Towards Stratified Medicine in Plasma Cell Myeloma

Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further targeted therapies currently in clinical trials. Whilst treatment decisions are mostly based on a patient’s age, fitness, including the presence of co-morbidities, and tumour burden, significant scope exists for better risk stratification, sub-classification of disease, and predictors of response to specific therapies. Clinical staging, recurring acquired cytogenetic aberrations, and serum biomarkers such as β-2 microglobulin, and free light chains are in widespread use but often fail to predict the disease progression or inform treatment decision making. Recent scientific advances have provided considerable insight into the biology of myeloma. For example, gene expression profiling is already making a contribution to enhanced understanding of the biology of the disease whilst Next Generation Sequencing has revealed great genomic complexity and heterogeneity. Pathways involved in the oncogenesis, proliferation of the tumour and its resistance to apoptosis are being unravelled. Furthermore, knowledge of the tumour cell surface and its interactions with bystander cells and the bone marrow stroma enhance this understanding and provide novel targets for cell and antibody-based therapies. This review will discuss the development in understanding of the biology of the tumour cell and its environment in the bone marrow, the implementation of new therapeutic options contributing to significantly improved outcomes, and the progression towards more personalised medicine in this disorder

An exact sequence for contact- and symplectic homology

A symplectic manifold $W$ with contact type boundary $M = \partial W$ induces a linearization of the contact homology of $M$ with corresponding linearized contact homology $HC(M)$. We establish a Gysin-type exact sequence in which the symplectic homology $SH(W)$ of $W$ maps to $HC(M)$, which in turn maps to $HC(M)$, by a map of degree -2, which then maps to $SH(W)$. Furthermore, we give a description of the degree -2 map in terms of rational holomorphic curves with constrained asymptotic markers, in the symplectization of $M$.Comment: Final version. Changes for v2: Proof of main theorem supplemented with detailed discussion of continuation maps. Description of degree -2 map rewritten with emphasis on asymptotic markers. Sec. 5.2 rewritten with emphasis on 0-dim. moduli spaces. Transversality discussion reorganized for clarity (now Remark 9). Various other minor modification

Intersections of quadrics, moment-angle manifolds, and Hamiltonian-minimal Lagrangian embeddings

We study the topology of Hamiltonian-minimal Lagrangian submanifolds N in C^m constructed from intersections of real quadrics in a work of the first author. This construction is linked via an embedding criterion to the well-known Delzant construction of Hamiltonian toric manifolds. We establish the following topological properties of N: every N embeds as a submanifold in the corresponding moment-angle manifold Z, and every N is the total space of two different fibrations, one over the torus T^{m-n} with fibre a real moment-angle manifold R, and another over a quotient of R by a finite group with fibre a torus. These properties are used to produce new examples of Hamiltonian-minimal Lagrangian submanifolds with quite complicated topology.Comment: 14 pages, published version (minor changes

From pelvic radiation to social isolation: a qualitative study of survivors’ experiences of chronic bowel symptoms after pelvic radiotherapy

\ua9 2024, The Author(s).Purpose: We explored survivors’ experiences of chronic bowel symptoms following pelvic radiotherapy, strategies employed in living with these symptoms, effects on daily activities, and roles at home and in the workplace. Methods: Semi-structured interviews were conducted with 28 individuals (10 gynaecological, 14 prostate, four anal/rectal cancer survivors) who had completed pelvic radiotherapy at least six months prior to data collection and who had experience of bowel symptoms during this post-treatment period. Reflexive thematic analysis was undertaken. Results: We propose four themes describing a process leading from experience of symptoms to withdrawal from activities and roles. These are (1) losing control (the experience of unintended anal leakage or discharge); (2) experiencing embarrassment and fear (the experience of embarrassment or fear of embarrassment as a result of discharge becoming public); (3) managing and reacting (acting to reduce the likelihood of discharge or to prevent this becoming public); and (4) restriction and withdrawal (avoiding specific activities or situations so as to reduce or remove the risk of embarrassment). Returning to the workplace presented additional challenges across these themes. Conclusions: Impacts of chronic bowel symptoms can be severe. Survivors employ a variety of methods and strategies in living with their symptoms. Some of these support continued role fulfilment but some constitute a withdrawal from pre-treatment roles. Current healthcare provision and statutory protections fail to fully meet needs following pelvic radiotherapy. Implications for cancer survivors. There is a need to develop and implement evidence-based services and supported self-management programmes for survivors experiencing chronic bowel problems post-radiotherapy

Marginal Deformations of Field Theories with AdS_4 Duals

We generate new AdS_4 solutions of D=11 supergravity starting from AdS_4 x X_7 solutions where X_7 has U(1)^3 isometry. We consider examples where X_7 is weak G_2, Sasaki-Einstein or tri-Sasakian, corresponding to d=3 SCFTs with N=1,2 or 3 supersymmetry, respectively, and where the deformed solutions preserve N=1,2 or 1 supersymmetry, respectively. For the special cases when X_7 is M(3,2), Q(1,1,1) or N(1,1)_I we identify the exactly marginal deformation in the dual field theory. We also show that the volume of supersymmetric 5-cycles of N(1,1)_I agrees with the conformal dimension predicted by the baryons of the dual field theory.Comment: 28 pages, 2 figures; v2. typos correcte

Vacuum interpolation in supergravity via super p-branes

We show that many of the recently proposed supersymmetric p-brane solutions of d=10 and d=11 supergravity have the property that they interpolate between Minkowski spacetime and a compactified spacetime, both being supersymmetric supergravity vacua. Our results imply that the effective worldvolume action for small fluctuations of the super p-brane is a supersingleton field theory for $(adS)_{p+2}$, as has been often conjectured in the past.Comment: 8p

Transfer of noncoding DNA drives regulatory rewiring in bacteria

Understanding the mechanisms that generate variation is a common pursuit unifying the life sciences. Bacteria represent an especially striking puzzle, because closely related strains possess radically different metabolic and ecological capabilities. Differences in protein repertoire arising from gene transfer are currently considered the primary mechanism underlying phenotypic plasticity in bacteria. Although bacterial coding plasticity has been extensively studied in previous decades, little is known about the role that regulatory plasticity plays in bacterial evolution. Here, we show that bacterial genes can rapidly shift between multiple regulatory modes by acquiring functionally divergent nonhomologous promoter regions. Through analysis of 270,000 regulatory regions across 247 genomes, we demonstrate that regulatory “switching” to nonhomologous alternatives is ubiquitous, occurring across the bacterial domain. Using comparative transcriptomics, we show that at least 16% of the expression divergence between Escherichia coli strains can be explained by this regulatory switching. Further, using an oligonucleotide regulatory library, we establish that switching affects bacterial promoter architecture. We provide evidence that regulatory switching can occur through horizontal regulatory transfer, which allows regulatory regions to move across strains, and even genera, independently from the genes they regulate. Finally, by experimentally characterizing the fitness effect of a regulatory transfer on a pathogenic E. coli strain, we demonstrate that regulatory switching elicits important phenotypic consequences. Taken together, our findings expose previously unappreciated regulatory plasticity in bacteria and provide a gateway for understanding bacterial phenotypic variation and adaptation.National Science Foundation (U.S.) (Grant DEB-0936234

On BPS preons, generalized holonomies and D=11 supergravities

We develop the BPS preon conjecture to analyze the supersymmetric solutions of D=11 supergravity. By relating the notions of Killing spinors and BPS preons, we develop a moving G-frame method (G=GL(32,R), SL(32,R) or Sp(32,R)) to analyze their associated generalized holonomies. As a first application we derive here the equations determining the generalized holonomies of k/32 supersymmetric solutions and, in particular, those solving the necessary conditions for the existence of BPS preonic (31/32) solutions of the standard D=11 supergravity. We also show that there exist elementary preonic solutions, i.e. solutions preserving 31 out of 32 supersymmetries in a Chern--Simons type supergravity. We present as well a family of worldvolume actions describing the motion of pointlike and extended BPS preons in the background of a D'Auria-Fre type OSp(1|32)-related supergravity model. We discuss the possible implications for M-theory.Comment: 11 pages, RevTeX Typos corrected, a short note and references adde

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up

In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan–Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- an