Roles of varying carbon chains and functional groups of legacy and emerging per-/polyfluoroalkyl substances in adsorption on metal-organic framework: Insights into mechanism and adsorption prediction.

Metal-organic frameworks (MOFs) are promising adsorbents for legacy per-/polyfluoroalkyl substances (PFASs), but they are being replaced by emerging PFASs. The effects of varying carbon chains and functional groups of emerging PFASs on their adsorption behavior on MOFs require attention. This study systematically revealed the structure-adsorption relationships and interaction mechanisms of legacy and emerging PFASs on a typical MOF MIL-101(Cr). It also presented an approach reflecting the average electronegativity of PFAS moieties for adsorption prediction. We demonstrated that short-chain or sulfonate PFASs showed higher adsorption capacities (µmol/g) on MIL-101(Cr) than their long-chain or carboxylate counterparts, respectively. Compared with linear PFASs, their branched isomers were found to exhibit a higher adsorption potential on MIL-101(Cr). In addition, the introduction of ether bond into PFAS molecule (e.g., hexafluoropropylene oxide dimeric acid, GenX) increased the adsorption capacity, while the replacement of CF2 moieties in PFAS molecule with CH2 moieties (e.g., 6:2 fluorotelomer sulfonate, 6:2 FTS) caused a decrease in adsorption. Divalent ions (such as Ca2+ and SO42-) and solution pH have a greater effect on the adsorption of PFASs containing ether bonds or more CF2 moieties. PFAS adsorption on MIL-101(Cr) was governed by electrostatic interaction, complexation, hydrogen bonding, π-CF interaction, and π-anion interaction as well as steric effects, which were associated with the molecular electronegativity and chain length of each PFAS. The average electronegativity of individual moieties (named Me) for each PFAS was estimated and found to show a significantly positive correlation with the corresponding adsorption capacity on MIL-101(Cr). The removal rates of major PFASs in contaminated groundwater by MIL-101(Cr) were also correlated with the corresponding Me values. These findings will assist with the adsorption prediction for a wide range of PFASs and contribute to tailoring efficient MOF materials.

CSNK1A1/CK1α suppresses autoimmunity by restraining the CGAS-STING1 signaling.

STING1 (stimulator of interferon response cGAMP interactor 1) is the quintessential protein in the CGAS-STING1 signaling pathway, crucial for the induction of type I IFN (interferon) production and eliciting innate immunity. Nevertheless, the overactivation or sustained activation of STING1 has been closely associated with the onset of autoimmune disorders. Notably, the majority of these disorders manifest as an upregulated expression of type I interferons and IFN-stimulated genes (ISGs). Hence, strict regulation of STING1 activity is paramount to preserve immune homeostasis. Here, we reported that CSNK1A1/CK1α, a serine/threonine protein kinase, was essential to prevent the overactivation of STING1-mediated type I IFN signaling through autophagic degradation of STING1. Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation. Consistently, SSTC3, a selective CSNK1A1 agonist, significantly attenuated the response of the CGAS-STING1 signaling by promoting STING1 autophagic degradation. Importantly, pharmacological activation of CSNK1A1 using SSTC3 markedly repressed the systemic autoinflammatory responses in the trex1-/- mouse autoimmune disease model and effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of CSNK1A1 in the autophagic degradation of STING1 to maintain immune homeostasis. Manipulating CSNK1A1 through SSTC3 might be a potential therapeutic strategy for alleviating STING1-mediated aberrant type I IFNs in autoimmune diseases.Abbreviations: BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; HTDNA: herring testes DNA; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; MEFs: mouse embryonic fibroblasts; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1.

UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation.

STING1 (stimulator of interferon response cGAMP interactor 1), the pivotal adaptor protein of CGAS (cyclic GMP-AMP synthase)-STING1 signaling, is critical for type I IFN production of innate immunity. However, excessive or prolonged activation of STING1 is associated with autoinflammatory and autoimmune diseases. Thus, preventing STING1 from over-activation is important to maintain immune homeostasis. Here, we reported that UXT (ubiquitously expressed prefoldin like chaperone), a small chaperone-like protein, was essential to prevent the excessive activation of STING1-mediated type I IFN signaling through autophagic degradation of STING1 via SQSTM1 (sequestosome 1). Upon DNA mimics or cyclic GMP-AMP (cGAMP) stimulation, UXT specifically interacted with STING1 and promoted STING1 degradation through selective macroautophagy/autophagy. Moreover, UXT was required for more efficient autophagic degradation of STING1 by facilitating the interaction of SQSTM1 and STING1. The in vivo role of UXT in attenuating the CGAS-STING1 signaling was further confirmed in the mouse model of DNA-virus infection and the TMPD (2,6,10,14-tetramethylpentadecane)-induced murine lupus model. Intriguingly, the expression of UXT was consistently impaired and exhibited a remarkable inverse correlation with type I IFN signature in the leukocytes and PBMCs (peripheral blood mononuclear cells) of several large SLE (systemic lupus erythematosus) cohorts. Importantly, the replenishment of UXT effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of UXT in autophagic degradation of STING1 to maintain immune homeostasis. UXT might be a potential therapeutic target for alleviating aberrant type I IFNs in autoimmune diseasesAbbreviations: 3-MA: 3-methyladenine; BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic gmp-amp synthase; cKO: conditional knockout; CXCL10: C-X-C motif chemokine ligand 10; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSV-1: herpes simplex virus type 1; HTDNA: herring testes DNA; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; RNA-seq: RNA sequencing; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TMPD: 2,6,10,14-tetramethylpentadecane; UXT: ubiquitously expressed prefoldin like chaperone.

The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion.

Virus infection has been consistently threatening public health. The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. cGAS recognizes the pathogenic DNA in the cytosol and then synthesizes 2'3'-cyclic GMP-AMP (2'3'cGAMP). As the second messenger, cGAMP activates STING and induces the following cascade to produce type I interferon (IFN-I) to protect against infections. However, viruses have evolved numerous strategies to hinder the cGAS-STING signal transduction, promoting their immune evasion. Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments.

Short-term Preoperative Denosumab With Surgery in Unresectable or Recurrent Giant Cell Tumor of Bone.

OBJECTIVE: The purpose of this retrospective study was to evaluate the clinical and oncological results of combination treatment of short-term preoperative denosumab (the receptor activator of nuclear factor kappa-B ligand inhibitor) with surgery in unresectable or recurrent cases of giant cell tumor of the bone (GCTB). METHODS: Between 2016 and 2018, 11 eligible patients (1 man, 10 women, mean age 38.1 years) with grade 3 GCTB were treated with a combination of short-term (six doses) preoperative denosumab and surgery in a single institution. The clinical, radiological, and pathological alteration after the denosumab treatment were compared. The oncological results of the combination therapy were also recorded. Meanwhile, adverse effects or complications of denosumab, if any, were reported. RESULTS: The median follow-up time after surgical procedure was 30 months (range 13-45 months). After 3-4 denosumab injections, pain relief was observed in all patients. In two spine patients, the neurological status improved after four doses of treatment. Intraoperatively, the margin of the tumor became clear and the intensity of the tumor increased while the blood supply around and within the lesion decreased. Within the lesion, the typically soft and loose tissue were replaced by the tough and dense fibro-osseous tissue. The mean diameter of the lesion before and after treatment was 61.55 ± 22.49 mm and 51.81 ± 21.12 mm, respectively, and the T-score was 1.02 (P = 0.32). Variable calcification was observed at the periphery and within the lesion. A total of three patients experienced local recurrence in this study. In the resection group, only one extremity patient had soft tissue recurrence that was treated with en-bloc excision. In the curettage group, two of three sacral tumor patients had local occurrence. Both refused re-operation and restarted the monthly denosumab injection thereafter, and the lesions remained stable at the final follow up. Finally, no adverse effects or complications related to denosumab treatment were found. CONCLUSION: For the unresectable or recurrent GCTB cases, short-term (six doses) preoperative use of denosumab improved clinical symptoms, decreased the tumor size, and increased the tumor density. The changes in tumors, in turn, simplified the tumor removal manipulation and, subsequently, decreased the local recurrence for the resection surgery. For the curettage, the denosumab-induced changes had mixed impacts, and shorter term (fewer than six doses) usage may be more appropriate. Our six-dose regime was deemed safe, while the safety of long-term use remains unknown.

Diagnostic yield of percutaneous core needle biopsy in suspected soft tissue lesions of extremities.

OBJECTIVE: This retrospective study was performed to investigate the diagnostic yield of percutaneous core needle biopsy (CNB) for suspected soft tissue lesions of the extremities. METHODS: The medical records of 139 consecutive patients who underwent percutaneous CNB for suspected soft tissue lesions of the extremities from January 2014 to December 2016 at a single institution were reviewed. The pathologic findings or clinical follow-ups were used to evaluate the performance of CNB. Alterations in the treatment regimen from pre- to post-biopsy were also analyzed. Complications, when present, were documented. RESULTS: In total, 141 biopsy procedures were performed in 139 patients. In total, 136 (96%) biopsies were successful, among which 5 were false-negative and 131 were diagnosed accurately. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CNB in the differentiation of malignant from benign lesions were 94%, 100%, 96%, 100%, and 90%, respectively. The treatment regimen was altered based on the biopsy findings in 25 cases. Two patients developed mild nerve injury but fully recovered during follow-up. CONCLUSIONS: CNB is effective and safe, with high sensitivity, specificity, and accuracy for the diagnosis of soft tissue lesions, especially for differentiating malignant from benign lesions.

Evaluation of the use of fluoroscopy guided needle biopsies for diagnosing cases of suspected pathological fractures.

AIM: Establishing an early and accurate diagnosis in cases of suspected pathological fractures is crucial to initiate optimal treatment without delay. The use of percutaneous biopsy has become popular over the past few years. However, there is a paucity of information regarding the efficacy and safety of percutaneous biopsy procedures guided by fluoroscopy. METHODS: A total of 137 percutaneous C-arm fluoroscopy-guided core needle biopsy (CNB) procedures were performed in 135 patients with suspected pathological fractures. The sensitivity, specificity, accuracy, and overall prognostic value of these procedures were evaluated. Complications, if any, were documented for all cases. RESULTS: The overall sensitivity, specificity, and accuracy were 82.0%, 100%, and 83.2%, respectively. The positive and negative predictive value was 100% and 28.1%, respectively. There were 23 "false negative" cases in our study, of which 15 were benign lesions and eight were malignant tumors. No "false-positives" were found. Major procedure-related complications occurred in three patients (2.2%). These complications, however, did not alter the prognosis of these patients. CONCLUSION: Percutaneous C-arm fluoroscopy-guided biopsy procedures are both effective and safe for diagnosis of suspected pathological fractures in the appendicular skeleton.

Reconstruction of bone defect with autograft fibula and retained part of tibia after marginal resection of periosteal osteosarcoma: a case report.

Periosteal osteosarcoma is a rare subtype of osteosarcoma. Wide surgical removal is the commonly used treatment-method algorithm. However, the limb-salvage procedure of periosteal osteosarcoma in the distal tibia is a technical challenge to orthopedic surgeons because of the scarcity of soft tissue and subcutaneous nature in the anteromedial aspect. We encountered a 16-year-old female patient with periosteal osteosarcoma in the distal half of the left tibia diagnosed preoperatively based upon the CT images and a needle biopsy. A unique identical surgical technique was applied in the case, including marginal resection of the periosteal osteosarcoma with part of the tibia retained at the same level of bone defect and reconstruction using the autologous fibula graft. A combination of cisplatin and doxorubicin was received as chemotherapy after the operation. Postoperative incisional biopsy was performed, and the hematoxylin-eosin-stained results confirmed the diagnosis of periosteal osteosarcoma. The patient was followed up for 11 years. Radiological and clinical evaluation was performed at each follow-up. The retained tibia incorporated well with the fibula autograft, and excellent limb functional recovery was achieved. The patient was free from neoplastic disease at the latest follow-up. In conclusion, young patients with periosteal osteosarcoma without intramedullary involvement can be treated by marginal resection of the lesion with part of the tibia retained at the level of bone defect and reconstructed using a long autologous fibula graft. Subsequent chemotherapy with administration of cisplatin and doxorubicin is recommended.

[Analysis of risk factors for deep vein thrombosis of the lower extremity for patients with bone metastases].

OBJECTIVE: To analyze the risk factors for deep vein thrombosis (DVT) of the lower extremity in patients with bone metastases. METHODS: Ninety patients with bone metastases were admitted to our hospital From January 2010 to December 2011, and their clinical data were retrospectively analyzed. There were 57 males and 33 females with a mean age of 61 years (range, 27 to 78 years). On admission, all cases were detected by color Doppler ultrasonography for DVT of bilateral lower extremities. Univariate and multivariate analyses were performed to determine the probable risk factors including gender, age, body weight, tumor location, bed confinement and etc. RESULTS: Among the 90 patients, DVT was found in 24 patients on admission and the DVT incidence was 26.7% (24/90). The univariate analysis showed that bed confinement, multiple metastasis, pathological fracture, primary lesion detected, blood group, fibrinogen and hematocrit were significantly related to the incidence of DVT (P < 0.05). The logistic multivariate regression analysis showed that bed confinement, pathological fracture and fibrinogen were independent risk factors for the incidence of DVT. CONCLUSIONS: Bed confinement, pathological fracture and fibrinogen are independent risk factors for the incidence of DVT for patients with bone metastases. Patients with bed confinement >3 days, pathological fracture or fibrinogen >4 g/L should be routinely screened for lower extremity DVT on admission. Once identified, the DVT patients should be treated as early as possible.

[Study on changes of vitamin nutrition status of population in a high-risk area of esophageal cancer].

OBJECTIVE: To study the changes of vitamin nutritional status of residents in a high-risk area of esophageal cancer. METHODS: 8 towns where nutrition survey had been done were selected, 2 villages were randomly selected from each town and 30 families were randomly selected per village. The blood and 4h burden urine samples were collected from subjects. The serum vitamin A, blood total ascorbic acid and glutathione reductase activition coefficient (AC) in red blood cell were determinde by using of trifluoroacetic acid colorimetry, 2, 4-dinitrophenylhydrazine colorimetric method and Sauberlich method respectively. The contents of vitamin B2 , reduction ascorbic acid and total ascorbic acid in 4h burden urine were measured by using of fluorescent pectrophotometry,2,6-Dichloro-N-(4-hydroxyphenyl)-1,4-benzoquinoneimine titrimetric method and 2,4-dinitrophenylhydrazine colorimetric method respectively. The results were analyzed and compared with those of in 1980, 1983 and 1984. The t-test or chi2-test was carried out. RESULTS: The level of serum retinal in residents living in Ren cun, Dongyao and Hejian is significantly higher than that of in 1982 (P < 0.01). The level of vitamin B2 in 4h burden urine in residents living in Yaocun, Rencun and Heshun are significantly higher than that of in 1982 or 1984 (P < 0.01). The number of ribflavin deficiency of population living in Dongyao, Hejian, Yaocun and Rencun are significantly lower than that of in 1982 or 1983 (P < 0.01) according to the content of 4h burden urine and glutathione reductase activation coefficient (AC) in red blood cell; the number of vitamin C deficiency of population living in Dongyao, Hejian,Yao cun, Ren cun and Heshun are significantly lower than that of in 1982 or 1983 (P < 0.01) according to blood total ascorbic acid and the ascorbic acid content of 4h-burden urine and. CONCLUSION: Vitamin nutritional status of residents in a high-risk area of esophageal cancer have been improved.