RESUMO
The nascent field of computationally aided molecular design will be built around the ability to make computation useful to synthetic chemists who draw on their empirically based chemical intuition to synthesize new and useful molecules. This fact poses a dilemma, as much of existing chemical intuition is framed in the language of chemical bonds, which are pictured as possessing physical properties. Unfortunately, it has been posited that calculating these bond properties is impossible because chemical bonds do not exist. For much of the computationalchemistry community, bonds are seen as mythical-the unicorns of the chemical world. Here, we show that this is not the case. Using the same formalism and concepts that illuminated the atoms in molecules, we shine light on the bonds that connect them. The real space analogue of the chemical bond becomes the bond bundle in an extended quantum theory of atoms in molecules (QTAIM). We show that bond bundles possess all the properties typically associated with chemical bonds, including an energy and electron count. In addition, bond bundles are characterized by a number of nontraditional attributes, including, significantly, a boundary. We show, with examples drawn from solid state and molecular chemistry, that the calculated properties of bond bundles are consistent with those that nourish chemical intuition. We go further, however, and show that bond bundles provide new and quantifiable insights into the structure and properties of molecules and materials.
Assuntos
Elétrons , Teoria Quântica , Ligação de HidrogênioRESUMO
NTRK fusions represent a new biomarker-defined population that can be treated with TRK inhibitors. Although rare, NTRK fusions are detected across a wide range of solid tumors. Previous reports suggest that NTRK fusions are limited to the secretory subtype of breast cancer. Here we examined NTRK fusions in a large real world next-generation sequencing (NGS) dataset and confirmed secretory versus non-secretory status using H&E images. Of 23 NTRK fusion-positive cases, 11 were classified as secretory, 11 as non-secretory, and one as mixed status. The secretory subtype trended younger, was predominantly estrogen receptor (ER)-, had lower tumor mutational burden, and exhibited lower levels of genomic loss of heterozygosity. The non-secretory subtype was enriched for TP53 mutations. The secretory subtype was enriched for ETV6-NTRK3 fusions in 7 of 11 cases, and the non-secretory subtype had NTRK1 fusions in 7 of 11 cases, each with a different fusion partner. Our data suggests NTRK fusions are present in both secretory and non-secretory subtypes, and that comprehensive genomic profiling should be considered across all clinically advanced breast cancers to identify patients that could receive benefit from TRK inhibitors.
Assuntos
Neoplasias da Mama/genética , Carcinoma/diagnóstico , Receptor trkA/genética , Idoso , Neoplasias da Mama/diagnóstico , Carcinoma/genética , Feminino , Fusão Gênica/efeitos dos fármacos , Fusão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Imuno-Histoquímica/métodos , Imuno-Histoquímica/estatística & dados numéricos , Pessoa de Meia-Idade , Receptor trkA/efeitos adversos , Receptor trkC/genéticaRESUMO
A novel form of charge density analysis, that of isosurface curvature redistribution, is formulated and applied to the toy problem of carbonyl oxygen activation in formaldehyde. The isosurface representation of the electron charge density allows us to incorporate the rigorous geometric constraints of closed surfaces toward the analysis and chemical interpretation of the charge density response to perturbations. Visual inspection of 2D isosurface motion resulting from applied external electric fields reveals how the isosurface curvature flows within and between atoms and that a molecule can be uniquely and completely partitioned into chemically significant regions of positive and negative curvatures. These concepts reveal that carbonyl oxygen activation proceeds primarily through curvature and charge redistribution within rather than between Bader atoms. Using gradient bundle analysisâthe partitioning of formaldehyde into infinitesimal volume elements bounded by QTAIM zero-flux surfacesâthe observations from visual isosurface inspection are verified. The results of the formaldehyde carbonyl analysis are then shown to be transferable to the substrate carbonyl in the ketosteroid isomerase enzyme, laying the groundwork for extending this approach to the problems of enzymatic catalysis.
RESUMO
For the better part of a century researchers across disciplines have sought to explain the crystallography of the elemental transition metals: hexagonal close packed, body centered cubic, and face centered cubic in a form similar to that used to rationalize the structure of organic molecules and inorganic complexes. Pauling himself tried with limited success to address the origins of transition metal stability. These early investigators were handicapped, however, by incomplete knowledge regarding the structure of metallic electron density. Here, we exploit modern approaches to electron density analysis to first comprehensively describe transition metal electron density. Then, we use topological partitioning and quantum mechanically rigorous treatments of kinetic energy to account for the structure of the density as arising from the interactions between metallic polyhedra. We argue that the crystallography of the early transition metals results from charge transfer from the so called "octahedral" to "tetrahedral cages" while the face centered cubic structure of the late transition metals is a consequence of anti-bonding interactions that increase octahedral hole kinetic energy.
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BACKGROUND: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. METHODS: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. INTERPRETATION: Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. FUNDING: Ignyta/F Hoffmann-La Roche.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Biomarcadores Tumorais/genética , Fusão Gênica , Indazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/genética , Idoso , Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Indazóis/efeitos adversos , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkC/antagonistas & inibidores , Receptor trkC/genética , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC. METHODS: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred. INTERPRETATION: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC. FUNDING: Ignyta/F Hoffmann-La Roche.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fusão Gênica , Indazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Indazóis/efeitos adversos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Fatores de TempoRESUMO
BACKGROUND: Endocrine therapy-based neoadjuvant treatment for luminal breast cancer allows efficient testing of new combinations before surgery. The activation of the phosphatidylinositol-3-kinase (PI3K) pathway is a known mechanism of resistance to endocrine therapy. Taselisib is an oral, selective PI3K inhibitor with enhanced activity against PIK3CA-mutant cancer cells. The LORELEI trial tested whether taselisib in combination with letrozole would result in an increased proportion of objective responses and pathological complete responses. METHODS: In this multicentre, randomised, double-blind, parallel-cohort, placebo-controlled phase 2, study, we enrolled postmenopausal women (aged ≥18 years) with histologically confirmed, oestrogen receptor (ER)-positive, HER2-negative, stage I-III, operable breast cancer, from 85 hospitals in 22 countries worldwide. To be eligible, patients had have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1, adequate organ function, and had to have evaluable tumour tissue for PIK3CA genotyping. Patients were randomly assigned (1:1) by means of a permuted block algorithm (block size of four) via an interactive voice or web-based response system, to receive letrozole (2·5 mg/day orally, continuously) with either 4 mg of oral taselisib or placebo (on a 5 days-on, 2 days-off schedule) for 16 weeks, followed by surgery. Randomisation was stratified by tumour size and nodal status. Site staff, patients, and the sponsor were masked to treatment assignment. Coprimary endpoints were the proportion of patients who achieved an objective response by centrally assessed breast MRI and a locally assessed pathological complete response in the breast and axilla (ypT0/Tis, ypN0) at surgery in all randomly assigned patients and in patients with PIK3CA-mutant tumours. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02273973, and is closed to accrual. FINDINGS: Between Nov 12, 2014, and Aug 12, 2016, 334 participants were enrolled and randomly assigned to receive letrozole and placebo (n=168) or letrozole and taselisib (n=166). Median follow-up was 4·9 months (IQR 4·7-5·1). The study met one of its primary endpoints: the addition of taselisib to letrozole was associated with a higher proportion of patients achieving an objective response in all randomly assigned patients (66 [39%] of 168 patients in the placebo group vs 83 [50%] of 166 in the taselisib group; odds ratio [OR] 1·55, 95% CI 1·00-2·38; p=0·049) and in the PIK3CA-mutant subset (30 [38%] of 79 vs 41 [56%] of 73; OR 2·03, 95% CI 1·06-3·88; p=0·033). No significant differences were observed in pathological complete response between the two groups, either in the overall population (three [2%] of 166 in the taselisib group vs one [1%] of 168 in the placebo group; OR 3·07 [95% CI 0·32-29·85], p=0·37) or in the PIK3CA-mutant cohort (one patient [1%) vs none [0%]; OR not estimable, p=0·48). The most common grade 3-4 adverse events in the taselisib group were gastrointestinal (13 [8%] of 167 patients), infections (eight [5%]), and skin-subcutaneous tissue disorders (eight [5%]). In the placebo group, four (2%) of 167 patients had grade 3 or worse vascular disorders, two (1%) had gastrointestinal disorders, and two (1%) patients had grade 3 or worse infections and infestations. There was no grade 4 hyperglycaemia and grade 3 cases were asymptomatic. Serious adverse events were more common in the taselisib group (eight [5%] patients with infections and seven [4%] with gastrointestinal effects) than in the placebo group (one [1%] patient each with grade 3 postoperative wound and haematoma infection, grade 4 hypertensive encephalopathy, grade 3 acute cardiac failure, and grade 3 breast pain). One death occurred in the taselisib group, which was not considered to be treatment-related. INTERPRETATION: The increase in the proportion of patients who achieved an objective response from the addition of taselisib to endocrine therapy in a neoadjuvant setting is consistent with the clinical benefit observed in hormone receptor-positive, HER2-negative, metastatic breast cancer. FUNDING: Genentech and F Hoffmann-La Roche.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Imidazóis/administração & dosagem , Letrozol/administração & dosagem , Oxazepinas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Imidazóis/efeitos adversos , Letrozol/efeitos adversos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Oxazepinas/efeitos adversos , Pós-Menopausa , Receptor ErbB-2/genética , Resultado do TratamentoRESUMO
PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Oxazepinas/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Mama/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Docetaxel/efeitos adversos , Docetaxel/farmacocinética , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Neoplasias Pulmonares/genética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Oxazepinas/efeitos adversos , Oxazepinas/farmacocinética , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Receptor ErbB-2/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
Our curiosity-driven desire to "see" chemical bonds dates back at least one-hundred years, perhaps to antiquity. Sweeping improvements in the accuracy of measured and predicted electron charge densities, alongside our largely bondcentric understanding of molecules and materials, heighten this desire with means and significance. Here we present a method for analyzing chemical bonds and their energy distributions in a two-dimensional projected space called the condensed charge density. Bond "silhouettes" in the condensed charge density can be reverse-projected to reveal precise three-dimensional bonding regions we call bond bundles. We show that delocalized metallic bonds and organic covalent bonds alike can be objectively analyzed, the formation of bonds observed, and that the crystallographic structure of simple metals can be rationalized in terms of bond bundle structure. Our method also reproduces the expected results of organic chemistry, enabling the recontextualization of existing bond models from a charge density perspective.
RESUMO
Mutationally activated kinases define a clinically validated class of targets for cancer drug therapy. However, the efficacy of kinase inhibitors in patients whose tumours harbour such alleles is invariably limited by innate or acquired drug resistance. The identification of resistance mechanisms has revealed a recurrent themethe engagement of survival signals redundant to those transduced by the targeted kinase. Cancer cells typically express multiple receptor tyrosine kinases (RTKs) that mediate signals that converge on common critical downstream cell-survival effectorsmost notably, phosphatidylinositol-3-OH kinase (PI(3)K) and mitogen-activated protein kinase (MAPK). Consequently, an increase in RTK-ligand levels, through autocrine tumour-cell production, paracrine contribution from tumour stroma or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar signalling output. Here, using a panel of kinase-'addicted' human cancer cell lines, we found that most cells can be rescued from drug sensitivity by simply exposing them to one or more RTK ligands. Among the findings with clinical implications was the observation that hepatocyte growth factor (HGF) confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells. These observations highlight the extensive redundancy of RTK-transduced signalling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Fator de Crescimento de Hepatócito/metabolismo , Indóis/farmacologia , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sulfonamidas/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Lapatinib , Ligantes , Melanoma/enzimologia , Melanoma/genética , Melanoma/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Quinazolinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , VemurafenibRESUMO
BACKGROUND: Readmission rates after surgical procedures are viewed as a marker of quality of care and as a driver to improve outcomes in the United Kingdom, they are not remunerated. However, readmissions are not wholly avoidable. The aim of this study was to develop a regional overview of readmissions to determine the proportion that might be avoidable and to examine predictors of readmissions at a unit level. METHODS: We undertook a prospective multicenter audit of readmissions following National Health Service funded general surgical procedures in five National Health Service hospitals and three independent sector providers over a 2-wk period. Basic demographic and procedure data were captured. Readmissions to hospitals were identified through acute admissions lists. Reason for readmission was identified, and the readmission data assessed by a senior surgical doctor as to whether it was avoidable. RESULTS: We identified 752 operations in the study period with all followed up to 30 d. The overall rate of readmissions was 4.7%, with 40% of these judged as being potentially avoidable. Pain and wound problems accounted for the vast majority of avoidable readmissions. The number of unavoidable readmissions was correlated with the workload of each center (r = 0.63, P = 0.06) and as with the higher (British United Provident Association) complexity of surgery (r = 0.90, P = 0.01). Patient and demographic factors were not associated with readmissions. CONCLUSIONS: This prospective audit describes readmission rates after general surgery. Volume and complexity of work are associated with readmission rates. A large proportion of readmissions could be reduced by attention to analgesia and outpatient arrangements for wound management.
Assuntos
Cirurgia Geral/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Estudos Prospectivos , Carga de Trabalho , Adulto JovemRESUMO
Predicting chemical reactivity is a major goal of chemistry. Toward this end, atom condensed Fukui functions of conceptual density functional theory have been used to predict which atom is most likely to undergo electrophilic or nucleophilic attack, providing regioselectivity information. We show that the most probable regions for electrophilic attack within each atom can be predicted through analysis of gradient bundle volumes, a property that depends only on the charge density of the neutral molecules. We also introduce gradient bundle condensed Fukui functions to compare the stereoselectivity information obtained from gradient bundle volume analysis. We demonstrate this method using the test set of molecular fluorine, oxygen, nitrogen, carbon monoxide, and hydrogen cyanide.
RESUMO
Breast cancers are categorized into three subtypes based on protein expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2/ERBB2). Patients enroll onto experimental clinical trials based on ER, PR, and HER2 status and, as receptor status is prognostic and defines treatment regimens, central receptor confirmation is critical for interpreting results from these trials. Patients enrolling onto experimental clinical trials in the metastatic setting often have limited available archival tissue that might better be used for comprehensive molecular profiling rather than slide-intensive reconfirmation of receptor status. We developed a Random Forests-based algorithm using a training set of 158 samples with centrally confirmed IHC status, and subsequently validated this algorithm on multiple test sets with known, locally determined IHC status. We observed a strong correlation between target mRNA expression and IHC assays for HER2 and ER, achieving an overall accuracy of 97 and 96%, respectively. For determining PR status, which had the highest discordance between central and local IHC, incorporation of expression of co-regulated genes in a multivariate approach added predictive value, outperforming the single, target gene approach by a 10% margin in overall accuracy. Our results suggest that multiplexed qRT-PCR profiling of ESR1, PGR, and ERBB2 mRNA, along with several other subtype associated genes, can effectively confirm breast cancer subtype, thereby conserving tumor sections and enabling additional biomarker data to be obtained from patients enrolled onto experimental clinical trials.
Assuntos
Algoritmos , Biomarcadores Tumorais/genética , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/metabolismo , RNA Neoplásico/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Ensaios Clínicos Fase III como Assunto , Feminino , Seguimentos , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Limite de Detecção , Estudos Multicêntricos como Assunto , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Curva ROC , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de SobrevidaRESUMO
Racial/ethnic disparities mar NSCLC care and treatment outcomes. While socioeconomic factors and access to healthcare are important drivers of NSCLC disparities, a deeper understanding of genetic ancestry-associated genomic landscapes can better inform the biology and the treatment actionability for these tumors. We present a comprehensive ancestry-based prevalence and co-alteration landscape of genomic alterations and immunotherapy-associated biomarkers in patients with KRAS and EGFR-altered non-squamous (non-Sq) NSCLC. KRAS was the most frequently altered oncogene in European (EUR) and African (AFR), while EGFR alterations predominated in East Asian (EAS), South Asian (SAS), and Admixed American (AMR) groups, consistent with prior studies. As expected, STK11 and KEAP1 alterations co-occurred with KRAS alterations while showing mutual exclusivity with EGFR alterations. EAS and AMR KRAS-altered non-Sq NSCLC showed lower rates of co-occurring STK11 and KEAP1 alterations relative to other ancestry groups. Ancestry-specific co-alterations included the co-occurrence of KRAS and GNAS alterations in AMR, KRAS, and ARID1A alterations in SAS, and the mutual exclusivity of KRAS and NF1 alterations in the EUR and AFR ancestries. Contrastingly, EGFR-altered tumors exhibited a more conserved co-alteration landscape across ancestries. AFR exhibited the highest tumor mutational burden, with potential therapeutic implications for these tumors.
RESUMO
PURPOSE: Despite being readily available and practical to administer, standardised instruments are not widely used in clinical practice. Concerns have been raised about the validity of applying such data to individuals. The aim of this qualitative study was to explore the practical difficulties of interpreting standardised HrQoL data for individual patients. METHODS: A purposive sample of 20 patients with colorectal cancer was chosen from 210 participants in a prospective HrQoL study. In an in-depth interview, individual participants were asked about their experiences and to review the accuracy of their own HrQoL data, collected over preceding months using four different instruments (FACT-C QLQ-C30/CR38 SF12 and EQ-5D). A framework qualitative analysis was used to develop emerging themes. RESULTS: A number of themes emerged from the analysis to explain why disparity arose between the patients' experiences and the questionnaire data in certain situations. These included weakly worded items that over emphasised health problems, incongruous items within scales causing unpredictable scores, insufficient levels of response causing insensitivity, and unrecognised reversal of item direction causing contradictory scores. Exogenous factors such as mood and co-morbidities also influenced HrQoL reporting. CONCLUSIONS: Data from standardised instruments can be used to measure the HrQoL of individuals in clinical practice, but the instruments used need careful selection and interpretation. Appropriate guidance linked to the themes of this study is provided.
Assuntos
Neoplasias Colorretais/psicologia , Psicometria/instrumentação , Qualidade de Vida , Inquéritos e Questionários , Idoso , Interpretação Estatística de Dados , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Pesquisa Qualitativa , Reprodutibilidade dos TestesRESUMO
Enzymes host active sites inside protein macromolecules, which have diverse, often incredibly complex, and atom-expensive structures. It is an outstanding question what the role of these expensive scaffolds might be in enzymatic catalysis. Answering this question is essential to both enzymology and the design of artificial enzymes with proficiencies that will match those of the best natural enzymes. Protein rigidifying the active site, contrasted with the dynamics and vibrational motion promoting the reaction, as well as long-range electrostatics (also known as electrostatic preorganization) were all proposed as central contributions of the scaffold to the catalysis. Here, we show that all these effects inevitably produce changes in the quantum mechanical electron density in the active site, which in turn defines the reactivity. The phenomena are therefore fundamentally inseparable. The geometry of the electron density-a scalar field characterized by a number of mathematical features such as critical points-is a rigorous and convenient descriptor of enzymatic catalysis and a reporter on the role of the protein. We show how this geometry can be analyzed, linked to the reaction barriers, and report in particular on intramolecular electric fields in enzymes. We illustrate these tools on the studies of electrostatic preorganization in several representative enzyme classes, both natural and artificial. We highlight the forward-looking aspects of the approach.
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Eletricidade Estática , Catálise , Domínio Catalítico , Movimento (Física)RESUMO
BACKGROUND: Emergency general surgery practice is high risk. Surgery is a key part of treatment, with resultant catabolic stress and frequent need for nutritional support. The aim of this study was to examine the current methods of defining and determining malnutrition in emergency general surgery. This included examining the use of nutrition screening and assessment tools and other measures of malnutrition. METHODS: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, trial registries, and relevant journals published between January 2000 and January 2022 were searched for studies of adult patients with any emergency general surgery diagnosis, managed conservatively or operatively, with an assessment of nutritional status. Mixed populations were included if more than 50 per cent of patients were emergency general surgery patients or emergency general surgery results could be separately extracted. Studies in which patients had received nutritional support were excluded. The protocol was registered with PROSPERO, the international prospective register of systematic reviews (CRD42021285897). RESULTS: From 6700 studies screened, 324 full texts were retrieved and 31 were included in the analysis. A definition of malnutrition was provided in 23 studies (75 per cent), with nutritional status being determined by a variety of methods. A total of seven nutrition screening tools and a total of nine 'assessment' tools were reported. To define malnutrition, the most commonly used primary or secondary marker of nutritional status was BMI, followed by albumin level. CONCLUSION: Wide variation exists in approaches to identify malnutrition risk in emergency general surgery patients, using a range of tools and nutrition markers. Future studies should seek to standardize nutrition screening and assessment in the emergency general surgery setting as two discrete processes. This will permit better understanding of malnutrition risk in surgical patients.
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Desnutrição , Adulto , Humanos , Revisões Sistemáticas como Assunto , Desnutrição/diagnóstico , Estado Nutricional , Sistema de RegistrosRESUMO
PURPOSE: To comprehensively characterize tissue-specific and molecular subclasses of multiple PIK3CA (multi-PIK3CA) mutations and assess their impact on potential therapeutic outcomes. EXPERIMENTAL DESIGN: We profiled a pan-cancer cohort comprised of 352,392 samples across 66 tumor types using a targeted hybrid capture-based next-generation sequencing panel covering at least 324 cancer-related genes. Molecularly defined subgroups, allelic configuration, clonality, and mutational signatures were identified and tested for association with PI3K inhibitor therapeutic response. RESULTS: Multi-PIK3CA mutations are found in 11% of all PIK3CA-mutant tumors, including 9% of low tumor mutational burden (TMB) PIK3CA-mutant tumors, and are enriched in breast and gynecologic cancers. Multi-PIK3CA mutations are frequently clonal and in cis on the same allele and occur at characteristic positions across tumor types. These mutations tend to be mutually exclusive of mutations in other driver genes, and of genes in the PI3K pathway. Among PIK3CA-mutant tumors with a high TMB, 18% are multi-PIK3CA mutant and often harbor an apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational signature. Despite large differences in specific allele combinations comprising multi-PIK3CA mutant tumors, especially across cancer types, patients with different classes of multi-PIK3CA mutant estrogen receptor-positive, HER2-negative breast cancers respond similarly to PI3K inhibition. CONCLUSIONS: Our pan-tumor study provides biological insights into the genetic heterogeneity and tissue specificities of multi-PIK3CA mutations, with potential clinical utility to guide PI3K inhibition strategies.
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Neoplasias da Mama , Fosfatidilinositol 3-Quinases , Humanos , Feminino , Fosfatidilinositol 3-Quinases/genética , Heterogeneidade Genética , Neoplasias da Mama/patologia , Mutação , Classe I de Fosfatidilinositol 3-Quinases/genéticaRESUMO
Taselisib is a potent ß-sparing phosphatidylinositol 3-kinase (PI3K) inhibitor that, with endocrine therapy, improves outcomes in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated (PIK3CAmut) advanced breast cancer. To understand alterations associated with response to PI3K inhibition, we analysed circulating tumour DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CAmut or PIK3CA no mutation was detected (NMD) per baseline ctDNA. The top mutated genes and tumour fraction estimates identified were analysed for their association with outcomes. In participants with PIK3CAmut ctDNA treated with taselisib + fulvestrant, tumour protein p53 (TP53; encoding p53) and fibroblast growth factor receptor 1 (FGFR1) alterations were associated with shorter progression-free survival (PFS) compared to participants with NMD in these genes. Conversely, participants with PIK3CAmut ctDNA harbouring a neurofibromin 1 (NF1) alteration or high baseline tumour fraction estimate experienced improved PFS upon treatment with taselisib + fulvestrant compared to placebo + fulvestrant. Broadly, alterations in oestrogen receptor (ER), PI3K and p53 pathway genes were associated with resistance to taselisib + fulvestrant in participants with PIK3CAmut ctDNA. Altogether, we demonstrated the impact of genomic (co-)alterations on outcomes with one of the largest clinico-genomic datasets of ER+, HER2-, PIK3CAmut breast cancer patients treated with a PI3K inhibitor.