation between the NQO1 expression and lung carcinogenesis. Based on this finding, we utilized ß-Lapachone (ß-Lap), an NQO1 bioactivatable drug, to suppress lung tumorigenesis. In this study, the efficacy and safety of low-dose ß-Lap were demonstrated in preventing lung tumorigenesis in vivo. In conclusion, our study suggests that long-term consumption of low-dose ß-Lap could potentially be an effective therapeutic strategy for the prevention of lung premalignant lesions. However, further studies and clinical trials are necessary to validate our findings, determine the safety of long-term ß-Lap usage in humans, and promote the use of ß-Lap in high-risk populations.

Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization.

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.

MiR-21-5p alleviates trigeminal neuralgia in rats through down-regulation of voltage-gated potassium channel Kv1.1. / MiR-21-5p通过下调电压门控钾离子通道Kv1.1è¡¨è¾¾å‡è½»å¤§é¼ ä¸‰å‰ç¥žç»ç—›.

OBJECTIVES: Trigeminal neuralgia (TN) is a common neuropathic pain. Voltage-gated potassium channel (Kv) has been confirmed to be involved in the occurrence and development of TN, but the specific mechanism is still unclear. MicroRNA may be involved in neuropathic pain by regulating the expression of Kv channels and neuronal excitability in trigeminal ganglion (TG). This study aims to explore the relationship between Kv1.1 and miR-21-5p in TG with a TN model, evaluate whether miR-21-5p has a regulatory effect on Kv1.1, and to provide a new target and experimental basis for the treatment of TN. METHODS: A total of 48 SD rats were randomly divided into 6 groups: 1) a sham group (n=12), the rats were only sutured at the surgical incision without nerve ligation; 2) a sham+agomir NC group (n=6), the sham rats were microinjected with agomir NC through stereotactic brain injection in the surgical side of TG; 3) a sham+miR-21-5p agomir group (n=6), the sham rats were microinjected with miR-21-5p agomir via stereotactic brain injection in the surgical side of TG; 4) a TN group (n=12), a TN rat model was constructed using the chronic constriction injury of the distal infraorbital nerve (dIoN-CCI) method with chromium intestinal thread; 5) a TN+antagonist NC group (n=6), TN rats were microinjected with antagonist NC through stereotactic brain injection method in the surgical side of TG; 6) a TN+miR-21-5p antagonist group (n=6), TN rats were microinjected with miR-21-5p antagonist through stereotactic brain injection in the surgical side of TG. The change of mechanical pain threshold in rats of each group after surgery was detected. The expressions of Kv1.1 and miR-21-5p in the operative TG of rats were detected by Western blotting and real-time reverse transcription polymerase chain reaction. Dual luciferase reporter genes were used to determine whether there was a target relationship between Kv1.1 and miR-21-5p and whether miR-21-5p directly affected the 3'-UTR terminal of KCNA1. The effect of brain stereotaxic injection was evaluated by immunofluorescence assay, and then the analogue of miR-21-5p (agomir) and agomir NC were injected into the TG of rats in the sham group by brain stereotaxic apparatus to overexpress miR-21-5p. The miR-21-5p inhibitor (antagomir) and antagomir NC were injected into TG of rats in the TN group to inhibit the expression of miR-21-5p. The behavioral changes of rats before and after administration were observed, and the expression changes of miR-21-5p and Kv1.1 in TG of rats after intervention were detected. RESULTS: Compared with the baseline pain threshold, the facial mechanical pain threshold of rats in the TN group was significantly decreased from the 5th to 15th day after the surgery (P<0.05), and the facial mechanical pain threshold of rats in the sham group was stable at the normal level, which proved that the dIoN-CCI model was successfully constructed. Compared with the sham group, the expression of Kv1.1 mRNA and protein in TG of the TN group was down-regulated (both P<0.05), and the expression of miR-21-5p was up-regulated (P<0.05). The results of dual luciferase report showed that the luciferase activity of rno-miR-21-5p mimics and KCNA1 WT transfected with 6 nmol/L or 20 nmol/L were significantly decreased compared with those transfected with mimic NC and wild-type KCNA1 WT, respectively (P<0.001). Compared with low dose rno-miR-21-5p mimics (6 nmol/L) co-transfection group, the relative activity of luciferase in the high dose rno-miR-21-5p mimics (20 nmol/L) cotransfection group was significantly decreased (P<0.001). The results of immunofluorescence showed that drugs were accurately injected into TG through stereotaxic brain. After the expression of miR-21-5p in the TN group, the mechanical pain threshold and the expression of Kv1.1 mRNA and protein in TG were increased. After overexpression of miR-21-5p in the sham group, the mechanical pain threshold and the expression of Kv1.1 mRNA and protein in TG were decreased. CONCLUSIONS: Both Kv1.1 and miR-21-5p are involved in TN and miR-21-5p can regulate Kv1.1 expression by binding to the 3'-UTR of KCNA1.

Exploration of treatment in childhood Langerhans cell histiocytosis based on inflammatory and malignant symptoms: a pilot study.

BACKGROUND: Multisystem childhood Langerhans cell histiocytosis (LCH) patients, especially those with risk organ (RO) involved, had not been satisfactorily treated under the international traditional schemes as high incidences of reactivation with late sequelae were largely reported. Over years, we have observed that LCH patients with varied clinical symptoms responded differently to different drugs, suggesting the current grouping strategies based only on the number of organs involved might be inadequate. LCH has been defined as an inflammatory myeloid tumor, thus this study has innovatively divided LCH pediatric patients into inflammatory or malignant symptoms group, and given different intensity treatment regimens to different groups. AIM: This clinical study aimed to explore a more appropriate patient grouping system according to the LCH symptom presentations and examine the clinical outcomes of treatment strategies in different groups. METHODS: According to the clinical manifestations, 37 cases of children were divided into Group A (only inflammatory symptoms) and Group B (malignant symptoms with or without inflammatory symptoms). Patients in Group A and B were initially treated with vindesine (VDS) and methylprednisolone (PSL), and VDS, PSL, pirarubicin (THP) and cyclophosphamide (CTX), respectively. Treatment responses were evaluated six weeks after the induction therapy in all patients, and the criteria were disease status and clinical scores of symptoms. RESULTS: Pre- and post-treatment scores were 1.22 ± 0.547 and 0.00 ± 0.00 in Group A, and 14.79 ± 1.686 and 1.00 ± 1.563 in Group B, respectively. All patients had subsequentlly received maintenance therapy without progressive disease. The 4-year overall survival (OS) rate was 100% in both groups and the 4-year event-free survival (EFS) was 94.4% in Group A and 89.5% in Group B, respectively. There were no obvious adverse events (AE) in Group A, whereas the main AE in Group B were alopecia and non-lethal hematological toxicity. CONCLUSION: Stratification according to patients' clinical symptoms, with low-intensity treatment for inflammatory symptoms (mild manifestations) and intensive treatment with multiple drugs for malignant symptoms (severe manifestations), is a positive exploration that simplifies stratification method, achieves good long-term remission of the disease, and obtains a higher survival rate and quality of life, which seemed to be more appropriate for LCH patients.

The effectiveness of non-pharmacological interventions on reducing pain in patients undergoing bone marrow aspiration and biopsy: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Patients often consider bone marrow aspiration and biopsy to be one of the most painful medical procedures. The effectiveness of non-pharmacological interventions to reduce pain during bone marrow aspiration and biopsy remains unclear. AIM: To synthesize existing evidence regarding the effectiveness of non-pharmacological interventions in mitigating procedural pain among patients undergoing bone marrow aspiration and biopsy. DESIGN: A systematic review and meta-analysis of randomized controlled trials. METHODS: Six electronic databases, including PubMed, EMBASE, CINAHL, PsycINFO, Cochrane Library and Web of Science were searched from inception to July 15, 2023. The risk of bias was assessed using the Cochrane Risk of Bias Tool Version 2.0. Meta-analysis was conducted using STATA 16. The certainty of the evidence was assessed by the GRADE approach. RESULTS: This meta-analysis included 18 studies derived from 17 articles involving a total of 1017 participants. The pooled results revealed statistically significant pain reduction effects using distraction (SMD: -.845, 95% CI: -1.344 to -.346, p < .001), powered bone marrow biopsy system (SMD: -.266, 95% CI: -.529 to -.003, p = .048), and acupoint stimulation (SMD: -1.016, 95% CI: -1.995 to -.037, p = .042) among patients undergoing bone marrow aspiration and biopsy. However, the pooled results on hypnosis (SMD: -1.228, 95% CI: -4.091 to 1.515, p = .368) showed no significant impact on pain reduction. Additionally, the pooled results for distraction did not demonstrate a significant effect on operative anxiety (MD: -2.942, 95% CI: -7.650 to 1.767, p = .221). CONCLUSIONS: Distraction, powered bone marrow biopsy system and acupoint stimulation are effective in reducing pain among patients undergoing bone marrow aspiration and biopsy. PATIENT OR PUBLIC CONTRIBUTION: Not applicable. RELEVANCE TO CLINICAL PRACTICE: This meta-analysis highlights the effectiveness of distraction, powered bone marrow biopsy system and acupoint stimulation for reducing pain in patients undergoing bone marrow biopsy. Healthcare professionals should consider integrating these interventions into pain management practices for these patients. REGISTRATION: (PROSPERO): CRD42023422854.

Targeting PARP14 with lomitapide suppresses drug resistance through the activation of DRP1-induced mitophagy in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy that remains incurable, primarily due to the high likelihood of relapse or development of resistance to current treatments. To explore and discover new medications capable of overcoming drug resistance in MM, we conducted cell viability inhibition screens of 1504 FDA-approved drugs. Lomitapide, a cholesterol-lowering agent, was found to exhibit effective inhibition on bortezomib-resistant MM cells in vitro and in vivo. Our data also indicated that lomitapide decreases the permeability of the mitochondrial outer membrane and induces mitochondrial dysfunction in MM cells. Next, lomitapide treatment upregulated DRP1 and PINK1 expression levels, coupled with the mitochondrial translocation of Parkin, leading to MM cell mitophagy. Excessive mitophagy caused mitochondrial damage and dysfunction induced by lomitapide. Meanwhile, PARP14 was identified as a direct target of lomitapide by SPR-HPLC-MS, and we showed that DRP1-induced mitophagy was crucial in the anti-MM activity mediated by PARP14. Furthermore, PARP14 is overexpressed in MM patients, implying that it is a novel therapeutic target in MM. Collectively, our results demonstrate that DRP1-mediated mitophagy induced by PARP14 may be the cause for mitochondrial dysfunction and damage in response to lomitapide treatment.