The Peptide–Drug Conjugate Melflufen Modulates the Unfolded Protein Response of Multiple Myeloma and Amyloidogenic Plasma Cells and Induces Cell Death

Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by clonal plasma cell secretion of misfolded light chains that assemble as toxic amyloid fibrils, depositing in vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell–directed therapeutics are expected to reduce production of toxic light chain by eliminating amyloidogenic cells in bone marrow, thereby diminishing amyloid fibril deposition and providing the potential for organ recovery. Melphalan flufenamide (melflufen) is a first-in-class peptide–drug conjugate that targets aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen is highly lipophilic, permitting rapid uptake by cells, where it is enzymatically hydrolyzed by aminopeptidases, resulting in intracellular accumulation of the alkylating agents, including melphalan. Previous data demonstrating sensitivity of myeloma cells to melflufen suggest that the drug might be useful in AL amyloidosis. We describe the effects of melflufen on amyloidogenic plasma cells in vitro and ex vivo, demonstrating enhanced cytotoxic effects in comparison to melphalan, as well as novel mechanisms of action through the unfolded protein response (UPR) pathway. These findings provide evidence that melflufen-mediated cytotoxicity extends to amyloidogenic plasma cells, and support the rationale for the evaluation of melflufen in patients with AL amyloidosis.Peer reviewe

The Vehicle, Fall 1982

Vol. 24, No. 1 Table of Contents Winter SurveillanceB.L. Davidsonpage 3 The InvitationBecky Lawsonpage 4 Check In, Check OutSteve Sandstrompage 4 On The Front Porch StepKeila Tooleypage 5 Old Greek ManDevon Flesorpage 5 Exotic PassionsBecky Lawsonpage 6 PhotographLisa Owenspage 7 Beyond The ThornsBrook Wilsonpage 8 Ritual Of HeatB.L. Davidsonpage 11 The GamerBecky Lawsonpage 12 It\u27s OverKeila Tooleypage 13 DreamJohn Stockmanpage 14 Silver DollarGina J. Grillopage 15 The DancerJessica Lewispage 16 Snapshots Of Rural IllinoisIsabel M. Parrottpage 16 The Last SeasonTheresa Whitesidepage 17 DrawingKaren Haneypage 17 Rotary LuncheonJessica Lewispage 18 Factory TourLinda Fraembspage 18 The ImmigrantsD.L. Lewispage 19 At Shedd AquariumLinda Fraembspage 20 The GuardianBecky Lewispage 20 Digital LifeEverett Tackettpage 21 Full ServiceScott Graypage 22 Dust ShowLinda A. Brownpage 23 At SixMaureen Foertschpage 24 DrawingJean Imherrpage 24 ReflectionMaggie Kennedypage 25 Cat DefiningBecky Lawsonpage 26 Ode To An Unread NewspaperLinda Fraembspage 26 GumSteve Sandstrompage 27 The DancerChrystal Clarkpage 27 PoemD.L. Lewispage 28 For LucyStacey Flanniganpage 29 An AbortionDevon Flesorpage 29 ReveriesKeila Tooleypage 30 Sunday Morning After Tequila With LemonScott Graypage 33 Staging A Living Jewel BoxMichelle Mitchellpage 34 The Other WomanStacey Flanniganpage 35 The Natural LookMichelle Mitchellpage 35 Poem To A Girl Named SandalsJohn Stockmanpage 36 PhotographLisa Owenspage 37 In The Balcony Of The Bijou On A Saturday NightScott Graypage 38 The Canadian Soccer PlayerBecky Lawsonpage 39 The HealingJohn Stockmanpage 39 AppeasedDevon Flesorpage 40 CodaJohn Stockmanpage 40https://thekeep.eiu.edu/vehicle/1040/thumbnail.jp

Contrasting Patterns of Transposable Element Insertions in Drosophila Heat-Shock Promoters

The proximal promoter regions of heat-shock genes harbor a remarkable number of P transposable element (TE) insertions relative to both positive and negative control proximal promoter regions in natural populations of Drosophila melanogaster. We have screened the sequenced genomes of 12 species of Drosophila to test whether this pattern is unique to these populations. In the 12 species' genomes, transposable element insertions are no more abundant in promoter regions of single-copy heat-shock genes than in promoters with similar or dissimilar architecture. Also, insertions appear randomly distributed across the promoter region, whereas insertions clustered near the transcription start site in promoters of single-copy heat-shock genes in D. melanogaster natural populations. Hsp70 promoters exhibit more TE insertions per promoter than all other genesets in the 12 species, similarly to in natural populations of D. melanogaster. Insertions in the Hsp70 promoter region, however, cluster away from the transcription start site in the 12 species, but near it in natural populations of D. melanogaster. These results suggest that D. melanogaster heat-shock promoters are unique in terms of their interaction with transposable elements, and confirm that Hsp70 promoters are distinctive in TE insertions across Drosophila

LGBTQ parenting post heterosexual relationship dissolution

The chapter examines parenting among sexual and gender minorities post heterosexual relationship dissolution (PHRD). Reviewing the literature around intersecting identities of LGBTQ parents, we consider how religion, race, and socioeconomic status are associated with routes into and out of heterosexual relationships and variation in the lived experience of sexual and gender identity minorities, in particular how LGBTQ parents PHRD feel about being out. Further consideration is given to examining how family relationships change and develop as parental sexual and/or gender identity changes. We also explore the impact of PHRD identity and parenthood on new partnerships and stepfamily experiences. The chapter addresses the reciprocal relationship between research on LGBTQ parenting and policy and legal influences that impact upon the experience of LGBTQ parenting PHRD when custody and access are disputed. Finally, the chapter includes future research directions and implications for practice in an area that has been revitalized in recent years

Numerical studies of flow over a sill: sensitivity of the non-hydrostatic effects to the grid size

A non-hydrostatic terrain-following model in cross sectional form is applied to study the processes in the lee of a sill in an idealized stratified fjord during super-critical tidal inflow. A sequence of numerical studies with horizontal grid sizes in the range from 100 to 1.5625 m are performed. All experiments are repeated using both hydrostatic and non-hydrostatic versions of the model, allowing a systematic study of possible non-hydrostatic pressure effects and also of the sensitivity of these effects to the horizontal grid size. The length scales and periods of the internal waves in the lee of the sill are gradually reduced and the amplitudes of these waves are increased as the grid size is reduced from 100 down to 12.5 m. With a further reduction in grid size, more short time and space scale motions become superimposed on the internal waves. Associated with the internal wave activity, there is a deeper separation point that is fairly robust to all parameters investigated. Another separation point nearer to the top of the sill appears in the numerical results from the high-resolution studies with the non-hydrostatic model. Associated with this shallower separation point, an overturning vortex appears in the same set of numerical solutions. This vortex grows in strength with reduced grid size in the non-hydrostatic experiments. The effects of the non-hydrostatic pressure on the velocity and temperature fields grow with reduced grid size. In the experiments with horizontal grid sizes equal to 100 or 50 m, the non-hydrostatic pressure effects are small. For smaller grid sizes, the time mean velocity and temperature fields are also clearly affected by the non-hydrostatic pressure adjustments

Law and LGBQ-Parent Families

This paper addresses how the law affects LGBQ-parent families. We first outline the legal landscape that LGBQ parents face in the US, underscoring that it varies drastically by state and creates inequity for families. Reviewing existing social science research, we then address how the law affects three processes for LGBQ people: desiring parenthood, becoming a parent, and experiencing parent- hood. Our review indicates that the law affects if and how LGBQ people become parents. LGBQ people consider the law as they make decisions about whether to pursue adoption, donor insemination, or surrogacy and often view the latter two pathways as the most legally secure. Further, the law continues to be salient for LGBQ parents throughout parenthood and affects family well-being. Specifically, legal inequity diminishes parent’s well-being, the relationship among couples who are parenting, and parents’ ability to effectively advocate for their children in institutional settings like healthcare contexts. Finally, we address directions for future research for scholars interested in the law, family processes and outcomes, and LGBQ families