Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure, it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease (CVD). Here, our findings revealed that sleep fragmentation (SF) displayed notable hepatic detrimental phenotypes, including steatosis and oxidative damage, along with significant abnormalities in cardiac structure and function. All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more, displaying memory properties. Mechanistically, persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in the liver was the key initiator of SF-accelerated damage phenotypes. SF epigenetically controlled the acetylation of histone H3 lysine 27 (H3K27ac) enrichment at the Nox4 promoter and markedly increased Nox4 expression in liver even after sleep recovery. Moreover, fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1 (Sirt1) transcription after circadian misalignment. Accordingly, genetic manipulation of liver-specific Nox4 or Sirt1, along with pharmacological intervention targeting NOX4 (GLX351322) or SIRT1 (Resveratrol), could effectively erase the epigenetic modification of Nox4 by reducing the H3K27ac level and ameliorate the progression of liver pathology, thereby counteracting SF-evoked sustained CVD. Collectively, our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.

Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, specifically mediated by melatonin (MEL) receptor 1a (MT1). T2DM mice with SF intervention displayed several deleterious phenotypes such as apoptosis, deregulated lipid metabolism, and impaired testicular function. Unexpectedly, sleep recovery (SR) for 2 consecutive weeks could not completely abrogate SF's detrimental effects on lipid deposition and testicular function. Interestingly, MEL and MT1 agonist 2-iodomelatonin (2IM) effectively improved lipid homeostasis, highlighting MEL/2IM as a promising therapeutic drug for SF-trigged testicular damage. Mechanistically, MEL and 2IM activated FGFR1 and sequentially restrained the crosstalk and physical interaction between TAB1 and TAK1, which ultimately suppressed the phosphorylation of TAK1 to block lipid deposition and cell apoptosis caused by SF. The ameliorating effect of MEL/2IM was overtly nullified in Fgfr1 knockout (Fgfr1-KO ^+/- ) diabetic mice. Meanwhile, testicular-specific overexpression of Tak1 abolished the protective effect of FGF1^mut on diabetic mouse testis. Our findings offer valuable insights into the molecular mechanisms underlying the testicular pathogenesis associated with SF and propose a novel therapeutic approach for addressing male infertility in T2DM.

OBJECTIVES: To investigate the associations between Tau protein deposition and brain biochemical metabolites detected by proton magnetic resonance spectroscopy (¹H-MRS) in patients with advanced Alzheimer's disease (AD). METHODS: From April, 2022 to December, 2024, 64 Tau-positive AD patients and 29 healthy individuals underwent ¹⁸F-APN-1607 PET/MR and simultaneously acquired multi-voxel ¹H-MRS in the Department of Nuclear Medicine, Nanjing First Hospital. Visual analysis and voxel-based analysis of PET/MR data were performed to investigate the Tau protein deposition patterns in AD patients. Valid voxels within the ¹H-MRS field of view were selected, and their standardized uptake value ratio (SUVr) in PET and metabolite levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, and Cho/Cr were recorded. The Tau-positive (Tau⁺) voxels and Tau-negative (Tau^-) voxels of the AD patients were compared for PET and ¹H-MRS parameters, and the correlations between the metabolites and Tau PET SUVr within Tau⁺ voxels were analyzed. RESULTS: Significant Tau protein deposition were observed in the AD patients, involving mainly the bilateral frontal lobes (30.07%), parietal lobes (29.96%), temporal lobes (21.07%), and occipital lobes (15.89%). A total of 1422 valid voxels in AD group (including 994 Tau⁺ and 428 Tau^- voxels) and 814 voxels in the control group were selected. The AD patients showed significantly decreased NAA level and increased SUVr compared with the control group (P<0.05). Subgroup analyses revealed that Tau⁺ voxels had higher SUVr and lower Cr and Cho/Cr than Tau^- voxels (P<0.05). Compared with the control group, Tau⁺ voxels exhibited higher SUVr and lower Cr (P<0.05), while Tau^- voxels showed lower NAA (P=0.004). No significant differences were found in Cho or NAA/Cr among the subgroups (P>0.05). Within Tau⁺ voxels, NAA, Cho, and Cr were negatively correlated with SUVr (P<0.001). CONCLUSIONS The patients with progressive AD have significant Tau protein deposition in the brain, which is correlated with alterations in metabolite levels. Decreased NAA is more prominent in early or pre-tau deposition stages, while Cr changes is more significant in the regions with Tau protein deposition, suggesting the potential of NAA and Cr as biomarkers for Tau protein deposition in AD for disease monitoring and treatment evaluation.
Humans ; Alzheimer Disease/diagnostic imaging* ; Aspartic Acid/metabolism* ; tau Proteins/metabolism* ; Creatine/metabolism* ; Brain/metabolism* ; Biomarkers/metabolism* ; Positron-Emission Tomography ; Male ; Female ; Proton Magnetic Resonance Spectroscopy ; Choline/metabolism* ; Aged ; Middle Aged

With the continuous advancement and innovation in medical equipment technology, the transition between high-flow oxygen therapy, non-invasive ventilation, and invasive ventilation can be easily achieved by adjusting the ventilation mode of ventilators. During the weaning phase for tracheotomized patients, it is necessary to disconnect the ventilator circuit, change the ventilator mode, and gradually extend the weaning time to achieve complete ventilator liberation. During the weaning process, due to patients' excessive dependence on the ventilator, there may be situations where respiratory endpoints and Y-connectors of the ventilator are reconnected for invasive ventilation. However, during the weaning process, the Y-connector and expiratory end connectors are exposed to the air, which cannot ensure the tightness of the ventilator circuit, easily increasing the probability of ventilator circuit contamination and subsequently the risk of ventilator-associated pneumonia (VAP). To overcome these issues, the research team of department of critical care medicine of Zhongda Hospital Southeast University has designed a ventilator circuit interface protective device for weaning and has obtained a National Utility Model Patent of China (ZL 2023 2 1453385.8). The main body of the protective device is a Y-connector plug, consisting of multiple components, including a sealing piece, a protective cover, a sealing plug, an interface 1 (connects with the patient's tracheal tube), an interface 2 (connects with the respiratory branch of the ventilator), and an interface 3 (connects with the expiratory branch of the ventilator), featuring a unique design and easy operation. During the patient's weaning training process, the interface 1 and interface 2 is disconnected from the patient's tracheal tube and respiratory branch, respectively. The interface 1 is plugged with a stopper, and the interface 2 is covered with a protective cover to ensure the tightness of the expiratory branch and Y-connector of the ventilator. During the period when the patient is using the ventilator, the protective cover and plug are removed, and connecting them together ensures the tightness of the device itself, reducing the incidence of VAP caused by ventilator circuit contamination, avoiding nosocomial infections, and shortening the prolonged use of invasive ventilation, increased complication rate, extended hospital stay, and increased medical cost associated with weaning.
Humans ; Ventilator Weaning/methods* ; Equipment Design ; Ventilators, Mechanical ; Respiration, Artificial/instrumentation* ; Pneumonia, Ventilator-Associated/prevention & control*

ObjectiveTo investigate the association of particulate matter and ozone with the prevalence of non-alcoholic fatty liver disease (NAFLD) in a district of Shanghai, and to provide epidemiological evidence for the further identification of early health hazards of air pollution and for the prevention and control of NAFLD. MethodsBased on Songjiang Sub-cohort of Shanghai Natural Population Cohort, a cross-sectional survey design was used to recruit participants from 2016 to 2017. Annual average exposure levels to air pollution from 2009 to 2017 were matched to the participant’s residential address using a high-resolution and high-quality ambient air pollutants dataset in China. NAFLD was diagnosed according to the “Guidelines for the prevention and treatment of metabolism⁃associated (non⁃alcoholic) fatty liver disease” by the Chinese Medical Association. Multivariate logistic regression models were employed to analyze the association between air pollution and the prevalence of NAFLD, and stratified analyses were used to compare differences by age, gender, obesity, and lifestyle habits within subgroups. ResultsA total of 32 791 individuals were included in the study. The prevalence of NAFLD among community residents in suburban Shanghai was 38.88%. For every 1 μg·m^-3 increase in PM₁, PM_2.5, PM₁₀, or O₃, the risk of NAFLD increased correspongdinglt, with the odds ratios (95%CI) of 1.071 (1.043‒1.099), 1.065 (1.042‒1.089), 1.041 (1.027‒1.055), or 1.061 (1.032‒1.091), respectively. There were differences in effects across different gender, age, and obesity status subgroups. ConclusionPM₁, PM_2.5, PM₁₀, and O₃ are positively associated with an increased risk of NAFLD. Stratified analyses reveal that individuals aged 65 years old or above exhibited greater susceptibility to PM₁, PM_2.5, and O₃, whereas those aged less than 65 years old are more vulnerable to PM₁₀. Males are more sensitive to PM₁ and O₃, and females are more susceptible to PM_2.5 and PM₁₀. The association between air pollutant exposure and NAFLD risk is more pronounced among obese participants compared to that in non-obese counterparts.

Alzheimer's disease(AD)is the most common neurodegenerative disease in the elderly,and its main pathological manifestations include senile plaques formed by β-amyloid deposition and neuronal fibrillar nodules formed by hyperphosphorylation of tau proteins.Lysosome is an important organelle in eukaryotic cells,containing a variety of hydrolytic enzymes that can break down proteins and other biomolecules.It is closely related to intracellular transport and autophagy,and is important for maintaining cellular homeostasis.This review summarizes the interaction between lysosomal dysfunction and the development and progression of AD and the potential therapeutic mechanisms in treating AD by regulating and restoring the functions of lysosomes.Lysosomal dysfunction can lead to neurodegenerative diseases such as AD.Modulation of lysosomal function is a promising treatment strategy for AD.It is expected that more drugs and therapeutic regimens based on this mechanism can be used in the clinical treatment for AD patients in the future.

Objective:To investigate the distribution patterns of TCM syndrome elements and syndrome types in cancer-related fatigue (CRF).Methods:A cross-sectional survey was conducted on tumor patients attending the outpatient clinic and wards of the Department of Oncology, Xiyuan Hospital of China Academy of Chinese Medical Sciences from January to December 2021. Descriptive analysis was used to compare the distribution difference of TCM syndrome elements, symptoms and tongue symptoms of CRF and non-CRF patients. The TCM symptoms of CRF were clustered to summarize the common TCM syndromes of CRF.Results:A total of 306 tumor patients were finally included, of which 229 (75%) were CRF and 77 (25%) were non-CRF. Qi deficiency, blood deficiency, and cold-dampness were the most common deficiency and excess syndrome elements in CRF, and liver deficiency, yin deficiency, and blood stasis syndrome elements occurred more frequently in non-CRF than in CRF. TCM symptoms with a frequency greater than 50% in CRF patients, from high to low, were: fatigue > shortness of breath > insomnia or dreaminess > mental fatigue > forgetfulness>lazy speech > impatience, irritability, depression with sighing. The most frequent tongue symptoms, tongue coating, and pulse symptoms were respectively pale tongue, white and greasy coating or smooth white, and pulse deficiency. The symptoms with greater than 30% frequency in 77 non-CRF patients were, from highest to lowest: impatience and irritability or depression with sighing > insomnia or dreaminess > shortness of breath > dry mouth and throat > lumbar spine pain (excluding traumatic) > numbness of limbs > forgetfulness. The highest-ranked tongue, tongue coating, and pulse symptoms were pale tongue, red tongue or less coating, no coating, and thin pulse, respectively. Through clustering analysis, six common syndromes of CRF were obtained, including qi and blood deficiency syndrome, heart and liver blood deficiency syndrome, kidney yang deficiency syndrome, qi and yin deficiency syndrome, spleen deficiency and qi stagnation syndrome, and cold dampness and spleen stagnation syndrome.Conclusions:CRF is a common symptom of different types of tumors. Generally, deficiency syndrome is the main symptom. Qi deficiency and blood deficiency are the common syndrome elements. Common symptoms of high frequency and tongue and pulse are fatigue, shortness of breath, mental fatigue, forgetfulness, pale tongue and thin pulse. The common TCM syndrome types can be preliminarily summarized into 6 types: qi and blood deficiency syndrome, heart and liver blood deficiency syndrome, kidney yang deficiency syndrome, qi and yin deficiency syndrome, spleen deficiency and qi stagnation syndrome, cold dampness and spleen stagnation syndrome.

Objective:To investigate and compare the clinical outcomes of the arterial pre-occlusion technique(APOT) and the traditional technique in the surgery of locally advanced pancreatic cancer with arterial involvement after conversion therapy.Methods:This is a retrospective cohort study. The clinical data of 145 patients with locally advanced pancreatic cancer with arterial involvement admitted to the Department of Hepato-Biliary-Pancreatic Surgery of the First Hospital Affiliated to Naval Medical University,from January 2020 to December 2022 were retrospectively analyzed. All patients completed neoadjuvant therapy for tumors, and the feasibility of radical surgical treatment was determined by a multidisciplinary collaborative team evaluation before surgery. According to whether the intraoperative artery was pre-occluded, 145 patients were divided into two groups, including 28 cases in the APOT group(16 males, 12 females, aged (59.0±9.4) years), and 117 cases in the routine surgery group(76 males, 41 females, aged (55.1±8.2) years). To ensure comparability of baseline data between the APOT group and the routine surgery group, a 1∶2 match was performed using the propensity score matching method, and the caliper value was 0.006 45. The t-test,the Mann-Whitney U test, χ2 test or Fisher′s exact test were used to compare the data between the two groups,respectively. Results:After matching the propensity score,there were 28 cases in the APOT group and 56 cases in the routine surgery group. There were no significant differences in gender,age,preoperative comorbidities,preoperative body mass index,surgical approaches,chemotherapy regimen,stereotactic body radiation therapy ratio,tumor markers,and type of invaded artery between the two groups (all P>0.05).The arterial occlusion time M(IQR) in the APOT group was 7.0(3.8)minutes(range:3 to 15 minutes),and no ischemic manifestations were observed in the distal target organs that blocked blood vessels after surgery. The operation time was (170.3±57.7)minutes in the APOT group and (235.0±80.2)minutes in the routine surgery group,and the difference was statistically significant ( t=-3.800, P<0.01). The APOT group also experienced less intraoperative blood loss(650(588)ml vs. 800(600)ml; U=1 026.500, P=0.021). No significant differences were found between the groups in combined vein resection and reconstruction,celiac trunk resection,early postoperative complications, readmission rates at 30 days,and postoperative length of stay(all P>0.05). Extra-arterial dissection was performed in all patients,with arterial resection and reconstruction in 3 cases: 2 cases in the APOT group(1 case involving the superior mesenteric artery and 1 case involving the common hepatic artery) and 1 case in the routine group(involving the common hepatic artery). Postoperative abdominal bleeding occurred in 4 cases,with 3 cases in the routine group,1 case in the routine group. The R0 resection rate was 85.7%(24/28) in the APOT group and 80.4%(45/56) in the routine group,without significant differences between the groups( P=0.763). The median overall survival time was 27.6 months for the APOT group and 22.5 months for the routine group,while the median disease-free survival was 11.7 months and 16.8 months,respectively,with no significant differences between the two groups( P=0.532, P=0.927). Conclusion:The arterial pre-occlusion technique can be used for extra-arterial dissection in patients with locally advanced pancreatic cancer involving the arteries,reducing surgery time and intraoperative blood loss.

Traumatic supraorbital fissure syndrome (TSOFS) is a symptom complex caused by nerve entrapment in the supraorbital fissure after skull base trauma. If the compressed cranial nerve in the supraorbital fissure is not decompressed surgically, ptosis, diplopia and eye movement disorder may exist for a long time and seriously affect the patients′ quality of life. Since its overall incidence is not high, it is not familiarized with the majority of neurosurgeons and some TSOFS may be complicated with skull base vascular injury. If the supraorbital fissure surgery is performed without treatment of vascular injury, it may cause massive hemorrhage, and disability and even life-threatening in severe cases. At present, there is no consensus or guideline on the diagnosis and treatment of TSOFS that can be referred to both domestically and internationally. To improve the understanding of TSOFS among clinical physicians and establish standardized diagnosis and treatment plans, the Skull Base Trauma Group of the Neurorepair Professional Committee of the Chinese Medical Doctor Association, Neurotrauma Group of the Neurosurgery Branch of the Chinese Medical Association, Neurotrauma Group of the Traumatology Branch of the Chinese Medical Association, and Editorial Committee of Chinese Journal of Trauma organized relevant experts to formulate Chinese expert consensus on the diagnosis and treatment of traumatic supraorbital fissure syndrome ( version 2024) based on evidence of evidence-based medicine and clinical experience of diagnosis and treatment. This consensus puts forward 12 recommendations on the diagnosis, classification, treatment, efficacy evaluation and follow-up of TSOFS, aiming to provide references for neurosurgeons from hospitals of all levels to standardize the diagnosis and treatment of TSOFS.