Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These ...genetic subtypes are associated with unique clinicopathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor- B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials.
Epigenetic deregulation of gene expression has a role in the initiation and progression of prostate cancer (PCa). The histone methyltransferase MMSET/WHSC1 (Multiple Myeloma SET domain) is ...overexpressed in a number of metastatic tumors, but its mechanism of action has not been defined. In this work, we found that PCa cell lines expressed significantly higher levels of MMSET compared with immortalized, non-transformed prostate cells. Knockdown experiments showed that, in metastatic PCa cell lines, dimethylation of lysine 36 and trimethylation of lysine 27 on histone H3 (H3K36me2 and H3K27me3, respectively) depended on MMSET expression, whereas depletion of MMSET in benign prostatic cells did not affect chromatin modifications. Knockdown of MMSET in DU145 and PC-3 tumor cells decreased cell proliferation, colony formation in soft agar and strikingly diminished cell migration and invasion. Conversely, overexpression of MMSET in immortalized, non-transformed RWPE-1 cells promoted cell migration and invasion, accompanied by an epithelial-mesenchymal transition (EMT). Among a panel of EMT-promoting genes analyzed, TWIST1 expression was strongly activated in response to MMSET. Chromatin immunoprecipitation analysis demonstrated that MMSET binds to the TWIST1 locus and leads to an increase in H3K36me2, suggesting a direct role of MMSET in the regulation of this gene. Depletion of TWIST1 in MMSET-overexpressing RWPE-1 cells blocked cell invasion and EMT, indicating that TWIST1 was a critical target of MMSET, responsible for the acquisition of an invasive phenotype. Collectively, these data suggest that MMSET has a role in PCa pathogenesis and progression through epigenetic regulation of metastasis-related genes.
Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM ...patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells on miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in severe combined immunodeficient/non-obese diabetic mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor-suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials.
In contrast to kidney transplantation where donor‐specific anti‐HLA antibodies (DSA) negatively impact graft survival, correlation of DSA with clinical outcomes in patients after orthotopic liver ...transplantation (OLT) has not been clearly established. We hypothesized that DSA are present in patients who develop chronic rejection after OLT. Prospectively collected serial serum samples on 39 primary OLT patients with biopsy‐proven chronic rejection and 39 comparator patients were blinded and analyzed for DSA using LABScreen® single antigen beads test, where a 1000 mean fluorescence value was considered positive. In study patients, the median graft survival was 15 months, 74% received ≥ one retransplant, 20% remain alive and 87% had ≥ one episode of acute rejection. This is in contrast to comparator patients where 69% remain alive, and no patient needed retransplant or experienced rejection. Thirty‐six chronic rejection patients (92%) and 24 (61%) comparator patients had DSA (p = 0.003). Chronic rejection versus comparator patients had higher mean fluorescence intensity (MFI) DSA. Although a further study with larger numbers of patients is needed to identify clinically significant thresholds, there is an association of high‐MFI DSA with chronic rejection after OLT.
Serial serum samples from 39 chronic rejection and 39 comparator liver transplant recipients show a strong association between donor‐specific antibody and chronic rejection, and the effects of preformed donor class I specific antibody can be mitigated by antibody induction therapy. See editorial by Briggs and Adams on page 1767.
Objective:Night-shift work is associated with ischaemic cardiovascular disorders. It is not currently known whether it may be causally linked to metabolic syndrome (MS), a risk condition for ...ischaemic cardiovascular disorders. The syndrome presents with visceral obesity associated with mild alterations in glucidic and lipidic homeostasis, and in blood pressure. The aim of this study was to assess whether a causal relationship exists between night-shift work and the development of MS.Methods:Male and female nurses performing night shifts, free from any component of MS at baseline, were evaluated annually for the development of the disorder during a 4-year follow-up. Male and female nurses performing daytime work only, visited during the same time period, represented the control group.Results:The cumulative incidence of MS was 9.0% (36/402) among night-shift workers, and 1.8% (6/336) among daytime workers (relative risk (RR) 5.0, 95% CI − 2.1 to 14.6). The annual rate of incidence of MS was 2.9% in night-shift workers and 0.5% in daytime workers. Kaplan–Meier survival curves of the two groups were significantly different (log-rank test; p<0.001). Multiple Cox regression analysis (forward selection method based on likelihood ratio) showed that among selected variables (age, gender, smoking, alcohol intake, familiar history, physical activity, and work schedule) the only predictors of occurrence of MS were sedentariness (hazard ratio (HR) 2.92; 95% CI 1.64 to 5.18; p = 0.017), and night-shift work (HR 5.10; 95% CI 2.15 to 12.11; p<0.001).Conclusions:The risk of developing MS is strongly associated with night-shift work in nurses. Medical counselling should be promptly instituted in night-shift workers with the syndrome, and in case of persistence or progression, a change in work schedule should be considered.
Abstract Peritoneal carcinomatosis (PC) from gastric cancer is a condition with a very bleak prognosis. Most authors consider it to be a terminal disease and recommend palliative therapy only. ...Multimodal therapeutic approaches to PC have emerged in the last decades, combining cytoreductive surgery (CRS) and peritonectomy procedures with perioperative intraperitoneal chemotherapy (IPEC), including hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC). We reviewed the pertinent literature concerning the HIPEC modality both for the treatment of established PC and the prevention of peritoneal recurrence after potentially curative gastric cancer (GC) surgery. Basically, the two procedures relate to different aspects of GC and they are not comparable, since the latter has been used as an adjuvant when PC is still not macroscopically evident and the former has been exclusively used in advanced gastric cancer stages with peritoneal dissemination. Data supporting beneficial effects once gastric PC is already manifest is scarce and limited to few centres with specific experience in this field. Conversely, with regards to the peritoneal perfusion for preventing PC in high risk gastric cancer patients, there are phase III trials and meta-analysis which support beneficial effects resulting from the HIPEC procedure. To offer a baseline guide, we summarized the actual status and general outcome obtained by this multimodal technique, in association or not with CRS as treatment of advanced GC.
Background and Aim
Discussing cost during medical encounters may decrease the financial impact of medical care on patients and align their treatment plans with their financial capacities. We aimed to ...examine which interventions exist and quantify their effectiveness to support cost conversations.
Methods
Several databases were queried (Embase; Ovid MEDLINE(R); Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily; the Cochrane databases; and Scopus) from their inception until January 31, 2020 using terms such as “clinician*”, “patient*”, “cost*”, and “conversation*”. Eligibility assessment, data extraction and risk of bias assessment were performed independently and in duplicate. We extracted study setting, design, intervention characteristics and outcomes related to patients, clinicians and quality metrics.
Results
We identified four studies (1327 patients) meeting our inclusion criteria. All studies were non‐randomised and conducted in the United States. Three were performed in a primary care setting and the fourth in an oncology. Two studies used decision aids that included cost information; one used a training session for health care staff about cost conversations, and the other directly delivered information regarding cost conversations to patients. All interventions increased cost‐conversation frequency. There was no effect on out‐of‐pocket costs, satisfaction, medication adherence or understanding of costs of care.
Conclusion
The body of evidence is small and comprised of studies at high risk of bias. However, an increase in the frequency of cost conversations is consistent. Studies with higher quality are needed to ascertain the effects of these interventions on the acceptability, frequency and quality of cost conversations.
► Antioxidant potential and antiproliferative effect of five monoterpenes was investigated. ► α-Terpineol presented good antioxidant activity in ORAC test. ► Limonene and α-terpineol presented ...equivalent antiproliferative profile in vitro. ► α-Terpineol had encouraging results against breast carcinoma and chronic myeloid leukemia. ► In vivo assays must be performed to confirm the anti-tumor potential of α-terpineol.
α-Terpineol is a relatively cheap and abundant aroma compound. It is widely used in food, cosmetics, and household products. Many of its monoterpene counterparts have been applied in antiproliferative assays, leading to promising results in the prevention or even treatment of cancers. However, despite its theoretic potential, no paper reports the evaluation of antiproliferative capacity of this alcohol. Thus, antioxidant potential of three monoterpenoids (carvone, perillyl alcohol, and α-terpineol) was measured using two methods: DPPH and ORAC. Also, the antiproliferative effect of these monoterpenoids against nine cancerous cell lines were performed and compared to limonene and doxorubicin. Results showed that all samples tested had very low antioxidant activity in the DPPH assay, but α-terpineol (2.72μmolTrolox equiv./μmol) could be compared to commercial antioxidants in the ORAC assay. The antiproliferative results obtained encourage future in vivo studies for α-terpineol, since this monoterpenoid presented cytostatic effect against six cell lines, especially for breast adenocarcinoma and chronic myeloid leukemia, in a range of 181–588μM.
PDF
