In this in-depth review, we examine the worldwide epidemiology of SLE and summarize current knowledge on the influence of race/ethnicity on clinical manifestations, disease activity, damage ...accumulation and outcome in SLE. Susceptibility to SLE has a strong genetic component, and trans-ancestral genetic studies have revealed a substantial commonality of shared genetic risk variants across different genetic ancestries that predispose to the development of SLE. The highest increased risk of developing SLE is observed in black individuals (incidence 5- to 9-fold increased, prevalence 2- to 3-fold increased), with an increased risk also observed in South Asians, East Asians and other non-white groups, compared with white individuals. Black, East Asian, South Asian and Hispanic individuals with SLE tend to develop more severe disease with a greater number of manifestations and accumulate damage from lupus more rapidly. Increased genetic risk burden in these populations, associated with increased autoantibody reactivity in non-white individuals with SLE, may explain the more severe lupus phenotype. Even after taking into account socio-economic factors, race/ethnicity remains a key determinant of poor outcome, such as end-stage renal failure and mortality, in SLE. Community measures to expedite diagnosis through increased awareness in at-risk racial/ethnic populations and ethnically personalized treatment algorithms may help in future to improve long-term outcomes in SLE.
Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis (RA), 40% of patients show poor clinical response, and there is an imperative to unravel ...the molecular pathways and mechanisms underlying non-response and disease progression. 5–20% of RA individuals do not respond to all current medications including biologic and targeted therapies, which suggests that distinct pathogenic processes underlie multi-drug refractoriness.
In this brief review we discuss advances from recent studies in precision medicine in rheumatoid arthritis.
Bulk RNA-Sequencing of synovial biopsies from RA individuals combined with histology and deep clinical phenotyping has revealed substantial insights into divergent pathogenic pathways which lead to disease progression and illuminated mechanisms underlying failure to response to specific treatments. Biopsy-driven randomised controlled trials, such as R4RA and the forthcoming STRAP trial, have enabled the development of machine learning predictive models for predicting response to different therapies.
In the Pathobiology of Early Arthritis Cohort (PEAC), gene expression analysis showed that individuals could be classified into three gene expression subgroups which correlated with histopathotypes defined by histological markers: pauci-immune fibroid pathotype characterised by fibroblasts and an absence of immune inflammatory cells; diffuse-myeloid pathotype characterised by macrophage influx; and the lympho-myeloid pathotype delineated by the presence of B cells, but typically containing a complex inflammatory infiltrate with ectopic lymphoid structure formation. In the R4RA biopsy-driven randomised controlled trial, patients were randomised to either rituximab or tocilizumab. Comprehensive analysis of synovial biopsies pre/post-treatment identified gene signatures of response associated with pathogenic pathways which could be tracked over time. A group of true refractory patients were identified who had failed anti-TNF prior to the study (it was an entry criterion) and then subsequently failed both trial biologics during the trial. RNA-Seq analysis and digital spatial profiling identified specific cell types including DKK3+ fibroblasts as being associated with the refractory state. We identified machine learning predictive models based on specific gene signatures which were able to predict future response to therapy as well as the refractory state.
RNA-sequencing of synovial biopsies has enabled substantial progress in understanding disease endotypes in RA and identifying synovial gene signatures which predict prognosis and future response to treatment.
Acquisitions can dramatically reshape interorganizational networks by combining previously separate nodes and allowing the acquirer to inherit the target’s ties, potentially creating network synergy. ...Network synergy is the extent to which combining an acquirer’s and a target’s networks through node collapse results in a more favorable structural position for the combined firm as the acquirer gains control of the target’s existing ties. We hypothesize that the likelihood of selecting a target increases when the expected network synergy is greater. Using data from the biotechnology industry (1995–2007), we find support for this hypothesis by showing that acquirers prefer targets that generate greater expected increases in network status and greater expected access to structural holes—even when we control for other known sources of synergies. We further show that these effects are driven by complementary combinations of the acquirer’s and target’s networks that go beyond the attractiveness of the target’s network per se. By integrating the networks and acquisitions literatures, we introduce a novel source of synergies, provide evidence of a previously unexplored mechanism of network change, and show how firms can exert agency in the process of network change.
By highlighting conditions under which viable interorganizational relationships do not materialize, we explore the limitations of interorganizational knowledge acquisition. In the empirical context ...of corporate venture capital (CVC), we analyze a sample of 1,646 start-up-stage ventures that received funding during the 1990s. Under a regime of weak intellectual property protection (IPP), an entrepreneur-CVC investment relationship is less likely to form when the entrepreneurial invention targets the same industry as corporate products. In contrast, under a strong IPP regime, industry overlap is associated with an increase in the likelihood of an investment relationship. Our findings suggest that many relationships do not form because the corporation will not invest unless the entrepreneur discloses his or her invention, and the entrepreneur may be wary of doing so, fearing imitation. To the extent that a CVC has greater capability and inclination to target same-industry ventures, such industry overlap would exacerbate imitation concerns under a weak IPP regime, yet facilitate an investment relationship under a strong IPP regime. Beyond CVC, this insight may explain patterns of other interorganizational relationships, including research and development alliances and technology licensing between start-ups and incumbents.
This commentary's title is not meant to be a rhetorical question. In congratulating Brouthers (2002) for the JIBS Decade Award, we have an opportunity to assess where we are within this field of ...inquiry, and what is our trajectory. I believe that we have accomplished a lot in this area of study. Nevertheless, I am concerned about its current trajectory, so much so that I think we should seriously question whether we need more entry mode studies — especially if we are going to get more of the same.
I highlight why taking causal identification seriously is important for the study of strategy and organizations. Nevertheless, the nature of the questions that are central to our field and the nature ...of the data we have to answer these questions complicates doing so. Because of this, I suggest that we explicitly consider identification as an issue that can be addressed only through a cumulative body of empirical research. I outline current research norms and practices that impede adopting this approach and recommend a set of actions to help overcome these norms and practices.
The necessity, logic, and forms of replication Bettis, Richard A.; Helfat, Constance E.; Shaver, J. Myles
Strategic management journal,
November 2016, Letnik:
37, Številka:
11
Journal Article
Recenzirano
Research summary: A replication study assesses whether the results of a particular prior study can be reproduced, including in new contexts with different data. Replication studies are critical for ...building a cumulative body of research knowledge. This article discusses and provides a typology of different types of replications, compares replications with other approaches to cumulating knowledge, and provides guidelines toward producing high-quality replication studies. The articles in this Special Issue provide examples of replication studies in strategic management. Managerial summary: Research studies sometimes draw implications for managerial practice. A single empirical study, however, is specific to a particular context, relies on a particular set of data, and uses a particular research design. As a consequence, a single study cannot establish whether the findings generalize to a different context and whether the research design is robust to alternative approaches. Replication studies can help to establish the range of applicability of prior studies and better support what implications can be drawn for managerial practice.
Many strategic investments require firms to make upfront outlays to generate profits at a later date. When firms have limited access to external capital, they have to rely on internally generated ...funds for these investments. In this case, their strategic investments are constrained by cash flow. I predict that by geographically diversifying sales (i.e., exporting), firms can relax this constraint because exporting signals more stable expected cash flows and firm quality, which can increase external capital providers' willingness to fund investments. Examining a representative sample of Spanish manufacturers from 1990 to 1998, I find support that exporting mitigates investment liquidity constraints allowing firms to make strategic investments they would not otherwise be able to make. This highlights how diversification can be a strategy to create and maintain competitive advantage.
Background
Retroperitoneal soft tissue sarcomas comprise a heterogeneous group of rare tumors of mesenchymal origin that include several well-defined histologic subtypes. In 2015, the Transatlantic ...Australasian RPS Working Group (TARPSWG) published consensus recommendations for the best management of primary retroperitoneal sarcoma (RPS). Since then, through international collaboration, new evidence and knowledge have been generated, creating the need for an updated consensus document.
Methods
The primary aim of this study was to critically evaluate the current evidence and develop an up-to-date consensus document on the approach to these difficult tumors. The resulting document applies to primary RPS that is non-visceral in origin, with exclusion criteria as previously described. The relevant literature was evaluated and an international group of experts consulted to formulate consensus statements regarding the best management of primary RPS. A level of evidence and grade of recommendation were attributed to each new/updated recommendation.
Results
Management of primary RPS was considered from diagnosis to follow-up. This rare and complex malignancy is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, and an individualized management plan should be made based on the 29 consensus statements included in this article, which were agreed upon by all of the authors. Whenever possible, patients should be enrolled in prospective trials and studies.
Conclusions
Ongoing international collaboration is critical to expand upon current knowledge and further improve outcomes of patients with RPS. In addition, prospective data collection and participation in multi-institution trials are strongly encouraged.
Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not ...respond to individual biologic therapies and 5-20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment-response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.
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