Bendamustine and rituximab (BR) versus dexamethasone,rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia

The treatment approaches for Waldenstrom macroglobulinemia (WM) are largely based upon information from single-arm phase II trials, without comparative data. We compared the efficacy of two commonly used regimens in routine practice (bendamustine-rituximab (BR) and dexamethasone, rituximab plus cyclophosphamide (DRC)) and evaluated their activity with respect to the patients’ MYD88^L265P mutation status. Of 160 consecutive patients, 60 received BR (43 with relapsed/refractory WM) and 100 received DRC (50 had relapsed/refractory WM). In the treatment-naïve setting, overall response rate (ORR) was 93% with BR versus 96% with DRC (p?=?0.55). Two-year progression-free survival (PFS) with BR and DRC was 88 and 61%, respectively (p?=?0.07). In salvage setting, ORR was 95% with BR versus 87% with DRC, p?=?0.45; median PFS with BR was 58 versus 32 months with DRC (2-year PFS was 66 versus 53%; p?=?0.08). Median disease-specific survival was not reached with BR versus 166 months with DRC (p?=?0.51). The time-to-event endpoints and depth of response were independent of the MYD88 mutation status. Grade ≥?3 adverse events of both regimens were comparable. A trend for longer PFS was observed with BR although the regimens have comparable toxicities. The activity of BR and DRC appears to be unaffected by patients’ MYD88 mutation status.     

Association between waist circumference (WC) values and hypertension,heart disease (HD) and diabetes,reported by the elderly – SABE survey: Health,wellness and aging, 2000 and 2006

The positive association between WC and systemic arterial hypertension (SAH), diabetes mellitus (DM) and HD calls for investigation in the elderly. The objective of the present study was to identify WC values, so as better to determine the risk of these diseases. This was a longitudinal study using the data of 405 elderly participants of the SABE Survey: Health, Well-being and Aging, undertaken in São Paulo, in 2000 and 2006. The study variables were WC, sex, age group, ethnicity, and body mass index (BMI) (2000) and SAH, DM and HD (2006). The area under the Receiver Operating Caracteristics (ROC) curve (AUC) and confidence intervals of 95% was used to estimate the performance of WC values in correctly discriminating among the elderly, according to the reference or not to diseases associated with WC. WC critical values were identified by the highest positive likelihood ratio (PLR), and negative likelihood ratio (NLR) equal to zero. The AUC showed the satisfactory performance of WC critical values in discriminating between reports of DM in individuals of 60–74 years of age. The WC critical values identified were ≥87 cm for women and ≥99 cm for men, which presented a better performance in relation to the AUC value than to the WC values commonly used. The WC critical values identified in this study showed better discriminatory power of foretelling reference to DM than did the WC values commonly used.     

Dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in coronavirus disease 2019 (COVID-19) – A systematic review,meta-analysis,and meta-regression

Background and aimsThis study aims to synthesize evidence on dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in COVID-19 patients and factors affecting it.MethodsWe performed a systematic literature search from PubMed, Scopus, and Embase databases from inception of databases up until 7 March 2021. Studies that met all of the following criteria were included: 1) observational studies or randomized controlled trials that report COVID-19 patients, 2) reporting DPP-4 inhibitor use, 3) mortality, and 4) mortality based on DPP-4 inhibitor use. The exposure was DPP-4 inhibitor, defined as DPP-4 inhibitor use that started prior to COVID-19 hospitalization. The control group was patients with no exposure to DPP-4 inhibitor. The outcome was mortality. The pooled effect estimate was reported as risk ratio (RR).ResultsThere were 4,477 patients from 9 studies in this systematic review and meta-analysis. 31% of (15%, 46%) the patients use DPP-4 inhibitor. Mortality occurs in 23% (15%, 31%) of the patients. DPP-4 inhibitor was associated with lower mortality in patients with COVID-19 (RR 0.76 [0.60, 0.97], p = 0.030, I2: 44.5%, p = 0.072). Meta-regression analysis showed that the association between DPP-4 inhibitor and mortality was significantly affected by metformin (RR 1.02 [1.00, 1.04], p = 0.048) and angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) use (RR 1.04 [1.01, 1.07], p = 0.006), but not age (p = 0.759), sex (reference: male, p = 0.148), and hypertension (p = 0.218).ConclusionDPP-4 inhibitor use was associated with lower mortality in COVID-19 patients, and the association was weaker in patients who were also taking metformin and/or ACE inhibitors.     

Effects of diabetes and hypoxia on gene markers of angiogenesis (HGF, cMET, uPA and uPAR, TGF-α, TGF-β, bFGF and Vimentin) in cultured and transplanted rat islets

Aims/hypothesis. The vascularisation of newly transplanted islets originates from the recipients. Because islets transplanted into a diabetic do less well than those transplanted into a euglycaemic environment, we examined the hypothesis that gene expression of angiogenic factors in grafts is delayed in diabetes. These factors include hepatocyte growth factor (HGF) and its receptor c-MET, and urokinase plasminogen activator (uPA) and its receptor uPAR, basic fibroblast growth factor (bFGF), TGF-α and TGFβ-1.¶Methods. Isolated rat islets were studied in vitro under normoxic and hypoxic culture conditions and gene expression was determined with semi-quantitative multiplex RT-PCR. We found that HGF but not c-MET expression was induced by hypoxia in vitro. Using syngeneic Lewis rats, gene expression was also studied in grafts on days 1, 3, 5, 7 and 14 after transplantation.¶Results. In grafts of normoglycaemic rats, HGF expression was enhanced on day 3 and maintained whereas expression of c-MET fell and remained down until day 14. Expression of uPA was up at day 3 and remained high; expression of uPAR was also up at day 3 but then fell to control levels at day 14. Expression of bFGF, TGF-α and TGFβ-1 persisted throughout. Vimentin, a marker of fibroblasts, had increased expression at day 1 which was further enhanced in subsequent days. In the grafts of diabetic recipients the expression of HGF, uPA and uPAR were delayed, being clearly expressed at day 5 rather than day 3. Vimentin expression was similarly delayed.¶Conclusion/interpretation. This apparent delay in angiogenesis provides a potential mechanism for the less favourable outcomes of islets transplanted into diabetic recipients. [Diabetologia (2000) 43: 763–772]     

Bendamustine, vincristine and prednisone (BOP) versus cyclophosphamide, vincristine and prednisone (COP) in advanced indolent non-Hodgkin’s lymphoma and mantle cell lymphoma: results of a randomised phase III trial (OSHO# 19)

Purpose: The purpose of this study was to compare the efficacy and toxicity of bendamustine, vincristine + prednisone (BOP) with a standard regimen of cyclophosphamide, vincristine + prednisone (COP) in patients with previously untreated advanced indolent non-Hodgkin’s lymphoma (NHL) and mantle cell lymphoma. Methods: A total of 164 patients with follicular lymphoma (grade 1/2), mantle cell lymphoma or lymphoplasmacytic lymphoma (immunocytoma) was randomised to treatment with vincristine 2 mg (day 1) and prednisone 100 mg/m² (days 1–5) + bendamustine 60 mg/m² (days 1–5) or + cyclophosphamide 400 mg/m² (days 1–5) for a total of eight 21-day cycles. Results: The rate of complete remission was 22% with BOP and 20% with COP. The projected 5-year survival rate was 61% with BOP and 46% with COP. The BOP-associated 5-year survival advantage almost reached significance in the subgroup of patients who responded to therapy (74% vs. 56%; P=0.05), and did reach significance in responders who did not receive interferon maintenance therapy (70% vs. 47%; P=0.03). Toxicity was acceptable in both treatment groups, although alopecia and leucopenia were more severe with COP. Conclusions: Bendamustine can efficaciously and safely replace cyclophosphamide, as used in standard COP therapy, for the treatment of patients with indolent NHL and mantle cell lymphoma. Long-term survival data suggest a clinically significant benefit for patients treated with BOP Funding support: Supported by a grant from ribosepharm GmbH, Clinical Research, Munich.     

生物安全培训课程(Biosafety and Biosecurity Training Course,BBTC)简介

<正>美国生物安全培训课程(Biosafety and Biosecurity Training Course,BBTC)是在美国科罗拉多州柯林斯堡举办的为期八天的一个密集培训班。BBTC由科罗拉多州立大学生物安全主任Robert Ellis博士发起并担任主任。Ellis博士同时兼任兽医和生物医学学院教授,是在美国颇有影响的生物安全专家,具有多年的生物安全实践和管理经验。他曾担任美国生物安全学会的主席,并因他在生物安全领域的杰出贡献,于     

Epidemiology of non-Hodgkin’s lymphoma (NHL): trends, geographic distribution, and etiology

While for most cancers incidence and mortality are decreasing, those of non-Hodgkins lymphoma (NHL) are steadily increasing. Research to define reasons for this increase is extensive, but has not yet resolved them. We have conducted a literature analysis on trends regarding changes in the incidence, geographic distribution, and etiologic factors of NHL. From our own and previous analyses, an increasing NHL incidence at a rate of 3–4% per year was observed for the 1970s and 1980s. This stabilized in the 1990s, nevertheless still with an annual rise of 1–2%, resulting in almost a doubling of the NHL incidence. This rise has been noted worldwide, particularly in elderly persons >55 years. Concerning gender subgroups, a male predominance throughout all age groups is apparent. Although the NHL incidence has historically been higher in whites than blacks, disproportional increases have recently been observed in the latter group. Increases in high-grade NHL and extranodal disease are predominant. Differences in geographic distribution are striking for follicular lymphoma, which is more common in Western countries than elsewhere. Asians have higher rates of aggressive NHL, T-cell lymphomas, and extranodal disease. In the Middle East, high rates of intestinal extranodal disease are observed, whereas in Africa, endemic Burkitts lymphoma accounts for a substantial proportion. Risks for developing NHL include immunosuppression and a causal link between infectious agents, and lymphomagenesis has also been determined, particularly for human T-cell leukemia/lymphoma virus type 1 (HTLV-1), Epstein-Barr virus (EBV), and Helicobacter pylori infections. Exposure to environmental agents and occupational risks have been studied; however, their significance is as yet uncertain.     

Advanced Glycation End Products (AGE) and Diabetes: Cause, Effect, or Both?

Hyperglycemia is associated with increased mortality and other complications amongst hospitalized patients. However, the studies of tight glycemic control in a range of critical illness settings, including intensive care, acute myocardial infarction, and stroke, have produced inconsistent and divergent results. We examine some of the factors that may have contributed to the differing results, and their implications for targeting tight glucose control in critical illness. With these in mind, most clinical guidelines now recommend moderate glucose control with an upper glucose target of <10 mmol/L (180 mg/dL) in critical illness while avoiding hypoglycemia.     

Hepatocellular proliferation,TNFα and inflammation in primary biliary cirrhosis (PBC)

The aims of this study were to investigate the rate of hepatocellular proliferation in PBC and its correlation with the site of inflammation and serum TNFα levels. Hepatic proliferation was evaluated in liver sections from 11 patients with PBC (two histological stage II, eight stage III, one stage IV) using the indirect immunoperoxidase technique with a monoclonal antibody against proliferating cell nuclear antigen (PCNA). Counter-staining with hematoxylin was performed and at least 500 nuclei were counted by two observers who blindly calculated the site of positive cells (perivenular, periportal/periseptal). The percentage of hepatocytes expressing PCNA was significantly higher in the periportal/periseptal regions than in the perivenular area (70 ± 5.8% vs. 36 ± 6.9%, P < 0.002). Hepatocellular PCNA expression in the periportal/periseptal (portal area) correlated with TNFα serum levels (r = 0.8, P < 0.03). In conclusion, hepatocellular proliferation in PBC significantly correlates with the site of inflammation and serum levels of TNFα. This data seems to confirm that inflammation and cytokines may stimulate hepatocyte DNA synthesis.     

Do histological, immunohistochemical, and metabolic (radioiodine and fluorodeoxyglucose uptakes) patterns of metastatic thyroid cancer correlate with patient outcome?

The aim of this study is to search for relationships between histology, radioiodine ((131)I) uptake, fluorodeoxyglucose (FDG) uptake, and disease outcome in patients with metastatic thyroid cancer. Eighty patients with metastatic thyroid cancer (34 males, 46 females, mean age at the time of the diagnosis of metastases: 55 years) were retrospectively studied. All patients were treated with radioactive iodine and evaluated by FDG-positron emission tomography (PET). Primary tumor tissue sample was available in all cases. Forty-five patients (56%) had a papillary, 12 (15%) a follicular, and 23 (29%) a poorly differentiated thyroid cancer. Cellular atypias, necrosis, mitoses, thyroid capsule infiltration, and vascular invasion were frequently detected (70, 44, 52, 60, and 71% respectively). Metastases disclosed FDG uptake in 58 patients (72%) and (131)I uptake in 37 patients (45%). FDG uptake was the only significant prognostic factor for survival (P=0.02). The maximum standardized uptake value and the number of FDG avid lesions were also related to prognosis (P=0.03 and 0.009). Age at the time of the diagnosis of metastases (P=0.001) and the presence of necrosis (P=0.002) were independent predictive factors of FDG uptake. Radioiodine uptake was prognostic for stable disease (P=0.001) and necrosis for progressive disease at 1 year (P=0.001). Histological subtype was not correlated with in vivo tumor metabolism and prognosis. In conclusion, FDG uptake in metastatic thyroid cancer is highly prognostic for survival. Histological subtype alone does not correlate with (131)I/FDG uptake pattern and patient outcome. Well-differentiated thyroid cancer presenting histological features such as necrosis and FDG uptake on PET scan should be considered aggressive differentiated cancers.     

RhoA and RhoC differentially modulate estrogen receptor α recruitment, transcriptional activities, and expression in breast cancer cells (MCF-7)

Purpose

RhoA and RhoC are closely related, small GTPases that are clearly involved in breast cancer tumorigenesis. Nonetheless, their specific roles in the control of estrogen receptor alpha (ERα) activities have not been elucidated.

Methods

We used siRNA sequences to specifically down-regulate RhoA and RhoC expression in ERα-positive breast adenocarcinoma MCF-7 cells. We then analyzed the consequences of down-regulation on ERα expression, ERα recruitment to the promoters of four target genes, and the mRNA levels of those genes.

Results

We demonstrated that RhoA and RhoC clearly and similarly modulated ERα recruitment to the vitellogenin estrogen responsive element (ERE) present in a luciferase reporter gene and to the promoters of progesterone receptor (PR), cathepsin D, and pS2 genes. Besides, RhoA up-regulated the ERE-luciferase reporter gene activity and PR mRNA expression and tended to down-regulate cathepsin D and pS2 mRNA expression. Conversely, RhoC inhibition had no significant effect at the mRNA level. Furthermore, RhoA inhibition, and to a lesser extent RhoC inhibition, increased ERα expression. No alteration in ERα mRNA levels was observed, suggesting potential post-translational control.

Conclusions

Taken together, our results strongly suggest that RhoA and RhoC play different, but clear, roles in ERα signaling. These GTPases are definitely involved, along with RhoB, in ERα recruitment and, to some extent, ERα cofactor balance. We hypothesize a differential role of RhoA in breast cancer tumors that depend on hormone status.     

Atypical β- and α(2)-adrenoceptor Activation, Dibutyryl cAMP and Iloprost Stimulate [(45)Ca(2+)] Uptake by Human Platelets

The effect of a range of α- and β-adrenoceptor agonists and antagonists on the in vitro uptake of [(45)Ca(2+)] by human platelets was investigated. Isoprenaline and adrenaline stimulated [(45)Ca(2+)] uptake. Isoprenaline-stimulated ([(45)Ca(2+)] uptake was inhibited by β-adrenoceptor antagonists (mabuterol [β(2)] > metoprolol [β(1)] > atenolol [β(1)] > pindolol [β(1)/β(2)]), but not by yohimbine [αz] or prazosin [αll. Adrenaline-stimulated [(45)Ca(2+)] uptake was inhibited (and in this order of potency) by yohimbine, mabuterol, metoprolol, prazosin, atenolol and pindolol. [(45)Ca(2+)] uptake was stimulated by β-adrenoceptor agonists (BRL37344 [β(3)] > terbutaline [β(2)] > xamoterol [β(1)] > salbutamol [β(2)]). Ca(2+) ionophore A23187-stimulated [(45)Ca(2+)] uptake was unaffected by pindolol, atenolol, metoprolol or mabuterol, indicating that these antagonists were not exerting nonspecitic inhibitory effects. [(45)Ca(2+)] uptake was also stimulated by dibutyryl cAMP and by iloprost (a stable prostacyclin analogue and stimulator of cAMP synthesis). It is concluded that: (1) β- adrenoceptor-linked Ca(2+) uptake is mediated by an atypical β-adrenoceptor, possibly of a β(3)-subtype; (2) the stimulatory action of β-adrenoceptor activation and prostacyclin may be mediated by adenylate cyclase, and (3) the paradoxical finding that both α- and β-adrenoceptor activation, cAMP and stimulators of CAMP elicit [(45)Ca(2+)] uptake suggests that the Ca(2+) mobilisation monitored by the present methodology is not associated with platelet aggregation but to adrenoceptor activation per se and possibly other signal transduction mechanisms that occur at the plasmalemma.     

Study of pro-inflammatory (TNF-α, IL-1α, IL-6) and T-cell-derived (IL-2, IL-4) cytokines in plasma and synovial fluid of patients with juvenile chronic arthritis: Correlations with clinical and laboratory parameters

Acute phase proteins, synovial fluid (SF) cellular infiltrates, pro-inflammatory (TNF-, IL-1, IL-6) and Th1 (IL-2) and Th2 (IL-4) derived cytokine levels both in plasma and SF were examined in pauciarticular and polyarticular juvenile chronic arthritis (JCA) patients during the active (n=22) and inactive (n=14) period in order to determine pathogenic mechanisms and correlations between cytokines and laboratory parameters showing disease activity. The erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) and IgG concentrations were found to be significantly elevated in the active period of JCA. In pauciarticular JCA patients, when compared with their peripheral blood lymphocyte subpopulations, SF CD3+ cells (73.1%) and HLA-DR+ active T cells (22.5%) were found to be significantly increased. In the active period of JCA, plasma TNF- and IL-6 concentrations were significantly elevated. Plasma IL-2 and IL-4 levels were not elevated and were found to be similar to those in the inactive phase and in healthy controls. SF IL-6, TNF- and IL-1 levels were extremely high in all the patients. SF IL-4 and IL-2 levels were all undetectable. There was a significant correlation between ESR values and plasma IL-6 levels and between serum CRP levels and plasma IL-6 and TNF- concentrations. In conclusion, increased local production of pro-inflammatory cytokines appears to account for the articular manifestations of JCA. The impaired production of anti-inflammatory Th2-derived cytokines (IL-4) seems to cause increased production of inflammatory cytokines acting on the balance between them. The deficit in IL-2 production was not suggested to be primarily involved in the pathogenesis. In addition, not only CRP and ESR values, but also plasma IL-6 and TNF- concentrations may be used as markers of disease activity.