INTRODUCTION

One of the novel strategies in cancer treatment is the combination of conventional chemotherapeutic drugs and natural products. In a previous study, co-treatment of the anti-cancer drug cyclophosphamide (CP) with honey from giant honey bee (Apis dorsata) resulted to a dose-dependent increase in its cytotoxic effect in human lung carcinoma (A549) cells. However, the molecular mechanism of this combinatorial effect remains unknown.

In this study, the effect of A. dorsata honey on the expression of selected CYP450 genes at the mRNA level, as well as the proapoptotic gene CASP8 and antiapoptotic gene BCL2 was investigated in CP-treated A549 cells.

MTT Assay was performed to determine the cell viability of A549 cells after treatment with CP with or without A. dorsata honey, as well as the EC50 of CP with honey thereafter. RT-qPCR was then performed to study the effect of A. dorsata honey on the expression of selected CYP450 genes as well as CASP8 and BCL2 genes in CPtreated A549 cells. LC-MS was carried out to screen for putative compounds in A. dorsata honey which may possibly have anti-cancer activity.

Honey in the lowest concentration (0.6% v/v) most effectively enhanced the cytotoxic effect of CP. CYP2J2 and CYP1B1 indicated a 2.38-fold and 1.49-fold upregulation, respectively as compared to untreated cells. This cytotoxic effect is further enhanced by upregulation of CASP8 that is paralleled by a downregulation of BCL2. Phytosphingosine and sphinganine are honey constituents which may be linked to the increased cytotoxicity of CP observed in A549 cells.

This study provides further knowledge on the molecular basis by which A. dorsata honey potentiates the cytotoxic effect of cyclophosphamide in A549 cells.

BACKGROUND: To compare the efficacy and safety of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL) at a single institution. METHODS: This retrospective study included 115 newly diagnosed patients with WR-DLBCL, of whom 68 patients received R-CHOP, and 47 patients received DA-EPOCH-R as their first-line treatment. The baseline features of the two groups were well balanced using a 1:1 propensity score matching method, and a total of 84 cases were obtained, including respective 42 cases in the R-CHOP and DA-EPOCH-R groups, for further survival and prognosis analysis. The primary objectives included progression-free survival (PFS) and overall survival (OS). RESULTS: During a median follow-up of 45 months, there were nine (21.4%) deaths in the R-CHOP group and two (4.8%) in the DA-EPOCH-R group. Kaplan-Meier analysis showed statistically significant improvements in PFS and OS in patients with DA-EPOCH-R compared with those treated with R-CHOP (log-rank test, P  = 0.025 and P  = 0.035, respectively). The 2-year PFS and OS rates in the DA-EPOCH-R group were 90.1% (95% confidence interval [CI]: 81.4-99.8%) and 95.2% (95% CI: 89.0-100.0%), respectively, and 80.5% (95% CI: 69.3-93.6%) and 90.5% (95% CI: 52.8-99.8%) in the R-CHOP group. Patients without B symptoms and elevated lactate dehydrogenase levels had a higher PFS in the DA-EPOCH-R group, with P values of 0.038 (hazard ratio [HR]: 0.11; 95% CI: 0.01-0.88) and 0.042 (HR: 0.19; 95% CI: 0.04-0.94), respectively. There were no statistically significant differences in clinical responses and treatment-related toxicities between the two groups. CONCLUSION Compared with patients received R-CHOP, those treated by DA-EPOCH-R had superior PFS, OS, and controlled toxicity in patients with WR-DLBCL.
Humans ; Rituximab/therapeutic use* ; Vincristine/therapeutic use* ; Retrospective Studies ; Prednisone/therapeutic use* ; Etoposide/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Cyclophosphamide/therapeutic use* ; Doxorubicin/therapeutic use*

OBJECTIVE: To investigate the in vivo intervention and relative mechanism of Genistein (GEN) on tumor-associated inflammatory and tumor thrombophilia in lymphoma-bearing mice. METHODS: Forty female Balb/c mice aged 5-6 weeks were injected with murine-derived Pro B-cell lymphoma cell line 38B9 to establish a lymphoma mouse model, which was randomly divided into control group, tumor-bearing group, GEN drug intervention group and cyclophosphamide (CTX）drug intervention group. Histopathologic was used to evaluate the tumorigenesis. Tumor formation was observed, and tumor tissues were collected of HE and immunohistochemical staining. ELISA and flow cytometry were used to detect the expression of inflammatory factors and the changes of thrombus indices in plasma after intervention of GEN and Cyclophosphamide (CTX) respectively. Immunohistochemistry method was used to detect the expression of CD19 in tomor tissues of tummor bearing mice. RESULTS: After 14 days of tumor bearing, the mice were tumorigenic. The lymphoma cells were diffusely distributed in the tumor tissue and the expression of CD19 in the tumor tissue was positive. The inflammatory factors such as IL-6, NETs and CLEC-2, and thrombotic indices such as TF, FIB and D-D in lymphoma-bearing mice were significantly higher than those before tumor-injection and lower than those after drug-intervention (all P<0.05). The levels of CLEC-2 and D-D in GEN group were significantly lower than those in CTX group (P<0.05). CONCLUSION Tumor-associated inflammation and thrombophilia exist in lymphoma-bearing mice. GEN shows better anti-inflammatory and anti-thrombotic effects compared with CTX by interfering with tumor inflammatory factors.
Mice ; Female ; Animals ; Genistein ; Lymphoma ; Cyclophosphamide ; Thrombophilia ; Inflammation ; Lectins, C-Type

Osteoarthritis is a prevalent global joint disease, which is characterized by inflammatory reaction and cartilage degradation. Cyasterone, a sterone derived from the roots of Cyathula officinalis Kuan, exerts protective effect against several inflammation-related diseases. However, its effect on osteoarthritis remains unclear. The current study was designed to investigate the potential anti-osteoarthritis activity of cyasterone. Primary chondrocytes isolated from rats induced by interleukin (IL)-1β and a rat model stimulated by monosodium iodoacetate (MIA) were used for in vitro and in vivo experiments, respectively. The results of in vitro experiments showed that cyasterone apparently counteracted chondrocyte apoptosis, increased the expression of collagen II and aggrecan, and restrained the production of the inflammatory factors inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), metalloproteinase-3 (MMP-3), and metalloproteinase-13 (MMP-13) induced by IL-1β in chondrocytes. Furthermore, cyasterone ameliorated the inflammation and degenerative progression of osteoarthritis potentially by regulating the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. For in vivo experiments, cyasterone significantly alleviated the inflammatory response and cartilage destruction of rats induced by monosodium iodoacetate, where dexamethasone was used as the positive control. Overall, this study laid a theoretical foundation for developing cyasterone as an effective agent for the alleviation of osteoarthritis.
Animals ; Rats ; Chondrocytes ; NF-kappa B ; Iodoacetic Acid ; Inflammation ; MAP Kinase Signaling System ; Apoptosis

There are clear indoor air pollution sources of trichloroethylene and tetrachloroethylene. A large number of epidemiological evidence has confirmed their carcinogenic toxicity and non-carcinogenic toxicity. Several countries and international organizations have paid attention to indoor air trichloroethylene and tetrachloroethylene. It has been also assessed that there should be certain potential health risk of indoor air trichloroethylene and tetrachloroethylene in China. Based on the latest research results of health risk assessment of indoor air trichloroethylene and tetrachloroethylene, the "Standards for indoor air quality (GB/T 18883-2022)" added trichloroethylene and tetrachloroethylene as indicators. The index limit of trichloroethylene is 6 μg/m³ for an 8-hour average concentration. The index limit of tetrachloroethylene is 120 μg/m³ for an 8-hour average concentration. The technical contents related to the determination of the standard limits of trichloroethylene and tetrachloroethylene in indoor air were analyzed and discussed, including the sources, the exposure, the health effects, the determination of the limit values, and the recommendations for standard implementation. It also proposed recommendations for the implementation of"Standards for indoor air quality (GB/T 18883-2022)".
Humans ; Tetrachloroethylene/analysis* ; Air Pollution, Indoor ; Trichloroethylene/analysis* ; China

Mammalian target of rapamycin (mTOR) controls cellular anabolism, and mTOR signaling is hyperactive in most cancer cells. As a result, inhibition of mTOR signaling benefits cancer patients. Rapamycin is a US Food and Drug Administration (FDA)-approved drug, a specific mTOR complex 1 (mTORC1) inhibitor, for the treatment of several different types of cancer. However, rapamycin is reported to inhibit cancer growth rather than induce apoptosis. Pyruvate dehydrogenase complex (PDHc) is the gatekeeper for mitochondrial pyruvate oxidation. PDHc inactivation has been observed in a number of cancer cells, and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide (NAD^+‍) exhaustion. In this paper, we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells. This inactivation reduces the sensitivity of cancer cells' response to rapamycin. As a result, rebooting PDHc activity with dichloroacetic acid (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, promotes cancer cells' susceptibility to rapamycin treatment in vitro and in vivo.
Humans ; Sirolimus/pharmacology* ; Dichloroacetic Acid/pharmacology* ; Pyruvate Dehydrogenase Complex ; TOR Serine-Threonine Kinases ; Mechanistic Target of Rapamycin Complex 1 ; Neoplasms/drug therapy*

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has a wide range of symptoms, and it is difficult for clinicians to make a quick and correct diagnosis. On November 11, 2021, a 36-year-old male patient with AAV was admitted to the emergency and critical care department of Yichang Central People's Hospital. He was admitted to the emergency intensive care unit (EICU) with gastrointestinal symptoms (abdominal pain, black stool) as the main physical signs, and was initially diagnosed as AAV with gastrointestinal hemorrhage (GIH). No bleeding point was found after repeated gastroscopy and colonoscopy. Abdominal emission CT (ECT) showed diffuse hemorrhage in the ileum, ascending colon and transverse colon. Multi-disciplinary consultation in the whole hospital considered the diffuse hemorrhage caused by small vascular lesions in the digestive tract caused by AAV. Pulse therapy with methylprednisolone 1 000 mg/d and immunosuppressive therapy with cyclophosphamide (CTX) 0.2 g/d were administered. The patient's symptoms quickly relieved and transferred out of the EICU. After 17 days of treatment, the patient finally died of massive gastrointestinal bleeding. A systematic review of relevant literatures combined with the case diagnosis and treatment process found that only a minority of AAV patients present with gastrointestinal symptoms as their first symptoms, and patients with GIH were very rare. Such patients had a poor prognosis. This patient delayed the use of induced remission and immunosuppressive agents due to the treatment of gastrointestinal bleeding, which may be the main cause of life-threatening GIH secondary to AAV. Gastrointestinal bleeding is a rare and fatal complication of vasculitis. Timely and effective induction and remission treatment is the key to survival. Whether patients should receive maintenance therapy, the duration of maintenance therapy, and the search for markers of disease diagnosis and treatment response are directions and challenges for further research.
Male ; Humans ; Adult ; Gastrointestinal Hemorrhage ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ; Critical Care ; Cyclophosphamide ; Death

Objective: To analyze the clinicopathologic characteristics and prognosis of testicular diffuse large B-cell lymphoma (DLBCL) . Methods: A retrospective analysis was performed on 68 patients with testicular DLBCL admitted to Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine from October 2001 to April 2020. The gene mutation profile was evaluated by targeted sequencing (55 lymphoma-related genes) , and prognostic factors were analyzed. Results: A total of 68 patients were included, of whom 45 (66.2% ) had primary testicular DLBCL and 23 (33.8% ) had secondary testicular DLBCL. The proportion of secondary testicular DLBCL patients with Ann Arbor stage Ⅲ-Ⅳ (P<0.001) , elevated LDH (P<0.001) , ECOG score ≥ 2 points (P=0.005) , and IPI score 3-5 points (P<0.001) is higher than that of primary testicular DLBCL patients. Sixty-two (91% ) patients received rituximab in combination with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) -based first-line regimen, whereas 54 cases (79% ) underwent orchiectomy prior to chemotherapy. Patients with secondary testicular DLBCL had a lower estimated 5-year progression-free survival (PFS) rate (16.5% vs 68.1% , P<0.001) and 5-year overall survival (OS) rate (63.4% vs 74.9% , P=0.008) than those with primary testicular DLBCL, and their complete remission rate (57% vs 91% , P=0.003) was also lower than that of primary testicular DLBCL. The ECOG scores of ≥2 (PFS: P=0.018; OS: P<0.001) , Ann Arbor stages Ⅲ-Ⅳ (PFS: P<0.001; OS: P=0.018) , increased LDH levels (PFS: P=0.015; OS: P=0.006) , and multiple extra-nodal involvements (PFS: P<0.001; OS: P=0.013) were poor prognostic factors in testicular DLBCL. Targeted sequencing data in 20 patients with testicular DLBCL showed that the mutation frequencies of ≥20% were PIM1 (12 cases, 60% ) , MYD88 (11 cases, 55% ) , CD79B (9 cases, 45% ) , CREBBP (5 cases, 25% ) , KMT2D (5 cases, 25% ) , ATM (4 cases, 20% ) , and BTG2 (4 cases, 20% ) . The frequency of mutations in KMT2D in patients with secondary testicular DLBCL was higher than that in patients with primary testicular DLBCL (66.7% vs 7.1% , P=0.014) and was associated with a lower 5-year PFS rate in patients with testicular DLBCL (P=0.019) . Conclusion: Patients with secondary testicular DLBCL had worse PFS and OS than those with primary testicular DLBCL. The ECOG scores of ≥2, Ann Arbor stages Ⅲ-Ⅳ, increased LDH levels, and multiple extra-nodal involvements were poor prognostic factors in testicular DLBCL. PIM1, MYD88, CD79B, CREBBP, KMT2D, ATM, and BTG2 were commonly mutated genes in testicular DLBCL, and the prognosis of patients with KMT2D mutations was poor.
Male ; Adult ; Humans ; Prognosis ; Retrospective Studies ; Myeloid Differentiation Factor 88 ; China/epidemiology* ; Testicular Neoplasms/drug therapy* ; Cyclophosphamide ; Rituximab/therapeutic use* ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Prednisone/therapeutic use* ; Doxorubicin/therapeutic use* ; Vincristine/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Immediate-Early Proteins/therapeutic use* ; Tumor Suppressor Proteins

Objective: To explore the stem cell collection rate and efficacy and safety of patients aged 70 and below with newly diagnosed multiple myeloma (MM) treated with the VRD (bortezomib, lenalidomide and dexamethasone) regimen followed by autologous stem cell transplantation (ASCT). Methods: Retrospective case series study. The clinical data of 123 patients with newly diagnosed MM from August 1, 2018, to June 30, 2020, at the First Affiliated Hospital of Soochow University and Suzhou Hopes Hematology Hospital, who were eligible for VRD regimen sequential ASCT, were collected. The clinical characteristics, efficacy after induction therapy, mobilization regimen of autologous stem cells, autologous stem cell collection rate, and side effects and efficacy of ASCT were retrospectively analyzed. Results: Of the 123 patients, 67 were males. The median patient age was 56 (range: 31-70) years. Patients with IgG, IgA, IgD, and light-chain types accounted for 47.2% (58/123), 23.6% (29/123), 3.2% (4/123), and 26.0% (32/123) of patients, respectively. In addition, 25.2% (31/123) of patients had renal insufficiency (creatinine clearance rate<40 ml/min). Patients with Revised-International Staging System (R-ISS) Ⅲ accounted for 18.2% (22/121) of patients. After induction therapy, the rates of partial response and above, very-good partial response (VGPR) and above, and complete response (CR)+stringent CR were 82.1% (101/123), 75.6% (93/123), and 45.5% (56/123), respectively. Overall, 90.3% (84/93) of patients were mobilized with cyclophosphamide+granulocyte colony-stimulating factor (G-CSF) and 8 patients with G-CSF or G-CSF+plerixafor due to creatinine clearance rate<30 ml/min and one of them was mobilized with DECP (cisplatin, etoposide, cyclophosphamide and dexamethasone)+G-CSF for progressive disease. The rate of autologous stem cell collection (CD34⁺cells≥2×10⁶/kg) after four courses of VRD regimen was 89.1% (82/92), and the rate of collection (CD34⁺cells≥5×10⁶/kg) was 56.5% (52/92). Seventy-seven patients treated with the VRD regimen sequential ASCT. All patients had grade 4 neutropenia and thrombocytopenia. Among the nonhematologic adverse events during ASCT, the highest incidence was observed for gastrointestinal reactions (76.6%, 59/77), followed by oral mucositis (46.8%, 36/77), elevated aminotransferases (44.2%, 34/77), fever (37.7%, 29/77), infection (16.9%, 13/77) and heart-related adverse events (11.7%, 9/77). Among the adverse events, grade 3 adverse events included nausea (6.5%, 5/77), oral mucositis (5.2%, 4/77), vomiting (3.9%, 3/77), infection (2.6%, 2/77), elevated blood pressure after infusion (2.6%, 2/77), elevated alanine transaminase (1.3%, 1/77), and perianal mucositis (1.3%, 1/77); there were no grade 4 or above nonhematologic adverse events. The proportion of patients who achieved VGPR and above after VRD sequential ASCT was 100% (75/75), and the proportion of patients who were minimal residual disease-negative (<10^-4 level) was 82.7% (62/75). Conclusion: In patients aged 70 and below with newly diagnosed MM treated with VRD induction therapy, the collection rate of autologous stem cells was good, and good efficacy and tolerability were noted after follow-up ASCT.
Male ; Humans ; Female ; Multiple Myeloma/diagnosis* ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Retrospective Studies ; Creatinine ; Hematopoietic Stem Cell Mobilization ; Transplantation, Autologous ; Dexamethasone/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Heterocyclic Compounds/therapeutic use* ; Bortezomib/therapeutic use* ; Cyclophosphamide/therapeutic use* ; Stomatitis/etiology*

Objective: To understand the social security situation of current cases of pneumoconiosis in non-coal mine industries in Jiangsu Province, and to provide reference for the treatment and security work of pneumoconiosis patients. Methods: From January to October 2020, a follow-up survey was conducted on 4038 cases of pneumoconiosis in non-coal mine industries of the province from October 1949 to December 2019. The age, type of pneumoconiosis, industry type, and social security status of the patients were collected. Namely, work-related injury insurance, employer compensation, basic medical insurance for urban and rural residents, major illness insurance, etc. SPSS 19.0 was used for statistical description and analysis. Results: The cases of pneumoconiosis in non-coal mine industries in Jiangsu Province ranged in age from 36 to 105 (70.78±8.43) years old, and had been exposed to dust for 1 to 55 (19.27±9.29) years. Silicosis was the main form (3875 cases, 95.96%), and non-metallic mining and dressing industry was the main form (2618 cases, 64.83%). A total of 3991 cases (98.84%) of pneumoconiosis patients enjoyed social security, most of them were urban and rural residents with basic medical insurance (3624 cases, 89.75%), but there were still 47 patients without any social security. 15 cases (0.37%) enjoyed the subsistence allowance, with the monthly allowance amount ranging from 104 to 3960 yuan, with the average amount of 954.87 yuan/month. Conclusion: In Jiangsu Province, the proportion of pneumoconiosis patients in non-coal mine industries enjoying social security is relatively high, but there are still patients who do not enjoy any social security, and the difference in the amount of subsistence allowance is slightly larger. It is necessary to further improve the medical security of pneumoconiosis patients and improve their quality of life.
Humans ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Social Security ; Prevalence ; Quality of Life ; Pneumoconiosis/epidemiology* ; Silicosis/epidemiology* ; Etoposide ; Ifosfamide ; Mesna ; Coal Mining ; China/epidemiology*