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Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between  ~ 10 and 100 nm accumulate in many solid tumors by the enhanced permeability and retention effect, but it is controversial whether the effect can be exploited for treatment of brain tumors. PLX038A is a long-acting prodrug of the topoisomerase 1 inhibitor SN-38. It is composed of a 15 nm 4-arm 40 kDa PEG tethered to four SN-38 moieties by linkers that slowly cleave to release the SN-38. The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the life span of mice harboring them. We addressed the important issue of whether the prodrug releases SN-38 systemically and then penetrates the brain to exert anti-tumor effects, or whether it directly penetrates the blood-tumor-brain-barrier and releases the SN-38 cargo within the tumor. We argue that the amount of SN-38 formed systemically is insufficient to inhibit the tumors, and show by PET imaging that a close surrogate of the 40 kDa PEG carrier in PLX038A accumulates and is retained in the GBM. We conclude that the prodrug penetrates the blood-tumor-brain-barrier, accumulates in the tumor microenvironment and releases its SN-38 cargo from within. Based on our results, we pose the provocative question as to whether the 40 kDa nanomolecule PEG carrier might serve as a Trojan horse to carry other drugs past the blood-tumor-brain-barrier and release them into brain tumors.

Abstract Although some studies have explored the role of meteorological factors in the development of tuberculosis (TB), the majority have been confined to single regions, leading to inconsistent findings. Consequently, we conducted a multi-city study not only to determine whether meteorological factors significantly influence the risk of developing TB but also to assess the magnitude of these effects and explore potential modifying factors. Data on daily reported TB cases and meteorological factors were collected from January 1, 2013, to December 31, 2022, across 11 cities in Zhejiang Province. A distributed lag non-linear model using a quasi-Poisson distribution was employed. Multivariate meta-regression was used to obtain overall pooled estimates and assess heterogeneity. From 2013 to 2022, 267,932 TB cases were reported in Zhejiang Province. Notably, a nonlinear relationship was observed between temperature and TB, with the relative risk (RR) peaking at 1.0 °C (RR = 1.882, 95% CI 1.173–3.020). The effect of low temperature was immediate and significant for a 13-day lag period, with the maximum effect at lag0 (RR = 1.014, 95% CI 1.008–1.021). The exposure-response curve between relative humidity (RH) and TB exhibited an M-shape, with the RR peaking at 47.7% (RR = 1.642, 95% CI 1.044–2.582). The lag effect of low RH was significant at lag 25–59, with the highest RR observed at lag 32 (RR = 1.011, 95% CI 1.001–1.022). Gross domestic product (GDP) per person, population density, and latitude demonstrated significant modification effects. Our study showed that low temperature and RH were associated with an increased risk of TB. Additionally, GDP per person, population density, and latitude may play important roles in explaining the association between RH and TB. These findings provide scientific evidence for the development of geographically specific public health policies.

Abstract MandibuloAcral Dysplasia associated to MTX2 gene (MADaM) is a recently described progeroid syndrome (accelerated aging disease) whose clinical manifestations include skin abnormalities, growth retardation, and cardiovascular diseases. We previously proposed that mtx-2-deficient C. elegans could be used as a model for MADaM and to support this, we present here our comprehensive phenotypic characterization of these worms using atomic force microscopy (AFM), transcriptomic, and oxygen consumption rate analyses. AFM analysis showed that young mtx-2-less worms had a significantly rougher, less elastic cuticle which becomes significantly rougher and less elastic as they age, and abnormal mitochondrial morphology. mtx-2 C. elegans displayed slightly delayed development, decreased pharyngeal pumping, significantly reduced mitochondrial respiratory capacities, and transcriptomic analysis identified perturbations in the aging, TOR, and WNT-signaling pathways. The phenotypic characteristics of mtx-2 worms shown here are analogous to many of the human clinical presentations of MADaM and we believe this validates their use as a model which will allow us to uncover the molecular details of the disease and develop new therapeutics and treatments.

Abstract Purpose To minimize radiation exposure to the small bowel (SB) in patients undergoing treatment for gynecological tumors by adopting a comfortable positioning method. Methods and patients All 76 women undergoing Intensity-Modulated Radiation Therapy (IMRT) were included in this study. Patients were immobilized in a supine position using a vacuum bag and thermoplastic cast formation. In the trial group (n = 36), patients raised their buttocks and a solid foam pad was placed under the sacral tail before immobilization. The control group (n = 40) received treatment in the standard supine position. The SB was delineated from the pubic symphysis to the total iliac bifurcation in computed tomography (CT) scans. Result In the trial group, a significant reduction in SB volume within the pelvic cavity was observed (mean 399.17 ± 158.7 cc) compared to the control group (mean 547.48 ± 166.9 cc), with a p-value less than 0.001. The trial group showed a statistically significant reduction in the absolute volume of irradiated SB at each dose, ranging from the low dose (10 Gy) to the high dose (45 Gy). In the control group, a negative correlation was found between SB and bladder volumes (R = -0.411, P = 0.008), whereas in the trial group, this correlation was weaker (R = -0.286, P = 0.091), with no significant relationship observed between bladder volume and SB. Conclusion The high buttocks supine position effectively reduces SB radiation exposure without the need for bladder distension. This positioning method holds promise for reducing SB irradiation in various pelvic tumors.

Pulmonary hypertension (PH) is a rare and life-threatening disease. Over past two decades, rapid advancements in treatment techniques have significantly improved the prognosis of two major subgroups of PH entities: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Given the underlying pathological feature of in situ thrombosis of small arteries, anti-coagulation was previously considered to be a supportive therapy for PAH to improve prognosis. However, due to a lack of robust evidence, it is not recommended by the current guidelines. In contrast, lifelong anticoagulation is recommended for CTEPH patients to prevent thrombus recurrence and in situ thrombosis, based on the thromboembolic etiology. Furthermore, with the advent of direct oral anticoagulants, there are now more options for anti-coagulation therapy in PH. Nevertheless, due to the complexity of PH etiology and the heterogeneity of treatment approaches, anti-coagulation management remains challenging. This article reviews and evaluates the current status and safety issue of anti-coagulation therapy for PH patients, providing guidance and insights for clinical practice and research in this field.

PRKAG2 is required for the maintenance of cellular energy balance. PRKAG2-AS1, a long non-coding RNA (lncRNA), was found within the promoter region of PRKAG2. Despite the extensive expression of PRKAG2-AS1 in endothelial cells, the precise function and mechanism of this gene in endothelial cells have yet to be elucidated. The localization of PRKAG2-AS1 was predominantly observed in the nucleus, as revealed using nuclear and cytoplasmic fractionation and fluorescence in situ hybridization. The manipulation of PRKAG2-AS1 by knockdown and overexpression within the nucleus significantly altered PRKAG2 expression in a cis-regulatory manner. The expression of PRKAG2-AS1 and its target genes, PRKAG2b and PRKAG2d, was down-regulated in endothelial cells subjected to oxLDL and Hcy-induced injury. This finding suggests that PRKAG2-AS1 may be involved in the mechanism behind endothelial injury. The suppression of PRKAG2-AS1 specifically in the nucleus led to an upregulation of inflammatory molecules such as cytokines, adhesion molecules, and chemokines in endothelial cells. Additionally, this nuclear suppression of PRKAG2-AS1 facilitated the adherence of THP1 cells to endothelial cells. We confirmed the role of nuclear knockdown PRKAG2-AS1 in the induction of apoptosis and inhibition of cell proliferation, migration, and lumen formation through flow cytometry, TUNEL test, CCK8 assay, and cell scratching. Finally, it was determined that PRKAG2-AS1 exerts direct control over the transcription of PRKAG2 by its binding to their promoters. In conclusion, downregulation of PRKAG2-AS1 suppressed the proliferation and migration, promoted inflammation and apoptosis of endothelial cells, and thus contributed to the development of atherosclerosis resulting from endothelial cell injury.

The continuous drive friction welding (CDFW) stands out for its low energy consumption within the welding realm. Polyetheretherketone (PEEK) represents a high-performance engineering thermoplastic, falling under the polyaryletherketone family. Renowned for its outstanding mechanical, thermal, and chemical attributes, PEEK finds utility across a diverse array of industries. However, the discovery of numerous voids at the weld interface has revealed limitations in the mechanical properties of PEEK welded samples. This study introduces an innovative approach named progressively increased welding area (PIWA) method, to mitigate voids within the weld interface. In general, the Taguchi method was used to optimize the process parameters of CDFW of dissimilar PEEK round rods to reduce random efforts by the trial-and-error method. It was found that the proposed PIWA method can definitely enhance the bending strength of rotational friction welded samples due to reduction of voids inside the weld interface. The optimal process parameters for the CDFW with the PIWA method involve a rotational speed of 2500 rpm, a cone angle of 120°, a cone top width of 8 mm, and a feed rate of 0.1 mm/s. The most influential factor affecting the bending strength of the PEEK welded samples is the feed rate, followed by cone angle, rotational speed, and cone top width. Specifically, the contribution ratios for feed rate, cone angle, rotational speed, and cone top width are about 71 %, 20 %, 7 %, and 2 %, respectively. The confirmation tests showed that the bending strength of the PEEK welded samples using optimal process parameters can be increased by approximately 68 % compared with the maximum bending strength of 180 MPa using the conventional method with a cone angle of 180° The proposed PIWA method has industrial applicability and practical value because this technique can enhance the mechanical properties of PEEK welded samples under low environmental pollution and energy consumption.

Investigation of the joining technology of 3D-printed parts into a large physical model has become an important research topic. Rotary friction welding (RFW) is one of the friction welding methods. Understanding the weld interface temperature changes in the weld center zone during RFW is critical because it is related to the weld quality of the welded parts using RFW. Traditionally, the number of revolutions is constant in the RFW. However, rare investigations focus on the fatigue specimen fabricated by RFW with variable rotational speed. This study used RFW with varying rotational speeds to fabricate fatigue specimens. The ANSYS software was used to predict the temperature history of rotary frictionally welded dissimilar polymer rods fabricated by a computer numerical control (CNC) turning machine with variable rotational speed. The RFW experiment of ABS/PC dissimilar polymer rods was conducted to investigate the temperature history and compared with the simulation results. It was found that the temperature history profiles were in good agreement with the experimental and simulation results. Compared with the weld interface heating rate obtained from the experimental results, the simulation results has average discrepancy rate about 4.48 %. Compared with the maximum temperature of the weld interface obtained from the experimental results, the simulation results has average discrepancy rate about 3.16 %. The fatigue life can be increased by approximately 1.4 times. Finally, a database of rotary frictionally welded dissimilar polymer rods fabricated by a CNC turning machine with variable rotational speed was proposed. The average Shore A surface hardness at the weld interface was enhanced by approximately 18 % compared to the base ABS material.

Abstract Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Cardiovascular surgery has a high risk of neurological complications, which can increase the burden of disease. Perioperative real⁃time monitoring of neurological function in cardiovascular surgery can assist clinicians to detect neurological abnormalities as early as possible, intervene and reduce the risk of neurological complications in time. The main monitoring indicators include cerebral oxygen saturation (ScO2), EEG, cerebral blood flow (CBF), etc. In this paper, the common perioperative neuromonitoring techniques and their research advances in cardiovascular surgery are reviewed to provide theoretical basis for reducing neurological complications and improve the prognosis of patients.