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Cocrystals are assemblies of more than one type of molecule stabilized through noncovalent interactions. They are promising materials for improved drug formulation in which the stability, solubility, or biocompatibility of the active pharmaceutical ingredient (API) is improved by including a coformer. In this work, a range of density functional theory (DFT) and density functional tight binding (DFTB) models are systematically compared for their ability to predict the lattice enthalpy of a broad range of existing pharmaceutically relevant cocrystals. These range from cocrystals containing model compounds 4,4'-bipyridine and oxalic acid to those with the well benchmarked APIs of aspirin and paracetamol, all tested with a large set of alternative coformers. For simple cocrystals, there is a general consensus in lattice enthalpy calculated by the different DFT models. For the cocrystals with API coformers the cocrystals, enthalpy predictions depend strongly on the DFT model. The significantly lighter DFTB models predict unrealistic values of lattice enthalpy even for simple cocrystals.
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Ionic liquids (ILs) nanostructuring at electrified interfaces is of both fundamental and practical interest as these materials are increasingly gaining prominence in energy storage and conversion processes. However, much remains unresolved about IL potential-controlled (re)organization under highly polarized interfaces, mostly due to the difficulty of selectively probing both the distal and proximal surface layers of adsorbed ions. In this work, the structural dynamics of the innermost layer (<10 nm from the surface) were independently interrogated from that of the ionic layers in the sub-surface region (>100 nm from the surface), using an infrared (IR) spectroscopy approach. By tuning the metal fill factor of gold films deposited on conductive metal oxide-modified IR internal reflection elements, the charge-driven (re)structuring of the inner and distal layers of 1-butyl-1-methylpyrrolidinium trifluoromethanesulfonate is unveiled. Within a relatively wide potential region (â¼±1 V) bounding the potential of zero charges, the ionic liquid is shown to undergo a reversible (i.e., soft) reorganization whereby the innermost layer of anions (cations) is exchanged by a layer of cations (anions). Kinetically unhindered changes in the number density of constituent cations and anions largely follow electrostatic expectations in the subsurface region, whereas the innermost layer exhibits a pronounced hysteresis and very slow relaxation. Under larger negative potential bias, IL restructuring is characterized by a highly irreversible (i.e., hard) and intense interfacial densification of the BMPy+ cations, consistent with the formation of nanoscale segregated liquids. The outcomes of this work reveal a plastic IL nanostructuring under a strong electric field.
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BACKGROUND: Cognition is frequently affected in persons with multiple sclerosis (MS). Cognitive impairment (CI) is associated with decreased quality of life (QOL) and employment status. Yet, CI assessed using patient-reported outcome measures is not as well studied and is thought to be influenced by other symptoms. Health Utilities Index 3 (HUI3) is a multi-attribute health-status classification system that assesses 8 different single attributes, including cognition. METHODS: The North American Consortium of Multiple Sclerosis (NARCOMS) Registry, a voluntary, self-report registry for persons with MS, Spring 2019 survey collected the HUI3 and self-reported assessment of health-related QOL (RAND-12), cognitive status, depression, fatigue, disability, employment, disease-modifying therapy use, and sociodemographic data. We assessed the relationship between patient-reported cognitive CI from the HUI3 (HUI-C), QOL, and employment while adjusting for factors previously associated with the outcomes. For employment outcomes, the cohort was limited to participants 65 years of age or younger. RESULTS: Of the 6,227 respondents, 56.4 % reported cognitive difficulty with the HUI-C. After adjusting for multiple covariates, cognitive difficulty was associated with 1.2 point lower physical QOL for each 0.1 decrease in HUI-C (p < 0.0001). Mental QOL decreased by 2 points for each 0.1 decrease in HUI-C (p < 0.0001). Cognitive difficulty was associated with a 10 % decreased odds of employment in the multivariable model (p < 0.0001). DISCUSSION: Patient-reported CI was associated with lower health-related and vocational outcomes for MS patients, even after accounting for age, income, depression, fatigue, and disability associated with cognition. The HUI-C is a single attribute score derived from the HUI3 that may facilitate the evaluation of CI in MS.
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Disfunção Cognitiva , Emprego , Esclerose Múltipla , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Sistema de Registros , Humanos , Emprego/estatística & dados numéricos , Disfunção Cognitiva/etiologia , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla/psicologia , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , AutorrelatoRESUMO
BACKGROUND AND OBJECTIVES: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. METHODS: In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. RESULTS: Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. DISCUSSION: Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among adults with active RRMS and ≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).
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Relação Dose-Resposta a Droga , Esclerose Múltipla Recidivante-Remitente , Humanos , Adulto , Masculino , Feminino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Pessoa de Meia-Idade , Adulto Jovem , Método Duplo-Cego , AdolescenteRESUMO
BACKGROUND AND OBJECTIVES: Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083). METHODS: In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28. RESULTS: Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, p = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, p = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; p = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion. DISCUSSION: Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.
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Imageamento por Ressonância Magnética , Natalizumab , Proteínas de Neurofilamentos , Humanos , Proteínas de Neurofilamentos/sangue , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Natalizumab/uso terapêutico , Biomarcadores/sangue , Gadolínio , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Progressão da Doença , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/sangue , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Avaliação da Deficiência , Fatores de TempoRESUMO
BACKGROUND: Very little is known about the mental health of the adult population of Ukraine following Russia's full-scale invasion in February 2022. In this study, we estimated the prevalence of seven mental health disorders, the proportion of adults screening positive for any disorder, and the sociodemographic factors associated with meeting requirements for each and any disorder. METHODS: A non-probability quota sample (N = 2,050) of adults living in Ukraine in September 2023 was collected online. Participants completed self-report questionnaires of the seven mental health disorders. Logistic regression was used to determine the predictors of the different disorders. RESULTS: Prevalence estimates ranged from 1.5% (cannabis use disorder) to 15.2% (generalized anxiety disorder), and 36.3% screened positive for any of the seven disorders. Females were significantly more likely than males (39.0% vs. 33.8%) to screen positive for any disorder. Disruption to life due to Russia's 2014 invasion of Ukraine, greater financial worries, and having fewer positive childhood experiences were consistent risk factors for different mental health disorders and for any or multiple disorders. CONCLUSION: Our findings show that approximately one in three adults living in Ukraine report problems consistent with meeting diagnostic requirements for a mental health disorder 18 months after Russia's full-scale invasion. Ukraine's mental healthcare system has been severely compromised by the loss of infrastructure and human capital due to the war. These findings may help to identify those most vulnerable so that limited resources can be used most effectively.
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Saúde Mental , Transtornos Relacionados ao Uso de Substâncias , Adulto , Masculino , Feminino , Humanos , Ucrânia/epidemiologia , Ansiedade/psicologia , Transtornos de Ansiedade/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
PURPOSE: We explore a new approach to the study of cognitive effort involved in listening to speech by measuring the brain activity in a listener in relation to the brain activity in a speaker. We hypothesize that the strength of this brain-to-brain synchrony (coupling) reflects the magnitude of cognitive effort involved in verbal communication and includes both listening effort and speaking effort. We investigate whether interbrain synchrony is greater in native-to-native versus native-to-nonnative communication using functional near-infrared spectroscopy (fNIRS). METHOD: Two speakers participated, a native speaker of American English and a native speaker of Korean who spoke English as a second language. Each speaker was fitted with the fNIRS cap and told short stories. The native English speaker provided the English narratives, and the Korean speaker provided both the nonnative (accented) English and Korean narratives. In separate sessions, fNIRS data were obtained from seven English monolingual participants ages 20-24 years who listened to each speaker's stories. After listening to each story in native and nonnative English, they retold the content, and their transcripts and audio recordings were analyzed for comprehension and discourse fluency, measured in the number of hesitations and articulation rate. No story retellings were obtained for narratives in Korean (an incomprehensible language for English listeners). Utilizing fNIRS technique termed sequential scanning, we quantified the brain-to-brain synchronization in each speaker-listener dyad. RESULTS: For native-to-native dyads, multiple brain regions associated with various linguistic and executive functions were activated. There was a weaker coupling for native-to-nonnative dyads, and only the brain regions associated with higher order cognitive processes and functions were synchronized. All listeners understood the content of all stories, but they hesitated significantly more when retelling stories told in accented English. The nonnative speaker hesitated significantly more often than the native speaker and had a significantly slower articulation rate. There was no brain-to-brain coupling during listening to Korean, indicating a break in communication when listeners failed to comprehend the speaker. CONCLUSIONS: We found that effortful speech processing decreased interbrain synchrony and delayed comprehension processes. The obtained brain-based and behavioral patterns are consistent with our proposal that cognitive effort in verbal communication pertains to both the listener and the speaker and that brain-to-brain synchrony can be an indicator of differences in their cumulative communicative effort. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25452142.
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Encéfalo , Cognição , Espectroscopia de Luz Próxima ao Infravermelho , Percepção da Fala , Humanos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Percepção da Fala/fisiologia , Masculino , Adulto Jovem , Feminino , Encéfalo/fisiologia , Encéfalo/diagnóstico por imagem , Projetos Piloto , Cognição/fisiologia , Multilinguismo , Fala/fisiologia , Idioma , AdultoRESUMO
The literature is filled with citations reporting an increased incidence of chronic dry eye disease, also known as keratoconjunctivitis sicca, in patients with systemic autoimmune diseases such as rheumatoid arthritis, Sjögren's Syndrome, systemic sclerosis and lupus. As the most environmentally exposed mucosal surface of the body, the conjunctiva constantly responds to environmental challenges which are typically self limited, but when persistent and unresolved may provoke pathogenic innate and adaptive immune reactions. Our understanding of the pathophysiological mechanisms by which systemic autoimmune diseases cause dry eye inducing ocular surface inflammation continues to evolve. Conjunctival immune tone responds to self or foreign danger signals (including desiccating stress) on the ocular surface with an initial non-specific innate inflammatory response. If unchecked, this can lead to activation of dendritic cells that present antigen and prime T and B cells resulting in an adaptive immune reaction. These reactions generally resolve, but dysfunctional, hyper-responsive immune cells found in systemic autoimmune diseases that are recruited to the ocular surface can amplify inflammatory stress responses in the ocular surface and glandular tissues and result in autoimmune reactions that disrupt tear stability and lead to chronic dry eye disease. We here propose that unique features of the ocular surface immune system and the impact of systemic immune dysregulation in autoimmune diseases, can predispose to development of dry eye disease, and exacerbate severity of existing dry eye.
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Doenças Autoimunes , Imunidade Inata , Ceratoconjuntivite Seca , Humanos , Ceratoconjuntivite Seca/imunologia , Doenças Autoimunes/imunologia , Túnica Conjuntiva/imunologia , Túnica Conjuntiva/patologia , Lágrimas/imunologia , Lágrimas/metabolismoRESUMO
ABSTRACT: Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease characterized by destruction of mucosal glands resulting in dry eye and dry mouth. Ocular presentations can be heterogenous in SS with corneal nerves abnormalities that are structural, functional, or both. Some individuals present with corneal hyposensitivity, with a phenotype of decreased tear production and epithelial disruption. Others present with corneal hypersensitivity, with a phenotype of neuropathic pain including light sensitivity and pain out of proportion to signs of tear dysfunction. A similar correlate can be found outside the eye, with dry mouth predominating in some individuals while pain conditions predominate in others. Understanding how nerve status affects SS phenotype is an important first step to improving disease management by targeting nerve abnormalities, as well as inflammation.
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Córnea , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/fisiopatologia , Síndrome de Sjogren/imunologia , Córnea/inervação , Córnea/patologia , Inflamação/fisiopatologia , Lágrimas/metabolismo , Lágrimas/fisiologia , Síndromes do Olho Seco/fisiopatologia , Síndromes do Olho Seco/etiologiaRESUMO
BACKGROUND: The recurrence or persistence of symptoms after thoracic outlet decompression (TOD) in patients with neurogenic thoracic outlet syndrome (NTOS) is not uncommon. Some authors have shown significantly better clinical outcomes in patients who underwent TOD with exarticulation of the first rib compared to a group who underwent TOD with preservation of the dorsal portion of the first rib. Several other case series have shown significant improvement after redo surgery with removal of the dorsal first rib remnant. This indicates the importance of the dorsal part of the first rib in NTOS. However, radical exarticulation may not always be necessary. In this study, we tried to answer the question of whether there is a morphological difference in the dorsal part of the first rib in NTOS patients that might help in the diagnosis and treatment of NTOS. METHODS: We used the CT data of 21 NTOS patients who underwent TOD surgery and measured the dorsal part of the first rib, then compared them with a quota sample. RESULTS: We found no difference in the dorsal part of the first rib between NTOS patients and the quota sample in our data. CONCLUSIONS: As there was no detectable difference, we were not able to use these data to help decide whether exarticulation is necessary in achieving adequate symptom relief. Therefore, we advocate exarticulation of the first rib when TOD is indicated.
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Despite the success of disease-modifying treatments in relapsing multiple sclerosis, for many individuals living with multiple sclerosis, progressive disability continues to accrue. How to interrupt the complex pathological processes underlying progression remains a daunting and ongoing challenge. Since 2014, several immunomodulatory approaches that have modest but clinically meaningful effects have been approved for the management of progressive multiple sclerosis, primarily for people who have active inflammatory disease. The approval of these drugs required large phase 3 trials that were sufficiently powered to detect meaningful effects on disability. New classes of drug, such as Bruton tyrosine-kinase inhibitors, are coming to the end of their trial stages, several candidate neuroprotective compounds have been successful in phase 2 trials, and innovative approaches to remyelination are now also being explored in clinical trials. Work continues to define intermediate outcomes that can provide results in phase 2 trials more quickly than disability measures, and more efficient trial designs, such as multi-arm multi-stage and futility approaches, are increasingly being used. Collaborations between patient organisations, pharmaceutical companies, and academic researchers will be crucial to ensure that future trials maintain this momentum and generate results that are relevant for people living with progressive multiple sclerosis.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Imunomodulação , PrevisõesRESUMO
To understand the speciation of solutes in aqueous solutions in high temperature radiation environments, we report the design and fabrication of a custom-built, high temperature (≤300 °C) titanium irradiation cell with in situ optical spectroscopy capabilities, as afforded by coupled fiber optic cables. The wetted surfaces of the 8-inch tall cylindrical cell with 3.5 in. diameter are entirely made of titanium, sapphire, and gold, which are chemically and radiolytically inert. The initial benchmarking results are reported, including the baseline spectrum of deionized water as a function of temperature, the stability of a spectrum over 4 h at 100 °C, and an irradiated Fricke dosimetry solution under ambient irradiator temperature conditions (27.0 ± 0.5 °C). The average gamma radiation dose rate in the cell in its current configuration is 26.1 ± 1.3 Gy min-1. This cell has application in studying several processes throughout the nuclear fuel cycle, including the reactor coolant behavior.
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BACKGROUND: Ibudilast has shown beneficial effects on several imaging outcomes in progressive multiple sclerosis (MS). Slowly enlarging lesions are a proposed imaging biomarker of compartmentalized inflammation within chronic active lesions. OBJECTIVE: To assess the treatment effect of ibudilast on slowly enlarging lesion volumes over 96 weeks from a phase II clinical trial of ibudilast (Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: In total, 255 participants with progressive MS from 28 sites were randomized to oral ibudilast or placebo. Participants with at least four analyzable magnetic resonance imaging (MRI) were included. Slowly enlarging lesions were quantified using Jacobian determinant maps. A linear model was used to assess the effect of ibudilast. Magnetization transfer ratio within slowly enlarging lesions was assessed to determine the effect of ibudilast on tissue integrity. RESULTS: In total, 195 participants were included in this analysis. Ibudilast significantly decreased slowly enlarging lesion volume (23%, p = 0.003). Ibudilast also reduced magnetization transfer ratio change in slowly enlarging lesions: 0.22%/year, p = 0.04. CONCLUSION: Ibudilast showed a significant effect on baseline volume of lesions that were slowly enlarging and magnetization transfer ratio in slowly enlarging lesions. The results support the use of slowly enlarging lesions for assessment of compartmentalized inflammation represented by chronic active lesions and provide further support for the neuroprotective effects of ibudilast in progressive MS.
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Indolizinas , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Pirazóis , Humanos , Encéfalo/patologia , Inflamação/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Piridinas/uso terapêuticoRESUMO
ABSTRACT Introduction: Allogeneic hematopoietic stem cell transplantation offers the opportunity for extended survival in patients with Hodgkin's and non-Hodgkin lymphomas who relapsed after, or were deemed ineligible for, autologous transplantation. This study reports the cumulative experience of a single center over the past 14 years aiming to define the impact of patient, disease, and transplant-related characteristics on outcomes. Methods: All patients with histologically confirmed diagnosis of Hodgkin's or non-Hodgkin lymphomas who received allogeneic transplantation from 2000 to 2014 were retrospectively studied. Results: Forty-one patients were reviewed: 10 (24%) had Hodgkin's and 31 (76%) had non-Hodgkin lymphomas. The median age was 50 years and 23 (56%) were male. The majority of patients (68%) had had a prior autologous transplantation. At the time of allogeneic transplantation, 18 (43%) patients were in complete and seven (17%) were in partial remission. Most (95%) patients received reduced-intensity conditioning, 49% received matched sibling donor grafts, 24% matched-unrelated donor grafts, and 27% received double umbilical cord blood grafts. The 100-day treatment-related mortality rate was 12%. After a median duration of follow up of 17.1 months, the median progression-free and overall survival was 40.5 and 95.8 months, respectively. On multivariate analysis, patients who had active disease at the time of transplant had inferior survival. Conclusions: Allogeneic transplantation results extend survival in selected patients with relapsed/refractory Hodgkin's and non-Hodgkin lymphomas with low treatment-related mortality. Patients who have active disease at the time of allogeneic transplantation have poor outcomes.
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Transplante Homólogo , Linfoma não Hodgkin , Doença de Hodgkin , Transplante de Células-Tronco HematopoéticasRESUMO
La leflunomida, es un nuevo medicamento con eficacia comprobada en artritis reumatoide, derivada del isoxazol que no guarda relación estructural con otros fármacos inmunomoduladores. La leflunomida se metaboliza rápidamente a su forma activa, el A77 1726. Se han identificado dos mecanismos de acción para el A77 1726: inhibición de la dihidroorotato deshidrogenasa (DHODH) e inhibición de la tirosina quinasa. La inhibición de la DHODH se produce a concentraciones más bajas de A77 1726 que las de la tirosina quinasa y en la actualidad se considera que es el principal modo de acción. Los leucocitos estimulados han de incrementar los niveles de ribonucleótidos entre 8 y 16 veces antes de pasar de la fase G a la fase S. El aumento de los niveles de ribonucleótidos sólo puede conseguirse mediante síntesis de novo de estas moléculas. Con niveles bajos de ribonucleótidos, la p.53, una molécula "sensora", se activa e impide el avance del ciclo celular. En consecuencia, sería predecible que un inhibidor de la síntesis de novo de la uridina monofosfato detuviese las células estimuladas en la fase G. En apoyo de este mecanismo de acción, los linfocitos humanos de la sangre periférica estimulados con un mitógeno in vitro y tratados con A77 1726 sufren una detención en la fase G esta inhibición es revertida por la uridina