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1.
Br J Haematol ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33822368

RESUMO

In the phase 3 POLLUX trial, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival in patients with relapsed/refractory multiple myeloma (RRMM) compared with lenalidomide and dexamethasone (Rd) alone. Here, we present patient-reported outcomes (PROs) from POLLUX, assessed using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaires. Changes from baseline are presented as least-squares mean changes with 95% confidence intervals (CIs) derived from a mixed-effects model. PRO assessment compliance rates were high and similar in both D-Rd and Rd groups through cycle 40 (week 156). In this on-treatment analysis, mean changes from baseline were significantly greater in EORTC QLQ-C30 global health status, physical functioning, and pain scores in the D-Rd group versus the Rd group at multiple time points; however, magnitude of changes was low, suggesting no meaningful impact on health-related quality of life (HRQoL). Subgroup results were similar to those in the overall population. In the POLLUX study, baseline HRQoL was maintained with prolonged D-Rd treatment. These findings complement the sustained and significant improvement in progression-free survival observed with D-Rd and supports its use in patients with RRMM. Clinical trial registration: NCT02076009.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33807454

RESUMO

This study aimed to evaluate the impact of the Coronavirus Disease 2019 (COVID-19) pandemic on out-of-hospital cardiac arrest (OHCA) in Singapore. We used data from the Singapore Civil Defence Force to compare the incidence, characteristics and outcomes of all Emergency Medical Services (EMS)-attended adult OHCA during the pandemic (January-May 2020) and pre-pandemic (January-May 2018 and 2019) periods. Pre-hospital return of spontaneous circulation (ROSC) was the primary outcome. Binary logistic regression was used to calculate the adjusted odds ratios (aOR) for the characteristics of OHCA. Of the 3893 OHCA patients (median age 72 years, 63.7% males), 1400 occurred during the pandemic period and 2493 during the pre-pandemic period. Compared with the pre-pandemic period, OHCAs during the pandemic period more likely occurred at home (aOR: 1.48; 95% CI: 1.24-1.75) and were witnessed (aOR: 1.71; 95% CI: 1.49-1.97). They received less bystander CPR (aOR: 0.70; 95% CI: 0.61-0.81) despite 65% of witnessed arrests by a family member, and waited longer for EMS (OR ≥ 10 min: 1.71, 95% CI 1.46-2.00). Pre-hospital ROSC was less likely during the pandemic period (aOR: 0.67; 95% CI: 0.53-0.84). The pandemic saw increased OHCA incidence and worse outcomes in Singapore, likely indirect effects of COVID-19.


Assuntos
Reanimação Cardiopulmonar , Serviços Médicos de Emergência , Parada Cardíaca Extra-Hospitalar , Adulto , Idoso , Feminino , Humanos , Masculino , Parada Cardíaca Extra-Hospitalar/epidemiologia , Singapura/epidemiologia
3.
Pediatr Nephrol ; 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712863

RESUMO

Kidney failure, one of the most prevalent diseases in the world and with increasing incidence, is associated with substantial morbidity and mortality. Currently available modes of kidney replacement therapy include dialysis and kidney transplantation. Though kidney transplantation is the preferred and ideal mode of kidney replacement therapy, this modality, however, is not without its risks. Kidney transplant recipients are constantly at risk of complications associated with immunosuppression, namely, opportunistic infections (e.g., Epstein-Barr virus and cytomegalovirus infections), post-transplant lymphoproliferative disorder, and complications associated with immunosuppressants (e.g., calcineurin inhibitor- and corticosteroid-associated new onset diabetes after transplantation and calcineurin inhibitor-associated nephrotoxicity). Transplantation tolerance, an acquired state in which immunocompetent recipients have developed donor-specific unresponsiveness, may be the Holy Grail in enabling optimal allograft survival and obviating the risks associated with immunosuppression in kidney transplant recipients. This review aims to discuss the biomarkers available to predict, identify, and define the transplant immune tolerant state and various tolerance induction strategies. Regrettably, pediatric patients have not been included in any tolerance studies and this should be the focus of future studies.

4.
Anal Chem ; 93(12): 5114-5122, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33749243

RESUMO

The in situ glycan profiling of a single tumor cell plays an important role in personalized cancer treatment. Herein, an integrated microfluidic system was designed for living single-cell trapping and real-time monitoring of galactosyl expression on the surface, combining closed bipolar electrode (BPE) arrays and electrofluorochromic (EFC) imaging. Galactosyl groups on human liver cancer HepG2 cells were used as the model analysts, galactose oxidase (GAO) could selectively oxidize hydroxyl sites of galactosyl groups on the cell surface to aldehydes, and then biotin hydrazide (BH) was used to label the aldehydes by aniline-catalyzed hydrazone ligation. With the biotin-avidin system, nanoprobes were finally introduced to the galactosyl groups on the cell surface with avidin as a bridge, which was prepared by simultaneously assembling ferrocene-DNA (Fc-DNA) and biotin-DNA (Bio-DNA) on gold nanoparticles (AuNPs) due to their large surface area and excellent electrical conductivity. After a labeled single cell was captured in the anodic microchannel, the Fc groups attached on the cell surface were oxidized under suitable potential, and the nonfluorescent resazurin on the cathode was correspondingly reduced to produce highly fluorescent resorufin, collected by fluorescence confocal microscope. The combination of EFC imaging and BPE realized monitoring galactosyl group expression of 5.0 × 108 molecules per cell. Furthermore, the proposed platform had the ability to distinguish a single cancer cell from a normal cell according to the expression level of galactosyl groups and to dynamically monitor the galactosyl group variation on the cell surface, providing a simple and accessible method for the single-cell analysis.

5.
Br J Haematol ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33555030

RESUMO

In the phase III CASTOR trial, daratumumab, bortezomib and dexamethasone (D-Vd) significantly extended progression-free survival compared with bortezomib and dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Here, we present patient-reported outcomes (PROs) from the CASTOR trial. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system questionnaire. Treatment effects through Cycle 8 were measured by a repeated measures mixed-effects model. After Cycle 8, PROs were only collected for patients in the D-Vd group who continued on daratumumab monotherapy. Compliance rates for PRO assessments were high and similar between treatment groups. Mean changes from baseline were generally similar between treatment groups for EORTC QLQ-C30 global health status (GHS), functioning and symptoms, and did not exceed 10 points for either treatment group. Subgroup analyses were consistent with the results observed in the overall population. There was no change in patients' health-related quality of life for the first eight cycles of therapy; thereafter, patients treated with daratumumab over the long-term reported improvements in GHS and pain. These results complement the significant clinical benefits observed with D-Vd in patients with RRMM and support its use in this patient population.

6.
Acta Pharmacol Sin ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608672

RESUMO

RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth. However, monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness. Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation. In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation) on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo. A combination of lovastatin (>3.75 µM) and 2-deoxy-D-glucose (>1.25 mM) synergistically reduced cell viability, arrested cells in the G2/M phase, and induced apoptosis. The combined treatment also reduced cellular oxygen consumption and extracellular acidification rate, resulting in decreased production of ATP and lower steady-state ATP levels. Energy depletion markedly activated AMPK, inhibited mTOR and RAS signaling pathways, eventually inducing autophagy, the cellular pro-survival process under metabolic stress, whereas inhibition of autophagy by chloroquine (6.25 µM) enhanced the cytotoxic effect of the combination of lovastatin and 2-deoxy-D-glucose. These in vitro experiment results were reproduced in a nude mouse xenograft model of HCT116 cells. Our findings suggest that concurrently targeting glycolysis, oxidative phosphorylation, and autophagy may be a promising regimen for the management of RAS-driven colorectal cancers.

7.
Ann Hematol ; 100(4): 1065-1077, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33599794

RESUMO

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03-185.00%) and 148.02% (90% CI, 113.32-193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Mieloma Múltiplo/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Grupo com Ancestrais do Continente Asiático/psicologia , Peso Corporal , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Injeções Subcutâneas , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/etnologia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Neutropenia/induzido quimicamente , Satisfação do Paciente , Intervalo Livre de Progressão , República da Coreia/epidemiologia , Taiwan/epidemiologia , Adulto Jovem
8.
J Clin Oncol ; 39(10): 1139-1149, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513030

RESUMO

PURPOSE: In relapsed and/or refractory multiple myeloma, daratumumab reduced the risk of progression or death by > 60% in POLLUX (daratumumab/lenalidomide/dexamethasone [D-Rd]) and CASTOR (daratumumab/bortezomib/dexamethasone [D-Vd]). Minimal residual disease (MRD) is a sensitive measure of disease control. Sustained MRD negativity and outcomes were evaluated in these studies. METHODS: MRD was assessed via next-generation sequencing (10-5) at suspected complete response (CR), 3 and 6 months following confirmed CR (POLLUX), 6 and 12 months following the first dose (CASTOR), and every 12 months post-CR in both studies. Sustained MRD negativity (≥ 6 or ≥ 12 months) was evaluated in the intention-to-treat (ITT) and ≥ CR populations. RESULTS: The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD-negativity rates were 32.5% versus 6.7% for D-Rd versus lenalidomide and dexamethasone (Rd) and 15.1% versus 1.6% for D-Vd versus bortezomib and dexamethasone (Vd; both P < .0001). Higher MRD negativity rates were achieved in ≥ CR patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%; P = .0001) and CASTOR (D-Vd, 52.8%; Vd, 17.4%; P = .0035). More patients in the ITT population achieved sustained MRD negativity ≥ 6 months with D-Rd versus Rd (20.3% v 2.1%; P < .0001) and D-Vd versus Vd (10.4% v 1.2%; P < .0001), and ≥ 12 months with D-Rd versus Rd (16.1% v 1.4%; P < .0001) and D-Vd versus Vd (6.8% v 0%). Similar results for sustained MRD negativity were observed among ≥ CR patients. More patients in the daratumumab-containing arms achieved MRD negativity and sustained MRD negativity, which were associated with prolonged progression-free survival. CONCLUSION: Daratumumab-based combinations induce higher rates of sustained MRD negativity versus standard of care, which are associated with durable remissions and prolonged clinical outcomes.

10.
Med Hypotheses ; 144: 110263, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33254568

RESUMO

In recent months, there are increasing reports of a Kawasaki disease-like syndrome in children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), termed 'Paediatric Multisystem Inflammatory Syndrome temporally associated with SARS-CoV-2 (PIMS-TS)' in the UK. Debate is ongoing regarding the nature of these pro-inflammatory syndromes. We herein propose that the platelet count may, at least in part, be able to help us differentiate between the two aforementioned syndromes. In a recent report, compared to a historical 'classical' Kawasaki disease (KD) cohort, patients with PIMS-TS had significantly lower platelet counts (188 vs 383 g/L, p < 0.0001). A possible explanation for this is their difference in underlying immunopathogenesis. In KD, the fundamental pathogenesis is thought to be immune complex-mediated, hence, the use of intravenous immunoglobulin (IVIg) which competes with the immunoglobulin Fc receptors (FcRs) on inflammatory cells, preventing the activation of these cells and thereby ameliorating the inflammatory response. If left untreated, these immune complexes activates the inflammatory cells (including monocytes and neutrophils), which also results in recruitment of platelets, resulting in the thrombocytosis we commonly see in KD. These immune complexes may also bind to platelets directly via FcRs on platelet membranes. In contrast, in viral-associated hyperinflammatory syndromes (e.g. PIMS-TS or MIS-C), there are mediators being secreted in the process of eradication of the virus (mainly to stimulate CD8+ cells to kill viral infected cells), which would inadvertently suppress bone marrow function and activate platelets, culminating in thrombocytopenia.

11.
Med Hypotheses ; : 110417, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33277107
13.
BMC Genomics ; 21(1): 886, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33308160

RESUMO

BACKGROUND: Ophiocordyceps sinensis is an important traditional Chinese medicine for its comprehensive active ingredients, such as cordycepin, cordycepic acid, and Cordyceps polysaccharide. O. sinensis zjut, a special strain isolated from O. sinensis, has similar pharmacological functions to wild O. sinensis. Currently, O. sinensis with artificial cultivation has been widely studied, but systematic fundamental research at protein levels has not been determined. RESULTS: Proteomes of O. sinensis zjut at different culture periods (growth period, 3rd day; pre-stable period, 6th day; and stable period, 9th day) were relatively quantified by relative isotope markers and absolute quantitative technology. In total, 4005 proteins were obtained and further annotated with Gene Ontology, Kyoto Encyclopedia of Genes and Genomes database. Based on the result of the annotations, metabolic pathways of active ingredients, amino acids and fatty acid were constructed, and the related enzymes were exhibited. Subsequently, comparative proteomics of O. sinensis zjut identified the differentially expressed proteins (DEPs) by growth in different culture periods, to find the important proteins involved in metabolic pathways of active ingredients. 605 DEPs between 6d-VS-3d, 1188 DEPs between 9d-VS-3d, and 428 DEPs between 9d-VS-6d were obtained, respectively. CONCLUSION: This work provided scientific basis to study protein profile and comparison of protein expression levels of O. sinensis zjut, and it will be helpful for metabolic engineering works to active ingredients for exploration, application and improvement of this fungus.

14.
ACS Biomater Sci Eng ; 6(10): 5588-5598, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33320589

RESUMO

Stiffening of the extracellular matrix (ECM) is considered a typical remolding of the microenvironment in multistep tumor progression. However, the molecular mechanisms by which the tumor cell responds to the ECM mechanical cues remain elusive. Here, we demonstrated that microRNA-29b (miR-29b) and its downstream signaling play critical regulatory roles that osteosarcoma cells sense the ECM stiffness to maintain the cancer stem cell-like ability. Polyacrylamide gels with a stiffness of 7, 20, and 55 kPa were used to mimic the rigidity of connective tissue, muscle tissue, and bone tissue. It was found that the stemness properties including self-renewal ability, differentiation potential, and drug resistance of osteosarcoma cells were strongly enhanced with reducing substrate stiffness, whereas spreading area, proliferation, and migration were inhibited. Moreover, miR-29 was obviously downregulated in soft substrate-cultured osteosarcoma cells, and the expression of stemness-related transcription factors (Sox2, Nanog, and Oct4) and the sphere formation ability were significantly inhibited by ectopic expression of miR-29b-5p. The soft substrate-induced miR-29 downregulation could increase Spin 1 expression and activate phosphatidylinositol 3-kinase (PI3K)/Akt and Stat3 signaling, which were suppressed by the increase in miR-29b-5p. Taken together, our results elucidated that miR-29 could be a novel mechanical sensor which manipulates osteosarcoma cell stemness. This finding uncovers the fact that the mechanical cue of the cancer niche could take part in the regulation of cancer progression through operating microRNAs and their downstream signaling.

15.
Emerg Infect Dis ; 26(12): 3083-3085, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33219789

RESUMO

We identified Candidatus Borrelia fainii, a human pathogenic bacterium causing New World relapsing fever in a Myotis bat in eastern China. This finding expands knowledge about the geographic distribution of Borrelia spp. and the potential for infection with New World relapsing fever in China.

16.
Quant Imaging Med Surg ; 10(11): 2212-2214, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33140000
17.
Proc Natl Acad Sci U S A ; 117(44): 27078-27079, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33024020
18.
Emerg Med Australas ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33074594

RESUMO

OBJECTIVE: To understand the impact of COVID-19 restrictions on emergency medical services (EMSs) utilisation and out-of-hospital cardiac arrest outcomes in Singapore. METHODS: This was a retrospective observational study comparing data collected by the Singapore Civil Defence Force on EMS utilisation in Singapore from 1 April to 31 May 2020 to previous figures. RESULTS: Overall, EMS call volume and total out-of-hospital cardiac arrests remained comparable to past years. There was an appreciable decline in prehospital return of spontaneous circulation rates, albeit not statistically lower than pre-COVID periods (P = 0.078). CONCLUSION: The findings contribute to a growing body of literature internationally on the potential impact of the COVID-19 pandemic on EMS utilisation and outcomes.

20.
Australas Emerg Care ; 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32962931

RESUMO

BACKGROUND: Western studies have highlighted alarmingly high rates of work-related violence experienced by emergency medical services (EMS) staff. As there is a paucity of Asian studies, we aimed to investigate the incidence of physical and verbal violence against the EMS crew in the Singapore Civil Defence Force (SCDF). METHODS: This was a cross-sectional study, utilising an online survey made available to all active paramedics in the SCDF. Paramedics with at least one year of work experience were eligible to participate. All responses were kept anonymous. RESULTS: The response rate was 50.9% (n = 246), out of 483 paramedics in service at the time of the study. The respondents consisted of 144 males (58.5%) and 102 females (41.5%). They were between 18 and 55 years old; 160 (65.0%) of them had worked in EMS for less than 6 years. The paramedics experienced high levels of verbal and physical violence, but there was reticence in reporting these incidents. The main risk factor for violence appeared to be alcohol intoxication. CONCLUSIONS: Paramedics may benefit from security escort for clients with history of alcohol intoxication or violence and more teaching on self-defence and soft restraints. Current training and protocols should be revised to meet these needs.

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