Citations

AbstractThe development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes.

Purpose Exploration of the effect of chronic recurrent seizures in focal epilepsy on brain volumes has produced many conflicting reports. To determine differences in brain structure in temporal lobe epilepsy (TLE) and extratemporal epilepsy (using frontal lobe epilepsy (FLE) a surrogate) further, we performed a retrospective analysis of a large cohort of patients with seizure-onset zone proven by intracranial monitoring. Methods A total of 120 TLE patients, 86 FLE patients, and 54 healthy controls were enrolled in this study. An analysis of variance of voxel-based morphometry (VBM) was used to seek morphometric brain differences among TLE patients, FLE patients, and healthy controls. Additionally, a vertex-based surface analysis was utilized to analyze the hippocampus and thalamus. Significant side-specific differences in hippocampal gray matter volume were present between the left TLE (LTLE), right TLE RTLE (RTLE), and control groups ( p<0.05, family-wise error (FWE) corrected). Results Vertex analyses revealed significant volume reduction in inferior parts of the left hippocampus in the LTLE group and lateral parts of the right hippocampus in the RTLE group compared to controls ( p<0.05, FWE corrected). Significant differences were also detected between the LTLE and control group in the bilateral medial and inferior thalamus ( p<0.05, FWE corrected). FLE patients did not exhibit focal atrophy of gray matter across the brain. Conclusion Our results highlight the variation in morphometric lateralized changes in the brain between different epilepsy onset zones, providing critical insight into the natural history of people with drug-resistant focal epilepsies.

AbstractIn 2018, the American College of Sports Medicine (ACSM) reconvened an international, multi‐disciplinary group of professionals to review pertinent published literature on exercise for people with cancer. The 2018 roundtable resulted in the publication of three articles in 2019. The three articles serve as an important update to the original ACSM Roundtable on Cancer, which convened in 2010. Although the focus of the three 2019 articles is on exercise, which is only one part of comprehensive cancer rehabilitation, the evidence presented in the 2019 ACSM articles has direct implications for physiatrists and other rehabilitation professionals who care for people with cancer. As such, the narrative review presented here has two primary objectives. First, we summarize the evidence within the three ACSM articles and interpret it within a familiar rehabilitation framework, namely the Dietz model of Cancer Rehabilitation, in order to facilitate implementation broadly within rehabilitation practice. Second, via expert consensus, we have tabulated relevant exercise recommendations for specific cancer populations at different points in the cancer care continuum and translated them into text, tables, and figures for ease of reference. Notably, the authors of this article are members of the Cancer Rehabilitation Physician Consortium (CRPC), a group of physicians who subspecialize in cancer rehabilitation medicine (CRM).

Focal adhesion kinase (FAK) is a key signaling protein for integrin mediated cell migration. Auto phosphorylation of FAK at tyrosine‐397 is induced upon integrin activation, which then serves as a high affinity binding site for src tyrosine kinase forming a FAK‐src complex. Fak‐Src complex is a potent regulator of subsequent downstream signaling for enhanced cell migration. Using stable lines of SW480 colon carcinoma cells expressing integrin subunit α9, we explored the importance of the FAK‐Src complex in α9β1‐dependent cell migration. We found that ligand binding of α9β1 rapidly activated src tyrosine kinase; with concomitant tyrosine phosphorylation of FAK, p130Cas and Erk MAP kinase; inhibition of src tyrosine kinase or ErkMAP kinase activity decreased α9β1‐dependent cell migration. Surprisingly, activated α9β1 induced phosphorylation of iNOS resulting in NO production and associated NO‐mediated cell migration. Src tyrosine kinase appeared to signal upstream of iNOS, Erk, FAK and p130Cas as its inhibition blocked α9β1‐dependent tyrosine phosphorylation of these molecules. FAK binding to src was however not required for integrin α9β1 induced cell migration; and FAK inhibition (by siRNA) did not alter integrin α9β1 induced src activation and phosphorylation of Erk, p130Cas, iNOS. Analysis of Chinese Hamester Overian cells that expressed intact or mutant forms of integrin α9‐subunit showed that the α9‐cytoplasmic domain was critical for α9β1 induced src tyrosine kinase activation, downstream signaling events and ultimately cell migration. Taken together these results suggest that src, in a FAK independent manner, serves as a key early signaling protein for α9β1‐dependent cell migration; it is activated at the α9 ‐cytoplasmic domain and subsequently initiates multiple signaling intermediates, including NO, to induce cell migration.

Introduction: Although alterations in mitochondrial function have been observed in senescent hearts, the molecular basis for aging-associated decline in energy metabolism in the human heart is not fully understood. Objective: To determine aging-related changes in functional activity and protein expression level of mitochondrial oxidative phosphorylation (OXPHOS) complexes and expression of genes regulating mitochondrial energetics in the human heart. Methods: Right atrial appendages from well-matched adult (29-57 y.o., n=19) and aged (65-85 y.o., n=22) patients undergoing elective CABG surgery were used. Functional activity of OXPHOS complexes was measured spectrophotometrically. Protein expression level of corresponding OXPHOS protein subunits was determined by Western blot. Gene expression profiling was performed using Affymetrix Human Genome U133 Plus 2.0 microarrays. Results: Mitochondria from senescent hearts demonstrated a significant decrease in complex I and V functional activity without significant changes in the rest of the complexes (Fig. A). At the protein expression level, there was reduction in complex I, III, and IV (Fig. B). This was associated with downregulation of the majority (86%, 90 of 105) of genes coding mitochondrial proteins (Fig. C). Forty-six percent (41 of 90) of the downregulated genes were confined to pathways regulating mitochondrial energetics. Conclusion: With aging, the functional activity of OXPHOS is reduced due to supression of protein expression and downregulation of genes regulating mitochondrial energetics. This provides a substrate for reduced energetic efficiency associated with senescence in the human atria.

Beta‐1 integrins are important mediators of cell migration but may do so through different signaling mechanisms. However, c‐src‐activation seems to be a key signaling intermediate. Nitric oxide (NO) synthesis is another novel molecule that modulates cell migration, which may be utilized during integrin mediated cell migration. We used α9 expressing SW480 colon carcinoma cells, to explore a role for src and NO in α9β1 mediated‐cell migration. We found that α9β1‐ligation leads to c‐Src phosphorylation (Tyr‐416) and Erk MAP kinase phosphorylation; phospho‐c‐src was maximum at 5 min, and phospho‐Erk maxima was at 20min. Pre‐treated cells with src and Erk kinase inhibitors, PP1 and PD98059, inhibited α9‐dependent cell motility. c‐src appeared to signal upstream of Erk since inhibition of c‐Src‐kinase blocked Erk phosphorylation. Furthermore, α9β1‐ligation enhanced NO synthesis through activation of inducible Nitric Oxide Synthase (iNOS), which was constitutively expressed in SW480 cells. Using the NO specific inhibitor L‐NAME, α9β1‐dependent cell migration was blocked. Also, enhanced iNOS phosphorylation and NO production were src kinase (but not Erk) dependent. These results suggest a novel signaling pathway for α9β1‐induced cell migration through c‐src kinase activation of iNOS and subsequent NO production.

SummaryBackgroundGastroparesis is a chronic gastric motility disorder. Dopamine D2/D3 receptor antagonists metoclopramide and domperidone are current treatment options but are associated with central nervous system and cardiovascular safety concerns, respectively, precluding chronic use. Trazpiroben (TAK‐906), a dopamine D2/D3 receptor antagonist, is under development for chronic treatment of moderate‐to‐severe gastroparesis. Nonclinical data suggest trazpiroben will have D2/D3 receptor antagonism comparable with metoclopramide or domperidone.AimsTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics (effect on prolactin and gastric function) of twice‐daily trazpiroben (5, 25 and 100 mg) in participants with gastroparesis.MethodsThis phase 2a pilot study evaluated gastric emptying using the gastric emptying breath test, with metoclopramide as an internal control. Gastric accommodation and gastroparesis symptoms were assessed using the nutrient drink test and American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index‐Daily Diary, respectively.ResultsOverall, 51 participants were enrolled. Trazpiroben was well tolerated, demonstrating a favourable safety profile without cardiovascular or central nervous system adverse events. All trazpiroben doses were rapidly absorbed and eliminated (t1/2z 4‐5 hours), and D2/D3 receptor target engagement confirmed by increased serum prolactin (peaking at trazpiroben 25 mg). No effect on gastric emptying was demonstrated with trazpiroben or metoclopramide (P > 0.05), although benefits in volume‐to‐fullness were seen at trazpiroben 5 mg (P > 0.05) and 25 mg (88.5 vs −26.3 mL; P = 0.019), and nonsignificant numerical aggregate symptom score improvements were observed with trazpiroben 25 mg vs placebo (P = 0.182).ConclusionsTrazpiroben was well tolerated with a favourable safety profile, supporting its further development for the treatment of gastroparesis. ClinicalTrials.gov identifier: NCT03268941.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.

Real-time RT-PCR is considered the gold standard confirmatory test for coronavirus disease 2019 (COVID-19). However, many scientists disagree, and it is essential to understand that several factors and variables can cause a false-negative test. In this context, cycle threshold (Ct) values are being utilized to diagnose or predict SARS-CoV-2 infection. This practice has a significant clinical utility as Ct values can be correlated with the viral load. In addition, Ct values have a strong correlation with multiple haematological and biochemical markers. However, it is essential to consider that Ct values might be affected by pre-analytic, analytic, and post-analytical variables such as collection technique, specimen type, sampling time, viral kinetics, transport and storage conditions, nucleic acid extraction, viral RNA load, primer designing, real-time PCR efficiency, and Ct value determination method. Therefore, understanding the interpretation of Ct values and other influential factors could play a crucial role in interpreting viral load and disease severity. In several clinical studies consisting of small or large sample sizes, several discrepancies exist regarding a significant positive correlation between the Ct value and disease severity in COVID-19. In this context, a revised review of the literature has been conducted to fill the knowledge gaps regarding the correlations between Ct values and severity/fatality rates of patients with COVID-19. Various databases such as PubMed, Science Direct, Medline, Scopus, and Google Scholar were searched up to April 2021 by using keywords including “RT-PCR or viral load”, “SARS-CoV-2 and RT-PCR”, “Ct value and viral load”, “Ct value or COVID-19”. Research articles were extracted and selected independently by the authors and included in the present review based on their relevance to the study. The current narrative review explores the correlation of Ct values with mortality, disease progression, severity, and infectivity. We also discuss the factors that can affect these values, such as collection technique, type of swab, sampling method, etc.