Case report: A left forearm mass with eccentric intramedullary ulnar destruction diagnosed as alveolar rhabdomyosarcoma and treated by wide resection and free vascularized fibular graft.

Background: Alveolar Rhabdomyosarcoma is a profoundly malignant soft-tissue sarcoma that predominantly affects children and adolescents. However, the medical field lacks consensus regarding the optimal surgical approach to be undertaken in cases where this tumor causes local bone destruction in the upper limb. Case description: A 17-year-old male presented a mass in his left forearm and CT and MRI indicated that the mass had penetrated the ulnar cortex and infiltrating the medulla, resulting in the formation of an eccentric trans-ventricular tumor focus. The sizable tumor affected the volar muscles of the forearm as well as the ulnar bone marrow, exerting pressure on the ulnar artery and vein. It was confirmed by needle biopsy that the mass is alveolar rhabdomyosarcoma. Following two courses of neoadjuvant chemotherapy, the tumor was widely excised en bloc. Autologous fibula with a vascular pedicle was utilized for reconstruction during the procedure. In the postoperative follow-up, no local recurrence of the tumor was observed. Furthermore, the patient retained satisfactory wrist flexion and pronation function in the left forearm. Conclusions: Alveolar rhabdomyosarcoma is an uncommon and highly aggressive form of soft tissue sarcoma. Scientific management necessitates a multidisciplinary approach, combining chemotherapy with surgery. In cases where the tumor invaded into compartment of the bone, careful consideration should be given to the boundaries of tumor resection, the extent of osteotomy, and the approach to musculoskeletal reconstruction when designing the surgical plan. Through reporting our own case and thoroughly reviewing previous clinical experiences, we aim to provide valuable insights for the treatment of this particular disease.

Mechanism study of toluene removal using iron/nickel bimetallic catalysts supported on biochar.

The present study utilized rice husk biomass as a carrier to synthesize rice husk biochar loaded with iron and nickel. Mono-metallic and bimetallic catalysts were prepared for the removal of toluene as the tar model. The efficiency of the catalysts for the removal of toluene was investigated, and finally, the removal mechanisms of mono-metallic and bimetallic catalysts for toluene were revealed. The experimental results showed that the bimetallic-loaded biochar catalysts had excellent toluene removal performance, which was closely related to the ratio of loaded Fe and Ni. Among them, the catalyst DBC-Fe2.5 %-Ni2.5 % (2.5 wt% iron loading and 2.5 wt% nickel loading) obtained through secondary calcination at 700 °C achieved the highest toluene removal efficiency of 92.76 %. The elements of Fe and Ni in the catalyst were uniformly dispersed on the surface and in the pores of the biochar, and the catalyst had a layered structure with good adsorption. Under the interaction of Fe and Ni, the agglomeration and sintering of Ni were reduced, and the surface acidity of the catalyst was increased, the surface acidity was favorable for toluene removal. The iron­nickel catalyst did not form significant alloys when calcined at 400 °C, whereas strong metal interactions occurred at 700 °C, resulting in the formation of Fe0.64Ni0.36 alloy and NiFe2O4 alloy. This NiFe alloy had abundant active sites to enhance the catalytic cracking of toluene and provide lattice oxygen for the reaction. Furthermore, the functional groups on the catalyst surface also had an impact on toluene removal. The catalyst prepared in this paper reduces the cost of tar removal, can be applied to the removal of industrial pollutant tars, reduces the pollution of the environment, and provides theoretical guidance and technical reference for the efficient removal of tar.

Corrigendum: Sequential PET/CT and pathological biomarker crosstalk predict response to PD-1 blockers alone or combined with sunitinib in propensity score-matched cohorts of cancer of unknown primary treatment.

[This corrects the article DOI: 10.3389/fonc.2023.1191611.].

Nomogram based on pretreatment hepatic and renal function indicators for survival prediction of locally advanced esophageal squamous cell carcinoma with treatment of neoadjuvant chemoradiotherapy plus surgery.

The parameters for survival prediction of esophageal squamous cell carcinoma (ESCC) patients treated with neoadjuvant chemoradiotherapy (NCRT) combined with surgery are unclear. Here, we aimed to construct a nomogram for survival prediction of ESCC patients treated with NCRT combined with surgery based on pretreatment serological hepatic and renal function tests. A total of 174 patients diagnosed as ESCC were enrolled as a training cohort from July 2007 to June 2019, and approximately 50% of the cases (n = 88) were randomly selected as an internal validation cohort. Univariate and multivariate Cox survival analyses were performed to identify independent prognostic factors to establish a nomogram. Predictive accuracy of the nomogram was evaluated by Harrell's concordance index (C-index) and calibration curve. ALT, ALP, TBA, TP, AST, TBIL and CREA were identified as independent prognostic factors and incorporated into the construction of the hepatic and renal function test nomogram (HRFTNomogram). The C-index of the HRFTNomogram for overall survival (OS) was 0.764 (95% CI 0.701-0.827) in the training cohort, which was higher than that of the TNM staging system (0.507 (95% CI 0.429-0.585), P < 0.001). The 5-year OS calibration curve of the training cohort demonstrated that the predictive accuracy of the HRFTNomogram was satisfactory. Moreover, patients in the high-risk group stratified by the HRFTNomogram had poorer 5-year OS than those in the low-risk group in the training cohort (27.4% vs. 80.3%, P < 0.001). Similar results were observed in the internal validation cohort. A novel HRFTNomogram might help predict the survival of locally advanced ESCC patients treated with NCRT followed by esophagectomy.

The prognosis of breast cancer patients with bone metastasis could be potentially estimated based on blood routine test and biochemical examination at admission.

PURPOSE: Due to the poor and unpredictable prognosis of breast cancer (BC) patients with bone metastasis, it is necessary to find convenient and available prognostic predictors. This study aimed to recognize the clinical and prognostic factors related to clinical laboratory examination and to construct a prognostic nomogram for BC bone metastasis. METHODS: We retrospectively analyzed 32 candidate indicators from clinical features and laboratory examination data of 276 BC patients with bone metastasis. Univariate and multivariate regression analyses were performed to identify significant prognostic factors related to BC with bone metastasis. Nomogram was constructed and estimated by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. RESULTS: Patients were randomly grouped into training (n = 197) and validation cohorts (n = 79). In training cohort, the multivariate regression analysis revealed that age, other organ metastasis sites, serum level of lactate dehydrogenase, globulin, white blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, and monocyte ratio were independent prognostic factors for BC with bone metastasis. The prognostic nomogram in training cohort exhibited areas under the ROC curve (AUCs) of 0.797, 0.782, and 0.794, respectively, for predicting 1-, 3-, and 5-year overall survival. In validation cohort, the nomogram still showed acceptable discrimination ability (AUCs: 0.723, 0.742, and 0.704) and calibration. CONCLUSION: This study constructed a novel prognostic nomogram for BC patients with bone metastasis. It could serve as a potential tool of survival assessment to help individual treatment decision-making for clinicians.

Our study investigated potential prognostic value of indicators from biochemical and blood routine examination for breast cancer patients with bone metastasis.Our study established a nomogram based on the indicators from biochemical and blood routine examination, which might enhance the ability to predict prognosis of breast cancer patients with bone metastasis.

Reducedhumoral response against variants of concern in childhood solid cancer patients compared to adult patients and healthy children after SARS-CoV-2 vaccination.

Introduction: Although there is extended research on the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in adult cancer patients (ACP), the immunogenicity to the variants of concern (VOCs) in childhood cancer patients (CCP) and safety profiles are now little known. Methods: A prospective, multi-center cohort study was performed by recruiting children with a solid cancer diagnosis and childhood healthy control (CHC) to receive standard two-dose SARS-CoV-2 vaccines. An independent ACP group was included to match CCP in treatment history. Humoral response to six variants was performed and adverse events were followed up 3 months after vaccination. Responses to variants were compared with ACP and CHC by means of propensity score-matched (PSM) analysis. Results: The analysis included 111 CCP (27.2%, median age of 8, quartile 5.5-15 years), 134 CHC (32.8%), and 163 ACP (40.0%), for a total 408 patients. Pathology included carcinoma, neural tumors, sarcoma, and germ cell tumors. Median chemotherapy time was 7 (quartile, 5-11) months. In PSM sample pairs, the humoral response of CCP against variants was significantly decreased, and serology titers (281.8 ± 315.5 U/ml) were reduced, as compared to ACP (p< 0.01 for the rate of neutralization rate against each variant) and CHC (p< 0.01 for the rate of neutralization against each variant) groups. Chemotherapy time and age (Pearson r ≥ 0.8 for all variants) were associated with the humoral response against VOCs of the CHC group. In the CCP group, less than grade II adverse events were observed, including 32 patients with local reactions, and 29 patients had systemic adverse events, including fever (n = 9), rash (n = 20), headache (n = 3), fatigue (n = 11), and myalgia (n = 15). All reactions were well-managed medically. Conclusions: The humoral response against VOCs after the CoronaVac vaccination in CCP was moderately impaired although the vaccine was safe. Age and chemotherapy time seem to be the primary reason for poor response and low serology levels.

Cognitive adverse events in patients with lung cancer treated with checkpoint inhibitor monotherapy: a propensity score-matched analysis.

Background: Cancer-related cognitive decline is a serious problem in long-term survival but no pivotal study has investigated whether checkpoint inhibitors (ICI) may be associated with cognitive adverse events. Methods: This propensity score-matched analysis recruited non-small cell lung cancer (NSCLC) patients prescribed with or without ICI monotherapy from three Chinese tertiary hospitals. Patients were excluded from study who developed brain metastasis or had disorders severely affecting cognitive abilities. Primary outcomes were changes in neuropsychological battery test (NBT) at baseline, 6- and 12-month sessions, and any NBT score changes that exceeded 3∗SD of baseline scores would be marked as objective cognitive adverse events (CoAE). Secondary endpoint was the 20-item Perceived Cognitive Impairment (PCI) sub-scale score change in Functional Assessment of Cancer Therapy-Cognitive Function questionnaire, administered at baseline, 3-, 6-, 9-, 12-, and 15-month follow-up session. Per-protocol ICI and control arms were matched with propensity scores that incorporated baseline variables to compare both NBT and PCI assessment results. Patients participating in PCI assessments were analysed in intention-to-treat analysis. Kaplan-Meier survival curves with log-rank tests were adopted to analyse incidence of perceived cognitive decline events (PCDE). Findings: Between March 12, 2020, and March 28, 2021, 908 participants were enrolled. Compared to control, 3 of 4 subtest of NBT scores in ICI arm showed significant cognitive decline in 6- and 12-month sessions, in which Trail Making Test score change (13.56 ± 11.73) reached threshold of cognitive deficit diagnosis in the 12-month session. In 1:1 matched 292 pairs from 908 patients, PCI score changes in ICI arms were -4.26 ± 8.54 (3rd month), -4.72 ± 11.83 (6th month), -6.16 ± 15.41 (9th month), -6.07 ± 15.71 (12th month), and -7.96 ± 13.97 (15th month). The scores were significantly lower than control arm in 3-, 6-, and 12-session follow-up. The result was validated after adjusting quality of life scores and in intention-to-treat analysis. Mean PCI change exceeded 1/2 SD of baseline PCI score (5.81) in 9-, 12-, and 15-month sessions in ICI arm, but not in control arm. PCDE incidence/prevalence was significantly higher in ICI arm (incidence 26.4% vs. 5.1%, and prevalence 16.2% vs. 1.7%). Immune-related adverse events related to incidence of PCDE after adjusting for baseline variables. Interpretation: ICI monotherapy seemed to relate to higher cognitive decline represented by score changes and incidence/prevalence rates. The decline deteriorated as treatment progressed, and immune-related adverse events seemed to be associated with higher cognitive adverse events incidence in the ICI treatment. Funding: The Fellowship of China Postdoctoral Science Foundation and National Natural Science Foundation of China Youth Science Fund Project.

The Natural Alkaloid (-)-N-Hydroxyapiosporamide Suppresses Colorectal Tumor Progression as an NF-κB Pathway Inhibitor by Targeting the TAK1-TRAF6 Complex.

Colorectal cancer (CRC) is an exceptionally deadly disease, whereas effective therapeutic drugs for CRC have declined over the past few decades. Natural products have become a reliable source of anticancer drugs. Previously we isolated an alkaloid named (-)-N-hydroxyapiosporamide (NHAP), which exerts potent antitumor effects, but its effect and mechanism in CRC remain unclear. This study aimed to reveal the antitumor target of NHAP and identify NHAP as a promising lead compound for CRC. Various biochemical methods and animal models were used to investigate the antitumor effect and molecular mechanism for NHAP. These results showed that NHAP exhibited potent cytotoxicity, induced both apoptosis and autophagic cell death of CRC cells, and inhibited the NF-κB signaling pathway by blocking the interaction of the TAK1-TRAF6 complex. NHAP also markedly inhibited CRC tumor growth in vivo without obvious toxicities and possessed good pharmacokinetic characteristics. These findings identify, for the first time, that NHAP is an NF-κB inhibitor with potent antitumor activity in vitro and in vivo. This study clarifies the antitumor target of NHAP against CRC, which will contribute to the future development of NHAP as a novel therapeutic lead compound for CRC.

Sequential PET/CT and pathological biomarker crosstalk predict response to PD-1 blockers alone or combined with sunitinib in propensity score-matched cohorts of cancer of unknown primary treatment.

Introduction: The efficacy of immune checkpoint inhibitors (ICIs), including toripalimab and pembrolizumab, has not been confirmed in the treatment of cancer of unknown primary (CUP), which has a very poor prognosis. Combined with anti-angiogenic therapies, ICIs are hypothesized to be effective in prolonging overall survival. The study aims to give evidence on the treatment effects of sunitinib combined with ICIs, find pathological biomarkers associated with changes in volumetric 18F FDG PET/CT parameters, and investigate inner associations among these markers associated with response on PET/CT. Methods: The study recruited patients receiving combined treatment (ICIs + sunitinib), compared the effects of combined treatment with those of separate treatment and age-matched negative controls, and analyzed propensity score-matched (PSM) pairs. Markers associated with survival were identified, and their inner associations were tested using structural equation modeling. Results: A total of 292 patients were enrolled in the final analysis, with 53 patients receiving combined treatment. Survival analysis demonstrated significantly prolonged survival in either combined or separate treatment, with the combined arm showing better response when PSM-paired using pre-treatment whole-body PET/CT parameters. The angiogenic markers KDR and VEGF mediate the PD-1 blockade impact on volumetric value changes in positive and negative manners. Conclusion: The anti-angiogenic agent sunitinib may potentiate PD-1 blockade by diminishing angiogenesis or its downstream effects. The combined separate treatment increased the survival of CUP patients, and the responses could be evaluated using volumetric PET/CT parameters.

Parent Acceptance toward Inactivated COVID-19 Vaccination in Children with Acute Lymphoblastic Leukemia: The Power of Oncologist and Alliance.

Objectives: The current study aims to survey the willingness of parents to vaccinate their children, who are childhood acute lymphoblastic leukemia survivors (CALLS), and identify factors associated with vaccine acceptance. Methods: Parents of CALLS on/off treatment, with the general condition of being amendable to vaccination, were recruited for interviews with attending oncologists about COVID-19 vaccination acceptance from July to November 2021 in China. After controlling for socioeconomic factors, the Association of Oncologists' recommendations and parent−oncologist alliance with acceptance status were investigated. For validation, propensity score-matched (PSM) analysis was used. Results: A total of 424 families were included in the study, with CALLS mean remission age of 5.99 ± 3.40 years. Among them, 91 (21.4%) agreed, 168 (39.6%) hesitated, and 165 (38.9%) parents disagreed with the vaccination. The most common reason that kept parents from vaccinating their children was lack of recommendations from professional personnel (84/165, 50.9%), and massive amounts of internet information (78/175, 44.6%) was the main nonhealthcare resource against vaccination. Logistic regression analysis showed that only the recommendation from the oncologist was associated with parents' vaccine acceptance (OR = 3.17, 95% CI = 1.93−5.20), as demonstrated by PSM comparison (42 in recommendation group vs. 18 in nonrecommendation group among 114 pairs, p < 0.001). An exploratory analysis revealed that parents with a better patient−oncologist alliance had a significantly higher level of acceptance (65.6% in alliance group vs. 15.6% in nonalliance group among 32 pairs, p < 0.001). Conclusions: Due to a lack of professional recommendation resources and the potential for serious consequences, parents were generally reluctant to vaccinate their CALLS. The recommendation of oncologists, which was influenced by the parent−oncologist alliance, significantly increased acceptance. This study emphasizes the critical role of oncologists in vaccinating cancer survivors and can be used to promote COVID-19 vaccines among vulnerable populations.

Serial negative response after standard and third (Booster) dose of COVID-19 inactivated vaccine is associated with low vitamin D levels in patients with solid cancers.

Introduction: The response is poorly understood to the third dose in patients with cancer who failed the standard dose of inactivated SARS-CoV-2 vaccines (CoronaVac). We aim to assess the immune response to the third dose and identify whether vitamin D deficiency is associated with serial serologic failure in patients with cancer. Methods: Solid cancer patients (SCP-N) and healthy controls (HCs) who were seronegative after the standard-dose vaccines in our previous study were prospectively recruited, from October 2021 to February 2022, to receive the third dose vaccines and anti-SARS-CoV-2S antibodies were measured. SCP-N who failed the third dose (serial seronegative group, SSG) were matched by propensity scores with the historical standard-dose positive cancer patient group (robust response group, RRG). An exploratory analysis was carried out to validate the role of vitamin D on the serology response. Results: The multi-center study recruited 97 SCP-N with 279 positive controls as RRG and 82 negative controls as HC group. The seroconversion rate after third-dose vaccination was higher in SCP-N than in HC (70.6% vs. 29.4%, p < 0.01). The matched comparison showed that patients in SSG had a significantly lower level of vitamin D and consumption rate than RRG or RRG-B (RRG with third-dose positive) (all p < 0.01). None had serious (over grade II) adverse events after the third dose. Conclusion: Solid cancer patients with second-dose vaccine failure may have a relatively poor humoral response to the third dose of COVID-19 vaccines as compared with the seronegative HC group. The consecutively poor humoral response could be associated with poor vitamin D levels and intake. Vitamin D status and cancer-related immune compromise may jointly affect the humoral response following booster vaccination.

Intramedullary nailing for pathological fractures of the proximal humerus caused by multiple myeloma: A case report and review of literature.

BACKGROUND: Multiple myeloma (MM) bone disease is indicative of MM, and reduces patient life quality. In addition to oncological, antineoplastic systemic therapy, surgical therapy in patients with MM is an essential treatment within the framework of supportive therapy measures and involves orthopedic tumor surgery. Nevertheless, there are few reports on intramedullary (IM) nailing in the treatment of MM-induced proximal humeral fracture to prevent fixation loss. We here describe a case of pathological fracture of the proximal humerus caused by MM successfully treated with IM nailing without removal of tumors and a review of the current literature. CASE SUMMARY: A 64-year-old male patient complaining of serious left shoulder pain and limited movement was admitted. The patient was finally diagnosed with MM (IgAλ, IIIA/II). After treatment of the pathological fracture with IM nailing, the patient's function recovered and his pain was rapidly relieved. Histopathological examination demonstrated plasma cell myeloma. The patient received chemotherapy in the Hematology Department. The humeral fracture displayed good union during the 40-mo follow-up, with complete healing of the fracture, and the clinical outcome was satisfactory. At the most recent follow-up, the patient's function was assessed using the Musculoskeletal Tumor Society score, which was 29. CONCLUSION: Early surgery should be performed for the fracture of the proximal humerus caused by MM. IM nailing can be used without removal of tumors. Bone cement augmentation for bone defects and local adjuvant therapy can also be employed.

Bindarit Reduces Bone Loss in Ovariectomized Mice by Inhibiting CCL2 and CCL7 Expression via the NF-κB Signaling Pathway.

OBJECTIVE: To investigate the changes in proinflammatory cytokines and chemokines, namely, C-C motif ligand (CCL) 2 and CCL7, in postmenopausal osteoporosis (PMOP) and to develop a new drug, bindarit (Bnd), for PMOP in an ovariectomized (OVX) mouse model. METHODS: Bone marrow macrophages (BMMs) from the femurs of five women with PMOP and five premenopausal women without osteoporosis were detected by RNA sequencing. BMMs from mice were differentiated into osteoclasts and treated with a synthetic inhibitor of CCL2 and CCL7, Bnd, or 17 beta estradiol (E2 ). Mouse BMMs were differentiated into osteoclasts with or without Bnd for 7 days and analyzed by RNA sequencing. Osteoblasts of mice were induced to undergo osteoblastogenesis and treated with Bnd. OVX mice were treated with E2 or Bnd after surgery. The protein and mRNA expression of CCL2 and CCL7 was detected using immunostaining and qPCR, respectively, in OVX and aged mice and in cells cultured in vitro. Osteoclast formation was detected using a tartrate-resistant acid phosphatase (TRAP) assay in vitro and in vivo. Alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) were detected using immunostaining to evaluate osteogenesis. Microcomputed tomography was conducted to analyze trabecular bone parameters, the structure model index, bone mineral density and other variables. Nuclear factor-κB (NF-κB) signaling pathway-related protein phosphorylation of IKKα/ß (p-IKKα/ß) and p-NFκB p65 was examined using western blotting. RESULTS: CCL2, CCL7 and their receptor of C-C chemokine receptor-2 (CCR2), and the NF-κB signaling pathway, were significantly increased in women with PMOP. CCL2 and CCL7 protein and mRNA expression was increased in OVX mice and aged female mice, but the increases were attenuated by E2 and Bnd. E2 and Bnd effectively inhibited osteoclastogenesis and the protein expression of CCL2 and CCL7 both in vitro and in vivo and reduced bone loss in OVX mice. Bnd did not affect the mineralization of osteoblasts directly in vitro but reduced bone turnover in vivo. p-IKKα/ß and p-NFκB p65 levels were increased in BMMs of mice after differentiation into osteoclasts but were significantly decreased by Bnd. CONCLUSION: The proinflammatory cytokines and chemokines CCL2, CCL7 and CCR2 were correlated with PMOP. Bnd attenuated the increases in CCL2 and CCL7 levels to affect osteoporosis in OVX mice via the NFκB signaling pathway. Thus, Bnd may be useful as a new therapeutic for the prevention of PMOP.

Identification of meroterpenoids from Bipolaris victoriae S27 and their potential activity against tumor metastasis and inhibition of the NF-κB signaling pathway.

Three undescribed meroterpenoids, named bipolacochlioquinones A-C, together with seven known compounds, were isolated from the plant endophytic fungus Bipolaris victoriae S27 derived from the fresh stems of Rubia podantha Diels. Their structures were mainly determined by extensive spectroscopic analysis. The relative configurations of bipolacochlioquinones A-C were assigned using the ROESY spectrum, comparison of their spectral data with that reported in the literatures, and NMR calculations. Moreover, their complete absolute configurations were further established by electronic circular dichroism calculations using density functional theory. Among them, bipolacochlioquinone A is found to represent the first example of previously undescribed 6/6/6/6/6 pentacyclic dioxane-containing cochlioquinones, and bipolacochlioquinone B possesses a rare 6/6/6/6/5 pentacyclic system bearing a tetrahydrofuran ring fused to a polyketide and a sesquiterpenoid subunit. All compounds were evaluated for their inhibitory effects on tumor growth, metastasis, and the NF-κB signaling pathway. Among them, bipolacochlioquinone C and cochlioquinone A show the most potent cytotoxicities and NF-κB inhibitory activities. The effects of bipolacochlioquinone C and cochlioquinone A on the expression of NF-κB-associated proteins were also evaluated using western blotting. These results indicate that bipolacochlioquinone C and cochlioquinone A can inhibit the growth and metastasis of HCT116 and MDA-MB-231 cells by suppressing the NF-κB signaling pathway.

Assessment of the diagnostic and prognostic relevance of ACAT1 and CE levels in plasma, peritoneal fluid and tumor tissue of epithelial ovarian cancer patients - a pilot study.

BACKGROUND: Abnormal accumulation of acyl-CoA cholesterol acyltransferase-1 (ACAT1) and ACAT1-mediated cholesterol esterified with fatty acids (CE) contribute to cancer progression in various cancers. Our findings of increased CE and ACAT1 levels in epithelial ovarian cancer (EOC) cell lines prompted us to investigate whether such an increase occurs in primary clinical samples obtained from human subjects diagnosed with EOC. We evaluated the diagnostic/prognostic potential of ACAT1 and CE in EOC by: 1) assessing ACAT1 and CE levels in plasma, peritoneal fluid, and ovarian/tumor tissues; 2) assessing diagnostic performance by Receiver Operating Characteristic (ROC) analysis; and 3) comparing expression of ACAT1 and CE with that of tumor proliferation marker, Ki67. METHODS: ACAT1 protein levels in plasma, peritoneal fluid and tissue were measured via enzyme-linked immunosorbent assay. Tissue expression of ACAT1 and Ki67 proteins were confirmed by immunohistochemistry and mRNA transcript levels were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). CE levels were assessed in plasma, peritoneal fluid (colorimetric assay) and in tissue (thin layer chromatography). RESULTS: Preoperative levels of ACAT1 and CE on the day of surgery were significantly higher in tissue and peritoneal fluid from EOC patients vs. the non-malignant group, which included subjects with benign tumors and normal ovaries; however, no significant differences were observed in plasma. In tissue and peritoneal fluid, positive correlations were observed between CE and ACAT1 levels, as well as between ACAT1/CE and Ki67. CONCLUSIONS: ACAT1 and CE accumulation may be linked to the aggressive potential of EOC; therefore, these mediators may be useful biomarkers for EOC prognosis and target-specific treatments.

Exosomal myeloperoxidase as a biomarker of deep venous thrombosis.

BACKGROUND: Deep vein thrombosis (DVT) often occurs following major orthopedic surgery. In this study, we investigated specific exosomal proteins as potential diagnostic biomarkers of DVT. METHODS: Proteomic analysis of exosomes from four DVT patients and healthy controls (n=4) was performed by mass spectrometry. The model animals were evaluated at 1 inferior vena cava ligation [(IVCL)-1D], 3 (IVCL-3D), and 7 (IVCL-7D) days after IVCL. Endothelial cells in the thrombus segment were examined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays and hematoxylin and eosin (HE) staining. Myeloperoxidase (MPO) expression in the damaged vessel was detected by immunofluorescence staining. Exosomes were co-cultured with human umbilical vein endothelial cells (HUVECs) and cell proliferation was estimated using Cell Counting Kit-8 (CCK-8) assays. RESULTS: A total of 78 differentially expressed proteins (DEPs; 38 downregulated and 40 upregulated) were identified in the DVT group. In the rat DVT model, endothelial cells were damaged continuously after thrombosis, with the most serious injury in the IVCL-3D group, after which signs of endothelial repair were apparent. The IVCL-1D group showed the highest levels of vascular endothelial cell apoptosis and MPO increased sharply in the IVCL-1D and IVCL-3D groups, but had almost disappeared in the IVCL-7D group. In co-culture, plasma exosomes isolated from DVT model rats were efficiently absorbed by HUVECs, with markedly lower HUVECs growth and higher levels of apoptosis in the IVCL-1D and IVCL-3D groups compared with the control group. CONCLUSIONS: Our findings suggest that exosomes may be involved in endothelial cell injury during DVT. The exosomal protein MPO is a potential biomarker of early stage DVT.

Increased expression of osteopontin in subchondral bone promotes bone turnover and remodeling, and accelerates the progression of OA in a mouse model.

Osteopontin (OPN) has been proved to be closely related to the pathogenesis of osteoarthritis (OA), but the role of OPN in the pathogenesis of OA has not been fully clarified. Current studies on OPN in OA mostly focus on articular cartilage, synovial membrane and articular fluid, while ignoring its role in OA subchondral bone turnover and remodeling. In this study, we used a destabilization OA mouse model to investigate the role of OPN in OA subchondral bone changes. Our results indicate that increased expression of OPN accelerates the turnover and remodeling of OA subchondral bone, promotes the formation of h-type vessels in subchondral bone, and mediates articular cartilage degeneration induced by subchondral bone metabolism. In addition, our results confirmed that inhibition of PI3K/AKT signaling pathway inhibits OPN-mediated OA subchondral bone remodeling and cartilage degeneration. This study revealed the role and mechanism of OPN in OA subchondral bone, which is of great significance for exploring specific biological indicators for early diagnosis of OA and monitoring disease progression, as well as for developing drugs to regulate the metabolism and turnover of subchondral bone and alleviate the subchondral bone sclerosis of OA.

Immune checkpoint blocking impact and nomogram prediction of COVID-19 inactivated vaccine seroconversion in patients with cancer: a propensity-score matched analysis.

BACKGROUND: Patients with cancer on active immune checkpoint inhibitors therapy were recommended to seek prophylaxis from COVID-19 by vaccination. There have been few reports to date to discuss the impact of progression cell death-1 blockers (PD-1B) on immune or vaccine-related outcomes, and what risk factors that contribute to the serological status remains to be elucidated. The study aims to find the impact of PD-1B on vaccination outcome and investigate other potential risk factors associated with the risk of seroconversion failure. METHODS: Patients with active cancer treatment were retrospectively enrolled to investigate the interaction effects between PD-1B and vaccination. Through propensity score matching of demographic and clinical features, the seroconversion rates and immune/vaccination-related adverse events (irAE and vrAE) were compared in a head-to-head manner. Then, a nomogram predicting the failure risk was developed with variables significant in multivariate regression analysis and validated in an independent cohort. RESULTS: Patients (n=454) receiving either PD-1B or COVID-19 vaccination, or both, were matched into three cohorts (vac+/PD-1B+, vac+/PD-1B-, and vac-/PD-1B+, respectively), with a non-concer control group of 206 participants. 68.1% (94/138), 71.3% (117/164), and 80.5% (166/206) were seropositive in vac+/PD-1B+cohort, vac+/PD-1B- cohort, and non-cancer control group, respectively. None of irAE or vrAE was observed to be escalated in PD-1B treatment except for low-grade rash.The vaccinated patients with cancer had a significantly lower rate of seroconversion rates than healthy control. A nomogram was thus built that encompassed age, pathology, and chemotherapy status to predict the seroconversion failure risk, which was validated in an independent cancer cohort of 196 patients. CONCLUSION: Although patients with cancer had a generally decreased rate of seroconversion as compared with the healthy population, the COVID-19 vaccine was generally well tolerated, and seroconversion was not affected in patients receiving PD-1B. A nomogram predicting failure risk was developed, including age, chemotherapy status, pathology types, and rheumatic comorbidity.

6'-O-Galloylpaeoniflorin Attenuates Osteoclasto-genesis and Relieves Ovariectomy-Induced Osteoporosis by Inhibiting Reactive Oxygen Species and MAPKs/c-Fos/NFATc1 Signaling Pathway.

Emerging evidence suggests bright prospects of some natural antioxidants in the treatment of osteoporosis. 6'-O-Galloylpaeoniflorin (GPF), an antioxidant isolated from peony roots (one of very widely used Oriental medicines, with various anti-inflammatory, antitumor, and antioxidant activities), shows a series of potential clinical applications. However, its effects on osteoporosis remain poorly investigated. The current study aimed to explore whether GPF can attenuate osteoclastogenesis and relieve ovariectomy-induced osteoporosis via attenuating reactive oxygen species (ROS), and investigate the possible mechanism. After the culture of primary murine bone marrow-derived macrophages/monocytes were induced by the use of macrophage colony-stimulating factor (M-CSF) and the receptor activator of NF-κB ligand (RANKL) and then treated with GPF. Cell proliferation and viability were assessed by Cell Counting Kit-8 (CCK-8) assay. Thereafter, the role of GPF in the production of osteoclasts and the osteogenic resorption of mature osteoclasts were evaluated by tartrate-resistant acid phosphatase (TRAP) staining, podosome belt formation, and resorption pit assay. Western blotting and qRT-PCR examination were performed to evaluate proteins' generation and osteoclast-specific gene levels, respectively. The ROS generation in cells was measured in vitro by 2',7'-Dichlorodi-hydrofluorescein diacetate (DCFH-DA). Ovariectomy-induced osteoporosis mouse administered with GPF or vehicle was performed to explore the in vivo potential of GPF, then a micro-CT scan was performed in combination with histological examination for further analysis. GPF suppressed the formation of osteoclasts and podosome belts, as well as bone resorption when induced by RANKL through affecting intracellular ROS activity, MAPKs signaling pathway, and subsequent NFATc1 translocation and expression, as well as osteoclast-specific gene expression in vitro. In vivo study suggested that exposure to GPF prevented osteoporosis-related bone loss in the ovariectomized mice. These findings indicate that GPF attenuates osteoclastogenesis and relieves ovariectomy-induced osteoporosis by inhibiting ROS and MAPKs/c-Fos/NFATc1 signaling pathway. This suggested that GPF may be potentially used to treat bone diseases like periodontitis, rheumatoid arthritis, and osteoporosis associated with osteoclasts.

Spleen tyrosine kinase (SYK) inhibitor PRT062607 protects against ovariectomy-induced bone loss and breast cancer-induced bone destruction.

Osteolytic diseases, including breast cancer-induced osteolysis and postmenopausal osteoporosis, are attributed to excessive bone resorption by osteoclasts. Spleen tyrosine kinase (SYK) is involved in osteoclastogenesis and bone resorption, whose role in breast cancer though remains controversial. Effects of PRT062607 (PRT), a highly specific inhibitor of SYK, on the osteoclast and breast cancer functionalities are yet to be clarified. This study demonstrated the in vitro inhibitory actions of PRT on the osteoclast-specific gene expression, bone resorption, and osteoclastogenesis caused by receptor activator of nuclear factor kappa B ligand (RANKL), as well as its in vitro suppressive effects on the growth, migration and invasion of breast carcinoma cell line MDA-MB-231, which were achieved through PLCγ2 and PI3K-AKT-mTOR pathways. Further, we proved that PRT could prevent post-ovariectomy (OVX) loss of bone and breast cancer-induced bone destruction in vivo, which agreed with the in vitro outcomes. In conclusion, our findings suggest the potential value of PRT in managing osteolytic diseases mediated by osteoclasts.