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Ectopic lipids in peripheral tissues have been implicated in attenuating insulin action in vivo. The botanical extract of Artemisia dracunculus L. (PMI 5011) improves insulin action, yet the precise mechanism is not known. We sought to determine whether the mechanism by which PMI 5011 improves insulin signaling is through regulation of lipid metabolism. After differentiation, cells were separately preincubated with free fatty acids (FFAs) and ceramide C2, and the effects on glycogen content, insulin signaling, and ceramide profiles were determined. The effect of PMI 5011 on ceramide accumulation and ceramide-induced inhibition of insulin signaling was evaluated. FFAs resulted in increased levels of total ceramides and ceramide species in L6 myotubes. Saturated FFAs and ceramide C2 inhibited insulin-stimulated phosphorylation of protein kinase B/Akt and reduced glycogen content. PMI 5011 had no effect on ceramide formation or accumulation but increased insulin sensitivity via restoration of Akt phosphorylation. PMI 5011 also attenuated the FFA-induced upregulation of a negative inhibitor of insulin signaling, i.e., protein tyrosine phosphatase 1B (PTP1B), and increased phosphorylation of PTP1B. PMI 5011 attenuates the reduction in insulin signaling induced by ceramide accumulation, but the mechanism of improved insulin signaling is independent of ceramide formation. [ABSTRACT FROM AUTHOR]

Background and purpose: 5-Hydroxytryptamine (5-HT) is a key regulator of the gastrointestinal system and we have shown that submucosal neuronal 5-HT3 receptors exerted a novel inhibitory effect on colonic ion transport. The aim of the present study was to investigate the precise mechanism(s) underlying this inhibitory effect. Experimental approach: Mucosa/submucosa or mucosa-only preparations from rat distal colon were mounted in Ussing chambers for measurement of short-circuit current ( Isc) as an indicator of ion secretion. Somatostatin release was determined with radioimmunoassay. Intracellular cAMP content was measured with enzyme-linked immunoadsorbent assay ( elisa). Immunohistochemical techniques were used to study the expression of 5-HT3 receptors, somatostatin and somatostatin receptors in colonic tissue. Key results: In rat distal colonic mucosa/submucosa preparations, pretreatment with 5-HT3 receptor antagonists enhanced 5-HT-induced increases in Isc. However, in mucosa-only preparations without retained neural elements, pretreatment with 5-HT3 receptor antagonists inhibited 5-HT-induced Δ Isc. Pretreatment with a somatostatin-2 (sst2) receptor antagonist in mucosa/submucosa preparations augmented 5-HT-induced Δ Isc. Combination of sst2 and 5-HT3 receptor antagonists did not cause further enhancement of 5-HT-induced Δ Isc. Moreover, both sst2 and 5-HT3 receptor antagonists enhanced 5-HT-induced increase in intracellular cAMP concentration in the mucosa/submucosa preparations. 5-HT released somatostatin from rat colonic mucosa/submucosa preparations, an effect prevented by pretreatment with 5-HT3 receptor antagonists. Immunohistochemical staining demonstrated the presence of 5-HT3 receptors on submucosal somatostatin neurons and of sst2 receptors on colonic mucosa. Conclusion and implications: Activation of neuronal 5-HT3 receptors in the submucosal plexus of rat colon suppressed 5-HT-induced ion secretion by releasing somatostatin from submucosal neurons. [ABSTRACT FROM AUTHOR]

PURPOSE: To discuss a new classification and the treatment principles of synovial chondromatosis (SC) in the inferior compartment of the temporomandibular joint (TMJ). PATIENTS AND METHODS: Five cases of SC in the inferior compartment were treated in an open manner between January 2008 and May 2011. Each case had different clinical and radiologic aspects and was treated with different surgical therapies. SC in the inferior compartment of the TMJ is classified into 3 stages. All patients were evaluated by computed tomography, magnetic resonance imaging, and clinical manifestations preoperatively and postoperatively. RESULTS: There were 3 kinds of manifestation modes from radiologic findings. Case 1 was in stage 1, in which multiple loose bodies are noted without bony erosion. This patient was treated by removal of loose bodies and affected synovium. Case 2 was in stage 2, in which multiple calcified nodules were conglutinated to the condyle; the condyle was enlarged with pressure erosions. This patient was treated by condylectomy and reconstruction with costochondral graft. Case 3, case 4, and case 5 were all in stage 3, in which the condyle was destroyed as a result of pressure erosions or by direct bony invasion of the mass and the inferior surface of the disc was involved. These patients were treated by condylectomy together with discectomy, as well as reconstruction with costochondral graft and pedicled deep temporal fascial fat flap. No recurrence occurred. The height of the ramus and the occlusion were maintained in the same condition as preoperatively. CONCLUSIONS: Our new classification of SC in the inferior compartment of the TMJ can better guide clinical treatment. [ABSTRACT FROM AUTHOR]

Background: Lymphangiogenesis has become a new research frontier in tumor metastasis since the discovery of reliable lymphatic markers that have allowed observation and isolation of lymphatic endothelium. Cyclooxygenase-2 (COX-2) has been reported to be involved in the critical steps in carcinogenesis. However, possible role of COX-2 in lymphangiogenesis and lymphatic metastasis is still poorly understood. In present study, we aimed to investigate the relationship between vascular endothelial growth factor-C (VEGF-C) and COX-2 in human breast cancer, and correlations with lymphangiogenesis and prognosis. Methods: Tissue samples of primary tumors from 70 patients undergoing intentionally curative surgical resections for breast cancer were immunohistochemically examined for VEGF-C, COX-2, and D2-40 expressions. The association between COX-2 and VEGF-C expressions and clinicopathological parameters as well as prognosis were analysised. To demonstrate the presence of proliferating lymphatic endothelial cells, 10 random cases with high LVD counts were selected for D2-40/Ki-67 double immunostaining. Results: A significant correlation was found between the expression of VEGF-C and COX-2 (r = 0.529, P < 0.001), and both elevated VEGF-C expression and elevated COX-2 expression were associated with higher lymph vessel density (LVD), lymph node metastasis and D2-40 positive lymphatic invasion (LVI) as well as worse disease free survival (DFS) and overall survival (OS) in a univariate analysis. In the double immunostain for the lymph vessel marker D2-40 and the proliferation marker Ki-67, the results confirmed Ki-67-positive nuclei in a proportion of lymph vessel endothelial cells. Conclusion: There is indeed lymphangiogenesis in breast cancer, the most compelling evidence being the presence of proliferating lymphatic endothelial cells. VEGF-C and COX-2 are coexpressed and significantly associated with lymphangiogenesis and prognosis in invasive breast cancer. Suggesting COX-2 may up-regulate VEGF-C expression and thus promote lymph node metastasis via lymphangiogenesis pathway in human breast cancer. [ABSTRACT FROM AUTHOR]

An ethanolic extract of Artemisia dracunculus L. (PMI 5011) has been observed to decrease glucose and insulin levels in animal models, but the cellular mechanisms by which insulin action is enhanced in vivo are not precisely known. In this study, we evaluated the effects of PMI 5011 to modulate gene expression and cellular signaling through the insulin receptor in skeletal muscle of KK-A(y) mice. Eighteen male KK-A(y) mice were randomized to a diet (w/w) mixed with PMI 5011 (1%) or diet alone for 8 weeks. Food intake, adiposity, glucose and insulin were assessed over the study, and at study completion, vastus lateralis muscle was obtained to assess insulin signaling parameters and gene expression. Animals randomized to PMI 5011 were shown to have enhanced insulin sensitivity and increased insulin receptor signaling, i.e., IRS-associated PI-3 kinase activity, Akt-1 activity and Akt phosphorylation, in skeletal muscle when compared to control animals (P<.01, P<.01 and P<.001, respectively). Gene expression for insulin signaling proteins, i.e., IRS-1, PI-3 kinase and Glut-4, was not increased, although a relative increase in protein abundance was noted with PMI 5011 treatment. Gene expression for specific ubiquitin proteins and specific 20S proteasome activity, in addition to skeletal muscle phosphatase activity, i.e., PTP1B activity, was significantly decreased in mice randomized to PMI 5011 relative to control. Thus, the data demonstrate that PMI 5011 increases insulin sensitivity and enhances insulin receptor signaling in an animal model of insulin resistance. PMI 5011 may modulate skeletal muscle protein degradation and phosphatase activity as a possible mode of action. [ABSTRACT FROM AUTHOR]

Although it is an effective treatment for acute myeloid leukemia (AML), chemotherapy leads to myelosuppression and poor hematopoietic reconstruction. Hematopoiesis is regulated by bone marrow (BM) endothelial cells (ECs), and BM ECs are dysfunctional in acute leukemia patients with poor hematopoietic reconstitution after allogenic hematopoietic stem cell transplantation. Thus, it is crucial to explore the underlying mechanism of EC impairment and establish strategies for targeted therapy. TGF-β signaling was found to be upregulated in ECs from AML patients in complete remission (CR ECs) and led to CR EC damage. Administration of a TGF-β inhibitor rescued the dysfunction of ECs caused by TGF-β1 expression in vitro, especially their hematopoiesis-supporting ability. Moreover, inhibition of TGF-β expression repaired the BM EC damage triggered by chemotherapy in both AML patients in vitro and in an AML-CR murine model, and restored normal hematopoiesis without promoting AML progression. Mechanistically, our data reveal alterations in the transcriptomic pattern of damaged BM ECs, accompanied by the overexpression of downstream molecules TGF-βR1, pSmad2/3, and functional genes related to adhesion, angiogenesis suppression and pro-apoptosis. Collectively, our findings reveal for the first time that the activation of TGF-β signaling leads to BM EC dysfunction and poor hematopoietic reconstitution. Targeting TGF-β represents a potential therapeutic strategy to promote multilineage hematopoiesis, thereby benefiting more cancer patients who suffer from myelosuppression after chemotherapy., Competing Interests: Declaration of competing interest The authors wish to confirm that there are no known conflicts of interest associated with this publication. All co-authors have seen and approved this version of the manuscript and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The consensus in 2018 from The Chinese Society of Haematology (CSH) on the monitoring, treatment, and prevention of leukaemia relapse after allogeneic haematopoietic stem cell transplantation (HSCT) facilitated the standardization of clinical practices in China and progressive integration with the world. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the following consensus: (1) integrate risk-adapted, measurable residual disease (MRD)-guided strategy on modified donor lymphocyte infusion (DLI) and interferon-α into total therapy, which was pioneered and refined by Chinese researchers; (2) provide additional evidence of the superiority of haploidentical HSCT (the dominant donor source in China) to matched HSCT for high-risk populations, especially for pre-HSCT MRD-positive patients; (3) support the rapid progress of techniques for MRD detection, such as next-generation sequencing (NGS) and leukaemia stem cell-based MRD detection; and (4) address the role of new targeted options in transplant settings. In conclusion, the establishment of a "total therapy" strategy represents a great step forward. We hope that the consensus updated by Chinese scholars will include the latest cutting-edge developments and inspire progress in post-HSCT relapse management., 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 B.V. All rights reserved.)

Objective: To investigate the prognosis and the factors that influence it in patients with non-gastric gastrointestinal stromal tumors (GISTs) who are at low risk of recurrence. Methods: This was a retrospective cohort study. Clinicopathologic and prognostic data from patients with non-gastric GISTs and at low risk of recurrence (i.e., very low-risk or low-risk according to the 2008 version of the Modified NIH Risk Classification), who attended 18 medical centers in China between January 2000 and June 2023, were collected. We excluded patients with a history of prior malignancy, concurrent primary malignancy, multiple GISTs, and those who had received preoperative imatinib. The study cohort comprised 1,571 patients with GISTs, 370 (23.6%) of whom were at very low-risk and 1,201 (76.4%) at low-risk of recurrence. The cohort included 799 (50.9%) men and 772 (49.1%) women of median age 57 (16-93) years. Patients were followed up to July 2024. The prognosis and its influencing factors were analyzed. Receiver operating characteristic curves for tumor diameter and Ki67 were established, and the sensitivity, specificity, area under the curve (AUC) and optimal cut-off value with 95% confidence intervals were calculated. Propensity score matching was implemented using the 1:1 nearest neighbor matching method with a matching tolerance of 0.02. Results: With a median follow-up of 63 (12-267) months, the 5- and 10-year overall survival (OS) rates of the 1,571 patients were 99.5% and 98.0%, respectively, and the 5- and 10-year disease-free survival (DFS) rates were 96.3% and 94.4%, respectively. During postoperative follow-up, 3.8% (60/1,571) patients had disease recurrence or metastasis, comprising 0.8% (3/370) in the very low-risk group and 4.7% (57/1,201) in the low-risk group. In the low-risk group, recurrence or metastasis occurred in 5.5% (25/457) of patients with duodenal GISTs, 3.9% (25/645) of those with small intestinal GISTs, 9.2% (6/65) of those with rectal GISTs, and 10.0% (1/10) of those with colonic GISTs. Among the 60 patients with metastases, 56.7% (34/60) of the metastases were located in the abdominal cavity, 53.3% (32/60) in the liver, and 3.3% (2/60) in bone. During the follow-up period, 13 patients (0.8%) died of disease. Receiver operating characteristic curves were plotted for tumor diameter and Ki67 and assessed using the Jordon index. This showed that the difference in DFS between the two groups was statistically significant when the cutoff value for tumor diameter was 3.5 cm (AUC 0.731, 95% CI: 0.670-0.793, sensitivity 77.7%, specificity 64.1%). Furthermore, the difference in DFS between the two groups was statistically significant when the cutoff value for Ki67 was 5% (AUC 0.693, 95% CI: 0.624-0.762, sensitivity 60.7%, specificity 65.3%). Multifactorial analysis revealed that tumor diameter ≥3.5 cm, Ki67 ≥5%, and R1 resection were independent risk factors for DFS in patients with non-gastric GISTs at low risk of recurrence (all P <0.05). Furthermore, age >57 years, Ki67 ≥5%, and R1 resection were also independent risk factors for OS in patients with non-gastric GISTs at low risk of recurrence (all P <0.05). We also grouped the patients according to whether they had received postoperative adjuvant treatment with imatinib for 1 or 3 years. This yielded 137 patients in the less than 1-year group, 139 in the 1-year plus group; and 44 in both the less than 3 years and 3-years plus group. After propensity score matching for age, tumor diameter, Ki67, and resection status, the differences in survival between the two groups were not statistically significant (all P >0.05). The 10-year DFS and OS were 87.5% and 95.5%, respectively, in the group treated with imatinib for less than 1 year and 88.5% and 97.8%, respectively, in the group treated for more than 1 year. The 10-year DFS and OS were 89.6% and 92.6%, respectively, in the group treated with imatinib for less than 3 years and 88.0% and 100.0%, respectively, in the group treated with imatinib for more than 3 years. Conclusion: The overall prognosis of primary, non-gastric, low recurrence risk GISTs is relatively favorable; however, recurrences and metastases do occur. Age, tumor diameter, Ki67, and R1 resection may affect the prognosis. For some patients with low risk GISTs, administration of adjuvant therapy with imatinib for an appropriate duration may help prevent recurrence and improve survival.

S-DNA is a double-stranded DNA that forms under tensions of >65 pN. Here, we report that S-DNA resists the cleavage of Cas12a and the restriction endonuclease Sma I. Taking advantage of this resistance, in magnetic tweezer experiments, we developed an assay to convert multiple-DNA-tethered beads into single-DNA-tethered beads and remove the only-one-end-tethered DNA molecule by cleaving the DNA that does not transition to S-DNA at about 80 pN. When multiple DNA molecules are tethered to a single bead, they share the tension, exist in the B-form, and allow the cleavage. Only-one-end-tethered DNA molecules, free of tension, are also cleaved. In versatile types of experiments, we proved the broad applications of this assay: measuring the correct DNA elasticity and DNA condensation dynamics by avoiding the false results due to interference of only-one-end-tethered DNA molecules and quantifying the accurate cleavage rates of Cas12a and the restriction endonucleases by eliminating the error caused by multiple-DNA-tethered beads. This convenient assay ensures correct and accurate results in high-throughput DNA stretching experiments.

The functional properties of the human brain arise, in part, from the vast assortment of cell types that pattern the cerebral cortex. The cortical sheet can be broadly divided into distinct networks, which are embedded into processing streams, or gradients, that extend from unimodal systems through higher-order association territories. Here using microarray data from the Allen Human Brain Atlas and single-nucleus RNA-sequencing data from multiple cortical territories, we demonstrate that cell-type distributions are spatially coupled to the functional organization of cortex, as estimated through functional magnetic resonance imaging. Differentially enriched cells follow the spatial topography of both functional gradients and associated large-scale networks. Distinct cellular fingerprints were evident across networks, and a classifier trained on postmortem cell-type distributions was able to predict the functional network allegiance of cortical tissue samples. These data indicate that the in vivo organization of the cortical sheet is reflected in the spatial variability of its cellular composition., Competing Interests: Competing interests: K.M.A. is an employee of Neumora Therapeutics. The remaining authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)