Doxorubicin-loaded PEG-CdTe QDs conjugated with anti-CXCR4 mAbs: a novel delivery system for extramedullary multiple myeloma treatment.

Extramedullary multiple myeloma (EMM) is defined as the presence of plasma cells outside the bone marrow of multiple myeloma patients, and its prognosis is poor. High-dose chemotherapy with autologous stem cell transplantation, as a good option on early lines of therapy, has retained the survival benefit of youny EMM patients, but is intolerant for the majority of old patients because of drug cytotoxicity. To essentially address the intolerance above, we designed a CXCR4-PEG-CdTe-DOX (where CXCR4: chemokine receptor 4; PEG-CdTe: polyethylene glycol-modified cadmium telluride; DOX:doxorubicin) nanoplatform. First, CXCR4 is highly expressed in extramedullary plasma cells. Second, PEG-CdTe a drug carrier that controls drug release, can reduce adverse reactions, prolong drug (e.g, DOX) circulation time in the body, and form a targeting carrier after connecting antibodies. In vitro experiments showed CXCR4-PEG-CdTe-DOX facilitated intracellular drug accumulation through active CXCR4 targeting and released DOX into the microenvironment in a pH-controlled manner, enhancing the therapeutic efficacy and apoptosis rate of myeloma cells (U266). Therefore, targeted chemotherapy mediated by CXCR4-PEG-CdTe-DOX is a promising option for EMM treatment.

4,8-Dicarboxyl-8,9-iridoid-1-glycoside inhibits apoptosis in human osteoarthritis chondrocytes via enhanced c-MYC-mediated cholesterol metabolism in vitro.

BACKGROUND: Osteoarthritis (OA) is a degenerative disease related to cholesterol metabolism disorders. However, current therapies for OA are insufficient and no convincing disease-modifying OA drugs exist. Therefore, we aimed to elucidate the mechanism by which borojoa iridoid glycoside (BIG) inhibits chondrocyte apoptosis in OA. METHODS: Borojoa pulp was heated to 70 °C, and the main active substance in borojoa, BIG, was extracted by fractionation at an ultraviolet 254-nm absorption peak. Chondrocytes were identified by immunohistochemistry and visualized by immunofluorescence confocal microscopy. The proliferation of chondrocytes cultured with BIG was determined by MTS assay. The apoptosis of chondrocytes cultured with BIG was tested by Annexin V-FITC/PI, and the cytokine, protein, and cholesterol levels in chondrocytes were detected by ELISA, RT‒qPCR, Western blot, and biochemistry analyses. Protein‒protein interactions were verified by a coimmunoprecipitation (Co-IP) assay. RESULTS: BIG promoted chondrocyte proliferation and reduced apoptosis in vitro. BIG induced an alteration of the total RNA profiles in chondrocytes, and bioinformatic analysis showed that BIG inhibited chondrocyte apoptosis by promoting c-MYC expression; KEGG analysis confirmed that BIG-inhibited apoptosis was enriched in the cell cycle pathway. Flow cell cycle experiments confirmed that BIG promoted chondrocyte proliferation by significantly increasing the S phase cell number. The c-MYC inhibitor 10058-F4 stimulated the increased expression of IL-1ß, IL-6, TNF-α, and AGEs and suppressed the cholesterol metabolism, which promoted chondrocyte apoptosis and autophagy. Co-IP analysis showed that BIG promoted the interaction of c-MYC and CH25H, Bcl-2, which suggests that BIG could inhibit chondrocyte apoptosis in part by enhancing c-MYC-mediated cholesterol metabolism. CONCLUSIONS: This study confirmed that BIG promotes chondrocyte proliferation and inhibits apoptosis and autophagy, and BIG improving OA is associated with cholesterol metabolism. The results identify a potential mechanism by which BIG enhances c-MYC-mediated CH25H regulation of cholesterol metabolism in vitro and suggest that BIG might be a promising new drug against OA.

Association between neutrophil-to-lymphocyte ratio and postoperative fatigue in elderly patients with hip fracture.

Background: and purpose: Postoperative fatigue (POF) is a common and distressing post-operative symptom. This study aimed to explore the relationship between neutrophil-to-lymphocyte ratio (NLR) and POF in elderly patients with hip fracture. Method: Elderly patients (age ≥65 years) with acute hip fracture admitted to the Department of Orthopedics of Anqing Municipal Hospital from June 2018 to June 2020 were included. Fatigue was assessed using the Fatigue Severity Scale at the 3-month follow-up postoperatively. Univariate and multivariate analyses were performed to explore the associations between NLR and POF. The diagnostic performance of NLR was analysed using Receiver Operating Characteristic (ROC) curve analysis and the Delong test. Result: A total of 321 elderly patients with hip fractures were included; 120 (37.4 %) of them were diagnosed with POF. Univariate analysis indicated significant differences in NLR, platelet-to-lymphocyte ratio (PLR), education, neutrophil count, lymphocyte count, Hamilton Depression Scale (HAMD) and Insomnia Severity Index (ISI) scores (P < 0.05). Multivariate analysis indicated neutrophil count (odds ratio [OR], 1.46; 95 % confidence interval [CI] 1.27-1.67), lymphocyte count (OR 0.32, 95 % CI 0.19-0.53), NLR (OR1.81, 95 % CI 1.50-2.17) and PLR (OR 1.005, 95 % CI 1.001-1.009) were significantly associated with POF. The areas under the ROC curves (AUCs) of neutrophil count, lymphocyte count, NLR and PLR were 0.712, 0.667, 0.775 and 0.605, respectively. The Delong test indicated that NLR had the best diagnostic performance (p < 0.05). Conclusion: NLR independently predicts POF in elderly patients with acute hip fracture.

Pan-Cancer Analysis Reveals the Relation between TRMT112 and Tumor Microenvironment.

Dysregulated epigenetic modifications play a critical role in cancer development where TRMT112 is a member of the transfer RNA (tRNA) methyltransferase family. Till now, no studies have revealed the linkage between TRMT112 expression and diverse types of tumors. Based on TCGA data, we first probed into the relation between TRMT112 and prognosis and the potential role of TRMT112 in tumor microenvironment across 33 types of tumor. TRMT112 presented with increased expression in most cancers, which was significantly prognostic. Furthermore, TRMT112 was associated with tumor-associated fibroblasts in a variety of cancers. Additionally, a positive relationship was identified between TRMT112 expression and multiple tumor-related immune infiltrations, such as dendritic cells, CD8+ T cells, macrophages, CD4+ T cells, neutrophils, and B cells in lung adenocarcinoma and breast invasive carcinoma. In summary, our results suggest that TRMT112 might be a potential prognostic predictor of cancers and involved in regulating multiple cancer-related immune responses to some extent.

Reduced CXCR4 expression in associated with extramedullary and predicts poor survival in newly diagnosed multiple myeloma.

BACKGROUND: Multiple myeloma (MM), a bone marrow-resident hematological malignancy of plasma cells, has remained largely incurable despite the recent advancement in novel therapies. The heterogeneity of myeloma cells makes risk stratification of MM important for therapeutic regimen planning. RESEARCH DESIGN AND METHODS: No immunohistochemical (IHC) predictive and prognostic marker of MM has been constructed yet. Herein, the prognostic value of chemokine (C-X-C motif) receptor 4 (CXCR4) expression in 48 newly diagnosed MM patients was explored using IHC. Correlations between CXCR4 expression and clinical features of MM were analyzed. RESULTS: CXCR4-positive patients significantly outperformed CXCR4-negative patients in both 3-year estimated overall survival (93.8% vs 45.8%, P = 0.0392) and progression-free survival (57.1% vs 40.9%, P = 0.0436). CONCLUSIONS: The incidence of extramedullary lesions in CXCR4-negative patients increased significantly compared with CXCR4-positive patients. Plasma cells that reduce CXCR4 expression have poor prognosis and increase the incidence of extramedullary lesions.

4,8-dicarboxyl-8,9-iridoid-1-glycoside Promotes Neural Stem Cell Differentiation Through MeCP2.

Background: Borojó (Borojoa patinoi Cuatrec) fruit has recently been shown to have a variety of health benefit, but the mechanisms have been little studied. The aim of this study was to investigate the effect of 4,8-dicarboxyl-8,9-iridoid-1-glycoside (388) on proliferation and differentiation of embryonic neural stem cells (NSCs). Methods: NSCs were treated with 388 and stem cell differentiation was determined by western blotting and immunofluorescence staining. The role of MeCP2 in 388-mediated embryonic NSCs differentiation was examined. Results: The results showed that in the presence of mitogen when NSCs proliferated and maintained their multipotency, treatment with 388 did not affect the viability of NSCs. Following mitogen withdrawal to initiate NSC differentiation, treatment with 388 at the doses of 10 and 50 µg/mL significantly increased neural differentiation in both cortex and spinal cord-derived culture. 388 also significantly up-regulated MeCP2 expression. The expression of the neuronal and oligodendrocytic markers was enhanced after addition of 388 in the differentiation culture. However, knockdown of MeCP2 results in inhibition of NSC differentiation, and the pro-differentiation effect of 388 was mostly abolished. Conclusions: This study confirmed that 388 stimulates differentiation of NSCs and identifies its mechanism of action by upregulating MeCP2.

Analysis of Pan-Cancer Revealed the Immunological and Prognostic Potential of CBX3 in Human Tumors.

Chromobox protein homolog 3 (CBX3) has been recognized as a member of the heterochromatin protein 1 family and participate in transcriptional activation or inhibition, cell differentiation and growth. Despite more and more evidence shows that CBX3 has a critical function in the development of some tumors, no systematic extensive analysis of CBX3 has been reported. Thus, we intended to examine the prognostic significance of CBX3 in 33 tumors and investigate its potential immune function. We employed several bioinformatics methods to explore the potential carcinogenic impact of CBX3 premised on the data sets collected from tumor genome maps, human protein maps, cBioPortal, and genotype tissue expression. The approaches include assessing the link between CBX3 and prognosis of different tumors, immune cell infiltration, micro-satellite instability (MSI), DNA methylation, and tumor mutational burden (TMB). The outcomes illustrated that CBX3 was increasingly expressed in 29 tumors. Moreover, CBX3 exhibited a negative correlation with the prognosis of many tumors. The expression of CBX3 was linked to MSI in 12 tumors and TMB in 16 tumors. In 24 tumors, the expression of CBX3 was linked to DNA methylation. Moreover, the CBX3 expression exhibited a negative relationship with the infiltration level of the majority of immune cells, but showed a positive link to T gamma delta cells, central memory T cells, and T helper cells, especially when invading breast carcinoma, thymic carcinoma, colon carcinoma, cutaneous melanoma, endometrial carcinoma, and lung squamous carcinoma. Our research indicates that CBX3 might be used as a prognostic indicator for different malignant tumors due to its function in tumor genesis as well as tumor immunity.

Trends in Dietary Patterns and Diet-related Behaviors in China.

Objectives: Determination of trends in diet-related behaviors and their interactions with cardio-metabolic diseases is an important research endeavor. Methods: We analyzed food categories, weight, eating frequency, eating location, cooking methods, time of food intake, dietary knowledge, food preference, nutritional structure over time, and their interaction with cardiometabolic risks, using t tests and χ² tests, based on the China Health and Nutrition Survey packages from 1997 to 2011. Results: Consumption of fruits, dairy products, snacks, fast food, and beverages has increased significantly, as a concomitant and marked decrease in rice consumption has occurred. Food categories, eating frequency, cooking methods, and at-home eating are gradually increasing and diversifying. Persons not only prefer to consume carbohydrate-rich foods like fruits and vegetables, but also enjoy energy-dense foods like meat, snacks, and beverages. There has been a switch from a predominantly plant-based diet to a Western style diet high in fat and animal-based foods. People have undergone significant changes in reducing the intake of energy, carbohydrates, and protein, but significantly increased their fat intake. Conclusion: Chinese dietary patterns and diet-related behaviors have undergone significant transition in the past few decades, trending towards diversification and modernization.

Daunorubicin-Loaded CdTe QDs Conjugated with Anti-CD123 mAbs: A Novel Delivery System for Myelodysplastic Syndromes Treatment.

INTRODUCTION: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increase risk of transformation to acute myeloid leukemia (AML). Daunorubicin (DNR) is an indispensable drug for the treatment of MDS and AML. However, its side effects including cardiac toxicity and bone marrow suppression severely limit clinical application. Many researches reported high expression of CD123 antigen on high-risk MDS cells, so we constructed a novel drug delivery system comprising daunorubicin-loaded CdTe QDs conjugated with anti-CD123 mAbs (DNR-CdTe-CD123) to develop targeted combination chemotherapy for MDS. METHODS: CdTe conjugated antiCD123 through amide bond, co-loaded with DNR with electrostatic bonding. Then, we determined characterization and release rate of DNR-CdTe-CD123. The therapeutic effect and side effect of drug delivery system were evaluated through in vitro and in vivo experiments. RESULTS: CdTe showed appropriate diameter and good dispersibility and DNR was loaded into CdTes with high encapsulation efficiency and drug loading. The maximum drug loading and encapsulation efficiency were 42.08 ± 0.64% and 74.52 ± 1.81%, respectively, at DNR concentration of 0.2mg/mL and anti-CD123 mAbs volume of 5ul (100ug/mL). Flow cytometry (FCM) showed that CD123 antigen was highly expressed on MUTZ-1 cells, and its expression rate was 72.89 ± 10.67%. In vitro experiments showed that the inhibition rate and apoptosis rate of MUTZ-1 cells treated with DNR-CdTe-CD123 were higher than those in the other groups (P<0.05). Compared with the other groups, the level of apoptosis-related protein (P53, cleaved caspase-9, Bax and cleaved caspase-3) were upregulated in DNR-CdTe-CD123 group (P<0.05). In vivo experiments, DNR-CdTe-CD123 can effectively inhibit the tumor growth of MDS-bearing nude mice and reduce the side effects of DNR on myocardial cells. CONCLUSION: The system of DNR-CdTe-CD123 enhances the therapeutic effects and reduce the side effects of DNR, thus providing a novel platform for MDS treatment.

CD5-negative chronic lymphocytic leukemia/small lymphocytic lymphoma in a patient with gastrointestinal mantle cell lymphoma: an unusual case report.

Richter's syndrome, the development of high-grade non-Hodgkin lymphoma in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), may be triggered by viral infections (eg, Epstein-Barr virus infection). Herein, we report an unusual case of CD5-negative CLL/SLL patient with gastrointestinal mantle cell lymphoma (MCL) and hepatitis B virus infection. CLL/SLL was diagnosed based on lymph node immunohistochemistry and bone marrow pathology. This patient was treated with seven cycles of multi-agent chemotherapy. During treatment, the hepatitis B viruses were activated. Then, after 20 months of antiviral treatment with entecavir, he developed abdominal discomfort and abdominal lymphadenopathy and was diagnosed with MCL based on intestinal biopsy. This work indicates that the hepatitis B virus in patients with CLL/SLL may accelerate the progress or transformation to MCL.

Prognostic Value of 1q21 Gain in Multiple Myeloma.

BACKGROUND: Multiple myeloma (MM) is a heterogeneous disease characterized by chromosomal translocation, deletion, and amplification in plasma cells, resulting in a huge heterogeneity in its outcomes. In the era of novel agents such as bortezomib, thalidomide, and the cycles of treatment, risk stratification by chromosomal aberrations may enable a more rational risk-stratification selection of therapeutic approaches in patients with MM. PATIENTS AND METHODS: We performed a retrospective study in 63 patients with MM; 29 (46.03%) with 1q21 gain and 34 (53.97%) without gain. RESULT: In all patients, we did not find that the patients with 1q21 gain had significantly better survival compared with patients without 1q21 gain (overall survival, P = .6916; progression-free survival, P = .8740). However, in 1q21 gain patients, we found that the bortezomib group had significantly better survival compared with the non-bortezomib group in terms of both the 3-year estimated overall survival (82.3% vs. 18.8%; P = .0154) and progression-free survival (62.8% vs. 8.75%; P = .0385). CONCLUSION: 1q21 gain detected by fluorescence in situ hybridization is not as high risk for poor prognosis with regard to time for overall survival. And the clinical outcome of patients with 1q21 gain can be improved in those who received no less than 4 cycles of bortezomib-based therapy (bortezomib, thalidomide, and dexamethasone).

Primary Philadelphia chromosome positive acute myeloid leukemia: A case report.

RATIONALE: Philadelphia chromosome positive acute myeloid leukemia (Ph+ AML) is a rare subtype of AML that is now included as a provisional entity in the 2016 revised WHO classification of myeloid malignancies. However, a clear distinction between de novo Ph+ AML and chronic myeloid leukemia blast crisis is challenging. It is still a matter of debate whether Ph+ AML patients should be treated with chemotherapy or tyrosine kinase inhibitors as first-line therapy. PATIENT CONCERNS: We reported here a case of a 46-year-old man who was diagnosed as Ph+ AML. This diagnosis was confirmed by bone marrow pathology and karyotype analysis of 46, XY, t (9; 22). Further examination, molecular genetic analysis showed BCR/ABL1 (p190) without ABL1 kinase domain mutations, and direct evidence demonstrated in AML by flow cytometry. DIAGNOSIS: The diagnosis of Ph+ AML was made on May 2016 according to morphology, immunology, cytogenetic, and molecular criteria, and multiple organ failure was also diagnosed. INTERVENTIONS: The patient was treated with dasatinib as the only medication after experiencing multiple organ failure. Then, he received 2 cycles of chemotherapy with IA (idarubicin 8 mg/m, day 1-3; cytarabine 100 mg/m, day 1-7) in August, 2016. OUTCOMES: The patient finally achieved a complete molecular remission. LESSONS: This case study suggests that dasatinib can be a safe and effective treatment for Ph+ AML patients with poor physical condition.

Doxorubicin-Loaded PEG-CdTe Quantum Dots as a Smart Drug Delivery System for Extramedullary Multiple Myeloma Treatment.

New drug treatments still do not improve the prognosis of extramedullary multiple myeloma (EMM) patients. Luckily, high-dose chemotherapy can raise the prognosis, but is intolerant to most patients because of drug cytotoxicity. Nanoparticles (NPs) are used as drug carriers to prolong drug circulation time, control drug release, reduce drug toxicity and bioavailability, and target specific sites. In this work, doxorubicin (DOX) was loaded in polyethylene glycol-modified cadmium telluride quantum dots (PEG-CdTe QDs). PEG-CdTe-DOX facilitated intracellular drug accumulation through polyethylene organizational compatibility and released DOX into the microenvironment in a pH-controlled manner, which enhanced the therapeutic efficacy and the apoptosis rate of myeloma cells (PRMI8226). PEG-CdTe-DOX improved the anti-tumor activity of DOX by regulating the protein expressions of apoptosis-associated genes. In summary, PEG-CdTe-DOX provides a specific and effective clinical treatment for EMM patients.

Acute lymphoblastic leukemia in a patient with IgG4-related disease.

IgG4-related disease (IgG4-RD) is a multi-organ immune-mediated condition characterized by tumor-like lesions, fibrosis, and lymphoplasmacytic infiltration to every organ. Recently, an association between IgG4-RD and malignant tumors has been suggested and IgG4-RD is closely related to the occurrence of malignant hematologic diseases. In this report, we describe a rare complication of acute lymphoblastic leukemia in a patient with IgG4-RD. An 81-year-old Chinese man was diagnosed with the lymphadenopathy associated with IgG4-related disease. The histopathological study revealed multiple plasma cells infiltration and immunostaining for IgG and IgG4 was performed on plasma cells and the IgG/IgG4 ratio was more than 40%. Eight months later, he developed acute lymphoblastic leukemia. It has been suggested that the incidence of malignant hematologic diseases may be high in patients with IgG4-RD and increased Th2 cells and Treg cells cytokines may result in the occurrence of hematologic malignancies. Therefore, the importance of accurate diagnosis and intense medical follow-up should be emphasized. Once the patients develop hematologic malignancies, they need to receive treatment timely.

Comparison of outcomes in hematological malignancies treated with haploidentical or HLA-identical sibling hematopoietic stem cell transplantation following myeloablative conditioning: A meta-analysis.

PURPOSE: Haploidentical and human leukocyte antigen (HLA)-identical sibling hematopoietic stem transplantation are two main ways used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In recent years, remarkable progress has been made in haploidentical allo-HSCT (HID-SCT), and some institutions found HID-SCT had similar outcomes as HLA-identical sibling allo-HSCT (ISD-SCT). To clarify if HID-SCT has equal effects to ISD-SCT in hematologic malignancies, we performed this meta-analysis. METHODS: Relevant articles published prior to February 2017 were searched on PubMed. Two reviewers assessed the quality of the included studies and extracted data independently. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated for statistical analysis. RESULTS: Seven studies including 1919 patients were included. The rate of platelet engraftment is significantly lower after HID-SCT versus ISD-SCT while there is no difference in neutrophil engraftment (OR = 2.58, 95% CI = 1.70-3.93, P < 0.00001). The risk of acute graft-versus-host disease (GVHD) is significantly higher after HID-SCT versus ISD-SCT (OR = 1.88, 95% CI = 1.42-2.49, P < 0.00001), but the relapse rate is lower in HID-SCT group (OR = 0.70, 95% CI = 0.55-0.90, P = 0.005). The incidence rates of overall survival (OS) and disease-free-survival/leukemia-free survival/relapse-free survival (DFS/LFS/RFS) after ISD-SCT are all significantly superior to HID-SCT (OR = 1.32, 95% CI = 1.08-1.62, P = 0.006; OR = 1.25, 95% CI = 1.03-1.52, P = 0.02). There is no significant difference in transplantation related mortality (TRM) rate after HID-SCT and ISD-SCT. CONCLUSION: After myeloablative conditioning, patients receiving ISD-SCT have a faster engraftment, lower acute GVHD and longer life expectancy compared to HID-SCT with GVHD prophylaxis (cyclosporine A, methotrexate, mycophenolate mofetil and antithymoglobulin; CsA + MTX + MMF + ATG). Currently, HID-SCT with GVHD prophylaxis (CsA + MTX + MMF + ATG) may not replace ISD-SCT when HLA-identical sibling donor available.