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Gui-Qi Zhu,1,2,* Kang Wang,3,* Biao Wang,1,2,* Yu-Jie Zhou,4,* Yi Yang,1,2 Er-Bao Chen,5 Zheng-Jun Zhou,1,2 Shao-Lai Zhou,1,2 Ying-Hong Shi,1,2 Jian Zhou,1,2 Zhi Dai1,2 1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; 2State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China; 3Department of Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China; 4Department of Gastroenterology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China; 5Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China *These authors contributed equally to this work Background and aim: To investigate the value of the aspartate aminotransferase-to-platelet ratio index (APRI) and build a new nomogram for hepatocellular carcinoma (HCC) patients undergoing postoperative adjuvant transarterial chemoembolization (PATACE).Methods: We retrospectively reviewed 351 patients with HCC undergoing PATACE. We collected baseline HCC patient characteristics to obtain the risk factors for determining poor disease-free survival (DFS) and early time to recurrence (TTR) after PATACE. The multivariate Cox proportional hazards model was used to build new nomogram based on significant prognostic factors of outcomes.Results: We generated the cutoff value of the APRI as 0.50 using the X-tile to distinguish patients with different outcomes in the whole cohort. Two hundred seventeen patients with high APRI had poorer survival (P

We presented the surgical procedures of full endoscopic total parotidectomy followed by the sternocleidomastoid muscle flap transplantation via a short postauricular hairline incision, and reported patient outcomes to evaluate the feasibility and efficacy of this novel approach. Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

In the present study, we presented the detailed procedure and experience of endoscope-assisted transoral procedure of accessory parotid gland (APG) tumor resection. The surgical steps and tips were described and summarized clearly in our video. Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Renal denervation (RDN) has been used for treating resistant hypertension. A few recent studies have shown vagal innervation of kidneys causing confusion. This study aimed to provide anatomical and functional evidence for renal autonomic innervation. Experiments were performed in male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Pseudorabies virus (PRV) in the paraventricular nucleus and rostral ventrolateral medulla was prevented by bilateral RDN, but not subdiaphragmatic vagotomy. PRV did not appear in the dorsal motor nucleus of the vagus and nucleus tractus solitarii 72 h after renal injection of PRV. Adrenergic fibers were approximately seven times more than cholinergic fibers in the main renal artery (MRA) and its first (1RA) and second grade (2RA) branches. Adrenergic fibers in 1RA were more than those in MRA and 2RA. Tyrosine hydroxylase immunoreactivity in these arteries was higher in SHR than in WKY. Norepinephrine (NE) increased and α-receptor antagonist reduced vascular ring tension of renal arteries. The effect of NE was greater in 1RA and 2RA than in MRA, which was prevented by α-receptor antagonist. Acetylcholine (ACh) or blockage of β-receptors, M receptors, or N receptors had no significant effects on vascular ring tension and the effect of NE. Renal blood flow was reduced by electrical stimulation of renal nerves but not affected by stimulation of the subdiaphragmatic vagus. These results provide anatomical and functional evidence that kidneys are innervated and renal blood flow is regulated by renal sympathetic nerves rather than the vagus. Renal vasoconstriction is regulated by NE and adrenergic fibers rather than ACh or cholinergic fibers in WKY and SHR. NEW & NOTEWORTHY Kidneys are innervated by renal nerves rather than the vagus. Adrenergic fibers in renal arteries are about seven times more than cholinergic fibers. Renal vasoconstriction is regulated by norepinephrine and adrenergic fibers rather than acetylcholine or cholinergic fibers. Renal blood flow is regulated by renal sympathetic nerves and is not affected by the vagus. These findings provide anatomical and functional evidence for renal autonomic innervation in normotensive and hypertensive rats.

Background: Sympathetic hyperactivity contributes to the pathogenesis of hypertension. However, it is unclear whether the excessive sympathetic activity is an independent and crucial factor for vascular remodeling in hypertension. This study focused on the effect of local sympathetic denervation with superior cervical ganglionectomy (SCGx) on vascular remodeling., Methods: Surgical bilateral SCGx was performed in 9-week-old male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Control rats received sham-operation without SCGx. All measurements were made 4 weeks after the surgery., Results: The effectiveness of SCGx was confirmed by the eye features of Horner syndrome, greatly reduced tyrosine hydroxylase (TH) contents in the superior cervical ganglion (SCG)-innervated arteries in the head. Although SCGx had no significant effects on blood pressure and heart rate in WKY and SHR, it attenuated vascular remodeling of facial artery and superficial temporal artery in SHR, two representative SCG-innervated extracranial arteries, without significant effects on non-SCG-innervated thoracic aorta and mesenteric artery. SCGx-treated SHR had more auricular blood flow and retina microvasculature than sham-operated SHR. However, SCGx had only a mild effect in attenuating the vascular remodeling of basilar artery and middle cerebral artery, two representative SCG-innervated intracranial arteries, in SHR. SCGx-treated SHR exhibited upregulation of α-smooth muscle actin, downregulation of proliferating cell nuclear antigen, and attenuation of oxidative stress and inflammation in facial artery and superficial temporal artery., Conclusions: Sympathetic denervation by SCGx in SHR attenuated local vascular remodeling, suggesting that sympathetic overactivity is a crucial pathogenic factor of vascular remodeling in SHR., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Leaf senescence is a complex process regulated by developmental and environmental factors, and plays a pivotal role in the development and life cycle of higher plants. Casein kinase 1 (CK1) is a highly conserved serine/threonine protein kinase in eukaryotes and functions in various cellular processes including cell proliferation, light signaling and hormone effects of plants. However, the biological function of CK1 in plant senescence remains unclear. Through systemic genetic and biochemical studies, we here characterized the function of Arabidopsis EL1-like (AEL), a CK1, in promoting leaf senescence by stimulating ethylene biosynthesis through phosphorylating transcription factor WRKY22. Seedlings lacking or overexpressing AELs presented delayed or accelerated leaf senescence, respectively. AELs interact with and phosphorylate WRKY22 at Thr57, Thr60 and Ser69 residues to enhance whose transactivation activity. Being consistent, increased or suppressed phosphorylation of WRKY22 resulted in the promoted or delayed leaf senescence. WRKY22 directly binds to promoter region and stimulates the transcription of 1-amino-cyclopropane-1-carboxylate synthase 7 gene to promote ethylene level and hence leaf senescence. Our studies demonstrated the crucial role of AEL-mediated phosphorylation in regulating ethylene biosynthesis and promoting leaf senescence by enhancing WRKY22 transactivation activity, which helps to elucidate the fine-controlled ethylene biosynthesis and regulatory network of leaf senescence., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Chemerin is an adipokine that contributes to metabolism regulation. Nucleus tractus solitarius (NTS) is the first relay station in the brain for accepting various visceral afferent activities for regulating cardiovascular activity. However, the roles of chemerin in the NTS in regulating sympathetic activity and blood pressure are almost unknown. This study aimed to determine the role and potential mechanism of chemerin in the NTS in modulating sympathetic outflow and blood pressure. Bilateral NTS microinjections were performed in anaesthetized adult male Sprague-Dawley rats. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were highly expressed in caudal NTS (cNTS). Microinjection of chemerin-9 to the cNTS increased RSNA, MAP and HR, which were prevented by CMKLR1 antagonist α-NETA, superoxide scavenger tempol or N-acetyl cysteine, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium or apocynin. Chemerin-9 increased superoxide production and NADPH oxidase activity in the cNTS. The increased superoxide production induced by chemerin-9 was inhibited by α-NETA. The effects of cNTS microinjection of chemerin-9 on the RSNA, MAP and HR were attenuated by the pretreatment with paraventricular nucleus (PVN) microinjection of NMDA receptor antagonist MK-801 rather than AMPA/kainate receptor antagonist CNQX. These results indicate that chemerin-9 in the NTS increases sympathetic outflow, blood pressure and HR via CMKLR1-mediated NADPH oxidase activation and subsequent superoxide production in anaesthetized normotensive rats. Glutamatergic inputs in the PVN are needed for the chemerin-9-induced responses., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury. Antioxid. Redox Signal. 41, 488-504.

Background: Currently, tumor budding (TB) is defined as an important factor for a poor prognosis in various types of cancers. The authors identified a significant presence of TB-like structures at the tumor invasive front in giant cell tumor of bone (GCTB), which may have the same biologic function as TB. The objective of this report was to describe the distribution of TB in GCTB and investigate its correlation with clinicopathologic characteristics, the immune microenvironment, survival prognosis, and response to denosumab treatment., Methods: This multicenter cohort study included 426 patients with GCTB who received treatment between 2012 and 2021 at four centers. Two independent pathologists performed visual assessments of TBL structures in hematoxylin-and-eosin-stained tumor sections. Immunohistochemistry was used to evaluate tumor-infiltrating lymphocyte subtypes (CD3-positive, CD4-positive, CD8-positive, CD20-positive, programmed cell death protein-1-positive, programmed cell death-ligand 1positive, and FoxP3-positive) as well as Ki-67 expression levels in 426 tissue samples. These parameters were then analyzed for associations with patient outcomes (local recurrence-free survival [LRFS] and overall survival [OS]), clinicopathologic characteristics, and response to denosumab treatment., Results: High-grade TB was associated with poorer LRFS and OS in both patient groups. In addition, TB was correlated with various clinicopathologic features, tumor-infiltrating lymphocyte expression, and response to denosumab treatment. TB outperformed the traditional Enneking and Campanacci staging systems in predicting patient LRFS and OS., Conclusions: The current data support the assessment of TBL structures as a reliable prognostic tool in GCTB, potentially aiding in the development of personalized treatment strategies for patients., (© 2024 American Cancer Society.)

This study aimed to report our experience about endoscopic neck dissection through a post-auricular hairline incision, followed by intraoral resection of oral cancer and free flap reconstruction. Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: The prognostic value of lymphocyte infiltration score (LIS) and its nearest neighbor distance to tumor cells (NNDTC) in giant cell tumor of bone (GCTB) is currently not well established. This study aims to characterize LIS and NNDTC and examine their correlation with denosumab treatment responsiveness, clinicopathologic features, and patient prognosis., Methods: Using multiplexed quantitative immunofluorescence, LIS was evaluated in 253 tumor specimens, whereas NNDTC was computed using HALO software. Subsequently, we analyzed the association of these parameters with patient outcomes (progression-free survival [PFS] and overall survival [OS]), clinicopathologic features, and denosumab treatment responsiveness., Results: Low LIS was indicative of both poor PFS and OS (both P < .001). In addition, LIS was significantly associated with sex ( P = .046), Enneking staging ( P < .001), Ki-67 expression ( P = .007), and denosumab treatment responsiveness ( P = .005). Lower CD8 + (tumor interior [TI]) NNDTC, and CD3 + (TI) NNDTC were associated with worse PFS ( P = .003 and .038, respectively), whereas lower CD8 + (TI) NNDTC was associated with worse OS ( P = .001), but CD8 + (tumor infiltrating margin) NNDTC had the opposite effect ( P = .002). Moreover, NNDTC showed a correlation with several clinicopathologic features. Importantly, LIS outperformed Enneking and Campanacci staging systems in predicting the clinical outcomes of GCTB., Conclusion: These findings suggest that LIS is a reliable predictive tool for clinically relevant outcomes and response to denosumab therapy in patients with GCTB. These parameters may prove to be useful in guiding prognostic risk stratification and therapeutic optimization for patients.

Isoleucine-proline-proline (Ile-Pro-Pro, IPP) is a natural food source tripeptide that inhibits angiotensin-converting enzyme (ACE) activity. The aim of this study was to determine the central and peripheral roles of IPP in attenuating sympathetic activity, oxidative stress and hypertension. Male Sprague-Dawley rats were subjected to sham-operated surgery (Sham) or two-kidney one-clip (2K1C) surgery to induce renovascular hypertension. Renal sympathetic nerve activity and blood pressure were recorded. Bilateral microinjections of IPP to hypothalamic paraventricular nucleus (PVN) attenuated sympathetic activity (-16.1 ± 2.5%, P < 0.001) and hypertension (-8.7 ± 1.5 mmHg, P < 0.01) in 2K1C rats by inhibiting ACE activity and subsequent angiotensin II and superoxide production in the PVN. Intravenous injections of IPP also attenuated sympathetic activity (-15.1 ± 2.1%, P < 0.001) and hypertension (-16.8 ± 2.3 mmHg, P < 0.001) via inhibiting ACE activity and oxidative stress in both PVN and arteries of 2K1C rats. The duration of the effects of the intravenous IPP was longer than those of the PVN microinjection, but the sympatho-inhibitory effect of intravenous injections occurred later than that of the PVN microinjection. Intraperitoneal injection of IPP (400 pmol/day for 20 days) attenuated hypertension and vascular remodeling via inhibiting ACE activity and oxidative stress in both PVN and arteries of 2K1C rats. These results indicate that IPP attenuates hypertension and sympathetic activity by inhibiting ACE activity and oxidative stress. The sympathoinhibitory effect of peripheral IPP is mainly caused by the ACE inhibition in PVN, and the antihypertensive effect is related to the sympathoinhibition and the arterial ACE inhibition. Long-term intraperitoneal IPP therapy attenuates hypertension, oxidative stress and vascular remodeling., (© 2024. The Author(s) under exclusive licence to University of Navarra.)

Objective: Proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to vascular remodeling. Asprosin, a newly discovered protein hormone, is involved in metabolic diseases. Little is known about the roles of asprosin in cardiovascular diseases. This study focused on the role and mechanism of asprosin on VSMC proliferation and migration, and vascular remodeling in a rat model of hypertension., Methods and Results: VSMCs were obtained from the aortic media of 8-week-old male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Asprosin was upregulated in the VSMCs of SHR. For in vitro studies, asprosin promoted VSMC proliferation and migration of WKY and SHR, and increased Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity, NOX1/2/4 protein expressions and superoxide production. Knockdown of asprosin inhibited the proliferation, migration, NOX activity, NOX1/2 expressions and superoxide production in the VSMCs of SHR. The roles of asprosin in promoting VSMC proliferation and migration were not affected by hydrogen peroxide scavenger, but attenuated by superoxide scavenger, selective NOX1 or NOX2 inhibitor. Toll-like receptor 4 (TLR4) was upregulated in SHR, TLR4 knockdown inhibited asprosin overexpression-induced proliferation, migration and oxidative stress in VSMCs of WKY and SHR. Asprosin was upregulated in arteries of SHR, and knockdown of asprosin in vivo not only attenuated oxidative stress and vascular remodeling in aorta and mesentery artery, but also caused a subsequent persistent antihypertensive effect in SHR., Conclusions: Asprosin promotes VSMC proliferation and migration via NOX-mediated superoxide production. Inhibition of endogenous asprosin expression attenuates VSMC proliferation and migration, and vascular remodeling of SHR., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown., Methods: Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry., Results: The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8., Conclusion: The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC., (© 2024. The Author(s).)

Freeze pretreatment combined with alkaline-hydrothermal method of rice straw for enzymatic hydrolysis was studied. Crystallization stress in the rice stem pores caused by water freezing at -20- -40 °C was modeled to illustrate the destruction mechanism. The stress was calculated as 22.5-38.3 MPa that were higher than the tensile yield stress of untreated stems (3.0 MPa), indicating ice formation damaging pore structure. After freeze at -20 °C, rice straw was further hydrothermally treated at 190 °C with 0.4 M Na 2 CO 3 , achieving 72.0 % lignin removal and 97.2 % cellulose recovery. Glucose yield rose to 91.1 % by 4.3 times after 24 h hydrolysis at 10 FPU loading of Cellic®CTec2 cellulase. The specific surface area of rice straw was 2.6 m 2 /g increased by 1.2 times after freeze. Freeze combined with alkaline-hydrothermal treatment is a green and energy-efficient method for improving enzymatic hydrolysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cervical cancer (CxCa) is the fourth most frequent cancer in women. This study aimed to determine the role and underlying mechanism of fibronectin type III domain-containing protein 5 (FNDC5) in inhibiting CxCa growth. Experiments were performed in human CxCa tissues, human CxCa cell lines (HeLa and SiHa), and xenograft mouse model established by subcutaneous injection of SiHa cells in nude mice. Bioinformatics analysis showed that CxCa patients with high FNDC5 levels have a longer overall survival period. FNDC5 expression was increased in human CxCa tissues, HeLa and SiHa cells. FNDC5 overexpression or FNDC5 protein not only inhibited proliferation, but also restrained invasion and migration of HeLa and SiHa cells. The effects of FNDC5 were prevented by inhibiting integrin with cilengitide, activating PI3K with recilisib or activating Akt with SC79. FNDC5 inhibited the phosphorylation of PI3K and Akt, which was attenuated by recilisib. PI3K inhibitor LY294002 showed similar effects to FNDC5 in HeLa and SiHa cells. Intravenous injection of FNDC5 (20 μg/day) for 14 days inhibited the tumor growth, and reduced the proliferation marker Ki67 expression and the Akt phosphorylation in the CxCa xenograft mouse model. These results indicate that FNDC5 inhibits the malignant phenotype of CxCa cells through restraining PI3K/Akt signaling. Upregulation of FNDC5 may play a beneficial role in retarding the tumor growth of CxCa., (© 2024 Wiley Periodicals LLC.)

Objective: and design Mild vascular inflammation promotes the pathogenesis of hypertension. Asprosin, a newly discovered adipokine, is closely associated with metabolic diseases. We hypothesized that asprosin might led to vascular inflammation in hypertension via NLRP3 inflammasome formation. This study shows the importance of asprosin in the vascular inflammation of hypertension., Methods: Primary vascular smooth muscle cells (VSMCs) were obtained from the aorta of animals, including spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), NLRP3 -/- and wild-type mice. Studies were performed in VSMCs in vitro , as well as WKY and SHR in vivo ., Results: Asprosin expressions were up-regulated in VSMCs and media of arteries in SHR. Asprosin overexpression promoted NLRP3 inflammasome activation via Toll-like receptor 4 (TLR4), accompanied with activation of NFκB signaling pathway in VSMCs. Exogenous asprosin protein showed similar roles in promoting NLRP3 inflammasome activation. Knockdown of asprosin restrained NLRP3 inflammasome and p65-NFκB activation in VSMCs of SHR. NLRP3 inhibitor MCC950 or NFκB inhibitor BAY11-7082 attenuated asprosin-caused VSMC proliferation and migration. Asprosin-induced interleukin-1β production, proliferation and migration were attenuated in NLRP3 -/- VSMCs. Local asprosin knockdown in common carotid artery of SHR attenuated inflammation and vascular remodeling., Conclusions: Asprosin promoted NLRP3 inflammasome activation in VSMCs by TLR4-NFκB pathway, and thereby stimulates VSMCs proliferation, migration, and vascular remodeling of SHR., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for diabetes treatment. The paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expressions were present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist exendin 9-39 (EX9-39) or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor apocynin, adenylyl cyclase (AC) inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, AC, and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in the PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contributes to sympathetic overactivity and hypertension., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Purpose: To assess the clinical benefits of surface-guided radiation therapy (SGRT) in terms of setup error, positioning time, and clinical target volume-to-planning target volume (CTV-PTV) margin in extremity soft tissue sarcoma (STS)., Methods and Materials: Fifty consecutive patients treated with radiation therapy were selected retrospectively. Treatment setup was performed with either laser-based imaging only (control group), or with laser-based and daily optical surface-based imaging (SGRT group). Pretreatment cone beam computed tomography images were acquired daily for the first 3 to 5 fractions and weekly thereafter, with the frequency adjusted as necessary. Translational and rotational errors were collected. CTV-PTV margin was calculated using the formula, 2.5Σ + 0.7σ., Results: Each group consisted of 10 and 15 upper and lower limb STSs, respectively. For patients with upper limb sarcomas, the translation errors were 1.64 ± 1.34 mm, 1.10 ± 1.50 mm, and 1.24 ± 1.45 mm in the SGRT group, and 1.48 ± 3.16 mm, 2.84 ± 2.85 mm, and 3.14 ± 3.29 mm in control group in the left-right, supero-inferior, and antero-posterior directions, respectively. Correspondingly, for patients with lower limb sarcomas, the translation errors were 1.21 ± 1.65 mm, 1.39 ± 1.71 mm, and 1.48 ± 2.10 mm in the SGRT group, and 1.81 ± 2.60 mm, 2.93 ± 3.28 mm, and 3.53 ± 3.75 mm in control group, respectively. The calculated CTV-PTV margins of the SGRT group and control group were 5.0, 3.8, 4.1 versus 5.9, 9.1, 10.1 mm for upper limb sarcomas; and 4.2, 4.7, 5.2 mm versus 6.3, 9.6, and 11.4 mm for lower limb sarcomas in the left-right, supero-inferior, and antero-posterior directions, respectively., Conclusions: Daily optical surface guidance can effectively improve the setup accuracy of extremity STS patients, and safely reduce the required CTV-PTV margins., (© 2024 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.)

Background: Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging., Results: Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo., Conclusions: Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis., (© 2024. The Author(s).)

Background: Benign prostatic hyperplasia (BPH) is a prevalent disease affecting elderly men, with chronic inflammation being a critical factor in its development. Omentin-1, also known as intelectin-1 (ITLN-1), is an anti-inflammatory protein primarily found in the epithelial cells of the small intestine. This study aimed to investigate the potential of ITLN-1 in mitigating BPH by modulating local inflammation in the prostate gland., Methods: Our investigation involved two in vivo experimental models. Firstly, ITLN-1 knockout mice (Itln-1 -/- ) were used to study the absence of ITLN-1 in BPH development. Secondly, a testosterone propionate (TP)-induced BPH mouse model was treated with an ITLN-1 overexpressing adenovirus. We assessed BPH severity using prostate weight index and histological analysis, including H&E staining, immunohistochemistry, and enzyme-linked immunosorbent assay. In vitro, the impact of ITLN-1 on BPH-1 cell proliferation and inflammatory response was evaluated using cell proliferation assays and enzyme-linked immunosorbent assay., Results: In vivo, Itln-1 -/- mice exhibited elevated prostate weight index, enlarged lumen area, and higher TNF-α levels compared to wild-type littermates. In contrast, ITLN-1 overexpression in TP-induced BPH mice resulted in reduced prostate weight index, lumen area, and TNF-α levels. In vitro studies indicated that ITLN-1 suppressed the proliferation of prostate epithelial cells and reduced TNF-α production in macrophages, suggesting a mechanism involving the inhibition of macrophage-mediated inflammation., Conclusion: The study demonstrates that ITLN-1 plays a significant role in inhibiting the development of BPH by reducing local inflammation in the prostate gland. These findings highlight the potential of ITLN-1 as a therapeutic target in the management of BPH., (© 2024. The Author(s).)

To investigate the safety and feasibility of gasless total endoscopic resection of deep lobe parotid gland tumors via a postauricular hairline plus temporal approach. The approach was designed as: a 4 to 5 cm main incision was designed at the postauricular hairline, and a 0.5 cm auxiliary incision was designed in the temporal hairline. The operating cavity was established with the assistance of a special retractor. "Anterograde" dissection of the facial nerve was performed throughout the procedure, along with partial or total gland removal of the tumor. All 16 operations were successfully completed without conversion to open surgery. During the operation, the trunk and branches of the facial nerve were completely preserved, the tumor was completely removed, and the incision healed. Six patients had mild facial paralysis after operation, and recovered completely after 3 to 6 months. There was no salivary fistula, Frey syndrome, infection, or other complications. The postoperative incision was concealed and the aesthetic effect was good. The postauricular hairline plus temporal approach gasless total endoscopic parotidectomy is safe and feasible. This technique can achieve the complete dissection of the total trunk to the branches of the facial nerve, and has good access to the tumors located in any part of the parotid gland region. On the basis of radical resection of the tumor, it achieves minimally invasive and aesthetic improvement.

Background: Metagenomic Next-Generation Sequencing (mNGS) is a rapid, non-culture-based, high-throughput technique for pathogen diagnosis. Despite its numerous advantages, only a few studies have investigated its use in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT)., Methods: We conducted a retrospective analysis of 404 mNGS tests performed on 264 patients after allo-HSCT. The tests were divided into three groups (Phase A, B, C) based on the time spent hospitalized post-transplantation, and we evaluated the analytical performance of mNGS in comparison with conventional microbiological tests (CMT), while also analyzing its clinical utility for clinical impacts., Results: Metagenomic sequencing demonstrated a significantly higher rate of positive microbiological findings as compared to CMT (334/404 (82.7 %) vs. 159/404 (39.4 %), respectively, P < 0.001). The detection rates by both mNGS and CMT varied across the three-phase (mNGS: A-60/89 (67.4 %), B-147/158 (93.0 %), C-125/157 (79.6 %), respectively, P < 0.001; CMT: A-21/89 (23.6 %), B-79/158 (50.0 %), C-59/157 (37.6 %), respectively, P < 0.001). The infection sites and types of pathogens were also different across the three phases. Compared to non-GVHD cases, mNGS detected more Aspergillus spp. and Mucorales in GVHD patients (Aspergillus: 12/102 (11.8 %) vs. 8/158 (5.1 %), respectively, P = 0.048; Mucorales: 6/102 (5.9 %) vs. 2/158 (1.3 %), respectively, P = 0.035). Forty-five (181/404) percent of mNGS tests yielded a positive impact on the clinical diagnosis, while 24.3 % (98/404) of tests benefited the patients in antimicrobial treatment., Conclusion: mNGS is an indispensable diagnostic tool in identifying pathogens and optimizing antibiotic therapy for hematological patients receiving allo-HSCT., Competing Interests: Conflicts of interest The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Copyright © 2023. Published by Elsevier B.V.)

Objectives: To explore the effect of electroacupuncture (EA) at "Baihui" (GV20) and "Shenting" (GV24) on the microvascular structure and related protein expression in the hippocampus of vascular dementia (VD) rat model, and to investigate the mechanism of EA in the treatment of VD., Methods: A total of 24 SD rats were randomly divided into sham operation, model, EA, and oxiracetam groups, with 6 rats in each group. Multiple cerebral infarction method was used to establish VD model. In the EA group, EA was applied to GV20 and GV24 for 30 min, once daily for 14 days. Rats in the oxiracetam group were treated with oxiracetam (50 mg/kg) by intraperitoneal injection, and the course of treatment was the same as that in the EA group. Learning and memory ability were evaluated by using Morris water maze test and new object recognition experiment. The cerebral blood flow was detected by laser doppler. The microvascular structure in the hippocampus was observed by transmission electron microscopy. The expression of vascular structure related proteins of platelet-derived growth factor receptor (PDGFR)-β, platelet endothelial cell adhesion molecule-1(CD31), neural cadherin N-Cadherin, Zonula occludens protein-1(ZO-1) in the hippocampus were measured by Western blot., Results: Compared with the sham operation group, the rats in the model group had a significant increase in time of first crossing the platform, a significant decrease in the number of crossing platform and the new object preference index ( P <0.05), a significant decrease in cerebral blood flow ( P <0.05), and a significant increase in the brain weight ( P <0.05). The structure boundary of pericyte and endothelial cells in the microvessels of the hippocampal CA1 area of model group was blurred, accompanied by obvious edema around the vessels and the reduction of tight junctions. The protein expression levels of PDGFR-β, CD31, N-Cadherin, ZO-1 were significantly decreased in the model group compared with those in the sham operation group ( P <0.05). Compared with the model group, the time of first crossing the platform of rats in the EA and oxiracetam group was shortened, the number of crossing platform were increased ( P <0.05), the cerebral blood flow was increased ( P <0.05), the brain weight was decreased ( P <0.05), the morphology and structure of pericyte and endothelial cells in the microvessels of hippocampal CA1 area were intact, accompanied by the increase of tight junctions. Additionally, Compared with the model group, the EA group had a significant increase in the new object preference index ( P <0.05), the protein expression levels of PDGFR-β, CD31, ZO-1 in the EA group were increased ( P <0.05), and the expression of PDGFR-β, N-Cadherin, ZO-1 in the oxiracetam group were increased ( P <0.05)., Conclusions: EA at GV20 and GV24 can improve the learning and memory ability of VD rats, and the mechanism may be related to the repair of microvascular structures and improvement of cerebral blood flow.

Primary liver cancer (PLC) poses a leading threat to human health, and its treatment options are limited. Meanwhile, the investigation of homogeneity and heterogeneity among PLCs remains challenging. Here, using single-cell RNA sequencing, spatial transcriptomic and bulk multi-omics, we elaborated a molecular architecture of 3 PLC types, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). Taking a high-resolution perspective, our observations revealed that CHC cells exhibit internally discordant phenotypes, whereas ICC and HCC exhibit distinct tumor-specific features. Specifically, ICC was found to be the primary source of cancer-associated fibroblasts, while HCC exhibited disrupted metabolism and greater individual heterogeneity of T cells. We further revealed a diversity of intermediate-state cells residing in the tumor-peritumor junctional zone, including a congregation of CPE + intermediate-state endothelial cells (ECs), which harbored the molecular characteristics of tumor-associated ECs and normal ECs. This architecture offers insights into molecular characteristics of PLC microenvironment, and hints that the tumor-peritumor junctional zone could serve as a targeted region for precise therapeutical strategies., (© 2023. The Author(s).)

Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging. In this study, we developed a novel BMSC-aptamer (BMSC-apt) functionalized hydrogel (BMSC-aptgel) and evaluated its functions in recruiting BMSCs and promoting bone regeneration. The functional hydrogels were synthesized between maleimide-terminated 4-arm polyethylene glycols (PEG) and thiol-flanked PEG crosslinker, allowing rapid in situ gel formation. The aldehyde group-modified BMSC-apt was covalently bonded to a thiol-flanked PEG crosslinker to produce high-density aptamer coverage on the hydrogel surface. In vitro and in vivo studies demonstrated that the BMSC-aptgel significantly increased BMSC recruitment, migration, osteogenic differentiation, and biocompatibility. In vivo fluorescence tomography imaging demonstrated that functionalized hydrogels effectively recruited DiR-labeled BMSCs at the fracture site. Consequently, a mouse femur fracture model significantly enhanced new bone formation and mineralization. The aggregated BMSCs stimulated bone regeneration by balancing osteogenic and osteoclastic activities and reduced the local inflammatory response via paracrine effects. This study's findings suggest that the BMSC-aptgel can be a promising and effective strategy for promoting in situ bone regeneration., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Objective: This meta-analysis was performed to investigate the effectiveness of acupuncture in post-stroke limb movement disorders., Materials and Methods: An electronic search of databases including MEDLINE/PubMed, Web of Science, the Cochrane database, EMBASE, CBM, CNKI, WanFang, and VIP was performed to collect randomized controlled clinical studies on acupuncture administered for post-stroke dyskinesia from inception to April 2023. Data including baseline information, Fugl-Meyer Assessment (FMA) scores, and Barthel Index (BI) were included and analyzed using the meta package in R language., Results: After searching and screening, 17 pieces of literature involving 1,928 participants were included, with 962 participants in the control group and 966 in the study group. Results from the included studies suggested significant benefits provided by acupuncture to improve FMA scores and BI. In specific, incorporation of acupuncture in the treatment of post-stroke limb movement disorders significantly reduced the overall FMA scores of patients by 3.45 (95% CI: 0.22, 6.69) points, the upper extremity FMA scores by 3.63 (95% CI: 0.64, 6.62) points, the lower extremity FMA scores by 3.56 (95% CI: 1.78, 5.35) points, and BI by 7.75 (95% CI: 3.35, 12.16) points., Conclusions: Acupuncture as an adjunct to the management of post-stroke limb movement disorders contributes significantly to enhancing the motor function and quality of life of patients. However, the evidence of this study is compromised by the limited quantity of the included randomized controlled trials (RCTs) and the mediocre methodological quality. Therefore, high-quality randomized controlled trials are required to validate the benefits of acupuncture on the motor function of patients with post-stroke limb movement disorders.

Background and Aims: The recurrence and metastasis of hepatocellular carcinoma (HCC) are mainly caused by microvascular invasion (MVI). Our study aimed to uncover the cellular atlas of MVI + HCC and investigate the underlying immune infiltration patterns with radiomics features., Methods: Three MVI positive HCC and three MVI negative HCC samples were collected for single-cell RNA-seq analysis. 26 MVI positive HCC and 30 MVI negative HCC tissues were underwent bulk RNA-seq analysis. For radiomics analysis, radiomics features score (Radscore) were built using preoperative contrast MRI for MVI prediction and overall survival prediction. We deciphered the metabolism profiles of MVI + HCC using scMetabolism and scFEA. The correlation of Radscore with the level of APOE + macrophages and iCAFs was identified. Whole Exome Sequencing (WES) was applied to distinguish intrahepatic metastasis (IM) and multicentric occurrence (MO). Transcriptome profiles were compared between IM and MO., Results: Elevated levels of APOE+ macrophages and iCAFs were detected in MVI + HCC. There was a strong correlation between the infiltration of APOE + macrophages and iCAFs, as confirmed by immunofluorescent staining. MVI positive tumors exhibited increased lipid metabolism, which was attributed to the increased presence of APOE+ macrophages. APOE + macrophages and iCAFs were also found in high levels in IM, as opposed to MO. The difference of infiltration level and Radscore between two nodules in IM was relatively small. Furthermore, we developed Radscore for predicting MVI and HCC prognostication that were also able to predict the level of infiltration of APOE + macrophages and iCAFs., Conclusion: This study demonstrated the interactions of cell subpopulations and distinct metabolism profiles in MVI + HCC. Besides, MVI prediction Radscore and MVI prognostic Radscore were highly correlated with the infiltration of APOE + macrophages and iCAFs, which helped to understand the biological significance of radiomics and optimize treatment strategy for MVI + HCC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective To explore the effect of shionone(SHI)on motor function in the mouse model of spinal cord injury(SCI)and probe into the underlying molecular mechanism.Methods C57BL/6 mice were treated to induce the SCI model and then assigned into a model group(SCI group),a SCI+SHI group,and a sham surgery(control)group.The Basso mouse scale(BMS)score was determined to evaluate the recovery of motor function in SCI mice.Hematoxylin-eosin(HE)staining,Nissl staining,and immunofluorescence staining were employed to examine the fibrosis,morphological changes of neurons,and neuron apoptosis in the spinal cord tissue of SCI mice,respectively.The mouse hippocampal neuronal cell line HT22 was cultured in vitro and then classified into tumor necrosis factor α(TNF-α)induction and SHI groups.Western blotting was employed to determine the expression of apoptosis-associated proteins.Network pharmacology,gene ontology annotation,and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were employed to predict the possible molecular targets and signaling pathways of SHI in promoting functional recovery from SCI.Furthermore,the prediction results were verified by in vitro and in vivo experiments.Results Compared with the SCI group,the SCI+SHI group showed increased BMS score on days 21,28,35,and 42( P =0.003, P =0.004, P =0.023,and P =0.007,respectively),reduced area of spinal cord fibrosis( P =0.021),increased neurons survived( P =0.001),and down-regulated expression of cleaved cysteine aspastic acid-specific protease 3(cleaved Caspase-3)( P =0.017).Compared with the TNF-α group,the SHI group presented down-regulated expression levels of cleaved Caspase-3 and Bax( P =0.010, P =0.001)and up-regulated expression level of Bcl-2( P =0.001).The results of bioinformatics analysis showed that SHI might improve the motor function of SCI mice via the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)signaling pathway.The results of in vivo and in vitro experiments showed that SHI inhibited the phosphorylation of PI3K and Akt in SCI mice or HT22 cells exposed to TNF-α(all P <0.05).The number of apoptotic HT22 cells after treatment with insulin-like growth factor 1 was higher than that in the SHI group( P =0.003).Conclusion SHI may inhibit neuron apoptosis via the PI3K/Akt signaling pathway,thereby promoting the recovery of motor function in SCI mice.

Enhanced proliferation and migration of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension. Adventitial fibroblasts (AFs)-derived extracellular vesicles (EVs) modulate vascular remodeling in spontaneously hypertensive rat (SHR). This study shows the important roles of EVs-mediated miR-21-3p transfer in VSMC proliferation and migration and underlying mechanisms in SHR. AFs and VSMCs were obtained from aorta of Wistar-Kyoto rat (WKY) and SHR. EVs were separated from AFs culture with ultracentrifugation method. MiR-21-3p content in the EVs of SHR was increased compared with those of WKY. MiR-21-3p mimic promoted VSMC proliferation and migration of WKY and SHR, while miR-21-3p inhibitor attenuated proliferation and migration only in the VSMCs of SHR. EVs of SHR stimulated VSMC proliferation and migration, which were attenuated by miR-21-3p inhibitor. Sorbin and SH3 domain containing 2 (SORBS2) mRNA and protein levels were reduced in the VSMCs of SHR. MiR-21-3p mimic inhibited, while miR-21-3p inhibitor promoted SORBS2 expressions in the VSMCs of both WKY and SHR. EVs of SHR reduced SORBS2 expression, which was prevented by miR-21-3p inhibitor. EVs of WKY had no significant effect on SORBS2 expressions. SORBS2 overexpression attenuated the roles of miR-21-3p mimic and EVs of SHR in promoting VSMC proliferation and migration of SHR. Overexpression of miR-21-3p in vivo promotes vascular remodeling and hypertension. These results indicate that miR-21-3p in the EVs of SHR promotes VSMC proliferation and migration via negatively regulating SORBS2 expression., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Owing to the threats that Salmonella poses to public health and the abuse of antimicrobials, bacteriophage therapy against Salmonella is experiencing a resurgence. Although several phages have been reported as safe and efficient for controlling Salmonella, the genetic diversity and relatedness among Salmonella phages remain poorly understood. In this study, whole-genome sequences of 91 Salmonella bacteriophages were obtained from the National Center for Biological Information genome database. Phylogenetic analysis, mosaic structure comparisons, gene content analysis, and orthologue group clustering were performed. Phylogenetic analysis revealed four singletons and two major lineages (I-II), including five subdividing clades, of which Salmonella phages belonging to morphologically distinct families were clustered in the same clade. Chimeric structures (n = 31), holin genes (n = 18), lysin genes (n = 66), DNA packaging genes (n = 55), and DNA metabolism genes (n = 24) were present in these phages. Moreover, phages from different subdivided clusters harboured distinct genes associated with host cell lysis, DNA packaging, and DNA metabolism. Notably, phages belonging to morphologically distinct families shared common orthologue groups. Although several functional modules of phages SS1 and SE16 shared > 99% nucleotide sequence identity with phages SI2 and SI23, the major differences between these phages were the absence and replication of functional modules. The data obtained herein revealed the genetic diversity of Salmonella phages at genomic, structural, and gene content levels. The genetic diversity of Salmonella phages is likely owing to the acquisition, loss, and replication of functional modules., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Due to increasing morbidity worldwide, fractures are becoming an emerging public health concern. This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures. Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis. Here, we show that metformin accelerated fracture healing in both osteoporotic and normal mice. Moreover, metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing. Mechanistically, metformin increased the expression of HIF-1α, an important positive regulator of type H vessel formation, by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells (HMECs). The results of HIF-1α or YAP1/TAZ interference in hypoxia-cultured HMECs using siRNA further suggested that the enhancement of HIF-1α and its target genes by metformin is primarily through YAP1/TAZ inhibition. Finally, overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair. In summary, our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition., (© 2023. West China School of Stomatology Sichuan University.)

Background and Purpose: Tumor recurrence after liver transplantation (LT) impedes the curative chance for hepatocellular carcinoma (HCC) patients. This study aimed to develop a deep pathomics score (DPS) for predicting tumor recurrence after liver transplantation using deep learning., Patients and Methods: Two datasets of 380 HCC patients who underwent LT were enrolled. Residual convolutional neural networks were used to identify six histological structures of HCC. The individual risk score of each structure and DPS were derived by a modified DeepSurv network. Cox regression analysis and Concordance index were used to evaluate the prognostic significance. The cellular exploration of prognostic immune biomarkers was performed by quantitative and spatial proximity analysis according to three panels of 7-color immunofluorescence., Results: The overall classification accuracy of HCC tissue was 97%. At the structural level, immune cells were the most significant tissue category for predicting post-LT recurrence (HR 1.907, 95% CI 1.490-2.440). The C-indices of DPS achieved 0.827 and 0.794 in the training and validation cohorts, respectively. Multivariate analysis for recurrence-free survival (RFS) showed that DPS (HR 4.795, 95% CI 3.017-7.619) was an independent risk factor. Patients in the high-risk subgroup had a shorter RFS, larger tumor diameter and a lower proportion of clear tumor borders. At the cellular level, a higher infiltration of intratumoral NK cells was negatively correlated with recurrence risk., Conclusions: This study established an effective DPS. Immune cells were the most significant histological structure related to HCC recurrence. DPS performed well in post-LT recurrence prediction and the identification of clinicopathological features., (© 2023. The Author(s).)

Electroacupuncture (EA) is well documented to treat irritable bowel syndrome (IBS). However, the mechanism of the central nervous system related to IBS and acupuncture stimulation is still not well known. In this study, a rat model of IBS was established by cold-restraint comprehensive stresses for 15 days, and it was found that the levels of corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH) in the peripheral serum were increased; the visceral sensitivity was enhanced; and the intestinal motility was accelerated, specifically, there was an enhancement in the discharge frequency of neurons in the paraventricular nucleus (PVN). EA treatment for 3 days, 20 min/day, alleviated the increase in the levels of CRH, CORT, and ACTH in the peripheral serum of rats, reduced the visceral sensitivity of IBS rats, and inhibited colon movement and discharge frequency of the neurons in the PVN. In addition, EA could reduce the excitability of CRH neurons and the expression of corticotropin-releasing hormone receptor 1 (CRHR1) and corticotropin-releasing hormone receptor 2 (CRHR2) in PVN. At the same time, the expression of CRH, CRHR1, and CRHR2 in the peripheral colon was decreased. Taken together, EA appears to regulate intestinal functional activity through the central CRH nervous system, revealing the central regulation mechanism of EA in IBS rats, and providing a scientific research basis for the correlation among the meridians, viscera, and brain. NEW & NOTEWORTHY The purpose of this research was to determine the central regulatory mechanism of electroacupuncture (EA) in rats with irritable bowel syndrome (IBS). Our results showed that combined with the serum changes in corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH), the improvement of IBS by EA was related to them. Furthermore, EA could regulate intestinal functional activity through the central CRH + nervous system.

The reconstruction of buccal-penetrating defects remains challenging. The present study aims to explore the application value of the lateral arm free flap (LAFF) on the reconstruction of buccal-penetrating defects with the hope of providing a better option for clinical practice. Nineteen patients with this kind of issue posed by either tumor resections or deformities in the craniofacial regions were recruited in this study, and LAFF was employed to reconstruct these defects by double folding and individually designing the flap. All the flaps prepared for these subjects in our study survived, and the postoperative assessment of these subjects receiving LAFF revealed that this approach to managing buccal-penetrating defects is able to achieve satisfactory results in terms of appearance and functional recovery. Therefore, our study suggests that LAFF is 1 of the promising flaps to reconstruct the buccal-penetrating defects., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Purpose: To evaluated the efficacy and safety of gelatinized Maca ( Lepidium meyenii ) for eugonadal patients with late onset hypogonadism symptoms (LOH)., Materials and Methods: Participants were instructed to receive 1,000 mg of Maca or placebo, two pills at a time, three times per day for 12 weeks before food intake. To evaluate the efficacy of the drug, Aging Males' Symptoms scale (AMS), Androgen Deficiency in the Aging Males (ADAM), International Prostate Symptom Score (IPSS), and International Index of Erectile Function (IIEF) questionnaires, serologic tests (total testosterone and free testosterone, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride), body weight, and waist circumference were assessed at 4 and 12 weeks after treatment., Results: A total of 80 participants were enrolled and randomly assigned to Maca treated group (n=41) or the placebo group (n=39). AMS, IIEF, and IPSS were significantly (p<0.05) improved in Maca treated group than in the placebo group. ADAM positive rate was also significantly (p<0.0001) decreased in Maca treated group., Conclusions: Maca may be considered an effective and safe treatment for eugonadal patients with late onset hypogonadism symptoms., Competing Interests: The authors have nothing to disclose., (Copyright © 2023 Korean Society for Sexual Medicine and Andrology.)

Background: The aim of this study was to evaluate the therapeutic effect of gasless endoscopic submandibular gland excision through hairline approach and the safety, feasibility and practicability of this technique., Methods: Twenty-five patients with submandibular gland lesions who underwent gasless endoscopic submandibular gland excision through hairline approach at the Department of Head and Neck Oncology of the West China Hospital of Stomatology from May 1 st 2021 to May 31 st 2022 were included in this prospective study. The variables were analyzed statistically with SPSS software version 23.0 (IBM Corp, Armonk, New York, USA)., Results: There was a female predominance (72%), female to male ratio was 2.6. The mean age was 30.6±10.2 years (range: 11 to 52 year). All 25 cases of endoscopic submandibular gland excision through hairline approach were done without conversion to conventional approach. This approach was indicated in 14 cases (56%) for pleomorphic adenoma, 8 cases (32%) for chronic sialadenitis, 2 cases (8%) for adenoid cystic carcinoma, and 1 case (4%) for lymphadenitis. The incision length mean was 4.8±0.4 mm (range: 4 to 5 mm); the operation duration mean was 100.6±39.7 min (range: 51 to 197 min); the intraoperative bleeding mean was 13.2±5.7 ml (range: 5 to 20 ml); the hospital length of stay mean was 4.5±0.8 days (range: 3 to 6 days). The follow-up mean was 10±3.4 months (range: 5 to 16 months). The patients were very satisfied with postoperative cosmetic result (score mean: 9.2±1). No recurrence of disease and complications such as postoperative bleeding, hematoma, nerve damage, skin necrosis, infection, and hair loss occurred., Conclusions: Gasless endoscopic submandibular gland excision through hairline approach is safe, feasible and practicable, resulting in a very satisfied cosmetic result without significant complications; the intraoperative bleeding is less, the operative field is clear, the operation duration decreases with accumulation of experience., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

The study of bacteriophages is experiencing a resurgence with the increasing development of antimicrobial resistance in Staphylococcus aureus. Nonetheless, the genetic features of highly efficient lytic S. aureus phage remain to be explored. In this study, two lytic S. aureus phages, SapYZU11 and SapYZU15, were isolated from sewage samples from Yangzhou, China. The phage morphology, one-step growth, host spectrum and lytic activity of these phages were examined, and their whole-genome sequences were analysed and compared with 280 published genomes of staphylococcal phages. The structural organisation and genetic contents of SapYZU11 and SapYZU15 were investigated. The Podoviridae phage SapYZU11 and Herelleviridae phage SapYZU15 effectively lysed all of the 53 S. aureus strains isolated from various sources. However, SapYZU15 exhibited a shorter latent period, larger burst size and stronger bactericidal ability with an anti-bacterial rate of approximately 99.9999% for 24 h. Phylogenetic analysis revealed that Herelleviridae phages formed the most ancestral clades and the S. aureus Podoviridae phages were clustered in the staphylococcal Siphoviridae phage clade. Moreover, phages in different morphology families contain distinct types of genes associated with host cell lysis, DNA packaging and lysogeny. Notably, SapYZU15 harboured 13 DNA metabolism-related genes, 5 lysin genes, 1 holin gene and 1 DNA packaging gene. The data suggest that S. aureus Podoviridae and Siphoviridae phages originated from staphylococcal Herelleviridae phages, and the module exchange of S. aureus phages occurred in the same morphology family. Moreover, the extraordinary lytic capacity of SapYZU15 was likely due to the presence of specific genes associated with DNA replication, DNA packaging and the lytic cycle., Competing Interests: Competing interests None declared., (Copyright © 2023. Published by Elsevier GmbH.)

Background: Tuberculosis (TB) remains a significant challenge for public health and is closely associated with malnutrition; however, few studies have attempted to screen malnutrition among TB patients. The study aimed to evaluate the nutrition status and build a new nutritional screening model for active TB., Methods: A retrospective, multicenter, large cross-sectional study was conducted in China from 1 January 2020 to 31 December 2021. All included patients diagnosed with active pulmonary TB (PTB) were evaluated both by Nutrition Risk Screening 2002 (NRS 2002) and Global Leadership Initiative on Malnutrition (GLIM) criteria. Univariate and multivariate analyses were conducted to screen the risk factors associated with malnutrition, and a new screening risk model, mainly for TB patients, was constructed., Results: A total of 14,941 cases meeting the inclusion criteria were entered into the final analysis. The malnutrition risk rate among PTB patients in China was 55.86% and 42.70%, according to the NRS 2002 and GLIM, respectively. The inconsistency rate between the two methods was 24.77%. A total of 11 clinical factors, including elderly, low body mass index (BMI), decreased lymphocyte cells, taking immunosuppressive agents, co-pleural TB, diabetes mellitus (DM), human immunodeficiency virus (HIV), severe pneumonia, decreased food intake within a week, weight loss and dialysis were identified as independent risk factors of malnutrition based on multivariate analyses. A new nutritional risk screening model was constructed for TB patients with a diagnostic sensitivity of 97.6% and specificity of 93.1%., Conclusions: Active TB patients have severe malnutrition status according to screening by the NRS 2002 and GLIM criteria. The new screening model is recommended for PTB patients as it is more closely tailored to the characteristics of TB., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-623/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Ginseng has been used in China as a superior medicinal material for thousands of years that can nourish the five internal organs, calm the mind and benefit wisdom. Due to its anti-inflammatory, antioxidant and neuroprotective activities, one of the active components of ginseng, ginsenoside Rg1, has been extensively investigated in the remedy of brain disorders, especially dementia and depression. In this review, we summarized the research progress on the action mechanisms of Rg1 ameliorating depression-like behaviors, including inhibition of hyperfunction of hypothalamic-pituitary-adrenal (HPA) axis, regulation of synaptic plasticity and gut flora. Rg1 may alleviate Alzheimer's disease in the early phase, as well as in the middle-late phases through repairing dendrite, axon and microglia- and astrocyte-related inflammations. We also proposed that Rg1 could regulate memory state (the imbalance of working and aversive memory) caused by distinct stimuli. These laboratory studies would further the clinical trials on Rg1. From the prospective of drug development, we discussed the limitations of the present investigations and proposed our ideas to increase permeability and bioavailability of Rg1. Taken together, Rg1 has the potential to treat neuropsychiatric disorders, but a future in-depth investigation of the mechanisms is still required. In addition, drug development will benefit from the clinical trials in one specific neuropsychiatric disorder., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)