Search

Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS.

Recent advances in additive manufacturing have enabled a new generation of electromagnetic applications to flourish. Complex geometries for dielectrics and conductors can now be simulated and rapidly fabricated from digital data. Powder bed fusion of metals is arguably the most widely adopted additive process by industry and can provide intricately-detailed structures in a wide range of high performance alloys. Copper and copper alloys have remained a challenge in this additive process, as the typical laser wavelength (approximately 1070 nm) used fails to provide sufficient absorption. Moreover, the high thermal conductivity of copper does not allow for the required heat generation for a stable melt pool. However, the recent commercial introduction of the green laser (515 nm wavelength) is enabling the printing of copper, which is particularly interesting for electrical and electromagnetic applications due to the high electrical conductivity and solderability. This paper describes the use of a green laser powder bed fusion system used to fabricate a complex fractal Sierpinski gasket ground structure with an isolated internal pyramid antenna built simultaneously—within and dielectrically isolated from the external ground element: a ship-in-the-bottle design paradigm. The electromagnetic performance, surface finish, dimensional compliance, and conductivity were measured and reported to inform the design of freestanding, geometrically-complex antennas.

The phenomenon of incivility and workplace bullying across industries worldwide is pervasive and harms individuals and the organization. It is well researched that the impact on targets of incivility and bullying behaviour is damaging, is often severe, and results in negative consequences for the targets and the organization. Furthermore, within the context of the dark triad, workplace bullies engage in varying levels of psychopathy to the detriment of the target. This chapter is designed to provide readers with a breadth and depth of knowledge related to the prevalence of the bullying phenomenon, predictors of bullying behaviour, psychopathology of the bully, and the psychological impact on targets.

BackgroundSince the novel coronavirus SARS-COV-2 was first identified to be circulating in the US on January 20, 2020, some of the worst outbreaks have occurred within state and federal prisons. The vulnerability of inmate populations, and the additional threats posed to the health of prison staff and the people they contact in surrounding communities underline the need to better understand the dynamics of transmission in the inter-linked inmate/staff/community sub-populations to better inform optimal control of SARS-COV-2.MethodsWe examined SARS-CoV-2 case data from 101 non-administrative federal prisons between 5/18/2020 to 01/31/2021 and examined the per capita size of outbreaks in staff and inmates compared to outbreaks in the communities in the counties surrounding the prisons during the summer and winter waves of the SARS-COV-2 pandemic. We also examined the impact of decarceration, comparing inmate, staff and community SARS-COV-2 outbreak sizes during the winter wave to the summer wave.ResultsFor both the summer and winter waves we found significant inter-correlations between per capita rates in the outbreaks among inmates, staff, and the community.Over-all during the pandemic, per capita rates were significantly higher in inmates than in both the staff and community (paired Student’s t-test p=0.03 and pConclusionsWe found significant evidence of community/staff/inmate inter-linkage of SARS-COV-2 transmission. Decarceration ameliorates both prison and community SARS-COV-2 per capita rates. Further study is warranted to determine which control measures aimed at inmates and/or staff are most efficacious at preventing or controlling outbreaks.

Public organizations, including institutions in the U.S. criminal justice (CJ) system, have been rapidly releasing information pertaining to COVID-19. Even CJ institutions typically reticent to share information, like private prisons, have released vital COVID-19 information. The boon of available pandemic-related data, however, is not without problems. Unclear conceptualizations, stakeholders’ influence on data collection and release, and a lack of experience creating public dashboards on health data are just a few of the issues plaguing CJ institutions surrounding releasing COVID-19 data. In this article, we detail issues that institutions in each arm of the CJ system face when releasing pandemic-related data. We conclude with a set of recommendations for researchers seeking to use the abundance of publicly available data on the effects of the pandemic.

Workplace bullying is a severe, violent, and pervasive issue present across the industry worldwide. Typically defined as interpersonal mistreatment that is more severe than incivility, it is a complex, deliberate, and maladaptive group of harmful actions towards individuals and creates oppressive work environments. Bullying can range from derogatory comments towards a target to social isolation and physical violence. Individuals typically evolve into the perpetrator role due to low self-esteem, dark personality traits, and anger management difficulties. Harassment and abusive incivility by managers and supervisors directed towards employees are associated with severe adverse and long-term outcomes, including psychological trauma, mental health disorders, and in extreme cases, suicide. The prevalence of workplace bullying ranges between 10-20% in multiple domains and cultures. When considering the economic, psychological, and health costs of incivility in the workplace, the epidemic of workplace bullying requires comprehensive prevention, intervention, and postvention strategies.

Additive Manufacturing is enabling the casting of complex geometries directly from digital design data, including 3D-scanned and reverse-engineered structures and even functionally graded lattices. By ink jetting binder into a bed of sand layer-by-layer, dimensionally precise sand molds and cores can be printed to serve as soft tooling for sand casting. However, the related increase in geometry complexity can lead to challenges in ensuring casting quality and yield. One recently explored remedy is to introduce sensors (the Internet of Things) to enable the collection of a diversity of data at difficult-to-access locations in molds in order to measure temperature, pressure, moisture, and core shift. This effort has explored measuring barometric pressure at strategic locations to evaluate the ventilation design of internal cores. Optimized and measurable ventilation can be leveraged to improve the quality of castings by reducing porosity and improving surface finish. By measuring the pressures that accumulate within cores due to binder decomposition, new ventilation designs and strategies—enabled with complex, 3D printed fluidic channels—can be explored. In this work, two castings with different metal temperatures were poured and internal pressures were measured and compared to simulations demonstrating that wireless disposable sensors can be used to measure pressure and that the measured pressure correlated with venting strategies now possible with 3D printed sand cores.

In this study, thermal buckling responses of a functionally graded (FG) cylindrical microshell are investigated. Material properties of the FG microshell are considered to be graded through the thi...

An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

3D sand printing is an emerging technology that is enabling new possibilities in metal casting with respect to part complexity, casting design, and rapid mold production. The 3D printing technology, also known as additive manufacturing, is a binder jetting process which involves selectively depositing a furan-based binder into a sand bed one thin layer at a time. Over the course of the process, layers are subsequently added until the entire part has been fabricated. Although the use of 3D-printed sand molds in the foundry industry is growing, significant hesitation to widespread implementation remains. In this work, an investigation was conducted to determine the influence of machine settings on the physical characteristics of 3D-printed sand. Two factorial matrices were constructed to directly measure the significance of six settings that change the resin content and compaction characteristics of the bonded sand. Factors include: X-resolution, printhead voltage, layer thickness, and the frequency, speed, and angle of the recoater blade. Responses include: density, permeability, strength, scratch hardness, loss on ignition, and print resolution. Several relationships are reported between machine settings and physical properties of the product. These results will help inform mold manufacturing as the foundry industry continues to adopt additive technologies.

The original publication of this article [1] contained 3 minor errors in Figs. 1, 3 and 5. In this correction article the updated figures are published. The figure captions describe the updated information in these figures.

There will be a revolution in industry and society as a result of Industry 5.0. Human-robot co-working, also known as cobots, is a key component of Industry 5.0. Industry 5.0 will overcome all the limitations of the previous industrial revolution. Humans and machines will work together in this revolution to increase the efficiency of processes by utilising human brainpower and creativity. To solve complex problems more efficiently and with less human intervention, Industry 5.0 provides a strong foundation for advanced digital manufacturing systems through interconnected networks, and it's designed to communicate with other systems, as well as powerful computing power. To enhance customer satisfaction, Industry 5.0 involves a shift from mass customization to mass personalization along with a shift from digital usage of data to intelligent use of data for sustainable development. On the basis of comparative analysis, this chapter outlines Industry 5.0's definition, its elements and components, and its application and future scope paradigm.

Our goal was to identify the factors with the strongest influence on the minimum lamina cribrosa (LC) oxygen concentration as potentially indicative of conditions increasing hypoxia risk. Because direct measurement of LC hemodynamics and oxygenation is not yet possible, we developed 3D eye-specific LC vasculature models. The vasculature of a normal monkey eye was perfusion-labeled post-mortem. Serial cryosections through the optic nerve head were imaged using fluorescence and polarized light microscopy to visualize the vasculature and collagen, respectively. The vasculature within a 450 μm-thick region containing the LC - identified from the collagen, was segmented, skeletonized, and meshed for simulations. Using Monte Carlo sampling, 200 vascular network models were generated with varying vessel diameter, neural tissue oxygen consumption rate, inflow hematocrit, and blood pressures (arteriole, venule, anterior boundary, and posterior boundary). Factors were varied over ranges of baseline ±20% with uniform probability. For each model we first obtained the blood flow, and from this the neural tissue oxygen concentration. ANOVA was used to identify the factors with the strongest influence on the minimum (10th percentile) oxygen concentration in the LC. The three most influential factors were, in ranked order, vessel diameter, neural tissue oxygen consumption rate, and arteriole pressure. There was a strong interaction between vessel diameter and arteriole pressure whereby the impact of one factor was larger when the other factor was small. Our results show that, for the eye analyzed, conditions that reduce vessel diameter, such as vessel compression due to elevated intraocular pressure or gaze-induced tissue deformation, may particularly contribute to decreased LC oxygen concentration. More eyes must be analyzed before generalizing.

INTRODUCTION AND OBJECTIVE:To evaluate the range of pathologies identified in patients attending the One Stop Haematuria Clinic (OSHC) and to examine the value of Ultrasound Urinary tract (USS KUB)...

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to impact the United States. While age and comorbid health conditions remain primary concerns in the community-based transmission of the virus, empirical evidence continues to suggest that substantial variability exists in the geographic and geodemographic distribution of COVID-19 infection rates. The purpose of this paper is to provide an alternative, spatiotemporal perspective on the pandemic using the state of Wisconsin as a case study. Specifically, in this paper, we explore the geographic nuances of COVID-19 and its spread in Wisconsin using a suite of spatial statistical approaches. We link detected hot spots of COVID-19 to local geodemographic profiles and the presence of high-risk facilities, including federal and state correctional facilities. The results suggest that the virus disproportionately impacts several communities and geodemographic groups and that proximity to risky facilities correlates to increased community infection rates.

The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to ∼1000x median depth of coverage. An orthogonal error-corrected sequencing approach verified >95% of the discovered mutations. We identified mutations in genes novel to cHL including: CDH5 and PCDH7; novel mutations in IL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells, allowing for the analysis for clinically relevant genomic variants in large cohorts of cHL patients.

Background: Our objective was to examine the temporal relationship between COVID-19 infections among prison staff, incarcerated individuals, and the general population in the county where the prison is located among federal prisons in the United States. Methods: We employed population-standardized regressions with fixed effects for prisons to predict the number of active cases of COVID-19 among incarcerated persons using data from the Federal Bureau of Prisons (BOP) for the months of March to December in 2020 for 63 prisons. Results: There is a significant relationship between the COVID-19 prevalence among staff, and through them, the larger community, and COVID-19 prevalence among incarcerated persons in the US federal prison system. When staff rates are low or at zero, COVID-19 incidence in the larger community continues to have an association with COVID-19 prevalence among incarcerated persons, suggesting possible pre-symptomatic and asymptomatic transmission by staff. Masking policies slightly reduced COVID-19 prevalence among incarcerated persons, though the association between infections among staff, the community, and incarcerated persons remained significant and strong. Conclusion: The relationship between COVID-19 infections among staff and incarcerated persons shows that staff is vital to infection control, and correctional administrators should also focus infection containment efforts on staff, in addition to incarcerated persons.

Additive manufacturing of ceramics has been actively investigated with the objective of fabricating complex structures that compete in terms of material performance with traditionally manufactured ceramics but with the benefit of increased geometric freedom. More specifically, zirconia provides high fracture toughness and thermal stability. In addition, its dielectric permittivity may be the highest among materials available for 3D printing, and may enable the next generation of complex electromagnetic structures. NanoParticle Jetting™ is a new material jetting process for selectively depositing nanoparticles and is capable of printing zirconia. Dense, fine-featured parts can be manufactured with layer thicknesses as small as 10 μm and jetting resolution of 20 μm after a final sintering step. For this study, 3D printed zirconia using NanoParticle Jetting™ was characterized in terms of chemistry, density, crystallography, sintering shrinkage and dielectric properties as a foundation for developing high performance radio frequency (RF) components. The experimental results indicate a yttria-stabilized ZrO2 structure exhibiting a bulk relative permittivity of 23 and a loss tangent of 0.0013 at microwave frequencies. A simple zirconia dielectric resonator antenna is measured, confirming the measured dielectric properties and illustrating a practical application of this material.

In this work, real-time in-process monitoring of core motion in metal castings is demonstrated through the use of two emerging technologies. 3D sand printing (3DSP) is a binder jetting additive manufacturing process that is quickly manifesting itself as a technological disrupter in the metal casting industry. Based on its direct digital manufacturing principle, 3DSP enables complex mold and core design freedom that has been previously unavailable to foundry engineers. In addition, the miniaturization and affordability of electronics and sensing equipment is rapidly accelerating. Here, these two shifting paradigms are leveraged together. An experimental casting and mold were designed in this research to demonstrate and evaluate wireless sensing of core shifts. With the use of 3D sand printing, precisely sized and located pockets were manufactured inside of cores. Miniature wireless Bluetooth sensors capable of measuring acceleration and rotation were then embedded inside the cores. From these, high fidelity data were captured wirelessly from the sensors during the casting process. With strategically designed core prints designed to allow varying levels of core motion, it is shown that core shifts can be measured and discriminated during casting in real time.

Monocytes/macrophages have begun to emerge as key cellular modulators of brain homeostasis and central nervous system (CNS) disease. In the healthy brain, resident microglia are the predominant macrophage cell population; however, under conditions of blood-brain barrier leakage, peripheral monocytes/macrophages can infiltrate the brain and participate in CNS disease pathogenesis. Distinguishing these two populations is often challenging, owing to a paucity of universally accepted and reliable markers. To identify discriminatory marker sets for microglia and peripheral monocytes/macrophages, we employed a large meta-analytic approach using five published murine transcriptional datasets. Following hierarchical clustering, we filtered the top differentially expressed genes (DEGs) through a brain cell type-specific sequencing database, which led to the identification of eight microglia and eight peripheral monocyte/macrophage markers. We then validated their differential expression, leveraging a published single cell RNA sequencing dataset and quantitative RT-PCR using freshly isolated microglia and peripheral monocytes/macrophages from two different mouse strains. We further verified the translation of these DEGs at the protein level. As top microglia DEGs, we identified P2ry12, Tmem119, Slc2a5 and Fcrls, whereas Emilin2, Gda, Hp and Sell emerged as the best DEGs for identifying peripheral monocytes/macrophages. Lastly, we evaluated their utility in discriminating monocyte/macrophage populations in the setting of brain pathology (glioma), and found that these DEG sets distinguished glioma-associated microglia from macrophages in both RCAS and GL261 mouse models of glioblastoma. Taken together, this unbiased bioinformatic approach facilitated the discovery of a robust set of microglia and peripheral monocyte/macrophage expression markers to discriminate these monocyte populations in both health and disease. Electronic supplementary material The online version of this article (10.1186/s40478-019-0665-y) contains supplementary material, which is available to authorized users.

The use of additive manufacturing (AM) provides an opportunity to fabricate composite tooling molds in a rapidly and cost effectively manner. This work has shown the use of a polymer based infiltrated ceramics produced via binder jetting for producing composite tooling molds. Here, molds based on silica sand as well as zircon sand have been printed on a S-Max 3D printer unit and subsequently impregnated with an epoxy system for yielding functional molds in the range of autoclave temperatures around 150–177 °C. The mechanical properties of the infiltrated 3D printed materials have been investigated and it was observed that the polymer-infiltrated systems resulted in a compressive and flexural strength one order of magnitude higher than the non-infiltrated printed ceramic material. A thermal analysis was also performed on both the infiltrated and non-infiltrated printed samples, and it was recorded that the incorporation of the polymer resulted in a larger coefficient of thermal expansion on the infiltrated systems. Here, a carbon fiber reinforced composite was manufactured with the infiltrated composite tooling molds printed in the S-Max unit, and it was observed that the assembled molds are capable of producing a successful composite material. The present work has demonstrated that a binder jetting process, is a feasible technology for producing thermostable low cost composite tooling molds.

In the last decade, the proliferation of new 3D printing technologies has enabled the fabrication of complex geometries in manifold materials for novel applications. One discipline that has been explored extensively in the context of additive manufacturing is electromagnetic devices such as antennas. Difficult-to-fabricate geometries are now possible and can deliver new antenna functionality and extend performance (e.g., lower frequency resonance in small volumes, wider bandwidth, narrow-beam directionality, and so on). Coupled with accurate 3D electromagnetic simulations, a new paradigm is emerging for antenna design and manufacture. Starting from a seed geometry, the state space can now be explored to identify new combinations and permutations of electromagnetically-beneficial shapes through multiple simulation iterations. Subsequently, the identified structures can be further validated and improved through rapid manufacturing using 3D printing for hardware evaluation in an anechoic chamber. However, to fully benefit from this emerging paradigm, an up-to-date survey of the most recent metal processes is required. This survey would determine which processes are well suited for building the next generation of antennas. For this purpose, a variety of metal 3D printing was employed to fabricate benchmark antennas with pathological geometries, including thin walls, overhanging features, and large aspect ratios. This survey can inform designers about potential structures to serve in novel antennas. A total of five processes have been preliminarily explored including selective laser melting, binder jetting, and plated vat photopolymerization, all of which delivered different advantages and disadvantages in terms of mechanical and electromagnetic performance.

Background Since the novel coronavirus SARS-COV-2 was first identified to be circulating in the US on January 20, 2020, some of the worst outbreaks have occurred within state and federal prisons. The vulnerability of incarcerated populations, and the additional threats posed to the health of prison staff and the people they contact in surrounding communities underline the need to better understand the dynamics of transmission in the inter-linked incarcerated population/staff/community sub-populations to better inform optimal control of SARS-COV-2. Methods We examined SARS-CoV-2 case data from 101 non-administrative federal prisons between 5/18/2020 to 01/31/2021 and examined the per capita size of outbreaks in staff and the incarcerated population compared to outbreaks in the communities in the counties surrounding the prisons during the summer and winter waves of the SARS-COV-2 pandemic. We also examined the impact of decarceration on per capita rates in the staff/incarcerated/community populations. Results For both the summer and winter waves we found significant inter-correlations between per capita rates in the outbreaks among the incarcerated population, staff, and the community. Over-all during the pandemic, per capita rates were significantly higher in the incarcerated population than in both the staff and community (paired Student’s t-test p = 0.03 and p Federal prisons decreased the incarcerated population by a relative factor of 96% comparing the winter to summer wave (one SD range [90%,102%]). We found no significant impact of decarceration on per capita rates of SARS-COV-2 infection in the staff community populations, but decarceration was significantly associated with a decrease in incarcerated per capita rates during the winter wave (Negative Binomial regression p = 0.015). Conclusions We found significant evidence of community/staff/incarcerated population inter-linkage of SARS-COV-2 transmission. Further study is warranted to determine which control measures aimed at the incarcerated population and/or staff are most efficacious at preventing or controlling outbreaks.

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate–taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate–taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was −1.24 points per month with the active drug and −1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate–taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR Clinicaltrials.gov number, NCT03127514.)

The clonal evolution of metastatic colorectal cancer reveals novel insights into cancer biology., Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine.

PURPOSE Precision oncology depends on the matching of tumor variants to relevant knowledge describing the clinical significance of those variants. We recently developed the Clinical Interpretations for Variants in Cancer (CIViC; civicdb.org ) crowd-sourced, expert-moderated, and open-access knowledgebase. CIViC provides a structured framework for evaluating genomic variants of various types (eg, fusions, single-nucleotide variants) for their therapeutic, prognostic, predisposing, diagnostic, or functional utility. CIViC has a documented application programming interface for accessing CIViC records: assertions, evidence, variants, and genes. Third-party tools that analyze or access the contents of this knowledgebase programmatically must leverage this application programming interface, often reimplementing redundant functionality in the pursuit of common analysis tasks that are beyond the scope of the CIViC Web application. METHODS To address this limitation, we developed CIViCpy ( civicpy.org ), a software development kit for extracting and analyzing the contents of the CIViC knowledgebase. CIViCpy enables users to query CIViC content as dynamic objects in Python. We assess the viability of CIViCpy as a tool for advancing individualized patient care by using it to systematically match CIViC evidence to observed variants in patient cancer samples. RESULTS We used CIViCpy to evaluate variants from 59,437 sequenced tumors of the American Association for Cancer Research Project GENIE data set. We demonstrate that CIViCpy enables annotation of > 1,200 variants per second, resulting in precise variant matches to CIViC level A (professional guideline) or B (clinical trial) evidence for 38.6% of tumors. CONCLUSION The clinical interpretation of genomic variants in cancers requires high-throughput tools for interoperability and analysis of variant interpretation knowledge. These needs are met by CIViCpy, a software development kit for downstream applications and rapid analysis. CIViCpy is fully documented, open-source, and available free online.

The present research is concerned with the elastic&ndash, plastic responses of functionally graded material (FGM) pipe, undergoing two types of loading conditions. For the first case, the FGM is subjected to sustained internal pressure combined with a cyclic bending moment whereas, in the second case, sustained internal pressure is applied simultaneously with a cyclic through-thickness temperature gradient. The properties of the studied FGM are considered to be variable through shell thickness according to a power-law function. Two different designs of the FGM pipe are adopted in the present research, where the inner surface in one case and the outer surface in the other are made from pure 1026 carbon steel. The constitutive relations are developed based on the Chaboche nonlinear kinematic hardening model, classical normality rule and von Mises yield function. The backward Euler alongside the return mapping algorithm (RMA) is employed to perform the numerical simulation. The results of the proposed integration procedure were implemented in ABAQUS using a UMAT user subroutine and validated by a comparison between experiments and finite element (FE) simulation. Various cyclic responses of the two prescribed models of FGM pipe for the two considered loading conditions are classified and brought together in one diagram known as Bree&rsquo, s diagram.