Lund Group Research Articles

Abstract IA03: Molecular subtypes of bladder cancer: Toward a more granular description of cancer heterogeneity

Abstract Whole-transcriptome mRNA expression profiling studies have established that muscle-invasive bladder cancers (MIBCs) can be subdivided into “basal/squamous” and “luminal” molecular subtypes that are associated with distinct biologic and clinical properties. In general, basal/squamous tumors tend to be more highly enriched in canonical cancer stem cell and epithelial-to-mesenchymal transition (EMT) biomarkers, and perhaps as a consequence, they are associated with advanced stage and metastatic disease at presentation. On the other hand, luminal tumors are enriched with breast cancer luminal biomarkers, peroxisome proliferator activator receptor (PPARG) expression and pathway activation, members of the miR-200 family of EMT repressors, and activating mutations and fusions targeting fibroblast growth factor receptor-3 (FGFR3). Past studies demonstrated that subsets of both basal and luminal MIBCs respond to neoadjuvant chemotherapy as measured by downstaging to <pT2 at cystectomy, although clinical benefit is greatest in patients with basal tumors, perhaps because they are associated with more subclinical metastatic disease. Completed phase II clinical trials employing small-molecule FGFR inhibitors have confirmed that some patients whose tumors contain activating mutations in FGFR3 obtain clinical benefit, confirming that FGFR3 is a viable target in luminal tumors. As the available datasets grow larger, it has become possible to further subdivide the basal/squamous and luminal tumors into additional molecular subtypes. A fraction of basal/squamous tumors lose expression of basal keratins, TP63, and E- and P-cadherins and exhibit molecular features of “complete” EMT. These tumors are similar to claudin-low breast cancers and appear to be more aggressive, exemplified in the observation that patients with claudin-low tumors fail to benefit from neoadjuvant chemotherapy. It appears likely that sarcomatoid tumors represent a phenotypic conversion to the extreme end of the EMT spectrum. Likewise, neuroendocrine and small cell bladder cancers also appear to evolve from basal/squamous tumors via mechanisms that involve combined inactivation of TP53 and RB1. Although the general determinants of basal/squamous molecular heterogeneity appear relatively straightforward, the extent of the heterogeneity that exists in luminal tumors is still emerging. The Lund group's overall dichotemization of luminal tumors into “genomically unstable” and “urothelial” is extremely attractive, but the determinants of heterogeneity within the urothelial tumors await definition. TCGA and the molecular subtypes consensus group identified a small but clinically aggressive luminal subtype that seems somewhat similar to carcinoma in situ (CIS), but precisely how it corresponds to the other luminal subtypes is also unclear. Finally, micropapillary tumors are enriched in luminal biomarkers and overexpression of ERBB2, but their biologic determinants are also unknown. Because non-muscle invasive bladder cancers (NMIBCs) are highly enriched with luminal tumors, it seems likely that the luminal subtypes will become more granular as larger NMIBC datasets are merged with the MIBCs. Citation Format: David J. McConkey, Woonyoung Choi, Colin P.N. Dinney, Arlene Siefker-Radtke, Bogdan Czerniak. Molecular subtypes of bladder cancer: Toward a more granular description of cancer heterogeneity [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA03.

Molecular subtypes of bladder cancer and first success in personalized treatment

In the literature review we described studies, the main purpose of which was to distribute bladder tumors by molecular subtypes. A similar classification has long been actively used in the treatment of breast cancer. The pioneering work in the molecular subtypes of bladder cancer includes the work by Lund group, the TCGA (The Cancer Genome Atlas) project, the MD Anderson study. We have also included data on attempts to apply molecular taxonomy of bladder cancer in treatment.

How to calculate α-decay rates in the future?

New elements discovered during past decades have been created in fusion reactions where a lighter nucleus is collided with a heavier one. The new elements created often decay by emitting α particles. From the half-lives of the decays and the energies of the emitted particles one may extract some properties of the new elements. In this talk the recent work performed by the Lund group to model α decay starting from nuclear density-functional theory is reviewed and a possible extension is mentioned.

Present role of PIXE in atmospheric aerosol research

In the 1980s and 1990s nearly half of the elemental analyses of atmospheric aerosol samples were performed by PIXE. Since then, other techniques for elemental analysis became available and there has been a steady increase in studies on organic aerosol constituents and other aspects of aerosols, especially in the areas of nucleation (new particle formation), optical properties, and the role of aerosol particles in cloud formation and properties. First, a brief overview and discussion is given of the developments and trends in atmospheric aerosol analysis and research of the past three decades. Subsequently, it is indicated that there is still invaluable work to be done by PIXE in atmospheric aerosol research, especially if one teams up with other aerosol researchers and performs complementary measurements, e.g., on small aerosol samples that are taken with high-time resolution. Fine examples of such research are the work done by the Lund group in the CARIBIC aircraft studies and the analysis of circular streaker samples by the Florence PIXE group. These and other examples are presented and other possibilities of PIXE are indicated.

Is CGRP a marker for chronic migraine?

Calcitonin gene-related peptide (CGRP) research was initiated by Poyner et al.,1 who found that the calcitonin gene encodes the 37–amino acid neuropeptide CGRP in neuronal tissue. Within months, the Lund group produced antibodies toward α-CGRP and developed sensitive methods to study the role of this peptide in the cranial circulation. Intracranial vessels and the trigeminal ganglion harbor this potent vasodilator peptide.2 Functionally, CGRP has a substantial role in the trigeminovascular reflex.3 The calcitonin family is now well-characterized and contains 6 members: calcitonin, amylin, adenomedullin-2, adrenomedullin, and CGRP (2 isoforms: α-CGRP and β-CGRP).4 The α- and β-isoforms of CGRP are similar in their biological activities but show different tissue distributions. β-CGRP is mainly found in enteric nerves and in the pituitary gland, while α-CGRP is found predominantly in sensory neurons and in the CNS.5 CGRP causes cranial vasodilatation and facilitates nociception. During a migraine attack, trigeminal activation results in the release of CGRP from presynaptic nerve terminals and induces vasodilatation and neurogenic inflammation in leptomeningeal and extracranial vessels, which gives rise to the typical throbbing pain of migraine. Goadsby and Edvinsson6 showed that plasma concentrations of CGRP are elevated in the external jugular venous blood during migraine headaches and that sumatriptan can abort the rise in CGRP and the headache.4 CGRP given IV causes headache only in migraine patients and CGRP antagonists are effective for the acute treatment of migraine.7 Until now, CGRP elevation in the plasma has not been reproduced in all studies.8 However, technical problems have sometimes hampered the proper measurements of CGRP.9

Which urinary diversion is best after radical cystectomy? The case for “incontinent” diversion

Which urinary diversion is best after radical cystectomy? The case for “incontinent” diversion

Systemic effects of carbon dioxide insufflation technique for de-airing in left-sided cardiac surgery

Systemic effects of carbon dioxide (CO2) insufflation during left-sided cardiac surgery were evaluated in a prospective randomized study, with regard to acid-base status, gas exchange, cerebral hemodynamics, and red blood cell morphology. Twenty patients undergoing elective left-sided cardiac surgery were randomized to de-airing procedure either by CO2 insufflation technique (CO2 group, n=10) or by Lund technique without CO2 insufflation (Lund group, n=10). Groups underwent assessment of acid-base status by intermittent arterial blood gases and in-line blood gas monitoring. Capnography was used to determine volume of CO2 produced. Cerebral hemodynamics was measured by transcranial Doppler sonography and near-infrared spectroscopy. Red cell morphology from cardiotomy suction and vent tubing was studied by scanning electron microscopy. Patients in the CO2 group consequently developed significantly higher levels of hypercapnia with a concomitant increase in the volume of CO2 produced despite significantly higher oxygenator gas flows compared with the Lund group. Effects on cerebral hemodynamics were observed in the CO2 group with significantly higher blood flow velocities in the middle cerebral artery and higher regional cerebral saturation. Red blood cell damage was observed in the CO2 group by scanning electron microscopy (97% in CO2 group vs 18% in Lund group). Insufflation of CO2 into the cardiothoracic wound cavity during left-sided cardiac surgery can induce hypercapnic acidosis and increased cerebral blood flow and local blood cell damage. These systemic effects should be monitored by in-line capnography and acid-base measurements for early and effective correction by increase in gas flows to the oxygenator.

Determination of lipoprotein lipase activity using a novel fluorescent lipase assay

A novel, real-time, homogeneous fluorogenic lipoprotein lipase (LPL) assay was developed using a commercially available substrate, the EnzChek lipase substrate, which is solubilized in Zwittergent. The triglyceride analog substrate does not fluoresce, owing to apposition of fluorescent and fluorescent quenching groups at the sn-1 and sn-2 positions, respectively, fluorescence becoming unquenched upon release of the sn-1 BODIPY FA derivative following hydrolysis. Increase in fluorescence intensity at 37°C was proportional to LPL concentration. The assay was more sensitive than a similar assay using 1,2-O-dilauryl-rac-glycero-3-glutaric acid-(6-methylresorufin ester) and was validated in biological samples, including determination of LPL-specific activity in postheparin mouse plasma. The simplicity and reproducibility of the assay make it ideal for in vitro, high-throughput screening for inhibitors and activators of LPL, thus expediting discovery of drugs of potential clinical value.

Application of Lund concept in treating brain edema after severe head injury

To explore if the new treatment with Lund concept could reduce the mortality of patients after severe brain injury. This study included 68 severe brain injury patients in whom Gloasgow coma score (GCS) was 3-8, and in 30 of them Lund concept was adopted, and the other 38 patients were taken care of by the conventional treatment in controlling intracranial pressure (ICP). Furthermore, in patients of the Lund group and control group ICP and cerebral perfusion pressure (CPP) were monitored continuously for 5 days. The amount of mannitol (g) used was markedly smaller in Lund group than that in the control group (139.6±25.0 vs. 587.5±31.8, P<0.01). The 28-day mortality of Lund group was significantly lower than that in control group (30.0% vs. 57.9%, P<0.05). In Lund group, the incidence of ICP exceeding 25 mm Hg (1 mm Hg=0.133 kPa) or 35 mm Hg or lowering of CPP by 50 mm Hg observed in the non-survivors (n=9) was greater than that observed in the survivors [n=21, (45.0±23.2)% vs. (7.2±3.6)%, (40.2±18.6)% vs. (2.2±1.6)%, (35.9±12.9)% vs. (3.1±2.4)%, all P<0.05]. By adopting the Lund concept, it is possible to reduce postoperative mortality after severe head injury.

Comparison of the effectiveness and safety of a new de-airing technique with a standardized carbon dioxide insufflation technique in open left heart surgery: A randomized clinical trial

We have compared the effectiveness, time required for de-airing, and safety of a newly developed de-airing technique for open left heart surgery (Lund technique) with a standardized carbon dioxide insufflation technique. Twenty patients undergoing elective open aortic valve surgery were randomized prospectively to the Lund technique (Lund group, n = 10) or the carbon dioxide insufflation technique (carbon dioxide group, n = 10). Both groups were monitored intraoperatively during de-airing and for 10 minutes after weaning from cardiopulmonary bypass by transesophageal echocardiography and online transcranial Doppler for the severity and the number of gas emboli, respectively. The systemic arterial partial pressure of carbon dioxide and pH were also monitored in both groups before, during, and after cardiopulmonary bypass. The severity of gas emboli observed on transesophageal echocardiography and the number of microembolic signals recorded by transcranial Doppler were significantly lower in the Lund group during the de-airing procedure (P = .00634) and in the first 10 minutes after weaning from cardiopulmonary bypass (P = .000377). Furthermore, the de-airing time was significantly shorter in the Lund group (9 vs 15 minutes, P = .001). The arterial pH during the cooling phase of cardiopulmonary bypass was significantly lower in the carbon dioxide group (P = .00351), corresponding to significantly higher arterial partial pressure of carbon dioxide (P = .005196) despite significantly higher gas flows (P = .0398) in the oxygenator throughout the entire period of cardiopulmonary bypass. The Lund de-airing technique is safer, simpler, and more effective compared with the carbon dioxide insufflation technique. The technique is also more cost-effective because the de-airing time is shorter and no extra expenses are incurred.

Bo Andersson

Bo Andersson

Fractal phase space as a diagnostic tool for high-energy multijet processes.

The fractal phase space introduced by the Lund group for the description of QCD multijet phenomena is discussed using a different choice of coordinates. We advocate these coordinates as a useful diagnostic tool in the analysis of complex event structures. Features of QCD such as color coherence or angular ordering, and the string effect, are described in this language.

Inelastic leptoproduction a la Lund

In the Lund Group, based upon a semiclassical treatment of the massless relativistic string (MRS) and coupled with experiences of e+e- annihilation reactions, the author has developed a model for inelastic leptoproduction. Although it does fit to all data from the EMC generation of experiments, the very large increase in the main dynamical variables at HERA energies will most certainly force one to be much more precise. Here is the present model, however, as it is implemented in the Monte Carlo programs ARIADNE, JETSET and LEPTO (the first two contain the main specific dynamics of the model).

Lepton-proton event simulation using the parton shower formalism with coherence effects in all branchings

A new parton shower event generator for lepton-hadron interactions is presented which includes coherence effects in both the time-like and space-like branchings. After comparison of the model with existing data from EMC, several predictions for the HERA experiments are made and a comparison with a similar Monte Carlo by the Lund group is shown. The two models are consistent, although there are slight differences which seem to originate partly from the reduced phase-space due to coherence in the space-like branching but mainly from the non-perturbative processes such as hadronisation.

The macrofluid concept versus the molecular mixture: A spin-echo-NMR study of the water/aerosol OT/Oil system

A recent study of the critical phenomena in macrofluidlike three-component microemulsions of the above-mentioned composition (1) showed the necessity to obtain more detailed information on the single components of the system. One of the most powerful techniques suited for this particular purpose is the wellestablished spin-echo-NMR method (2-4). Time-average values of self-diffusion coefficients of all the components, including new structural entities (with sufficiently long lifetimes compared to the typical time scale of this technique) can easily be determined. Interesting details of the system are inferred from the concentration and temperature-dependent self-diffusion coefficients which supplement our ideas on these systems. Thus we contribute results which are consistent with the view of other authors, in particular the Lund group (5, 6), and which help to settle the apparently still pending discussion regarding the reality of large, ordered structures. Actually, such structures have been already anticipated by Tolman (7) as early as 1913 for one-component fluids near their critical points. This comparison is appealing since the behavior of a binary fluid mixture which undergoes phase separation and a one-component macrofluid, which undergoes percolation, are, in many respects, closely analogous to the condensation of a simple gas (8). It is probably necessary to elucidate on this point. A simple binary mixture phase separation