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Tomas Tonjo Torka Department of Animal Science, College of Agriculture, Arba Minch University, Arba Minch, Southern EthiopiaCorrespondence: Tomas Tonjo Torka, Email tommedmicro@gmail.comIntroduction: Bacterial foodborne infections are a major public health concern globally, and the emergence of antimicrobial-resistant bacteria in food worsens the associated problems which are alarming issues. The current study aimed to isolate E. coli, determine antimicrobial resistance patterns, estimate the prevalence of extended-spectrum beta-lactamase-producing E. coli, and determinants of raw cow milk contamination at selling points in and around Chencha, Southern Ethiopia from January 2021 to April, 2022.Methods: A total of 384 milk samples were collected randomly using a cross-sectional study and processed in the laboratory for evaluation of microbial load, bacterial isolation, and antimicrobial susceptibility patterns. The determinants were assessed through a prepared questionnaire, and descriptive statistics and multivariable logistic regression analysis were performed using SPSS version 21.Results: Out of 384 milk samples analyzed for microbial loads, 5.3± 1.68 log and 2.17± 1.51 log CFU/mL respectively were the mean values of total viable count and total coliform count. A total of 118 (30.7%) samples were contaminated with E. coli of about 11.8% extended-spectrum beta-lactamase producers. Notably, 91 (77.1%) of isolates were multiple drug-resistant isolates. The multivariable logistic regression showed that variables of educational status of milk handlers, hand washing activities, nose picking habit of milk handlers, milk container cleaning activity, milk container type, physical abnormal milk checking status, and attended training on hygienic food handling practices type were significantly associated with the milk contamination in the study area.Conclusion: The results implied that the raw milk samples served in the study area contained bacterial pathogens and a higher microbial load than recommended standards. Our data also confirmed the presence of multiple drug resistant and extended-spectrum beta-lactamase producing E. coli. Therefore, a close follow-up and training of milk handlers is needed. Besides, consumers should be made aware of the risks of consuming raw milk.Keywords: antimicrobial susceptibility patterns, associated factors, Gamo zone, milk borne Escherichia coli

The combination of rituximab and lenalidomide (R-len) stands as an established treatment for relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, the reproducibility of clinical trial results in routine clinical practice is unknown. To address this gap in knowledge, we reviewed our experience with patients diagnosed with R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) treated with this combination. Eighty-four patients underwent treatment with R-len, 69 (82%) affected by FL and 15 (18%) by MZL. The median age at the time of treatment initiation was 65 years (range, 39-94), 38 patients (45%) had a pre-treatment FLIPI score of 3-5, 19 (23%) had a bulky disease, 29 (37%) had a lymphoma refractory to the last treatment line, while in 20 (24%) cases the disease was refractory to rituximab. The best overall response rate (ORR) was 82%, and 52% achieved a complete response (CR). The best CR rates for FL and MZL patients were 55% and 40%, respectively. With a median follow-up of 22 months, the median progression-free survival (mPFS) was 22 months (95% CI 19-36) and the 2-year overall survival (OS) was 83% (95% CI 74-93). The median duration of CR (DoCR) was 46 months (95% CI 22-NR). Factors associated with shorter PFS in multivariate analysis were bulky disease and rituximab refractoriness. The most common adverse events (AE) included hematologic toxicity, fatigue and gastrointestinal disorders, such as diarrhea and constipation. Neutropenia and thrombocytopenia were the most common severe toxicities (grade ≥3 in 25% and 4%, respectively). No new safety signals were reported. Real-life results of R-len in patients with R/R iNHL appear consistent with those reported in prospective studies, and further support its use as comparator arm in controlled clinical trials.

Objective Health-related quality of life (HRQoL) outcomes are important in making clinical and policy decisions. This study aimed to examine the HRQoL reporting in cancer drug trials leading to Food and Drug Administration (FDA) approvals.Methods and analysis This retrospective cohort study analysed HRQoL data for trials leading to FDA approvals between July 2015 and May 2020. Proportion of included trials that reported HRQoL, latency between FDA approval and first report of HRQoL data, HRQoL outcomes, and their correlation with OS (overall survival) and PFS (progression-free survival) were analysed.Results Of the 233 trials associated with 207 FDA approvals, HRQoL was reported in 50% of trials, of which only 42% had the data reported by the time of FDA approval. There were no changes in frequency of HRQoL reporting between 2015 and 2020. HRQoL data were first reported in the primary publication in only 30% trials. Of the 115 trials with HRQoL data available, HRQoL improved in 43%, remained stable in 53% and worsened in 4% of trials. Among the trials that led to FDA approvals based on surrogate endpoints (79%), HRQoL was reported in 45% and improved only in 18% trials. There was no association between OS and PFS benefit and HRQoL outcomes.Conclusion Rates of HRQoL reporting were suboptimal in trials that led to FDA approvals with no improvements seen between 2015 and 2020. HRQoL reporting was often delayed and not presented in the primary publication. HRQoL reporting was further sparse in trials with approvals based on surrogate endpoints and HRQoL improved in only a minority of them.

Abstract Background Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes. Methods The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases. Results In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p

Abstract Chimeric antigen receptor T-cell therapy (CAR-T) has been successful in treating relapsed/refractory B-cell lymphomas. However, its role in the treatment of diseases involving the central nervous system (CNS) is not well studied. We performed a multicenter retrospective cohort study to evaluate the outcomes of patients with secondary CNS lymphoma (SCNSL) who received CAR-T. Eligibility required active CNSL at the time of apheresis. The objectives included evaluation of overall survival (OS), progression-free survival (PFS), identification of predictors of complete response (CR) post-CAR-T, and assessment of risk factors for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Sixty-one patients were included in the analysis. The overall response rate was 68% with a CR rate of 57%. In the multivariable analysis, patients who experienced any grade CRS had higher odds of achieving CR (OR = 3.9, 95% CI = 1.01–15.39, p = 0.047). The median PFS was 3.3 months (95% CI = 2.6–6.0 months) with 6- and 12-month PFS rates of 35% and 16%, respectively. The median OS was 7.6 months (95% CI = 5.0–13.5 months) with 6- and 12-month OS rates of 59% and 41%, respectively. Any grade CRS and ICANS were 70% (n = 43) and 57% (n = 34), respectively with grade ≥ 3 CRS and ICANS rates of 16% and 44%. Factors associated with increased risk of CRS and ICANS included receiving axi-cel or having leptomeningeal ± parenchymal + CNS involvement, respectively. Despite achieving high response rates, most patients experience early relapse or death following CAR-T in SCNSL. The current study provides a benchmark for future trials exploring novel therapeutic options in SCNSL.

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non-B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non-recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19.SignificanceOur study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies. This article is highlighted in the In This Issue feature, p. 171.

Australia is following a global trend in doctoral education policy to improve PhD completion times and rates. It is widely believed that accurate data on PhD completion are needed to assess the success of reforms and drive changes in doctoral education. In this article, new national completion data (2005-2018) provided by the Australian Department of Education and Training (DET) have been employed to examine changes and continuities in the Australian doctoral education system. The findings demonstrate that Australian completion rates and times have changed only slightly over time, exceed normative expectations and systematically differ by student characteristics, disciplines and institutions. The article suggests that better completions data are needed to guide detailed research into the structural conditions that determine completion. This knowledge would help to base future reforms on evidence rather than normative expectations and to realign expected with actual completion times and rates.

Abstract Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53–4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis.

Abstract Background Quantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG‐PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5‐point scale (5‐PS). Methods In CALGB 50303, patients with DLBCL received frontline R‐CHOP or DA‐EPOCH‐R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5‐PS with progression‐free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes. Results Agreement between local and central review was moderate (kappa = 0.53) for VSS and high (kappa = 0.81) for ∆SUV categories (

A decade ago, replications were typically not conducted and appreciated in social psychology, although replications play a central role in ensuring trust in scientific fields. Without systematic replication efforts, it is not clear whether findings are trustworthy. As journals can function as gatekeepers for publications, they can influence whether researchers conduct (and publish) replications. Yet, the scholarly culture in social psychology might have changed over the last decade because numerous highly visible studies did not replicate past findings. In light of these insights and the resulting learning opportunities for the field, we predicted an increase in the expressed support for replications in the policies of social psychology journals from 2015 (i.e., the year the replication problem became widely known) to 2022. We coded whether and how replications were mentioned in the author guidelines on the websites of social psychology journals (N = 51). As expected, replications were welcomed more often in 2022 (25%) than they were in 2015 (12%), but they were not mentioned on the websites of most journals (71% in 2022 vs. 82% in 2015). An exploratory analysis suggested that journals that expressed support for replications on their websites were also more likely to publish articles about replication. Further, exploratory analyses of the journals’ TOP factors indicated similar rates of support for replications as for other rigor and transparency promoting policies. In sum, our findings suggest that appreciation for replication has increased, but is not yet part of mainstream culture in social psychology.

Abstract Pevonedistat (TAK924) is a Nedd8-activating enzyme inhibitor with preclinical activity in non-Hodgkin lymphoma (NHL). This open-label, Phase I, multicenter, investigator-sponsored study enrolled patients with relapsed/refractory (R/R) NHL and chronic lymphocytic leukemia (CLL). The primary objective was safety. Pevonedistat was given intravenously on days 1, 3, 5 of a 21-day cycle for 8 cycles at five dose levels (15 to 50 mg/m2); ibrutinib was administered at 420 or 560 mg orally daily continuously. Eighteen patients with NHL were enrolled, including 8 patients with mantle cell lymphoma (MCL) and 4 patients with CLL. One dose-limiting toxicity (mediastinal hemorrhage) occurred at 50 mg/m2 of pevonedistat which is the estimated maximum tolerated dose. Bruising and diarrhea were the most common adverse events (56% and 44%). Atrial fibrillation occurred in 3 patients (17%). Grade ≥3 toxicities included arthralgia, atrial fibrillation, bone pain, diarrhea, hypertension, and mediastinal hemorrhage (one patient each). The overall response rate (ORR) was 65% (100% ORR in MCL). Pevonedistat disposition was not modified by ibrutinib. scRNA-Seq analysis showed that pevonedistat downregulated NFκB signaling in malignant B-cells in vivo. Thus, pevonedistat combined with ibrutinib demonstrated safety and promising early efficacy in NHL and CLL. NAE inhibition downregulated NFκB signaling in vivo.

The goal of industrial/organizational (IO) psychology, is to build and organize trustworthy knowledge about people-related phenomena in the workplace. Unfortunately, as with other scientific disciplines, our discipline may be experiencing a “crisis of confidence” stemming from the lack of reproducibility and replicability of many of our field's research findings, which would suggest that much of our research may be untrustworthy. If a scientific discipline's research is deemed untrustworthy, it can have dire consequences, including the withdraw of funding for future research. In this focal article, we review the current state of reproducibility and replicability in IO psychology and related fields. As part of this review, we discuss factors that make it less likely that research findings will be trustworthy, including the prevalence of scientific misconduct, questionable research practices (QRPs), and errors. We then identify some root causes of these issues and provide several potential remedies. In particular, we highlight the need for improved research methods and statistics training as well as a re-alignment of the incentive structure in academia. To accomplish this, we advocate for changes in the reward structure, improvements to the peer review process, and the implementation of open science practices. Overall, addressing the current “crisis of confidence” in IO psychology requires individual researchers, academic institutions, and publishers to embrace system-wide change.

PurposeVenetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.Experimental designTo address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].ResultsWe identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.ConclusionsFor BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501.

Abstract Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: “ibrutinib responders”—patients who achieved complete or partial response (CR/PR) to ibrutinib; “stable disease (SD)”; and “primary progressors (PP)”—patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23–7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03–8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17–37.62, p

Sixteen cycles of Brentuximab vedotin (BV) after autologous stem cell transplant (ASCT) in high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated an improved 2-year progression-free survival (PFS) over placebo. However, most patients are unable to complete all 16 cycles at full dose due to toxicity. This retrospective, multicenter study investigated the effect of cumulative maintenance BV dose on 2-year PFS. Data were collected from patients who received at least one cycle of BV maintenance after ASCT with one of the following high-risk features: primary refractory disease (PRD), extra-nodal disease (END), or relapse 75% of the planned total cumulative dose, cohort 2 with 51-75% of dose, and cohort 3 with ≤50% of dose. The primary outcome was 2-year PFS. A total of 118 patients were included. Fifty percent had PRD, 29% had RL

When the coronavirus pandemic hit, most doctoral supervision moved online around the globe. Virtual meetings using videoconferencing technology (VCT) suddenly replaced in person encounters raising the question of whether supervisory interaction has been altered due to changing delivery modes. This article applies a practice-theoretical approach to explore how doctoral advisors and candidates interact in the virtual space and how they experienced the transition to online supervision. Drawing on 11 recorded Zoom meetings and 35 interviews with doctoral advisors and candidates in the social sciences and physics, the study has found that field-specific supervision models fit VCT environments differently. The findings indicate that team-based supervision is more difficult to sustain online than one-on-one supervision where advisors and candidates change little in their usual interaction.

Abstract We aimed to investigate stress-reactive rumination in response to social stress and its association with social anxiety and trait rumination. From previous investigations we know that people with a certain vulnerability to rumination show increased stress-reactive rumination. However, up to date the possible influence of social anxiety on this relationship is still unclear. Therefore, we reanalyzed the data of two of our previous studies assessing healthy low and high trait ruminators and depressed patients performing the Trier Social Stress Test (TSST). We measured cortical oxygenation using functional Near-Infrared Spectroscopy (fNIRS) as well as different behavioral outcome measures (subjective stress levels, negative affect, state rumination). On a behavioral level, we found an influence of both, social anxiety and trait rumination, on state rumination, even when correcting for the other factor, respectively, implying two potentially independent factors of influence. On a neural level, we observed reduced activation in brain regions of the cognitive control network (CCN) for higher social anxiety and trait rumination, which might be a result of reduced cognitive and attentional control. Results indicate a specific role of social anxiety, at least on a behavioral level, and therefore implicate a crucial factor to be considered in the treatment of depression.

Staphylococcus aureus is pathogenic bacterium contaminating milk and milk products causing bacterial food poisoning. In the current study sites, there is no information on methicillin-resistant Staphylococcus aureus. Thus, the current study sought to assess the risk factors that contribute to the contamination of raw cow milk, the bacterial load, and the prevalence of methicillin-resistant Staphylococcus aurous. A cross-sectional study was conducted, January to December, 2021, on randomly selected 140 milk samples from selling point of Arba Minch Zuria and Chencha districts. Fresh milk samples were processed and tested for bacterial load, bacterial isolation, and methicillin susceptibility patterns. Questionnaire survey was conducted on 140 producers and collectors to assess hygienic factors attributed to contamination of raw cow milk with Staphylococcus aureus. The overall prevalence of S. aureus was 42.1% (59/140) (95% confidence interval (CI): 34.80–51.40%). About 15.6% (22/140) of the milk samples assessed had the viable count and total S. aureus count higher than 5log cfu/mL with 5.3 + 1.68 and 1.36 + 1.7log cfu/ml−1 bacterial loads, respectively. The rate of isolation of S. aureus was significantly high in milk from highland than lowland (p=0.030). The multivariable logistic regression revealed that educational status (OR: 6.00; 95% CI: 4.01–8.07), picking one’s nose while working on milk (OR: 1.41; 95% CI: 0.54–2.25), cleaning the milk can (OR: 4.5; 95% CI: 2.61–5.17), hand washing activities (OR: 3.4; 95% CI: 1.670–6.987), check for abnormal milk (OR: 2; 95% CI: 1.55–2.75), and container for milk (OR: 3; 95% CI: 0.12–0.67) were risk factors significantly associated with the occurrence of S. aureus in milk. In conclusion, the highest rate of resistance was observed to ampicillin (84.7%) and cefoxitin (76.3%). All isolates are resistant to at least two types of antimicrobial drugs, while 65.0% of the isolates were found to be multidrug-resistant. The higher prevalence, high load, and antimicrobial resistance of S. aureus indicate the higher public health risk due to the widespread consumption of raw milk in the area. Furthermore, consumers in the study area should be aware of the risks associated with consuming raw milk.

Since the 1980s scholars have been increasingly confronted with expectations to orient themselves toward societal and economic priorities. This normative demand for societal responsiveness is inscribed in discourses aimed at increasing the usefulness, competitiveness, and control of academia. New performance criteria, funding conditions, and organizational forms are central drivers of this debate -- thereby, they change the conditions in which scholars conduct research and advance their careers. However, little is known so far about the impact these institutional changes have on the habitus of academics. This article analyzes how stable and consistent habitus formations among academics turn out to be in the course of institutional changes. We compare the habitus formations of two generations of German scholars before and after institutional changes gained pace in Germany. Three distinct habitus formations can be identified, which we refer to as "self-fulfilling," "self-surpassing," and "self-asserting." These habitus formations hold across the two generations, but the lines between them become blurry in the new generation.

Genuine happiness is impossible without authentic concern for and corresponding behaviour towards the well-being of others. Such an incorporation of others into the self refers to a "democratic self" and the related regard for the common good. The author argues that the honesty of professionals who work in or for an educational or vocational setting is vital for the good of the individual and the common good. By introducing "democratic selves", recent advancements in Dialogical Self Theory (DST) point to an inclusion of the common good. However, given the importance of virtues for one's own and the common good, the theory and its applications are in need of integrating virtues and in particular honesty.

Abstract We studied the biological activity of pevonedistat, a first‐in‐class NEDD8‐activating enzyme (NAE) inhibitor, in combination with various cytotoxic chemotherapy agents and small molecule inhibitors in lymphoma preclinical models. Pevonedistat induced cell death in activated B‐cell (ABC) diffuse large B‐cell lymphoma (DLBCL) cell lines and to a lesser degree in germinal center B‐cell (GCB) DLBCL cell lines. In pevonedistat sensitive cells, we observed inhibition of NF‐κB activity by p65 co‐localization studies, decreased expression of BCL‐2/Bcl‐XL, and upregulation of BAK levels. Pevonedistat enhanced the activity of cytarabine, cisplatin, doxorubicin, and etoposide in ABC‐, but not in the GCB‐DLBCL cell lines. It also exhibited synergy with ibrutinib, selinexor, venetoclax, and A‐1331852 (a novel BCL‐XL inhibitor). In vivo, the combination of pevonedistat and ibrutinib or pevonedistat and cytarabine prolonged survival in SCID mice xenograft models when compared with monotherapy controls. Our data suggest that targeting the neddylation pathway in DLBCL is a viable therapeutic strategy and support further clinical studies of pevonedistat as a single agent or in combination with chemotherapy or novel targeted agents.

Abstract Background The treatment of diffuse large B-cell lymphoma (DLBCL) is limited by the development of resistance to therapy, and there is a need to develop novel therapeutic strategies for relapsed and refractory aggressive lymphoma. Metformin is an oral agent for type 2 diabetes that has been shown to decrease cancer risk and lower mortality in other types of cancer. Methods We performed a retrospective analysis of the RPCCC database looking at patients with DLBCL treated with front-line chemotherapy. We also performed pre-clinical studies looking at the effect of metformin on cell viability, cell number, Ki67, ATP production, apoptosis, ROS production, mitochondrial membrane potential, cell cycle, effect with chemotherapeutic agents, and rituximab. Finally, we studied mouse models to see the anti-tumor effect of metformin. Results Among diabetic patients, metformin use was associated with improved progression-free survival (PFS) and overall survival (OS) compared to diabetic patients not on metformin. Our pre-clinical studies showed metformin is itself capable of anti-tumor effects and causes cell cycle arrest in the G1 phase. Metformin induces apoptosis, ROS production, and increased mitochondrial membrane permeability. Metformin exhibited additive/synergistic effects when combined with traditional chemotherapy or rituximab in vitro. In vivo, metformin in combination with rituximab showed improved survival compared with rituximab monotherapy. Conclusions Our retrospective analysis showed that metformin with front-line chemotherapy in diabetic patients resulted in improved PFS and OS. Our pre-clinical studies demonstrate metformin has potential to re-sensitize resistant lymphoma to the chemo-immunotherapy and allow us to develop a hypothesis as to its activity in DLBCL.

Recent research has emphasized rumination as an important maintaining factor in various mental disorders. However, operationalization and therefore induction of rumination in experimental settings poses a major challenge in terms of ecological validity. As stress seems to play a key role in everyday situations eliciting rumination, we conducted two stress paradigms while assessing behavioral and neurophysiological measures.Aiming to replicate previous findings on induced rumination by means of the Trier Social Stress Test (TSST) and comparing them to physiological (pain) stress, a clinical sample of patients with Major Depressive Disorder (MDD; n = 22) and healthy controls (HC; n = 23) was recruited. Cortical blood oxygenation was assessed during the stress paradigms using functional near-infrared spectroscopy (fNIRS). Further, we used ecological momentary assessment (EMA) of stress, rumination and mood to be able to correlate ruminative responses during induced stress and everyday rumination.Our results showed that social stress but not physiological stress induced depressive rumination in MDD but not in HC. Further, rumination reactivity in response to social stress but not to physiological stress was significantly associated with rumination reactivity in everyday life as assessed with EMA. With respect to cortical oxygenation, MDD subjects showed hypoactivity in the Cognitive Control Network during the TSST, which mediated the differences between MDD and HC in post-stress rumination.Our findings emphasize the role of negative social triggers in depressive rumination and validate the TSST as an induction method for depressive rumination. The results inform future developments in psychotherapeutic treatment for depressive rumination.

Funding is an important mechanism for exercising influence over ever more parts of academic systems. In order to do so, funding agencies attempt to export their functional and normative prerequisites for financing to new fields. One essential requirement for fundees is then to construct research processes in the form of a project beforehand, one that is limited in time, scope and content. This article demonstrates how the public funding of doctoral programs expands this model of project research from experienced academics to the socialization process for the new academic generation. This process of "projectification" underlies funding-driven institutional changes in doctoral training. A multi-level comparative study of German policies, funding mechanisms and organizational frameworks for doctoral training demonstrates the emergence of a specific model of predefined PhD projects. The investigation of doctoral training practices reveals that socio-epistemic preconditions regulate whether research fields adopted or rejected this demanding model. This result contradicts widespread claims about a radical change in doctoral training and suggests focusing on the actual practices of field-specific doctoral research.

Abstract Background Overexpression of AXL receptor tyrosine kinase (AXL) in various human cancers correlates with reduced patients overall survival and resistance to first line therapies. Therefore, several AXL tyrosine kinase inhibitors (TKIs) are currently under clinical evaluation. Results AXL TKI BMS777607 treatment increased AXL protein levels after 24 h as observed by Western blot and flow cytometry analysis. Mechanistically, this inhibition-induced AXL cell surface accumulation was neither associated with epigenetic modifications, nor altered transcriptional and translational regulation. Further, we saw no impact on glycosylation and receptor shedding by α-secretases. However, we observed that BMS777607 increased the glycosylated 140 kDa AXL protein abundance, which was impaired in the kinase dead mutant AXL (K567R). We demonstrated that AXL kinase activity and subsequent kinase phosphorylation is necessary for GAS6-dependent receptor internalization and degradation. Blocking of kinase function by BMS777607 resulted in ubiquitination prohibition, impaired internalization and subsequent cell surface accumulation. Subsequently, AXL cell surface accumulation was accompanied by increased proliferation of 3D-Speroids induced by low μM levels of BMS777607 treatment. Conclusion Our data suggest a re-evaluation of anti-AXL clinical protocols due to possible feedback loops and resistance formation to targeted AXL therapy. An alternative strategy to circumvent feedback loops for AXL targeting therapies may exist in linkage of AXL TKIs to a degradation machinery recruiting unit, as already demonstrated with PROTACs for EGFR, HER2, and c-Met. This might result in a sustained inhibition and depletion of the AXL from tumor cell surface and enhance the efficacy of targeted anti-AXL therapies in the clinic.

Background: Patient safety is one of the most important and vital issues in the health systems of different countries. Team working and communication are very important in preventing and reducing medical errors. This Study aimed to investigate the relationship between the patient's safety and nurses' team working in surgical and intensive care units in Gilan province selected hospitals. Methods: This analytical study was conducted in 30 selected hospitals in Gilan province in 2015. The statistical population of the study consisted of all nurses working in surgical and intensive care units (n = 600), and safety authorities of 30 selected hospitals. Team working data were collected by the teamwork assessment questionnaire and the patient's safety data by the checklist of mandatory standards of patient safety. Data were analyzed by spearman correlation and SPSS 16 software. Results: According to the results, there was a significant relationship between the patient's safety and nurses' team working (p < 0.05). Conclusion: According to relationship between team working and patient's safety, financing in teamwork culture promotion can prevent serious injuries and possible complications from patients and returns the investment to the hospital.