Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are ...based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models.
We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors.
We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (
and
single nucleotide variants SNVs), the DNA repair pathway (deletion 17p,
, and
SNVs), and
(translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort.
SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.
Chimeric antigen receptor (CAR) T cells (CARTs) have shown tremendous potential for the treatment of certain B-cell malignancies, including patients with relapsed/refractory multiple myeloma (MM). ...Targeting the B-cell maturation antigen (BCMA) has produced the most promising results for CART therapy of MM to date, but not all remissions are sustained. Emergence of BCMA escape variants has been reported under the selective pressure of monospecific anti-BCMA CART treatment. Thus, there is a clinical need for continuous improvement of CART therapies for MM. Here, we show that a novel trimeric APRIL (a proliferation-inducing ligand)–based CAR efficiently targets both BCMA+ and BCMA− MM. Modeled after the natural ligand-receptor pair, APRIL-based CARs allow for bispecific targeting of the MM-associated antigens BCMA and transmembrane activator and CAML interactor (TACI). However, natural ligands as CAR antigen-binding domains may require further engineering to promote optimal binding and multimerization to adequately trigger T-cell activation. We found that using a trimeric rather than a monomeric APRIL format as the antigen-binding domain enhanced binding to BCMA and TACI and CART activity against MM in vitro and in vivo. Dual-specific, trimeric APRIL-based CAR are a promising therapeutic approach for MM with potential for preventing and treating BCMA escape.
•A trimeric extracellular moiety of APRIL has enhanced binding to BCMA and TACI compared with monomeric APRIL when incorporated into a CAR.•T cells transduced with a trimeric APRIL-based CAR are a promising approach for the treatment of MM.
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During July–August 2013, a gastroenteritis outbreak occurred among rafters at Idaho’s Middle Fork of the Salmon River. To identify the agent, source, and risk factors for illness, we solicited ill ...and well persons who rafted during July 1–September 23 to respond to an online survey, and conducted a case-control study. Cases were defined as nausea, vomiting, or diarrhea ≤25 days after rafting; control subjects were rafters who did not have these symptoms. Illness was associated with having consumed filtered river water—70% (69/98) of case subjects and 38% (106/280) of control subjects had consumed filtered water (odds ratio OR = 3.9; 95% confidence interval CI 2.4, 6.4). In a follow-up online survey of 33 case subjects and 73 control subjects, boiling water for drinking was protective against illness; 2/18 case subjects, compared with 15/33 control subjects, had boiled their drinking water (OR = 0.2; 95% CI 0.03, 0.9). From ill rafters, norovirus (n = 3) and Giardia (n = 8) were detected in stool specimens. Norovirus was detected on surfaces and E. coli in surface water used for drinking. Adherence to backcountry drinking water treatment recommendations is advised.
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Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Climate change is increasing the likelihood and magnitude of disaster impacts. The nonprofit sector’s ability to address disaster survivors’ needs will become an increasingly important aspect of ...adapting to a changing climate. Disaster recovery also provides time for nonprofits to affect community resilience to future disasters and climate change. This article analyzes a unique phenomenon of the sector during disaster recovery: Long-term Recovery Groups. These groups are increasingly encouraged by government and national nonprofits, yet little academic research exists on them. We assess the existence and location of groups, their missions and tasks, and their legal structure. We find heterogeneity in structure and location but similarity in stated goals of addressing failures of government and private sector recovery practices. These groups emerge, as expected, in areas with disaster losses and in areas with slightly greater social vulnerability. Most groups, though, miss the opportunity to include climate change as part of their mission.
This is a critical moment in history for nonprofit organizations. As the number of nonprofits in the U.S. continue to rise, so will the number of top leadership roles within have to be filled. With a ...culture of generally having to do more with fewer resources, many have contemplated where tomorrow's nonprofit leaders will come from. No one truly knows the exact number of leaders this sector will require in the future, while some have predicted large numbers, others don't believe the deficit will be too extreme. The Bridgespan Group (2006) conducted a survey that addressed the above, concluding, the leader deficit would be large based on newly created roles within nonprofits, vacancies due to Baby Boomer retirements, and a lack of resources by nonprofits to retain top talent. Soon after the release of their white paper, others refuted their findings. Generally, others did not believe the leadership gap would be as bad as predicted based on the sector being used to maximizing their resources, talent from the corporate sector transitioning into the nonprofit sector, and the belief that donor support will continue to rise year after year. Regardless of the above and which side you believe in terms of how many nonprofit sector leaders will be required in the near or far, engaging in this dialogue is important. According to the National Center for Charitable Statistics (2016) more than 1.5 million nonprofits exists in the U.S., they account for more than 9% of wages and salaries in the U.S., and GDP is more than 5% from nonprofits in the U.S. The Bridgespan Group's work highlighted the phenomenon of the nonprofit leader deficit and offered potential solutions to what type of leaders the nonprofit industry could benefit from in the future. They recommended identifying nonprofit leaders who possess functional business skills, and identifying candidates based on those who show cultural affinity towards an organization's mission (organizational fit based on candidates' experience interacting with mission-driven organizations). Their methodology consisted of an informal survey with complete responses from 433 nonprofit senior executives in the best position to answer questions regarding senior manager hiring within nonprofits. Along with adding to the overall body of research geared towards the nonprofit sector, this study contributed to the leadership literature by increasing the number of quantitative studies from the follower perspective, and adds to the Authentic Leadership Questionnaire's continued validation efforts. The purpose of this study is to examine the relationship between followers' perception of Authentic Leadership behaviors and followers' perception of Consideration Emphasis and Production Emphasis behaviors at nonprofit organizations, and to examine the relationship between followers' perception of Authentic Leadership behaviors and followers' self-rated Job Satisfaction within nonprofit organizations. Authentic Leadership was measured via the Authentic Leadership Questionnaire (ALQ), developed by Avolio, Gardner, and Walumbwa (2007). Heuermanand and Olson (1997) defined authenticity in leaders as those with personal values that translate into action to build trust with followers. Determining whether nonprofit leaders utilized a Consideration Emphasis and/or a Production Emphasis in the nonprofit work environment was rated using the Leadership Behavior Description Questionnaire Form XII (LBDQ-XII), developed by Stodgill (1963). Leaders who employ a consideration approach can be viewed as those who support and develop their employees, while those with a production emphasis are said to focus on initiating structure within the workplace. Judge, Piccolo, and Ilies (2004) found leader performance as the main effect (predictor) to come out of consideration and initiating structure studies. Nonprofit employee job satisfaction was measured using the Abridged Job Descriptive Index (AJDI) and the Abridged Job in General (AJiG) scales. The AJDI and The AJiG scales were provided by Bowling Green State University (2009). A series of multiple regressions, some leading to the need for running ANOVAs with post hocs, were conducted to determine if there is a relationship between the authentic leadership constructs (self awareness, transparency, moral/ethical, balanced processing), the leader behavior descriptor constructs of consideration and production emphasis, and employee job satisfaction.
While a large fraction of application code is devoted to graphical user interface (GUI) functions, support for reuse in this domain has largely been confined to the creation of GUI toolkits ...("widgets"). We present a novel architectural style directed at supporting larger grain reuse and flexible system composition. Moreover, the style supports design of distributed, concurrent applications. Asynchronous notification messages and asynchronous request messages are the sole basis for intercomponent communication. A key aspect of the style is that components are not built with any dependencies on what typically would be considered lower-level components, such as user interface toolkits. Indeed, all components are oblivious to the existence of any components to which notification messages are sent. While our focus has been on applications involving graphical user interfaces, the style has the potential for broader applicability. Several trial applications using the style are described.
While a large fraction of application system code is devoted to user interface (UI) functions, support for reuse in this domain has largely been confined to creation of UI toolkits ("widgets"). We ...present a novel architectural style directed at supporting larger grain reuse andjexible system composition. Moreover, the style supports design of distributed, concurrent, applications. A key aspect of the style is that components are not built with any dependencies on what typically would be considered lower-level components, such as user interface toolkits. Indeed, all components are oblivious to the existence of any components to which notification messages are sent. Asynchronous notification messages and asynchronous request messages are the sole basis for inter-component communication. While our focus has been on applications involving graphical user interfaces, the style has the potential for broader applicability. Several trial applications using the style are described.
Chimera Anderson, Kenneth M.; Taylor, Richard N.; Whitehead, E. James
Conference on Hypertext and Hypermedia: Proceedings of the 1994 ACM European conference on Hypermedia technology; 19-23 Sept. 1994,
09/1994
Conference Proceeding
Emerging software development environments are characterized by heterogeneity: they are composed of diverse object stores, user interfaces, and tools. This paper presents an approach for providing ...hypertext services in this heterogeneous setting. Central notions of the approach include the following. Anchors are established with respect to interactive views of objects, rather than the objects themselves. Composable, n-ary links can be established between anchors on different views of objects stored in distinct object bases. Viewers (and objects) may be implemented in different programming languages afforded by a client-server architecture. Multiple, concurrently active viewers enable multimedia hypertext services. The paper describes the approach and presents an architecture which supports it. Experience with the Chimera prototype and its relationship to other systems is described.
Chimera Anderson, Kenneth M; Taylor, Richard N; Whitehead, Jr, E James
ACM transactions on information systems,
07/2000, Letnik:
18, Številka:
3
Journal Article
Recenzirano
Emerging software development environments are characterized by heterogeneity: they are composed of diverse object stores, user interfaces, and tools. This paper presents an approach for providing ...hypermedia services in this heterogeneous setting. Central notions of the approach include the following: anchors are established with respect to interactive views of objects, rather than the objects themselves; composable, n -ary links can be established between anchors on different views of objects which may be stored in distinct object bases; viewers may be implemented in different programming languages; and, hypermedia services are provided to multiple, concurrently active, viewers. The paper describes the approach, supporting architecture, and lessons learned. Related work in the areas of supporing heterogeneity and hypermedia data modeling is discussed. The system has been employed in a variety of contexts including research, development, and education.
Chimera Anderson, Kenneth M.; Taylor, Richard N.; Whitehead, E. James
ACM transactions on information systems,
07/2000, Letnik:
18, Številka:
3
Journal Article
Recenzirano
Emerging software development environments are characterized by heterogeneity: they are composed of diverse object stores, user interfaces, and tools. This paper presents an approach for providing ...hypermedia services in this heterogeneous setting. Central notions of the approach include the following: anchors are established with respect to interactive
views
of objects, rather than the objects themselves; composable,
n
-ary links can be established between anchors on different views of objects which may be stored in distinct object bases; viewers may be implemented in different programming languages; and, hypermedia services are provided to multiple, concurrently active, viewers. The paper describes the approach, supporting architecture, and lessons learned. Related work in the areas of supporing heterogeneity and hypermedia data modeling is discussed. The system has been employed in a variety of contexts including research, development, and education.
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