RÉSUMÉ
Knowing the conformational ensembles formed by mismatches is crucial for understanding how they are generated and repaired and how they contribute to genomic instability. Here, we review structural and energetic studies of the A-C mismatch in duplex DNA and use the information to identify critical conformational states in its ensemble and their significance in genetic processes. In the 1970s, Topal and Fresco proposed the A-C wobble stabilized by two hydrogen bonds, one requiring protonation of adenine-N1. Subsequent NMR and X-ray crystallography studies showed that the protonated A-C wobble was in dynamic equilibrium with a neutral inverted wobble. The mismatch was shown to destabilize duplex DNA in a sequence- and pH-dependent manner by 2.4-3.8 kcal/mol and to have an apparent pKa ranging between 7.2 and 7.7. The A-C mismatch conformational repertoire expanded as structures were determined for damaged and protein-bound DNA. These structures included Watson-Crick-like conformations forming through tautomerization of the bases that drive replication errors, the reverse wobble forming through rotation of the entire nucleotide proposed to increase the fidelity of DNA replication, and the Hoogsteen base-pair forming through the flipping of the adenine base which explained the unusual specificity of DNA polymerases that bypass DNA damage. Thus, the A-C mismatch ensemble encompasses various conformational states that can be selectively stabilized in response to environmental changes such as pH shifts, intermolecular interactions, and chemical modifications, and these adaptations facilitate critical biological processes. This review also highlights the utility of existing 3D structures to build ensemble models for nucleic acid motifs.
RÉSUMÉ
Elucidating how damage impacts DNA dynamics is essential for understanding the mechanisms of damage recognition and repair. Many DNA lesions alter their propensities to form low-populated and short-lived conformational states. However, NMR methods to measure these dynamics require isotopic enrichment, which is difficult for damaged nucleotides. Here, we demonstrate the utility of the 1H chemical exchange saturation transfer (CEST) NMR experiment in measuring the dynamics of oxidatively damaged 8-oxoguanine (8OG) in the mutagenic 8OGsyn·Aanti mismatch. Using 8OG-H7 as an NMR probe of the damaged base, we directly measured 8OG syn-anti flips to form a lowly populated (pop. â¼ 5%) and short-lived (lifetime â¼50 ms) nonmutagenic 8OGanti·Aanti. These exchange parameters were in quantitative agreement with values from 13C off-resonance R1ρ and CEST on the labeled partner adenine. The Watson-Crick-like 8OGsyn·Aanti mismatch also rescued the kinetics of Hoogsteen motions at distant A-T base pairs, which the G·A mismatch had slowed down. The results lend further support for 8OGanti·Aanti as a minor conformational state of 8OG·A, reveal that 8OG damage can impact Hoogsteen dynamics at a distance, and demonstrate the utility of 1H CEST for measuring damage-dependent dynamics in unlabeled DNA.
Sujet(s)
Guanine , Guanine/analogues et dérivés , Guanine/composition chimique , Altération de l'ADN , ADN/composition chimique , Conformation d'acide nucléique , Résonance magnétique nucléaire biomoléculaire , Spectroscopie par résonance magnétiqueRÉSUMÉ
PURPOSE: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood. EXPERIMENTAL DESIGN: Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays. RESULTS: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo. CONCLUSIONS: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.
Sujet(s)
Cytokines , Inhibiteurs de points de contrôle immunitaires , Humains , Mâle , Femelle , Inhibiteurs de points de contrôle immunitaires/effets indésirables , Adulte d'âge moyen , Sujet âgé , Cytokines/métabolisme , Peau/anatomopathologie , Peau/immunologie , Peau/métabolisme , Peau/effets des médicaments et des substances chimiques , Adulte , Toxidermies/étiologie , Toxidermies/anatomopathologie , Toxidermies/immunologie , Prurit/immunologie , Prurit/induit chimiquement , Prurit/anatomopathologie , Prurit/étiologie , Prurit/génétique , Tumeurs/traitement médicamenteux , Tumeurs/immunologie , Tumeurs/anatomopathologie , Maladies de la peau/induit chimiquement , Maladies de la peau/immunologie , Maladies de la peau/anatomopathologie , Maladies de la peau/étiologie , Exanthème/induit chimiquement , Exanthème/anatomopathologie , Sujet âgé de 80 ans ou plus , Psoriasis/traitement médicamenteux , Psoriasis/immunologie , Psoriasis/anatomopathologie , Psoriasis/génétique , Eczéma/anatomopathologie , Eczéma/traitement médicamenteuxRÉSUMÉ
Elucidating how damage impacts DNA dynamics is essential for understanding the mechanisms of damage recognition and repair. Many DNA lesions alter the propensities to form lowly-populated and short-lived conformational states. However, NMR methods to measure these dynamics require isotopic enrichment, which is difficult for damaged nucleotides. Here, we demonstrate the utility of the 1H chemical exchange saturation transfer (CEST) NMR experiment in measuring the dynamics of oxidatively damaged 8-oxoguanine (8OG) in the mutagenic 8OGsynâ¢Aanti mismatch. Using 8OG-H7 as an NMR probe of the damaged base, we directly measured 8OG syn-anti flips to form a lowly-populated (pop. ~ 5%) and short-lived (lifetime ~ 50 ms) non-mutagenic 8OGantiâ¢Aanti. These exchange parameters were in quantitative agreement with values from 13C off-resonance R1ρ and CEST on a labeled partner adenine. The Watson-Crick-like 8OGsynâ¢Aanti mismatch also rescued the kinetics of Hoogsteen motions at distance A-T base pairs, which the Gâ¢A mismatch had slowed down. The results lend further support for 8OGantiâ¢Aanti as a minor conformational state of 8OGâ¢A, reveal that 8OG damage can impact Hoogsteen dynamics at a distance, and demonstrate the utility of 1H CEST for measuring damage-dependent dynamics in unlabeled DNA.
RÉSUMÉ
Many biochemical processes use the Watson-Crick geometry to distinguish correct from incorrect base pairing. However, on rare occasions, mismatches such as G·T/U can transiently adopt Watson-Crick-like conformations through tautomerization or ionization of the bases, giving rise to replicative and translational errors. The propensities to form Watson-Crick-like mismatches in RNA:DNA hybrids remain unknown, making it unclear whether they can also contribute to errors during processes such as transcription and CRISPR/Cas editing. Here, using NMR R1ρ experiments, we show that dG·rU and dT·rG mismatches in two RNA:DNA hybrids transiently form tautomeric (Genol·T/U $ \mathbin{\lower.3ex\hbox{$\buildrel\textstyle\rightarrow\over {\smash{\leftarrow}\vphantom{_{\vbox to.5ex{\vss}}}}$}}$ G·Tenol/Uenol) and anionic (G·T-/U-) Watson-Crick-like conformations. The tautomerization dynamics were like those measured in A-RNA and B-DNA duplexes. However, anionic dG·rU- formed with a ten-fold higher propensity relative to dT-·rG and dG·dT- and this could be attributed to the lower pKa (ΔpKa â¼0.4-0.9) of U versus T. Our findings suggest plausible roles for Watson-Crick-like G·T/U mismatches in transcriptional errors and CRISPR/Cas9 off-target gene editing, uncover a crucial difference between the chemical dynamics of G·U versus G·T, and indicate that anionic Watson-Crick-like G·U- could play a significant role evading Watson-Crick fidelity checkpoints in RNA:DNA hybrids and RNA duplexes.
Sujet(s)
Systèmes CRISPR-Cas , Édition de gène , Hybridation d'acides nucléiques , Appariement de bases , ADN/génétique , ADN/composition chimique , Conformation d'acide nucléique , ARN/composition chimiqueRÉSUMÉ
OBJECTIVES: Postural orthostatic tachycardia syndrome (POTS) is a debilitating and under-recognized condition of the autonomic nervous system. This study applied Leventhal's Common-Sense Model of Illness Representations to explore the journey to a diagnosis of POTS and to understand its relevance to poorly understood conditions which have common comorbidities. DESIGN: An inductive qualitative approach was used to explore the processes by which patients formulate explanations and management of symptoms within the search for a diagnostic label and to investigate illness identity in the context of existing diagnoses or multimorbidity. METHODS: Participants (n = 29) for this nested qualitative study were recruited from a larger longitudinal study of people who had been newly referred to a specialist POTS service. Semi-structured interviews were conducted via video call. Three researchers coded and analysed data using Reflexive Thematic Analysis and elements of Grounded Theory. RESULTS: The analysis resulted in three overarching themes: 'Seeking physiological coherence and validation', 'Individual persistence', and 'Navigating the cumulative burden'. 'Accessibility and disparities of health care' was noted as a contextual factor. Receiving a POTS diagnosis was regarded by participants as providing legitimacy and increased access to treatment. Overall, delays in the diagnostic journey and the lack of a clear diagnosis impacted negatively on patients through increased uncertainty and a lack of clear guidance on how to manage symptoms. Findings also suggested there were great complexities in assigning symptoms to labels in the context of multimorbidity. CONCLUSIONS: Participants' stories highlighted the urgent need for better recognition of POTS so that the self-regulatory process can be initiated from the early stages of symptom detection.
Sujet(s)
Syndrome de tachycardie orthostatique posturale , Humains , Syndrome de tachycardie orthostatique posturale/diagnostic , Syndrome de tachycardie orthostatique posturale/thérapie , Syndrome de tachycardie orthostatique posturale/épidémiologie , Études longitudinales , ComorbiditéRÉSUMÉ
PURPOSE: The combination of trastuzumab and pertuzumab (HP) as part of a taxane-based regimen has shown benefit in the adjuvant and metastatic HER2 + breast cancer setting. In the CLEOPATRA trial, pruritus was reported in 11-17.6% of patients. The clinical phenotype and potential treatment strategies for this event have not been reported. METHODS: A retrospective review of 2583 patients receiving trastuzumab and pertuzumab for the treatment of HER2 + breast cancer from 11/23/2011 to 6/21/2021 was performed at Memorial Sloan Kettering Cancer Center (MSKCC). Patient demographics, pruritus characteristics, and treatments as documented in the electronic medical record (EMR) were included in this analysis. RESULTS: Of 2583 pts treated with HP, 122 (4.72%) with pruritus were identified. On average, patients experienced pruritus 319.0 days (8-3171) after initiation of HP. The upper extremities (67.4%), back (29.3%), lower extremities (17.4%), and shoulders (14.1%) were the most commonly affected regions. Grade 1/2 pruritus (97.6%) occurred in most cases. Patients responded primarily to treatment with topical steroids (52.2%), antihistamines (29.9%), emollients (20.9%), and gabapentinoids (16.4%). Of those with pruritus, 4 patients (3.3%) required treatment interruption or discontinuation. CONCLUSIONS: Pruritus is uncommon in patients on trastuzumab and pertuzumab, generally a chronic condition, with gabapentinoids or antihistamines representing effective therapies.
Sujet(s)
Anticorps monoclonaux humanisés , Tumeurs du sein , Humains , Femelle , Trastuzumab , Tumeurs du sein/complications , Tumeurs du sein/traitement médicamenteux , Récepteur ErbB-2 , Antihistaminiques/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirablesRÉSUMÉ
Trust is a key feature of social relationships. Common measures of trust, questionnaires and economic games, lack ecological validity. Hence, we sought to introduce an immersive, virtual reality (VR) measure for the behavioral assessment of trust across remote and in-person settings, building on the maze task of Hale et al. (2018). Our 'Wayfinding Task' consists of an interconnected urban environment for participants to navigate on the advice of two characters of differing trustworthiness. We present four studies implementing the Wayfinding Task in remote and in-person testing environments and comparing performance across head-mounted display (HMD)-based VR and desktop setups. In each study, the trustworthiness of two virtual characters was manipulated, through either a fact sheet providing trustworthiness information, or a behavior-based trustworthiness manipulation task termed the Door Game, based on Van der Biest et al., 2020. Participants then completed the Wayfinding Task. Overall, we found that participant behavior in the Wayfinding Task reflected the relative trustworthiness of the two characters; in particular, the trustworthy character was approached more often for advice, reflecting data from our Door Game. We found mostly null results for our novel outcome measure, interpersonal distance. Remote testing successfully achieved these effects. While HMD-based VR and desktop setups both showed these effects, there was a stronger effect of trustworthiness in the HMD VR version of the task. These results have implications for the measurement of trust in behavioral settings and the use of remote and VR-based testing in social experiments.
Sujet(s)
Lunettes intelligentes , Réalité de synthèse , Humains , Confiance , Relations interpersonnelles , Enquêtes et questionnairesRÉSUMÉ
Background: Immune-related cutaneous adverse events (ircAEs) are frequent and may reduce quality of life and consistent dosing. IL12/23 has been implicated in psoriasis, which is reminiscent of the psoriasiform/lichenoid ircAE phenotype. We report the use of ustekinumab as a therapeutic option. Methods: Patients at Memorial Sloan Kettering Cancer Center, New York, who received immune checkpoint inhibitors and were treated with ustekinumab or had the keywords "ustekinumab" or "Stelara" in their clinical notes between 1 March 2017 and 1 December 2022 were retrospectively identified via a database query. Documentation from initial and follow-up visits was manually reviewed, and response to ustekinumab was categorized into complete cutaneous response (CcR, decrease to CTCAE grade 0), partial cutaneous response (PcR, any decrease in CTCAE grade exclusive of decrease to grade 0), and no cutaneous response (NcR, no change in CTCAE grade or worsening). Labs including complete blood count (CBC), cytokine panels, and IgE were obtained in a subset of patients as standard of care. Skin biopsies were reviewed by a dermatopathologist. Results: Fourteen patients with psoriasiform (85.7%), maculopapular (7.1%), and pyoderma gangrenosum (7.1%) ircAEs were identified. Ten (71.4%) receiving ustekinumab had a positive response to treatment. Among these 10 responders, 4 (40%) demonstrated partial cutaneous response and 6 (60%) demonstrated complete cutaneous resolution. Six patients (42.9%) experienced interruptions to their checkpoint inhibitor treatment as a result of intolerable ircAEs, and following ircAE management with ustekinumab, two (33.3%) were successfully rechallenged with their checkpoint inhibitors. On histopathology, patients primarily had findings of interface or psoriasiform dermatitis. No patients reported an adverse event related to ustekinumab. Conclusions: Ustekinumab showed a benefit in a subset of patients with psoriasiform/lichenoid ircAEs. No safety signals were identified. However, further prospective randomized controlled trials are needed to confirm our findings.
RÉSUMÉ
Immune-related cutaneous adverse events (ircAEs) commonly occur in patients on treatment with immune checkpoint inhibitors and can significantly reduce patient quality of life. These are often treated with immunomodulatory agents, including glucocorticoids, immunosuppressants, and biologics. While often effective at managing symptoms, these therapies can cause several adverse events which may limit their use. In addition, immunomodulatory agents should be used with particular caution in patients receiving immunotherapy, as the efficacy of the oncologic regimen may potentially be undermined. In this review, we summarize the safety of systemic therapies that are used in the management of ircAEs, with a particular focus on the resultant risk of secondary tumor progression in patients with active cancer.
RÉSUMÉ
Many biochemical processes use the Watson-Crick geometry to distinguish correct from incorrect base pairing. However, on rare occasions, mismatches such as Gâ¢T/U can transiently adopt Watson-Crick-like conformations through tautomerization or ionization of the bases, giving rise to replicative and translational errors. The propensities to form Watson-Crick-like mismatches in RNA:DNA hybrids remain unknown, making it unclear whether they can also contribute to errors during processes such as transcription and CRISPR/Cas editing. Here, using NMR R 1ρ experiments, we show that dGâ¢rU and dTâ¢rG mismatches in two RNA:DNA hybrids transiently form tautomeric (G enol â¢T/U âGâ¢T enol /U enol ) and anionic (Gâ¢T - /U - ) Watson-Crick-like conformations. The tautomerization dynamics were like those measured in A-RNA and B-DNA duplexes. However, anionic dGâ¢rU - formed with a ten-fold higher propensity relative to dT - â¢rG and dGâ¢dT - and this could be attributed to the lower pK a (Δ pK a â¼0.4-0.9) of U versus T. Our findings suggest plausible roles for Watson-Crick-like Gâ¢T/U mismatches in transcriptional errors and CRISPR/Cas9 off-target gene editing, uncover a crucial difference between the chemical dynamics of Gâ¢U versus Gâ¢T, and indicate that anionic Watson-Crick-like Gâ¢U - could play a significant role evading Watson-Crick fidelity checkpoints in RNA:DNA hybrids and RNA duplexes.
Sujet(s)
Anticorps bispécifiques , Antinéoplasiques , Lymphome malin non hodgkinien , Leucémie-lymphome lymphoblastique à précurseurs B , Leucémie-lymphome lymphoblastique à précurseurs B et T , Humains , Lymphocytes T , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Lymphome malin non hodgkinien/traitement médicamenteux , Anticorps bispécifiques/effets indésirables , Antinéoplasiques/effets indésirables , Leucémie-lymphome lymphoblastique à précurseurs B/traitement médicamenteuxRÉSUMÉ
Adoptive cellular immunotherapy, mainly hematopoietic stem cell transplant and CAR-T cell therapy have revolutionized treatment of patients with acute leukemia. Indications and inclusion criteria for these treatments have expanded in recent years. While these therapies are associated with significant improvements in disease response and overall survival, patients may experience adverse events from associated chemotherapy conditioning, engraftment, cytokine storm, supportive medications, and post-transplant maintenance targeted therapies. Supportive oncodermatology is a growing specialty to manage cutaneous toxicities resulting from the anti-cancer therapies. In this review, we summarize diagnosis and management of the common cutaneous adverse events including drug eruptions, graft-versus-host disease, neoplastic and paraneoplastic complications in patients undergoing cellular therapies.
Sujet(s)
Maladie du greffon contre l'hôte , Transplantation de cellules souches hématopoïétiques , Leucémie aigüe myéloïde , Humains , Transplantation de cellules souches hématopoïétiques/effets indésirables , Transplantation de cellules souches hématopoïétiques/méthodes , Maladie du greffon contre l'hôte/étiologie , Maladie du greffon contre l'hôte/thérapie , Leucémie aigüe myéloïde/thérapie , Transplantation homologue/effets indésirables , Immunothérapie adoptive/méthodes , Maladie aigüe , Conditionnement pour greffe/méthodesRÉSUMÉ
Immune checkpoint inhibitors (ICI) target the PD-1/PD-L1 and CTLA-4 pathways and allows the immune system to deliver antitumor effects. However, it is also associated with well-documented immune-related cutaneous adverse events (ircAEs), affecting up to 70-90% of patients on ICI. In this study, we describe the characteristics of and patient outcomes with ICI-associated steroid-refractory or steroid-dependent ircAEs treated with dupilumab. Patients with ircAEs treated with dupilumab between March 28, 2017, and October 1, 2021, at Memorial Sloan Kettering Cancer Center were included in this retrospective study, which assessed the rate of clinical response of the ircAE to dupilumab and any associated adverse events (AEs). Laboratory values were compared before and after dupilumab. All available biopsies of the ircAEs were reviewed by a dermatopathologist. Thirty-four of 39 patients (87%, 95% CI: 73% to 96%) responded to dupilumab. Among these 34 responders, 15 (44.1%) were complete responders with total ircAE resolution and 19 (55.9%) were partial responders with significant clinical improvement or reduction in severity. Only 1 patient (2.6%) discontinued therapy due to AEs, specifically, injection site reaction. Average eosinophil counts decreased by 0.2 K/mcL (p=0.0086). Relative eosinophils decreased by a mean of 2.6% (p=0.0152). Total serum immunoglobulin E levels decreased by an average of 372.1 kU/L (p=0.0728). The most common primary inflammatory patterns identified on histopathological examination were spongiotic dermatitis (n=13, 33.3%) and interface dermatitis (n=5, 12.8%). Dupilumab is a promising option for steroid-refractory or steroid-dependent immune-related cutaneous adverse events, particularly those that are eczematous, maculopapular, or pruritic. Among this cohort, dupilumab was well-tolerated with a high overall response rate. Nonetheless, prospective, randomized, controlled trials are warranted to confirm these observations and confirm its long-term safety.
Sujet(s)
Anticorps monoclonaux , Dermatite , Humains , Anticorps monoclonaux/usage thérapeutique , Études rétrospectives , Études prospectives , Dermatite/traitement médicamenteuxRÉSUMÉ
PURPOSE: Dermatologic adverse events (dAEs) occur frequently in hospitalized patients and can significantly reduce quality of life. Physicians grade dAEs using the Common Terminology Criteria of Adverse Events (CTCAE). However, they often underestimate symptom frequency and severity. The patient-reported outcomes (PRO) version of the CTCAE (PRO-CTCAE) was developed to assess symptoms from the patient's perspective. In this study, we assessed the patient-reported burden of dAEs via the PRO-CTCAE questionnaire and compared results with dAE assessment by treating oncologists and dermatologists. METHODS: Patients admitted to Memorial Sloan Kettering Cancer Center from 6/1/2018 to 4/30/2019 and received a dermatology consultation were eligible. Once enrolled, participants completed a PRO-CTCAE questionnaire on 14 dermatologic symptoms. CTCAE grades assigned by oncology and dermatology were obtained from clinical notes, and kappa statistics were calculated to evaluate the level of agreement between physician and patient evaluations. RESULTS: A total of 100 patients (mean age 59.4, 55% male) were prospectively enrolled. The most common patient-reported dAEs were rash (72%), swelling (67%), pruritus (64%), bruising (53%), and hives (37%). Oncologists and dermatologists underreported dAEs except for rash (median kappa values 0.3 [0.02-0.84] and 0.32 [0.02-0.87], respectively). Oncologists and dermatologists were concordant with each other's documented assessment of dAEs (median kappa value 0.985 [0.55-1]). CONCLUSION: Oncology patient-reported dAEs in a tertiary academic oncologic referral center were under-recognized by providers. PRO-CTCAE may be a useful tool to optimize inpatient dermatologic care for cancer patients by detecting and allowing management of patient-reported dAEs.
Sujet(s)
Exanthème , Tumeurs , Humains , Mâle , Adulte d'âge moyen , Femelle , Qualité de vie , Tumeurs/traitement médicamenteux , Mesures des résultats rapportés par les patients , Enquêtes et questionnairesRÉSUMÉ
Purpose: The combination of trastuzumab and pertuzumab (HP) as part of a taxane-based regimen has shown benefit in the adjuvant and metastatic HER2+ breast cancer setting. In the CLEOPATRA trial, pruritus was reported in 11-17.6% of patients. The clinical phenotype and potential treatment strategies for this event have not been reported. Methods: A retrospective review of 2583 patients receiving trastuzumab and pertuzumab for the treatment of HER2+ breast cancer from 11/23/2011 to 6/21/2021 was performed at Memorial Sloan Kettering Cancer Center (MSKCC). Patient demographics, pruritus characteristics, and treatments as documented in the electronic medical record (EMR) were included in this analysis. Results: Of 2583 pts treated with HP, 122 (4.72%) with pruritus were identified. On average, patients experienced pruritus 319.0 days (8-3171) after initiation of HP. The upper extremities (67.4%), back (29.3%), lower extremities (17.4%), and shoulders (14.1%) were the most commonly affected regions. Grade 1/2 pruritus (97.6%) occurred in most cases. Patients responded primarily to treatment with topical steroids (52.2%), antihistamines (29.9%), emollients (20.9%), and gabapentinoids (16.4%). Of those with pruritus, 4 patients (3.3%) required treatment interruption or discontinuation. Conclusions: Pruritus is uncommon in patients on trastuzumab and pertuzumab, generally a chronic condition, with gabapentinoids or antihistamines representing effective therapies.
RÉSUMÉ
Replicative errors contribute to the genetic diversity needed for evolution but in high frequency can lead to genomic instability. Here, we show that DNA dynamics determine the frequency of misincorporating the Aâ¢G mismatch, and altered dynamics explain the high frequency of 8-oxoguanine (8OG) Aâ¢8OG misincorporation. NMR measurements revealed that Aantiâ¢Ganti (population (pop.) of >91%) transiently forms sparsely populated and short-lived Aanti+â¢Gsyn (pop. of ~2% and kex = kforward + kreverse of ~137 s-1) and Asynâ¢Ganti (pop. of ~6% and kex of ~2,200 s-1) Hoogsteen conformations. 8OG redistributed the ensemble, rendering Aantiâ¢8OGsyn the dominant state. A kinetic model in which Aanti+â¢Gsyn is misincorporated quantitatively predicted the dAâ¢dGTP misincorporation kinetics by human polymerase ß, the pH dependence of misincorporation and the impact of the 8OG lesion. Thus, 8OG increases replicative errors relative to G because oxidation of guanine redistributes the ensemble in favor of the mutagenic Aantiâ¢8OGsyn Hoogsteen state, which exists transiently and in low abundance in the Aâ¢G mismatch.
Sujet(s)
Altération de l'ADN , ADN , Humains , Appariement de bases , ADN/composition chimique , MutagenèseRÉSUMÉ
Watson-Crick base pairs (bps) are the fundamental unit of genetic information and the building blocks of the DNA double helix. However, A-T and G-C can also form alternative 'Hoogsteen' bps, expanding the functional complexity of DNA. We developed 'Hoog-finder', which uses structural fingerprints to rapidly screen Hoogsteen bps, which may have been mismodeled as Watson-Crick in crystal structures of protein-DNA complexes. We uncovered 17 Hoogsteen bps, 7 of which were in complex with 6 proteins never before shown to bind Hoogsteen bps. The Hoogsteen bps occur near mismatches, nicks and lesions and some appear to participate in recognition and damage repair. Our results suggest a potentially broad role for Hoogsteen bps in stressed regions of the genome and call for a community-wide effort to identify these bps in current and future crystal structures of DNA and its complexes.
Sujet(s)
Appariement de bases , Protéines de liaison à l'ADN/composition chimique , ADN/composition chimique , Conformation d'acide nucléique , Domaines protéiques , Séquence nucléotidique , Sites de fixation/génétique , Biologie informatique/méthodes , Cristallographie aux rayons X , ADN/génétique , ADN/métabolisme , Protéines de liaison à l'ADN/génétique , Protéines de liaison à l'ADN/métabolisme , Bases de données génétiques , Liaison hydrogène , Modèles moléculaires , Mutation , Liaison aux protéines , ThermodynamiqueRÉSUMÉ
Urticarial vasculitis is a rare clinicopathologic entity that is characterized by chronic or recurrent episodes of urticarial lesions. Skin findings of this disease can be difficult to distinguish visually from those of chronic idiopathic urticaria but are unique in that individual lesions persist for ≥24 hours and can leave behind dusky hyperpigmentation. This disease is most often idiopathic but has been linked to certain drugs, infections, autoimmune connective disease, myelodysplastic disorders, and malignancies. More recently, some authors have reported associations between urticarial vasculitis and COVID-19, as well as influenza A/H1N1 infection. Urticarial vasculitis can extend systemically as well, most often affecting the musculoskeletal, renal, pulmonary, gastrointestinal, and ocular systems. Features of leukocytoclastic vasculitis seen on histopathologic examination are diagnostic of this disease, but not always seen. In practice, antibiotics, dapsone, colchicine, and hydroxychloroquine are popular first-line therapies, especially for mild cutaneous disease. In more severe cases, immunosuppressives, including methotrexate, mycophenolate mofetil, azathioprine, and cyclosporine, as well as corticosteroids, may be necessary for control. More recently, select biologic therapies, including rituximab, omalizumab, and interleukin-1 inhibitors have shown promise for the treatment of recalcitrant or refractory cases.
RÉSUMÉ
Here we report the development of a ternary version of the LexA::VP16/LexAop system in which the DNA-binding and trans-activating moieties are independently targeted using distinct promoters to achieve highly restricted, intersectional expression patterns. This Split LexA system can be concatenated with the Gal4/upstream activating sequence system to refine the expression patterns of existing Gal4 lines with minimal genetic manipulations.