Abstract
CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 ...patients are treated across 10 dose levels (50–650 mg/m
2
) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m
2
days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.
The COVID-19 pandemic represents one of the greatest ever challenges for healthcare. In the UK and beyond, acute medical units (AMUs) are the first point of assessment and care for the majority of ...medical inpatients. By their design and systems, they inevitably played an important role in the COVID-19 response but to date little has been published on how the COVID-19 pandemic has affected how AMUs have reorganised their resources, processes and structure.
This retrospective study in August 2020 of 10 AMUs across Europe and Australasia used a standardised questionnaire to investigate existing practice and structure of AMUs, the national context of local hospital experience, changes to practice during the COVID-19 pandemic and views regarding future practice.
Changes to AMU structure, process and organisation are described in two contexts: preventing and controlling the spread of COVID-19 and adding value to the patient's acute care journey in the local context. We describe novel practices that have arisen and highlight areas of concern.
The AMUs were able to adapt to meet the demands of acute care delivery during the first wave of the COVID-19 pandemic. Operational planning and prioritisation of resources must be optimised to ensure sustainability of these services for future waves.
One in 10 independently living adults aged 65 years old and older is considered frail, and frailty is associated with poor postoperative outcomes. This systematic review aimed to examine the ...association between frailty assessments and postoperative outcomes in patients with vascular disease. Electronic databases – MEDLINE, Embase, and the Cochrane Library – were searched from inception until January 2022, resulting in 648 articles reviewed for potential inclusion and 16 studies selected. Demographic data, surgery type, frailty measure, and postoperative outcomes predicted by frailty were extracted from the selected studies. The risk of bias was assessed using the Newcastle–Ottawa Scale. The selected studies (mean age: 56.1–76.3 years) had low-to-moderate risk of bias and included 16 vascular (elective and nonelective) surgeries and eight frailty measures. Significant associations (p < 0.05) were established between mortality (30-day, 90-day, 1-year, 5-year), 30-day morbidity, nonhome discharge, adverse events, failure to rescue, patient requiring care after discharge, and amputation following critical limb ischaemia. The strongest evidence was found between 30-day mortality and frailty. Composite 30-day morbidity and mortality, functional status at discharge, length of stay, spinal cord deficit, and access site complications were found to be nonsignificantly associated with frailty. With frailty being significantly associated with several adverse postoperative outcomes, preoperative frailty assessments can potentially be clinically useful in helping practitioners predict and guide the pre-, peri-, and postoperative management of frail with vascular disease.
Identifying older people with clinical frailty, reliably and at scale, is a research priority. We measured frailty in older people using a novel methodology coding frailty syndromes on routinely ...collected administrative data, developed on a national English secondary care population, and explored its performance of predicting inpatient mortality and long length of stay at a single acute hospital.
We included patient spells from Secondary User Service (SUS) data for those ≥65 years with attendance to the emergency department or admission to West Middlesex University Hospital between 01 July 2016 to 01 July 2017. We created eight groups of frailty syndromes using diagnostic coding groups. We used descriptive statistics and logistic regression to explore performance of diagnostic coding groups for the above outcomes.
We included 17,199 patient episodes in the analysis. There was at least one frailty syndrome present in 7,004 (40.7%) patient episodes. The resultant model had moderate discrimination for inpatient mortality (area under the receiver operating characteristic curve (AUC) 0.74; 95% confidence interval (CI) 0.72–0.76) and upper quartile length of stay (AUC 0.731; 95% CI 0.722–0.741). There was good negative predictive value for inpatient mortality (98.1%).
Coded frailty syndromes significantly predict outcomes. Model diagnostics suggest the model could be used for screening of elderly patients to optimise their care.
Purpose
Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association ...between CK2 activation and paclitaxel resistance in a gastric cancer (GC).
Experimental design
CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model.
Results
Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%,
p
= 0.017) and shorter progression-free survival (2.8 vs. 4.8 months,
p
= 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities.
Conclusions
These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.
•CX-5461 may enhance immune checkpoint inhibitor (ICI) therapeutic efficacy.•CX-5461 triggers cGAS-STING-IFN pathway, eliciting STAT1-mediated PD-L1 expression.•CX-5461+ICI leads to improved ...immunotherapeutic effects in CRC.•They increase cytotoxic T-cell and reduce myeloid-derived suppressor cell numbers.•CX-5461 can turn cold CRC tumors into hot ones.
Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy can improve the limited efficacy of colorectal cancer (CRC) immunotherapy. CX-5461 causes substantial DNA damage and genomic instability and can increase ICIs’ therapeutic efficacies through tumor microenvironment alteration.
We analyzed whether CX-5461 enhances ICIs’ effects in CRC and discovered that CX-5461 causes severe DNA damage, including cytosolic dsDNA appearance, in various human and mouse CRC cells. Our bioinformatics analysis predicted CX-5461-based interferon (IFN) signaling pathway activation in these cells, which was verified by the finding that CX-5461 induces IFN-α and IFN-β secretion in these cells. Next, cGAMP, phospho-IRF3, CCL5, and CXCL10 levels exhibited significant posttreatment increases in CRC cells, indicating that CX-5461 activates the cGAS-STING-IFN pathway. CX-5461 also enhanced PD-L1 expression through STAT1 activation. CX-5461 alone inhibited tumor growth and prolonged survival in mice. CX-5461+anti-PD-1 or anti-PD-L1 alone exhibited synergistic growth-suppressive effects against CRC and breast cancer. CX-5461 alone or CX-5461+anti-PD-1 increased cytotoxic T-cell numbers and reduced myeloid-derived suppressor cell numbers in mouse spleens.
Therefore, clinically, CX-5461 combined with ICIs for CRC therapy warrants consideration because CX-5461 can turn cold tumors into hot ones.
•Hyperinflammatory phenotypes exist for critically ill patients with COVID-19.•This distinct phenotype is also demonstrated in relatively mild COVID-19 illness.•Can be easily identified by a ...C-reactive protein level at presentation.•Hyperinflammatory phenotype predicts poor outcomes, even in mild COVID-19.•C-reactive protein may be used to guide prognostication and therapeutics for COVID-19.
In critically ill patients with COVID-19, distinct hyperinflammatory and hypoinflammatory phenotypes have been described, with different outcomes and responses to therapy. We investigated if similar phenotypes exist in non-severe illness.
Consecutive patients with polymerase chain reaction (PCR) confirmed SARS-CoV-2 were examined. Baseline demographics and laboratory investigations were tabulated, including serum C-reactive protein. Patients were divided into those who were hyperinflammatory (defined as C-reactive protein >17 mg/l) or hypoinflammatory. Adverse outcomes, defined as requiring oxygenation, intensive care, or death, were recorded during the hospital stay. Clinical characteristics and outcomes were compared.
Of the 1781 patients examined, 276 (15.5%) had a hyperinflammatory phenotype. They were older (51.8 ± 17.2 vs 40.3 ± 13.8 years, P <0.001), had a lower PCR cycle threshold (PCR cycle threshold value 19.3 ± 6.3 vs 22.7 ± 15.4, P = 0.025) at presentation, and more medical comorbidities. The hyperinflammatory phenotype was independently associated with adverse clinical outcomes, even after adjusting for age, medical history and viral load on multivariable analyses (adjusted odds ratio 5.78, 95% confidence interval 2.86-11.63).
Even in non-severe COVID-19, there are distinct hyper- and hypoinflammatory phenotypes, with the hyperinflammatory phenotype strongly associated with adverse clinical outcomes, that could be distinguished with a simple biomarker.
Ageing is a risk factor for diabetes mellitus (DM) and frailty. It is associated with body composition changes including increase in fat mass (FM), central fat distribution, decrease in fat free mass ...(FFM) and skeletal muscle which are risk factors for DM. This study aims to evaluate gender differences in body composition in pre-frail diabetics and association with physical performance, cognitive function and perceived health. In addition, we aim to explore the association of obesity, sarcopenia, sarcopenic obesity, and body composition in pre-frail older adults to DM status.
Cross-sectional study of 192 pre-frail community dwelling older adults (≥ 65 years). Data was collected on demographics, physical function, cognition, frailty, sarcopenia, perceived health and body composition using the InBody S10. Univariate and multivariate logistic regression were undertaken to explore the association of sarcopenic obesity, obesity, sarcopenia and body composition measures to DM status.
There were insignificant within-gender differences for physical function, cognition and body composition, except for a higher prevalence of obesity defined by body mass index (BMI) and body fat percentage (BF%), increased fat mass index(FMI) and fat free mass index(FFMI) in females with DM. There were significant between-gender differences for those with DM where females overall had lower education levels, lower perceived health, higher prevalence of depression and low mental vitality, lower overall physical function (low short physical performance battery scores, low gait speed and hand grip strength), lower cognitive scores, lower muscle mass and muscle quality with higher FMI, FM/FFM and visceral fat area(VFA). BMI, VFA>100 cm
, FMI and FFMI were found to be independently associated with DM status after multivariable adjustment.
Within pre-frail DM vs non-DM, there were insignificant differences in body composition, physical function, cognition and perceived health within gender except for FMI, BF% and FFMI in females. There were significant differences between gender in pre-frail DM in muscle mass, quality, functional, cognitive and mental status. Further longitudinal studies are required to understand the pathogenesis, trajectory of DM and protective role of oral hypoglycemics in pre-frail older adults.
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