RESUMO
BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.
Assuntos
COVID-19 , Neoplasias , Idoso , Teste para COVID-19 , Feminino , Humanos , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Pandemias , SARS-CoV-2RESUMO
The traditional Mach-Zehnder modulator (MZM) figure of merit (FOM) has been defined as (Vπ2)/υ3dBe, and works effectively for LiNbO3 long haul modulators. However, for plasma dispersion based electro-optic modulators, or any modulator that has an inherent relationship between its bandwidth, required drive voltage, and optical insertion loss/gain, this FOM is inappropriate. This is particularly true for short reach links with no optical amplification. In the following, we propose a new modulator FOM (M-FOM) based on device metrics that are essential for short-reach links, such as the peak-to-peak drive voltage, modulator rise-fall time, and relative optical modulation amplitude. Link sensitivity measurements from two MZMs that have different bandwidths and optical losses are compared using our M-FOM to demonstrate its utility. Furthermore, we present a novel application protocol of our M-FOM to provide deeper insight into the relative system impact that modulator performance has on data links with no optical amplification, by taking the ratio of M-FOMs from two modulators driven with the same radio frequency drive power.
RESUMO
A novel high-speed Mach-Zehnder modulator (MZM) fully integrated into a 90 nm CMOS process is presented. The MZM features 'double-pass' optical phase shifter segments, and the first use of integrated inductors in a 'velocity-matched' distributed-electrode configuration.
RESUMO
A silicon microring modulator utilizing an interleaved p-n junction phase shifter with a V(π)L of 0.76 V-cm and a minimum off-resonance insertion loss of less than 0.2 dB is demonstrated. The modulator operates at 25 Gbps at a drive voltage of 1.6 V and 2-3 dB excess optical insertion loss, conditions which correspond to a power consumption of 471 fJ/bit. Eye diagrams are characterized at up to 40 Gbps, and transmission is demonstrated across more than 10 km of single-mode fiber with minimal signal degradation.
Assuntos
Dispositivos Ópticos , Semicondutores , Processamento de Sinais Assistido por Computador/instrumentação , Silício , Telecomunicações/instrumentação , Artefatos , Desenho Assistido por Computador , Desenho de Equipamento , Humanos , MiniaturizaçãoRESUMO
When diphtheria toxin and NAD are added to soluble fractions containing aminoacyl transfer enzymes isolated from rabbit reticulocytes or from HeLa cells, free nicotinamide is released and, simultaneously, an inactive ADP ribose derivative of transferase II is formed. The reaction is reversible, and in the presence of excess nicotinamide, toxin catalyzes the restoration of aminoacyl transfer activity in intoxicated preparations. In living cultures of HeLa cells, the internal NAD concentration is sufficiently high to account for the rapid conversion, catalyzed by a few toxin molecules located in the cell membrane, of the entire cell content of free transferase II to its inactive ADP ribose derivative. Completely inactive ammonium sulfate fractions containing soluble proteins isolated from cells that have been exposed for several hours to excess toxin, can be reactivated to full aminoacyl transfer activity by addition of nicotinamide together with diphtheria toxin. Transferase II appears to be a highly specific substrate for the toxin-stimulated splitting of NAD and thus far no other protein acceptor for the ADP ribose moiety has been found.
Assuntos
Toxina Diftérica/farmacologia , Células HeLa/efeitos dos fármacos , NAD/metabolismo , Biossíntese de Proteínas , Aminoácidos/metabolismo , Animais , Isótopos de Carbono , Fenômenos Químicos , Química , Técnicas de Cultura , Eletroforese , Células HeLa/enzimologia , Células HeLa/metabolismo , Isótopos de Iodo , Coelhos , Reticulócitos/enzimologia , Transferases/metabolismoRESUMO
The blood clearance and distribution in the tissues of (125)I after intravenous injection of small doses (1.5-5 MLD or 0.08-0.25 microg) of (125)I-labeled diphtheria toxin has been followed in guinea pigs and rabbits and compared with the fate of equivalent amounts of injected (125)I-labeled toxoid and bovine serum albumin. Toxoid disappeared most rapidly from the blood stream and label accumulated and was retained in liver, spleen, and especially in kidney. Both toxin and BSA behaved differently. Label was found widely distributed among all the organs except the nervous system and its rate of disappearance from the tissues paralleled its disappearance from the circulation. There was no evidence for any particular affinity of toxin for muscle tissue or for a "target" organ. Previous reports by others that toxin causes specific and selective impairment of protein synthesis in muscle tissue were not confirmed. On the contrary, both in guinea pigs and rabbits, a reduced rate of protein synthesis was observed in all tissues that had taken up the toxin label. In tissues removed from intoxicated animals of both species there was an associated reduction in aminoacyl transferase 2 content. It is concluded that the primary action of diphtheria toxin in the living animal is to effect the inactivation of aminoacyl transferase 2. The resulting inhibition in rate of protein synthesis leads to morphologic damage in all tissues reached by the toxin and ultimately to death of the animal.
Assuntos
Aminoácidos/metabolismo , Toxina Diftérica , Biossíntese de Proteínas , Transferases/metabolismo , Aminoácidos/análise , Animais , Testes Imunológicos de Citotoxicidade , Diafragma/metabolismo , Toxina Diftérica/sangue , Toxoide Diftérico , Cobaias , Injeções Intravenosas , Intestino Delgado/metabolismo , Rim/metabolismo , Pulmão/metabolismo , Músculos/metabolismo , Miocárdio/metabolismo , Pâncreas/metabolismo , Coelhos , Soroalbumina Bovina , Baço/metabolismoRESUMO
Certain strains of Staphylococcus aureus associated with toxic shock syndrome elaborate material that induces human blood monocytes to secrete interleukin-1 (IL-1). IL-1 was detected both by its ability to cause fever in rabbits using the leukocytic pyrogen (LP) assay and by its mitogenic activity towards thymocytes in the so-called lymphocyte-activating factor (LAF) assay. Anti-human IL-1 prevents the manifestation of both activities. Filtrates of control strains of S. aureus manifest neither activity. Thus, culture filtrates derived from toxic shock syndrome (TSS)-associated strains cause biphasic fever in rabbits when injected intravenously. The fever lasts several hours. Plasma taken at the peak of the fever and injected into a second set of rabbits produces a brief monophasic fever typical of LP. Further, human monocytes release LP when incubated with TSS filtrates in vitro. The monocyte products also stimulate the proliferation of mouse thymocytes in the presence of phytohemagglutinin in a manner characteristic of LAF. A bacterial filtrate is much less effective without an intermediate incubation with monocytes. The stimulation of monocyte IL-1 production is easily quantified, provides a simple method of assaying the TSS toxin, and since it involves human cells, is directly relevant to the human disease. The assay was used to monitor the purification of TSS toxin. Only 0.1 ng/ml of the purified material is required to induce monocyte IL-1 production. It is thus more potent than endotoxin. In contrast to endotoxin, its effect is not blocked by polymyxin B. We conclude that in TSS the sudden fever and probably other components of the acute phase response may be attributed to a massive release of IL-1.
Assuntos
Toxinas Bacterianas , Enterotoxinas/farmacologia , Febre/etiologia , Interleucina-1/biossíntese , Superantígenos , Animais , Enterotoxinas/isolamento & purificação , Feminino , Humanos , Interleucina-1/isolamento & purificação , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , CoelhosRESUMO
Exoenzyme C3 from Clostridium botulinum types C and D specifically ADP-ribosylated a 21-kilodalton cellular protein, p21.bot. Guanyl nucleotides protected the substrate against denaturation, which implies that p21.bot is a G protein. When introduced into the interior of cells, purified exoenzyme C3 ADP-ribosylated intracellular p21.bot and changed its function. NIH 3T3, PC12, and other cells rapidly underwent temporary morphological alterations that were in certain respects similar to those seen after microinjection of cloned ras proteins. When injected into Xenopus oocytes, C3 induced migration of germinal vesicles and potentiated the cholera toxin-sensitive augmentation of germinal vesicle breakdown by progesterone, also as caused by ras proteins. Nevertheless, p21.bot was immunologically distinct from p21ras.
Assuntos
ADP Ribose Transferases/metabolismo , Adenosina Difosfato Ribose/metabolismo , Proteínas de Bactérias/metabolismo , Toxinas Botulínicas , Clostridium botulinum/enzimologia , Proteínas de Ligação ao GTP/metabolismo , Pentosiltransferases/metabolismo , ADP Ribose Transferases/imunologia , Animais , Proteínas de Bactérias/imunologia , Clostridium botulinum/imunologia , Proteínas de Ligação ao GTP/imunologia , Ponto Isoelétrico , Meiose/efeitos dos fármacos , Peso Molecular , Pentosiltransferases/imunologia , XenopusRESUMO
The ADP-ribosylation of membrane G proteins is difficult to achieve in tissues that are rich in membrane-bound NAD glycohydrolase (NAD+ glycohydrolase, EC 3.2.2.5). For many animal species this problem can be surmounted by inhibiting NAD hydrolysis with a combination of the anti-tuberculous drug, isonicotinic acid hydrazide, and the NAD analog, 3-acetylpyridine adenine dinucleotide, which act synergistically. In their presence, the ADP-ribosylation of cholera and pertussis toxin substrates reach plateau levels even with only 10 microM NAD. Although 3-acetylpyridine adenine dinucleotide acts as a weak substrate for the toxins, it is simple to estimate its contribution to the ADP-ribosylation and thus to determine the total amount of ADP-ribosylation substrate present in a tissue sample. NAD glycohydrolases that are insensitive to isonicotinic acid hydrazide are also less sensitive to 3-acetylpyridine adenine dinucleotide, but may be inactivated by dithiothreitol. Isonicotinic acid hydrazide adenine dinucleotide, the product of an exchange reaction catalysed by NAD glycohydrolase, runs with NAD in most thin-layer chromatographic systems. It can be separated from NAD, and quantitated, if the chromatographic solvent contains benzaldehyde. Isonicotinic acid hydrazide itself inhibits NAD glycohydrolase. It need not first be converted into isonicotinic acid hydrazide adenine dinucleotide.
Assuntos
Adenosina Difosfato Ribose/metabolismo , Toxina da Cólera/farmacologia , Isoniazida/farmacologia , Proteínas de Membrana/metabolismo , NAD+ Nucleosidase/metabolismo , NAD/análogos & derivados , Toxina Pertussis , Fatores de Virulência de Bordetella/farmacologia , Animais , Química Encefálica , Bovinos , Columbidae , Sinergismo Farmacológico , Membrana Eritrocítica/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Camundongos , NAD/farmacologia , NAD+ Nucleosidase/antagonistas & inibidores , SuínosRESUMO
Incubation of fat cell ghosts with activated cholera toxin, nucleoside triphosphate, cytosol, and NAD results in increased adenylate cyclase activity and the transfer of ADP-ribose to membrane proteins. The major ADP-ribose protein comigrates on sodium dodecyl sulfate-polyacrylamide gels with the putative GTP-binding protein of pigeon erythrocyte membranes (Mr 42 000), which is also ADP-ribosylated by cholera toxin. The treatment with cholera toxin enhances the stimulation of the fat cell membrane adenylate cyclase by GTP, but the stimulation by guanyl-5'-yl imidodiphosphate is unaltered. Subsequent stimulation of fat cell adenylate cyclase by 10 micrometers epinephrine is not particularly affected. These changes were qualititatively the same for membranes isolated from fat cells of hypothyroid rats. Although the cyclase of these membranes has a reduced response to epinephrine, guanyl-5'-yl imidodiphosphate or GTP, as compared to euthyroid rat fat cell membranes, the defect is not rectified by toxin treatment and cannot be explained by a deficiency in the cholera toxin target.
Assuntos
Adenosina Difosfato Ribose/metabolismo , Adenilil Ciclases/metabolismo , Tecido Adiposo/metabolismo , Toxina da Cólera/farmacologia , Proteínas de Membrana/metabolismo , Açúcares de Nucleosídeo Difosfato/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Membrana Celular/metabolismo , Ativação Enzimática , Epinefrina/farmacologia , Feminino , Guanosina Trifosfato/farmacologia , Guanilil Imidodifosfato/farmacologia , Hipotireoidismo/metabolismo , RatosAssuntos
Toxina Diftérica/biossíntese , Difteria/etiologia , Animais , Bacteriófagos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Fenômenos Químicos , Química , Corynebacterium diphtheriae/metabolismo , Difteria/microbiologia , Toxina Diftérica/isolamento & purificação , Toxina Diftérica/farmacologia , Toxina Diftérica/toxicidade , Feminino , Genética Microbiana , Cobaias , Células HeLa/metabolismo , Humanos , Lisogenia , Camundongos , Biossíntese de Proteínas/efeitos dos fármacos , Coelhos , RatosRESUMO
EM9 is a mutagen-sensitive CHO cell whose phenotype resembles that of normal CHO cells exposed to 3-aminobenzamide, an inhibitor of poly(ADP-ribose) synthesis. This phenotype suggested that EM9 might be defective in poly(ADP-ribose) metabolism, but we now cannot find any abnormality in the synthesis or in the degradation of poly(ADP-ribose) in permeabilized EM9 cells. Thus the effects of 3-aminobenzamide on wild-type cells may be due to the inhibition of processes other than poly(ADP-ribose) synthesis. 3-Aminobenzamide enhances the cytotoxicity of EMS toward EM9 and control cells to the same degree.
Assuntos
Mutagênicos/toxicidade , Mutação , Açúcares de Nucleosídeo Difosfato/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Animais , Linhagem Celular , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Desoxirribonucleases/metabolismo , Desoxiuridina/análogos & derivados , Desoxiuridina/toxicidade , Detergentes/farmacologia , Metanossulfonato de Etila/toxicidade , Feminino , Isomerismo , Cinética , Lisofosfatidilcolinas/farmacologia , Testes de Mutagenicidade , NAD/metabolismo , Octoxinol , Ovário , Polietilenoglicóis/farmacologiaRESUMO
12 normal, self-reported dextral subjects (6 men, 6 women) were assessed with a hand dynamometer with 10 trials per hand for 10 consecutive wk. The test-retest reliability of the 10-trial average across the 10 sessions averaged .91 for men and .94 for women for both preferred and nonpreferred hands. Fatigue effects over trials were statistically significant for both sexes and hands except for women's preferred hand. Skill acquisition effects over sessions were only statistically significant for men's nonpreferred and women's preferred hands.
Assuntos
Lateralidade Funcional/fisiologia , Mãos/fisiologia , Adulto , Feminino , Humanos , Masculino , Músculos/fisiologia , Prática Psicológica , Fatores SexuaisRESUMO
The response format of the Speech Sounds Perception Test confounds speech perception with irrelevant method variance. To rectify this problem the response format was revised by randomizing the response locations. An empirical comparison of the revised and original forms was undertaken with forensic (n=59) and psychiatric (n=67) samples. The empirical results coupled with the logical problem in the original form indicates that a revision is necessary.
Assuntos
Transtornos Mentais/psicologia , Testes Neuropsicológicos , Fonética , Percepção da Fala , Adulto , Transtorno da Personalidade Antissocial/psicologia , Dano Encefálico Crônico/psicologia , Humanos , Masculino , Psicometria , Transtornos Psicóticos/psicologiaRESUMO
18 normal, self-reported dextral subjects (9 men, 9 women) were assessed with a Halstead Manual Finger Tapping device, with 10 trials per hand for 10 consecutive wk. The test-retest reliability of the 10-trial average between the 10 sessions averaged .94 for men and .86 for women, for both preferred and nonpreferred hands. There were no statistically significant effects of increases in performance over sessions or effects of fatigue over trials for either sex or hand. There were, however, significant increases over trials for men for both preferred and nonpreferred hands.
Assuntos
Destreza Motora , Testes Neuropsicológicos , Adulto , Fadiga/psicologia , Feminino , Lateralidade Funcional , Humanos , Masculino , Prática PsicológicaRESUMO
26 normal, self-reported dextral subjects (12 men, 14 women) were assessed with a Purdue Pegboard 5 times at weekly intervals to evaluate temporal stability and efficacy of lateralization with this test. There was a statistically significant increase in performance over time for men on the right- and left-hand placing subtests and for women on the assemblies subtest. For men/women the test-retest reliability over the 5 sessions averaged .63/.76 for the right-hand, .64/.79 for the left-hand, .67/.81 for both-hands, .81/.83 for assemblies, and .33/.22 for the right/left-hand ratio.