SPP1+ TAM Regulates the Metastatic Colonization of CXCR4+ Metastasis-Associated Tumor Cells by Remodeling the Lymph Node Microenvironment.

Lymph node metastasis, the initial step in distant metastasis, represents a primary contributor to mortality in patients diagnosed with oral squamous cell carcinoma (OSCC). However, the underlying mechanisms of lymph node metastasis in OSCC remain incompletely understood. Here, the transcriptomes of 56 383 single cells derived from paired tissues of six OSCC patients are analyzed. This study founds that CXCR4+ epithelial cells, identified as highly malignant disseminated tumor cells (DTCs), exhibited a propensity for lymph node metastasis. Importantly, a distinct subset of tumor-associated macrophages (TAMs) characterized by exclusive expression of phosphoprotein 1 (SPP1) is discovered. These TAMs may remodel the metastatic lymph node microenvironment by potentially activating fibroblasts and promoting T cell exhaustion through SPP1-CD44 and CD155-CD226 ligand-receptor interactions, thereby facilitating colonization and proliferation of disseminated tumor cells. The research advanced the mechanistic understanding of metastatic tumor microenvironment (TME) and provided a foundation for the development of personalized treatments for OSCC patients with metastasis.

TIPE2 inhibits the migration and invasion of epithelial ovarian cancer cells by targeting Smad2 to reverse TGF-ß1-induced EMT.

Epithelial ovarian cancer is the deadliest gynecologic malignancy, characterized by high metastasis. Transforming growth factor-ß1 (TGF-ß1) drives epithelial- mesenchymal transformation (EMT), a key process in tumor metastasis. Tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 (TIPE2) acts as a negative regulator of innate and adaptive immunity and involves in various cancers. However, its relationship with TGF-ß1 in ovarian cancer and its role in reversing TGF-ß1-induced EMT remain unclear. This study examined TIPE2 mRNA and protein expression using quantitative RT-PCR (qRT-PCR), western blot and immunohistochemistry. The effects of TIPE2 overexpression and knockdown on the proliferation, migration and invasion of epithelial ovarian cancer cells were assessed through 5-ethynyl-2-deoxyuridine, colony-forming, transwell migration and invasion assays. The relationship between TIPE2 and TGF-ß1 was investigated using qRT-PCR and enzyme-linked immunosorbent assay, while the interaction between TIPE2 and Smad2 was identified via co-immunoprecipitation. The results revealed that TIPE2 protein was significantly down-regulated in epithelial ovarian cancer tissues and correlated with the pathological type of tumor, patients' age, tumor differentiation degree and FIGO stage. TIPE2 and TGF-ß1 appeared to play an opposite role to each other during the progression of human ovarian cancer cells. Furthermore, TIPE2 inhibited the metastasis and EMT of ovarian cancer cells by combining with Smad2 in vitro or in an intraperitoneal metastasis model. Consequently, these findings suggest that TIPE2 plays a crucial inhibitory role in ovarian cancer metastasis by modulating the TGF-ß1/Smad2/EMT signaling pathway and may serve as a potential target for ovarian cancer, providing important direction for future diagnostic and therapeutic strategies.

Comparison of hematopoietic stem cell transplantation and repeated intensified immunosuppressive therapy as second-line treatment for relapsed/refractory severe aplastic anemia.

The optimal treatment for patients with severe aplastic anemia (SAA) who fail an initial course of antithymocyte globulin (ATG) plus cyclosporine has not yet been established. We compared the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated immunosuppressive therapy (IST) (n = 33) for relapsed/refractory SAA between 2007 and 2022. In the IST group, patients were retreated with ATG (n = 16) or high-dose cyclophosphamide (n = 17). The overall response rate was 57.6% at 6 months and 60.6% at 12 months. In the allo-HSCT group, patients received a transplant from a matched sibling donor (n = 6), matched unrelated donor (n = 7), or haploidentical donor (n = 23). All patients achieved neutrophil engraftment, and there were no cases of primary graft failure. The cumulative incidences (CIs) of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 36.1% ± 0.7% and 13.9% ± 0.3% at day +100, respectively. The 4-year CI of chronic GVHD (cGVHD) was 36.2% ± 0.7%, with moderate to severe cGVHD at 14.9% ± 0.4%. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3, 6, and 12 months (63.9%, 83.3%, and 86.1%, respectively, p < 0.001). The estimated 4-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) was similar; however, the failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 56.6% ± 8.8%, p = 0.049). Of note, children in the HSCT cohort were all alive without treatment failures, exhibiting superior OS (100% vs. 50.0% ± 17.7%, p = 0.004) and FFS (100% vs. 50.0% ± 17.7%, p = 0.004) than children in the IST cohort. Subgroup analysis revealed that younger patients (age ≤ 35 years), especially children, and those with refractory SAA benefited more from HSCT. Therefore, for these patients, salvage HSCT may be more preferable than a second course of IST.

Long-term distress throughout one's life: health-related quality of life, economic and caregiver burden of patients with neurofibromatosis type 1 in China.

Introduction: Neurofibromatosis type 1 (NF1) is a rare genetic disorder, with lack of evidence of disease burden in China. We aimed to describe the economic burden, health-related quality of life (HRQL), and caregiver burden of NF1 patients in China. Methods: We conducted an online cross-sectional survey employing the China Cloud Platform for Rare Diseases, with 223 caregivers of NF1 pediatric patients (patients under 18), and 226 adult patients. Economic burden was estimated using direct and indirect costs related to NF1 in 2021, and the Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI-GH). HRQL measures included EQ-5D-Y proxy version and PedsQL™ 4.0 Generic Core Scales (PedsQL GCS) proxy version for pediatric patients, and EQ-5D-5L and PedsQL™ 3.0 Neurofibromatosis Module (PedsQL NFM) for adult patients. Caregiver burden was estimated by Zarit Burden Interview (ZBI). Results: For pediatric patients, the average direct cost in 2021 was CNY 33,614 (USD 4,879), and employed caregivers' annual productivity loss was 81 days. EQ-5D-Y utility was 0.880 ± 0.13 and VAS score was 75.38 ± 20.67, with 52.6% patients reporting having problems in "pain/discomfort" and 42.9% in "anxiety/depression." PedsQL GCS total score was 68.47 ± 19.42. ZBI score demonstrated that 39.5% of caregivers had moderate-to-severe or severe burden. For adult patients, average direct cost in 2021 was CNY 24,531 (USD 3,560). Patients in employment reported an absenteeism of 8.5% and presenteeism of 21.6% according to the results of WPAI-GH. EQ-5D-5L utility was 0.843 ± 0.17 and VAS score was 72.32 ± 23.49, with more than half of patients reporting having problems in "pain/discomfort" and "anxiety/depression" dimensions. PedsQL NFM total score was 68.40 ± 15.57. Conclusion: Both pediatric and adult NF1 patients in China had a wide-ranging economic burden and low HRQL, especially in the psychological dimension. Caregivers for NF1 pediatric patients experienced considerable caregiver burden. More attention and support from policymakers and stakeholders are required to relieve NF1 patients' and caregivers' distress.

PDCD4 triggers α-synuclein accumulation and motor deficits via co-suppressing TFE3 and TFEB translation in a model of Parkinson's disease.

TFE3 and TFEB, as the master regulators of lysosome biogenesis and autophagy, are well characterized to enhance the synaptic protein α-synuclein degradation in protecting against Parkinson's disease (PD) and their levels are significantly decreased in the brain of PD patients. However, how TFE3 and TFEB are regulated during PD pathogenesis remains largely vague. Herein, we identified that programmed cell death 4 (PDCD4) promoted pathologic α-synuclein accumulation to facilitate PD development via suppressing both TFE3 and TFEB translation. Conversely, PDCD4 deficiency significantly augmented global and nuclear TFE3 and TFEB distributions to alleviate neurodegeneration in a mouse model of PD with overexpressing α-synuclein in the striatum. Mechanistically, like TFEB as we reported before, PDCD4 also suppressed TFE3 translation, rather than influencing its transcription and protein stability, to restrain its nuclear translocation and lysosomal functions, eventually leading to α-synuclein aggregation. We proved that the two MA3 domains of PDCD4 mediated the translational suppression of TFE3 through binding to its 5'-UTR of mRNA in an eIF-4A dependent manner. Based on this, we developed a blood-brain barrier penetrating RVG polypeptide modified small RNA drug against pdcd4 to efficiently prevent α-synuclein neurodegeneration in improving PD symptoms by intraperitoneal injections. Together, we suggest PDCD4 as a PD-risk protein to facilitate α-synuclein neurodegeneration via suppressing TFE3 and TFEB translation and further provide a potential small RNA drug against pdcd4 to treat PD by intraperitoneal injections.

Distinct phenotype and prognosis of immune-mediated necrotizing myopathy based on clinical-serological-pathological classification.

OBJECTIVE: The aim of the study was to investigate the characteristics and prognosis of patients with immune-mediated necrotizing myopathy (IMNM) based on clinical, serological and pathological classification. METHODS: A total of 138 patients with IMNM who met the 2018 European Neuromuscular Center criteria for IMNM including 62 anti-SRP, 32 anti-HMGCR-positive and 44 myositis specific antibody-negative were involved in the study. All patients were followed up and evaluated remission and relapse. Clustering analysis based on clinical, serological, and pathological parameters was used to define subgroups. RESULTS: Clustering analysis classified IMNM into three clusters. Cluster 1 patients (n = 35) had the highest CK levels, the shortest disease course, severe muscle weakness, and more inflammation infiltration in muscle biopsy. Cluster 2 patients (n = 79) had the lowest CK level and moderate inflammation infiltrate. Cluster 3 patients (n = 24) had the youngest age of onset, the longest disease course and the least frequency of inflammatory infiltration. Patients in cluster 3 had the longest time-to-remission (median survival time: 61[18.3, 103.7] vs 20.5[16.2, 24.9] and 27[19.6, 34.3] months) and shortest relapse-free time than those in cluster 1 and 2 (median remission time 95%CI: 34[19.9, 48.0] vs 73[49.0, 68.7] and 73[48.4, 97.6] months). Patients with age of onset >55 years, more regeneration of muscle fibers, more CD4+T infiltration, and MAC deposition had more favorable outcomes regarding time to achieving remission. CONCLUSIONS: Stratification combining clinical, serological, and pathological features could distinguish phenotypes and prognosis of IMNM. The pathological characteristics may impact the long-term prognosis of patients with IMNM.

Tumour vasculature at single-cell resolution.

Tumours can obtain nutrients and oxygen required to progress and metastasize through the blood supply1. Inducing angiogenesis involves the sprouting of established vessel beds and their maturation into an organized network2,3. Here we generate a comprehensive atlas of tumour vasculature at single-cell resolution, encompassing approximately 200,000 cells from 372 donors representing 31 cancer types. Trajectory inference suggested that tumour angiogenesis was initiated from venous endothelial cells and extended towards arterial endothelial cells. As neovascularization elongates (through angiogenic stages SI, SII and SIII), APLN+ tip cells at the SI stage (APLN+ TipSI) advanced to TipSIII cells with increased Notch signalling. Meanwhile, stalk cells, following tip cells, transitioned from high chemokine expression to elevated TEK (also known as Tie2) expression. Moreover, APLN+ TipSI cells not only were associated with disease progression and poor prognosis but also hold promise for predicting response to anti-VEGF therapy. Lymphatic endothelial cells demonstrated two distinct differentiation lineages: one responsible for lymphangiogenesis and the other involved in antigen presentation. In pericytes, endoplasmic reticulum stress was associated with the proangiogenic BASP1+ matrix-producing pericytes. Furthermore, intercellular communication analysis showed that neovascular endothelial cells could shape an immunosuppressive microenvironment conducive to angiogenesis. This study depicts the complexity of tumour vasculature and has potential clinical significance for anti-angiogenic therapy.

Brain Short-Chain Fatty Acids Induce ACSS2 to Ameliorate Depressive-Like Behavior via PPARγ-TPH2 Axis.

Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis. In summary, brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.

IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease.

Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.

Influence of Polypropylene Fiber on Concrete Permeability under Freeze-Thaw Conditions and Mechanical Loading.

Polypropylene fiber reinforcement is an effective method to enhance the durability of concrete structures. With the increasing public interest in the widespread use of polypropylene fiber reinforced concrete (PFRC), the necessity of evaluating the mechanism of polypropylene fiber (PF) on the permeability of concrete has become prominent. This paper describes the influence of PF on the concrete permeability exposed to freeze-thaw cycles under compressive and tensile stress. The permeability of PFRC under compressive and tensile loads is accurately measured by a specialized permeability setup. The permeability of PFRC under compressive and tensile loads, the volume change of PFRC under compressive load, and the relationship between compressive stress levels at minimum permeability and minimum volume points of PFRC are discussed. The results indicate that the addition of PF adversely affects the permeability of concrete without freeze-thaw damage and cracks. However, it decreases the permeability of concrete specimens exposed to freeze-thaw cycles and cracking. Under compressive load, the permeability of PFRC initially decreases slowly and follows by a significant increase as the compressive stress level increases. This phenomenon correlates with the volume change of the specimen. The compressive stress level of the minimum permeability point and compressive stress level of the minimum volume point of PFRC exhibit a linear correlation, with a fitted proportional function parameter γ ≈ 0.98872. Under tensile load, the permeability of PFRC increases gradually with radial deformation and follows by a significant increase. The strain-permeability curves of PFRC under loading are studied and consist of two stages. In stage I, the permeability of PFRC gradually decreases with the increase of strain under compressive load, while the permeability increases with the increase of strain under tensile load. In stage II, under compressive load, the permeability of PFRC increases with the increase of freeze-thaw cycles, whereas under tensile load, the permeability gradually decreases with the increase of freeze-thaw cycles. The reduction of PF on the permeability of PFRC under tensile load is greater than that under compressive load. In future research, the relationship between strain and permeability of PFRC can be integrated with its constitutive relationship between stress and strain to provide a reference for the application of PF in the waterproofing of concrete structures.

Addition of ruxolitinib to standard graft-versus-host disease prophylaxis for allogeneic stem cell transplantation in aplastic anemia patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers rapid hematopoietic and immune reconstitution for aplastic anemia (AA). As a non-malignant disorder, attenuation of GVHD remains a clinical priority in AA patients. Our study sought to investigate the safety and efficacy of the prophylactic use of ruxolitinib in allogeneic HSCT. A total of 35 AA patients were retrospectively consecutively treated with allo-HSCT whereby ruxolitinib was added to the standard GVHD prophylaxis regimen (rux group). The addition of peri-transplant ruxolitinib did not impact the engraftment and graft function, while better recovery of CD4+ Tregs in the rux group was observed. Interestingly, the rux group demonstrated significantly lower incidence of bacterial/fungal infections (17.14% vs 45.71%). Compared to the control group, the rux group exhibited significantly lower incidence of moderate to severe aGVHD (17.1% vs 48.6%) with a trend toward lower severe aGVHD (8.6% vs 20%) and cGVHD (26.2 vs 38.3). The rux group also demonstrated a trend toward higher GVHD and failure-free survival (GFFS: 85.7% vs 68.6%) and lower TRM (2.9% vs 14.3%). Addition of ruxolitinib to standard GVHD prophylaxis regimen, thus, represents a safe and highly efficient method for the attenuation of GVHD with better outcome of allo-HSCT.

Effect of Macro Fibers on the Permeability and Crack Surface Topography of Layered Fiber Reinforced Concrete.

This paper describes the effects of macro fibers on permeability and crack surface topography of layered fiber-reinforced concrete (FRC) specimens with different layering ratios under uniaxial tensile load. The crack permeability of layered FRC specimens is investigated by a self-designed permeability setup. The topographical analysis of crack surfaces is investigated by a custom-designed laser scanning setup. The results show that when the fiber volume content and layering ratio of the FRC layer are constant, the tensile toughness of layered FRC specimens depends on the proportion of steel fiber in macro fibers, and with an increase in the proportion of steel fiber, the tensile toughness of layered FRC specimens increases. For the layered FRC specimens, the crack permeability is much lower than that of the normal concrete (NC) specimen. A significant positive synergistic effect on crack impermeability can be achieved by the combination of steel fiber and polypropylene fiber in the SF80PP2.3 specimen. The crack surface roughness parameter (Rn) values of the NC layer in layered FRC specimens are all higher than those of the NC specimen, and the crack surface Rn of the FRC layer in layered FRC specimens is higher than that of the unlayered FRC specimens. This can effectively increase the head loss of cracks and reduce the crack permeability of layered FRC specimens.

Hybrid Fiber Influence on the Crack Permeability of Cracked Concrete Exposed to Freeze-Thaw Cycles.

This paper describes hybrid fiber's influence on the crack permeability of cracked concrete exposed to freeze-thaw cycles. A permeability setup and a laser-scanning setup have been designed to measure the crack permeability and the fractured surface roughness of cracked hybrid fiber-reinforced concrete, containing polypropylene fiber and steel fiber, under a splitting tensile load. The results show that, when the effective crack width of the specimens is less than 25 µm, the rough crack surface significantly reduces the concrete's crack permeability. As the crack width increases, the effect of the concrete crack surface on crack permeability gradually decreases, and the crack permeability of the concrete is closer to the Poiseuille flow model. The permeability parameter α derived from the Poiseuille flow model is effective for assessing the crack permeability of concrete. Compared to the modified factor ξ of crack permeability, the permeability parameter α can effectively evaluate and quantify the development trend of crack permeability within a certain range of crack widths. The permeability parameter α of SF20PP2.3, subjected to the same freeze-thaw cycles, decreases by 16.3-94.8% compared to PP4.6 and SF40, and SF20PP2.3 demonstrates a positive synergistic effect on the crack impermeability of cracked concrete. The crack impermeability of SF40PP2.3, subjected to the same freeze-thaw cycles, lies between that of PP6.9 and SF60. The roughness of crack surface (X) and the crack permeability (Y) are highly correlated and follow an exponential curve (Y = 1.0415 × 107·e-6.025·X) in concrete. This demonstrates that hybrid fibers enhance crack impermeability by increasing the crack surface roughness. Furthermore, the combination of polypropylene fiber and steel fiber effectively promotes the formation of micro-cracks and facilitates the propagation of multiple cracks in the concrete matrix. This combination increases the head loss of water flow through the concrete and decreases the crack permeability.

ACSS2 controls PPARγ activity homeostasis to potentiate adipose-tissue plasticity.

The appropriate transcriptional activity of PPARγ is indispensable for controlling inflammation, tumor and obesity. Therefore, the identification of key switch that couples PPARγ activation with degradation to sustain its activity homeostasis is extremely important. Unexpectedly, we here show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) critically controls PPARγ activity homeostasis via SIRT1 to enhance adipose plasticity via promoting white adipose tissues beiging and brown adipose tissues thermogenesis. Mechanistically, ACSS2 binds directly acetylated PPARγ in the presence of ligand and recruits SIRT1 and PRDM16 to activate UCP1 expression. In turn, SIRT1 triggers ACSS2 translocation from deacetylated PPARγ to P300 and thereafter induces PPARγ polyubiquitination and degradation. Interestingly, D-mannose rapidly activates ACSS2-PPARγ-UCP1 axis to resist high fat diet induced obesity in mice. We thus reveal a novel ACSS2 function in coupling PPARγ activation with degradation via SIRT1 and suggest D-mannose as a novel adipose plasticity regulator via ACSS2 to prevent obesity.

IL-37d enhances COP1-mediated C/EBPß degradation to suppress spontaneous neutrophil migration and tumor progression.

The spontaneous migration of bone marrow neutrophils (BMNs) is typically induced by distant tumor cells during the early stage of the tumor and critically controls tumor progression and metastases. Therefore, identifying the key molecule that prevents this process is extremely important for suppressing tumors. Interleukin-37 (IL-37) can suppress pro-inflammatory cytokine generation via an IL-1R8- or Smad3-mediated pathway. Here, we demonstrate that human neutrophil IL-37 is responsively reduced by tumor cells and the recombinant IL-37 isoform d (IL-37d) significantly inhibits spontaneous BMN migration and tumor lesion formation in the lung by negatively modulating CCAAT/enhancer binding protein beta (C/EBPß) in a Lewis lung carcinoma (LLC)-inducing lung cancer mouse model. Mechanistically, IL-37d promotes C/EBPß ubiquitination degradation by facilitating ubiquitin ligase COP1 recruitment and disrupts C/EBPß DNA binding abilities, thereby reducing neutrophil ATP generation and migration. Our work reveals an anti-tumor mechanism for IL-37 via destabilization of C/EBPß to prevent spontaneous BMN migration and tumor progression.

D-mannose acts as a V-ATPase inhibitor to suppress inflammatory cytokines generation and bacterial killing in macrophage.

Vacuolar-type H+-ATPase (V-ATPase) critically controls phagosome acidification to promote pathogen digestion and clearance in macrophage. However, the specific subunits of V-ATPase have been evidenced to play contradictory functions in inflammatory cytokines generation and secretion exposure to external bacterial or LPS stimulation. Therefore, identifying the unique function of the separate subunit of V-ATPase is extremely important to regulate macrophage function. Here, we found that D-mannose, a C-2 epimer of glucose, suppressed ATP6V1B2 lysosomal translocation to inhibit V-ATPase activity in macrophages, thereby causing the scaffold protein axis inhibitor protein (AXIN) recruitment to lysosomal membrane and AMPK activation. Correspondingly, LPS-stimulated macrophage M1 polarization was significantly suppressed by D-mannose via down-regulating NF-κB signaling pathway in response to AMPK activation, while IL-4 induced macrophage M2 polarization were not affected. Furthermore, the failure of lysosomal localization of ATP6V1B2 caused by D-mannose also led to the acidification defects of lysosome. Therefore, D-mannose displayed a remarkable function in inhibiting macrophage phagocytosis and bacterial killing. Taken together, D-mannose acts a novel V-ATPase suppressor to attenuate macrophage inflammatory production but simultaneously prevent macrophage phagocytosis and bacterial killing.

Hepatocyte TIPE2 is a fasting-induced Raf-1 inactivator that drives hepatic gluconeogenesis to maintain glucose homeostasis.

BACKGROUND: The liver regulates metabolic balance during fasting-feeding cycle. Hepatic adaptation to fasting is precisely modulated on multiple levels. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a negative regulator of immunity that reduces several liver pathologies, but its physiological roles in hepatic metabolism are largely unknown. METHODS: TIPE2 expression was examined in mouse liver during fasting-feeding cycle. TIPE2-knockout mice, liver-specific TIPE2-knockout mice, liver-specific TIPE2-overexpressed mice were examined for fasting blood glucose and pyruvate tolerance test. Primary hepatocytes or liver tissues from these mice were evaluated for glucose production, lipid accumulation, gene expression and regulatory pathways. TIPE2 interaction with Raf-1 and TIPE2 transcription regulated by PPAR-α were examined using gene overexpression or knockdown, co-immunoprecipitation, western blot, luciferase reporter assay and DNA-protein binding assay. RESULTS: TIPE2 expression was upregulated in fasted mouse liver and starved hepatocytes, which was positively correlated with gluconeogenic genes. Liver-specific TIPE2 deficiency impaired blood glucose homeostasis and gluconeogenic capacity in mice upon fasting, while liver-specific TIPE2 overexpression elevated fasting blood glucose and hepatic gluconeogenesis in mice. In primary hepatocytes upon starvation, TIPE2 interacted with Raf-1 to accelerate its ubiquitination and degradation, resulting in ERK deactivation and FOXO1 maintenance to sustain gluconeogenesis. During prolonged fasting, hepatic TIPE2 deficiency caused aberrant activation of ERK-mTORC1 axis that increased hepatic lipid accumulation via lipogenesis. In hepatocytes upon starvation, PPAR-α bound with TIPE2 promoter and triggered its transcriptional expression. CONCLUSIONS: Hepatocyte TIPE2 is a PPAR-α-induced Raf-1 inactivator that sustains hepatic gluconeogenesis and prevents excessive hepatic lipid accumulation, playing beneficial roles in hepatocyte adaptation to fasting.

Clinical Features and Treatment Progress of Invasive Mucormycosis in Patients with Hematological Malignancies.

The incidence rate of invasive mucormycosis (IM) in patients with hematological malignancies (HMs) is increasing year by year, ranging from 0.07% to 4.29%, and the mortality rate is mostly higher than 50%. With the ongoing pandemic of COVID-19, COVID-19-associated mucormycosis (CAM) also became a global health threat. Patients with high risk factors such as active HMs, relapsed/refractory leukemia, prolonged neutropenia may still develop breakthrough mucormycosis (BT-MCR) even under the prophylaxis of Mucorales-active antifungals, and such patients often have higher mortality. Rhizopus spp. is the most common genus associated with IM, followed by Mucor spp. and Lichtheimia spp. Pulmonary mucormycosis (PM) is the most common form of IM in patients with HMs, followed by rhino-orbital-cerebral mucormycosis (ROCM) and disseminated mucormycosis. The prognosis of IM patients with neutrophil recovery, localized IM and receiving early combined medical-surgical therapy is usually better. As for management of the disease, risk factors should be eliminated firstly. Liposome amphotericin B (L-AmB) combined with surgery is the initial treatment scheme of IM. Those who are intolerant to L-AmB can choose intravenous formulations or tablets of isavuconazole or posaconazole. Patients who are refractory to monotherapy can turn to combined antifungals therapy.

Treatment With the Combination of Rituximab and Intravenous γ Globulin Is Effective in Promoting Engraftment in Donor-Specific Antibody Positive Patients Receiving Myeloablative Conditioning Haploidentical Stem Cell Transplantation.

Donor-specific anti-HLA antibodies (DSAs) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective procedures are needed for those who demand urgent transplantation and have no other donor options. We here retrospectively analyzed 13 patients with DSAs successfully treated with desensitization of rituximab and intravenous γ globulin (IVIg) before HaploSCT from March 2017 to July 2022. All 13 patients had DSA mean fluorescence intensity >4000 of at least 1 loci before desensitization. Of the 13 patients, 10 patients were with the initial diagnosis of malignant hematological diseases, and 3 were diagnosed with aplastic anemia. Patients were treated with 1 (n = 3) or 2 (n = 10) doses of rituximab (375 mg/m2 for 1 dose). All patients receive the same total dose of 0.4 g/kg of IVIg within 72 hours before haploidentical stem cell administration to neutralize the remaining DSA. All patients achieved neutrophil engraftment, and 12 patients achieved primary platelet engraftment. The patient with primary platelet engraftment failure received purified CD34-positive stem cell infusion nearly 1 year after transplantation and achieved platelet engraftment thereafter. The estimated 3-year overall survival is 73.4%. Although further studies on larger numbers of patients are needed, it is clear that the combination of IVIg and rituximab is an effective way to clear DSA and has a strong effect on promoting engraftment and survival for patients with DSA. It is a practical and adaptable combination of treatment options.