Mortality Among Adults With Cancer Undergoing Chemotherapy or Immunotherapy and Infected With COVID-19

Importance: Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. // Objective: To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. // Design, Setting, and Participants: The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. // Exposures: SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. // Main Outcomes and Measures: The primary end point was all-cause mortality within the primary hospitalization. // Results: Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19–related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). // Conclusions and Relevance: The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed

Étude des mécanismes de translocation du peptide vecteur Pénétratine sur membranes modèles formées à l’interface de gouttes

Cell-penetrating peptides can cross cell membranes and deliver biologically active molecules into cells with a limited cytotoxycity. They are internalized by endocytic pathways as well as by direct translocation. Although interaction partners of the plasma membrane have been identified, the molecular mechanisms of the direct translocation pathway remain hypothetical and the key structures of these mechanisms are not clearly identified. We studied the translocation of the cell-penetrating peptide Penetratin on membrane models formed at the droplets interface. Our experiments demonstrated a stochastic and cooperative character of the translocation process. The presence of anionic lipids is crucial for the recruitment of the peptide and its translocation. However, the nature of the anionic polar head group of lipids dictates the favourability of the bilayer crossing. Indeed, translocation was observed on POPG bilayers but not on POPS bilayers. Experiments on asymmetric bilayers showed that the composition of the distal leaflet is decisive for the translocation. Investigation on the membrane potential in the presence of Penetratin was studied in order to obtain insights into the bilayer destabilisation. Finally, a last approach consists in developing a microfluidic chip to obtain a high-performance platform for the study of cell-penetrating peptides.Les peptides vecteurs se caractérisent par leur capacité à traverser les membranes cellulaires. Ils peuvent transporter des cargaisons au sein des cellules avec une faible cytotoxicité et présentent donc un intérêt particulier pour la délivrance de molécules bioactives. Leur internalisation a lieu par endocytose et translocation directe. Bien que des partenaires d’interaction de la membrane plasmique aient été identifiés, les mécanismes moléculaires de la translocation directe restent hypothétiques et les structures clés de ces mécanismes n’ont pu être clairement identifiées. Nous avons étudié la translocation du peptide vecteur Pénétratine sur un modèle original de membranes formées à l’interface de gouttes. Nos expériences ont montré que la translocation revêt un caractère coopératif et stochastique et est dépendante de la présence de lipides anioniques nécessaires au recrutement du peptide et à sa traversée. Cependant, la nature de la tête polaire des lipides anioniques a un impact sur la translocation et le recrutement du peptide par ces lipides est une condition nécessaire mais non suffisante à la translocation. Celle-ci est favorisée en présence de lipides POPG mais pas en présence de lipides POPS. Les expériences sur bicouches asymétriques ont également montré que le feuillet distal est impliqué dans ce processus. Le potentiel de membrane en présence de Pénétratine a été étudié afin de dégager des pistes de description de la déstabilisation de la bicouche. En parallèle, nous nous sommes penchés sur le développement d’une puce microfluidique pour la formation et le piégeage des membranes afin d’obtenir une plateforme performante pour l’étude des peptides vecteurs

Study of the translocation mechanisms of the cell-penetrating peptide Penetratin on droplet interface bilayers

Les peptides vecteurs se caractérisent par leur capacité à traverser les membranes cellulaires. Ils peuvent transporter des cargaisons au sein des cellules avec une faible cytotoxicité et présentent donc un intérêt particulier pour la délivrance de molécules bioactives. Leur internalisation a lieu par endocytose et translocation directe. Bien que des partenaires d’interaction de la membrane plasmique aient été identifiés, les mécanismes moléculaires de la translocation directe restent hypothétiques et les structures clés de ces mécanismes n’ont pu être clairement identifiées. Nous avons étudié la translocation du peptide vecteur Pénétratine sur un modèle original de membranes formées à l’interface de gouttes. Nos expériences ont montré que la translocation revêt un caractère coopératif et stochastique et est dépendante de la présence de lipides anioniques nécessaires au recrutement du peptide et à sa traversée. Cependant, la nature de la tête polaire des lipides anioniques a un impact sur la translocation et le recrutement du peptide par ces lipides est une condition nécessaire mais non suffisante à la translocation. Celle-ci est favorisée en présence de lipides POPG mais pas en présence de lipides POPS. Les expériences sur bicouches asymétriques ont également montré que le feuillet distal est impliqué dans ce processus. Le potentiel de membrane en présence de Pénétratine a été étudié afin de dégager des pistes de description de la déstabilisation de la bicouche. En parallèle, nous nous sommes penchés sur le développement d’une puce microfluidique pour la formation et le piégeage des membranes afin d’obtenir une plateforme performante pour l’étude des peptides vecteurs.Cell-penetrating peptides can cross cell membranes and deliver biologically active molecules into cells with a limited cytotoxycity. They are internalized by endocytic pathways as well as by direct translocation. Although interaction partners of the plasma membrane have been identified, the molecular mechanisms of the direct translocation pathway remain hypothetical and the key structures of these mechanisms are not clearly identified. We studied the translocation of the cell-penetrating peptide Penetratin on membrane models formed at the droplets interface. Our experiments demonstrated a stochastic and cooperative character of the translocation process. The presence of anionic lipids is crucial for the recruitment of the peptide and its translocation. However, the nature of the anionic polar head group of lipids dictates the favourability of the bilayer crossing. Indeed, translocation was observed on POPG bilayers but not on POPS bilayers. Experiments on asymmetric bilayers showed that the composition of the distal leaflet is decisive for the translocation. Investigation on the membrane potential in the presence of Penetratin was studied in order to obtain insights into the bilayer destabilisation. Finally, a last approach consists in developing a microfluidic chip to obtain a high-performance platform for the study of cell-penetrating peptides

Triacylglycerols sequester monotopic membrane proteins to lipid droplets

International audienceTriacylglycerols (TG) are synthesized at the endoplasmic reticulum (ER) bilayer and packaged into organelles called lipid droplets (LDs). LDs are covered by a single phospholipid monolayer contiguous with the ER bilayer. This connection is used by several monotopic integral membrane proteins, with hydrophobic membrane association domains (HDs), to diffuse between the organelles. However, how proteins partition between ER and LDs is not understood. Here, we employed synthetic model systems and found that HD-containing proteins strongly prefer monolayers and returning to the bilayer is unfavorable. This preference for monolayers is due to a higher affinity of HDs for TG over membrane phospholipids. Protein distribution is regulated by PC/PE ratio via alterations in monolayer packing and HD-TG interaction. Thus, HD-containing proteins appear to non-specifically accumulate to the LD surface. In cells, protein editing mechanisms at the ER membrane would be necessary to prevent unspecific relocation of HD-containing proteins to LDs

A High‐Affinity Calmodulin‐Binding Site in the CyaA Toxin Translocation Domain is Essential for Invasion of Eukaryotic Cells

This article also appears in:Hot Topic: MembranesInternational audienceThe molecular mechanisms and forces involved in the translocation of bacterial toxins into host cells are still a matter of intense research. The adenylate cyclase (CyaA) toxin from Bordetella pertussis displays a unique intoxication pathway in which its catalytic domain is directly translocated across target cell membranes. The CyaA translocation region contains a segment, P454 (residues 454-484), which exhibits membrane-active properties related to antimicrobial peptides. Herein, the results show that this peptide is able to translocate across membranes and to interact with calmodulin (CaM). Structural and biophysical analyses reveal the key residues of P454 involved in membrane destabilization and calmodulin binding. Mutational analysis demonstrates that these residues play a crucial role in CyaA translocation into target cells. In addition, calmidazolium, a calmodulin inhibitor, efficiently blocks CyaA internalization. It is proposed that after CyaA binding to target cells, the P454 segment destabilizes the plasma membrane, translocates across the lipid bilayer and binds calmodulin. Trapping of CyaA by the CaM:P454 interaction in the cytosol may assist the entry of the N-terminal catalytic domain by converting the stochastic motion of the polypeptide chain through the membrane into an efficient vectorial chain translocation into host cells

COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study

Background Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK. Methods We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case–fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models. Findings 319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case–fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40–49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1·57, 95% CI 1·15–2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case–fatality rate (2·25, 1·13–4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09–4·08; p=0·028). Interpretation Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk–benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies