Background: Accumulating evidence has indicated that the dysregulation of immunological environment has an important role in the pathogenesis of myelodysplastic syndromes (MDS). The previous studies about the levels of the inflammatory cytokines in MDS, such as TNF-α, IFN-γ, IL-6, IL-8, and IL-17, have yielded controversial results. Thus, we performed a meta-analysis to assess the levels of these inflammatory cytokines in MDS. Methods: A systematic search in PubMed, MEDLINE, Cochrane Library, Web of Science, CNKI, and CBM was conducted to find eligible studies. Meta-analyses were performed using STATA 12.0 for Windows. Heterogeneity between included studies was assessed by I ² test. We chose SMD as the summary statistic. Results: A total of 697 individuals from 11 studies were included in this study. Our results suggest the levels of TNF-α, IL-6, IL-8 were significantly higher in MDS patients compared with controls, SMD and 95%CI was 1.48 (0.60, 2.36), 0.71 (0.16, 1.25) and 0.69 (0.28, 1.09), respectively. Moreover, the levels of IL-17 have decreased in the high-risk MDS, the SMD and 95% CI was 2.96 (0.78, 5.15). Conclusion: A close association between immunological microenvironment disorders and the pathogenesis of MDS was revealed in this meta-analysis. More importantly, the profiles of inflammatory cytokines appear to change along the progression of the disease.

Invasive fungal infections especially in immunocompromised patients represent a dominating cause of mortality. The most commonly used antifungal agents can be divided into three broad categories, including triazoles, echinocandins and polyenes. Antifungal resistance is on the increase, posing a growing threat to the stewardship of immunocompromised patients with fungal infections. The paucity of currently available antifungals leads to the rapid emergence of drug resistance and thus aggravates the refractoriness of invasive fungal infections. Therefore, deep exploration into mechanisms of drug resistance and search for new antifungal targets are required. This review highlights the therapeutic strategies targeting Hsp90, calcineurin, trehalose biosynthesis and sphingolipids biosynthesis, in an attempt to provide clinical evidence for overcoming drug resistance and to form the rationale for combination therapy of conventional antifungals and agents with novel mechanisms of action. What’s more, this review also gives a concise introduction of three new-fashioned antifungals, including carboxymethyl chitosan, silver nanoparticles and chromogranin A-N46.

Background: Primary lymphoma of bone (PLB) is an extremely rare malignancy arising in the skeletal system. There is no consensus over the best definition of PLB. Most of the published articles are single-institutional retrospective studies with a limited sample size. The rarity of PLB and discrepancies on diagnostic criteria has resulted in a vague understanding of PLB. Methods: We retrospectively analyzed the clinical characteristics and prognostic factors of 2558 PLB patients who were registered in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2016. Survival rates were calculated using the Kaplan–Meier method. The effects of various factors on survival outcomes were analyzed by using the log-rank test. Univariate and multivariate analyses were conducted by using the Cox proportional hazards model to determine independent prognostic factors. Results: The median follow-up time of all eligible patients was 58 months. There seemed no sex preponderance in PLB incidence. The most involved sites are axial skeletons. The most common histological subtype was diffuse large B-cell lymphoma. The 3-, 5-, 10-, and 20-year overall survival (OS) rates were 70.70%, 65.70%, 54.40% and 39.50%, respectively. PLB patients whose primary tumor sites were appendicular and craniofacial skeletons had a significant survival advantage [hazard ratio (HR) = 0.694, 95% confidence interval (CI) 0.552–0.872; HR = 0.729, 95% CI 0.597–0.889, respectively] over those with axial skeletons as primary tumor sites. Patients with Hodgkin lymphoma, non-Hodgkin lymphoma (NHL)–mature B-cell lymphoma, and NHL-precursor-cell lymphoblastic lymphoma also had a significant OS advantage (HR = 0.392, 95% CI 0.200–0.771; HR = 0.826, 95% CI 0.700–0.973; and HR = 0.453, 95% CI 0.223–0.923, respectively). Patients with Ann Arbor stage III–IV at diagnosis were at higher risk of death than those with stage I–II (HR = 1.348, 95% CI 1.107–1.641). Chemotherapy was an independent favorable prognostic factor (HR = 0.734, 95% CI 0.605–0.890). Conclusions: Primary anatomic site, histology type, higher Ann Arbor stage and chemotherapy were independent prognostic factors. Chemotherapy played a pivotal role in PLB treatment.

Background: To evaluate the efficacy and safety of rituximab-based combination therapy for Waldenström macroglobulinemia (WM), we conducted this meta-analysis by pooling the rates of overall response, major response, complete response, and grade ≥3 hematological adverse events. Methods and materials: We searched for relevant studies in the databases of PubMed, Web of Science, Embase, and the Cochrane Library. The qualitative assessment of all the included articles was conducted with reference to the Newcastle–Ottawa Scale. A random-effects model was selected to perform all pooled analyses. Results: We identified altogether 22 studies with a total of 806 symptomatic WM patients enrolled. The pooled analysis indicated that the rituximab-based combination therapy achieved an overall response rate (ORR) of 84% (95% CI: 81%–87%), a major response rate (MRR) of 71% (95% CI: 66%–75%), and a complete response rate (CRR) of 7% (95% CI: 5%–10%). Rituximab plus conventional alkylating agents–containing chemotherapy (subgroup A) yielded an ORR of 86% (95% CI: 81%–89%), an MRR of 74% (95% CI: 69%–79%), and a CRR of 8% (95% CI: 4%–14%). Rituximab plus purine analog (subgroup B) resulted in an ORR of 85% (95% CI: 79%–89%), an MRR of 74% (95% CI: 66%–81%), and a CRR of 9% (95% CI: 4%–15%). Rituximab plus proteasome inhibitor (subgroup C) resulted in an ORR of 86% (95% CI: 81%–90%), an MRR of 68% (95% CI: 58%–77%), and a CRR of 7% (95% CI: 3%–11%). Rituximab plus immunomodulatory drug (subgroup D) attained relatively lower response rates, with an ORR of 67% (95% CI: 51%–81%), an MRR of 56% (95% CI: 27%–83%), and a CRR of 5% (95% CI: 1%–12%). Common grade ≥3 hematological adverse events consisted of neutropenia (33%, 95% CI: 17%–52%), thrombocytopenia (7%, 95% CI: 3%–11%), and anemia (5%, 95% CI: 3%–9%). Conclusion: Rituximab in combination with an alkylating agent, purine analog, or proteasome inhibitor is highly effective with tolerable hematological toxicities for WM.

Multiple myeloma (MM) is the second most common hematological neoplasm. Wide administration of bortezomib significantly improves the survival of MM patients compared with conventional chemotherapy. Bromodomain-containing protein 4 (BRD4) inhibitors also have been demonstrated to retard cell proliferation and induce cellular apoptosis in various cancers. However, it is unclear whether the BRD4 inhibitor nitroxoline plus bortezomib has a synergistic anti-tumor effect on MM. Cell viability was determined via 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle and cell apoptosis were assessed via flow cytometry. Protein expression levels were determined via western blotting. The expression of apoptosis-related proteins in xenograft tissue were detected by means of immunohistochemistry. Treatment with nitroxoline or bortezomib suppressed cell proliferation, and caused G0/G1 phase arrest and apoptosis in H929 and RPMI8226 cells. Furthermore, nitroxoline intensified the retardation of cell proliferation, as well as further enhanced the G0/G1 phase arrest and apoptosis induced by bortezomib in H929 and RPMI8226 cells. The western blot analysis revealed that nitroxoline or bortezomib treatment markedly diminished the levels of Bcl-2 and cyclin D1, and increased the levels of p21, Bax, cleaved PARP and cleaved caspase-3. Combination of these two agents was observed to result in further marked changes on these levels compared with nitroxoline or bortezomib treatment alone. What is more, in the xenograft tumor model, combinative treatment markedly inhibited tumor growth compared with the single drug treatment. Combination of bortezomib with nitroxoline has a synergistic anti-tumor activity in MM cells and may be a novel treatment method for MM.

Purpose. Poly(ADP-ribose) polymerase 1 (PARP1) is necessary for single-strand break (SSB) repair by sensing DNA breaks and facilitating DNA repair through poly ADP-ribosylation of several DNA-binding and repair proteins. Inhibition of PARP1 results in collapsed DNA replication fork and double-strand breaks (DSBs). Accumulation of DSBs goes beyond the capacity of DNA repair response, ultimately resulting in cell death. This work is aimed at assessing the synergistic effects of the DNA-damaging agent temozolomide (TMZ) and the PARP inhibitor niraparib (Nira) in human multiple myeloma (MM) cells. Materials and Methods. MM RPMI8226 and NCI-H929 cells were administered TMZ and/or Nira for 48 hours. CCK-8 was utilized for cell viability assessment. Cell proliferation and apoptosis were detected flow-cytometrically. Immunofluorescence was performed for detecting γH2A.X expression. Soft-agar colony formation assay was applied to evaluate the antiproliferative effect. The amounts of related proteins were obtained by immunoblot. The combination index was calculated with the CompuSyn software. A human plasmacytoma xenograft model was established to assess the anti-MM effects in vivo. The anti-MM activities of TMZ and/or Nira were evaluated by HE staining, IHC, and the TUNEL assay. Results. The results demonstrated that cotreatment with TMZ and Nira promoted DNA damage, cell cycle arrest, and apoptotic death in cultured cells but also reduced MM xenograft growth in nude mice, yielding highly synergistic effects. Immunoblot revealed that TMZ and Nira cotreatment markedly increased the expression of p-ATM, p-CHK2, RAD51, and γH2A.X, indicating the suppression of DNA damage response (DDR) and elevated DSB accumulation. Conclusion. Inhibition of PARP1 sensitizes genotoxic agents and represents an important therapeutic approach for MM. These findings provide preliminary evidence for combining PARP1 inhibitors with TMZ for MM treatment.