Metal based therapeutics are a precious class of drugs in oncology research that include examples of theranostic drugs, which are active in both diagnostic, specifically imaging, and therapeutics ...applications. Ruthenium compounds have shown selective bioactivity and the ability to overcome the resistance that platinum-based therapeutics face, making them effective oncotherapeutic competitors in rational drug invention approaches. The development of antineoplastic ruthenium therapeutics is of particular interest because ruthenium containing complexes NAMI-A, KP1019, and KP1339 entered clinical trials and DW1/2 is in preclinical levels. The very robust, conformationally rigid organometallic Ru(II) compound DW1/2 is a protein kinase inhibitor and presents new Ru(II) compound designs as anticancer agents. Over the recent years, numerous strategies have been used to encapsulate Ru(II) derived compounds in a nanomaterial system, improving their targeting and delivery into neoplastic cells. A new photodynamic therapy based Ru(II) therapeutic, TLD-1433, has also entered clinical trials. Ru(II)-based compounds can also be photosensitizers for photodynamic therapy, which has proven to be an effective new, alternative, and noninvasive oncotherapy modality.
The aim of this article is to describe and analyse how climate activists in the city of Milan try to intervene in the production and consumption of fossil fuels. The material worked on here was ...accumulated over three years (2019–2021): it consists of field notes through participant observation, conversations held on messaging apps and documents made available to participants in the local coalition about the internal workings and strategic objectives of the activists. The article explores their political experiments to slow down the pace of climate change and transform the socio-political conditions that underpin the trajectory of business-as-usual. Along the way, we will witness the emergence of various agents and practices that seek to intervene to reduce or block business-as-usual—through actions that can erode the material and immaterial spaces for the reproduction of fossil fuels.
Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene ...aberrations and response to olaparib in metastatic castration-resistant prostate cancer.
In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing.
711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7–35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0–69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1–54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1–42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2–32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2–52·5) of 46 and 13 (30·2%; 17·2–46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9–72·5) of 28 and 13 (48·1%; 28·7–68·1) of 27. The most common grade 3–4 adverse event in both cohorts was anaemia (15 31% of 49 patients in the 300 mg cohort and 18 37% of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort.
Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice.
Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.
Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies to overcome this are ...urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC.
We determined associations between BET expression, AR-driven transcription, and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer models.
Nuclear BRD4 protein expression increases significantly (
≤ 0.01) with castration resistance in same patient treatment-naïve (median
-score; interquartile range: 100; 100-170) and CRPC (150; 110-200) biopsies, with higher expression at diagnosis associating with worse outcome (HR, 3.25; 95% CI, 1.50-7.01;
≤ 0.001). BRD2, BRD3, and BRD4 RNA expression in CRPC biopsies correlates with AR-driven transcription (all
≤ 0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression. Furthermore, BETi reduce growth of prostate cancer cells and patient-derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (
≤ 0.001) of a patient-derived xenograft model of CRPC with AR amplification and AR-V7 expression.
BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof-of-mechanism pharmacodynamic studies.
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Abstract Metastatic involvement of the viscera in men with advanced castration-resistant prostate cancer (CRPC) has been poorly characterised to date. In 359 CRPC patients treated between June 2003 ...and December 2011, the frequency of radiologically detected visceral metastases before death was 32%. Of the 92 patients with computed tomography performed within 3 mo of death, 49% had visceral metastases. Visceral metastases most commonly involved the liver (20%) and lung (13%). Median survival from diagnosis of visceral disease was 7.1 mo (95% confidence interval, 5.9–8.3). Survival was affected by the degree of bone involvement at detection of visceral disease, varying from 6.1 mo in men with more than six bone metastases to 18.2 mo in men with no bone metastases ( p = 0.001). Heterogeneity was noted in clinical phenotypes and prostate-specific antigen trends at development of visceral metastases. Visceral metastases are now more commonly detected in men with CRPC, likely due to the introduction of novel survival-prolonging treatments.
A new framework of loop quantization that assimilates conformal and scale invariance is constructed and is found to be applicable to a large class of physically important theories of gravity and ...gravity-matter systems. They include general relativity and scale-invariant scalar-tensor and dilaton theories. Consequently, matter to be coupled to such theories is restricted to be conformal or scale invariant. Standard model-type systems naturally fall into this category. The new loop quantization follows from a novel conformally generalized Holst action principle. In contrast to standard loop quantum gravity, the resulting quantum geometry is not beset by the Immirzi ambiguity and has no definitive area gaps within the considered large class of theories of gravitation. As an additional feature, the scale invariance gives rise to a conserved Weyl current and we discuss briefly its possible implication on the problem of time in quantum gravity.
The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients ...who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.
The need to design structures and structural elements that are more efficient in terms of performance is a key aspect of engineering. For a given material to be used at its maximum capacity, ...considering non-linear characteristics is mandatory. The non-linear regime is a subject of extreme interest for this reason and is an area with intense research activity. In this work, advanced discretization techniques (i.e., meshless methods) are applied in the elastoplastic analysis of 2D and 3D structural elements. The literature shows that meshless methods are capable of producing more accurate and smoother strain and stress fields, which are the variable fields required in the non-linear models describing elastoplasticity. Thus, in this study, the Radial Point Interpolation Method (RPIM) and the Natural Neighbor Radial Point Interpolation Method (NNRPIM) are combined with a non-linear iterative algorithm, fully developed by the authors, with the objective of analyzing for the first time the elastoplastic behavior of a two-bay asymmetric frame and bowstring bridge considering 2D and 3D analysis. The accuracy and robustness of the RPIM and the NNRPIM are shown in the end, comparing the obtained results with FEM solutions and the available literature.
Despite its high prevalence and negative consequences, depression is often underdiagnosed. We aimed to estimate the prevalence and sociodemographic and health related factors associated with ...depression underdiagnosis among a nationally representative population-based sample in Brazil. Method: We used data from 70,806 participants (15–107 years old) of the Brazilian National Survey (PNS 2019). Depression underdiagnosis was considered for participants with a Patient Health Questionnaire-9 (PHQ-9) score >9 and with no diagnosis made by a health provider. Logistic regression models were performed to assess the crude and adjusted association between depression underdiagnosis and sociodemographic and health related factors. Population attributable risk fractions were calculated for significant predictors. Results: The prevalence of depression (according the PHQ-9) was 11.2% (IC95% 10.8:11.7). Depression underdiagnosis prevalence was 63.6% (IC95% 62.0%:65.2%) and was more frequent among male, elderly population, those with lower income, lower schooling, living in the North/Central region of the country, with best health perception, lower number of chronic disease and medical appointments. A significant percentage of depression underdiagnosed cases in Brazil in 2019 would be prevent by improving education (10.18%), income (3.99%), access to health visits (5.59%) and addressing barriers for depression diagnosis among males (5.44%), elderlies (3.32%), and population from the North region (8.29%). Conclusion(s): depression underdiagnosis is common in Brazil. Preventive measures should target the sociodemographic and health related factors associated with depression underdiagnosis.
Long non-coding RNAs (lncRNAs) are characterized as having 200 nucleotides or more and not coding any protein, and several been identified as differentially expressed in several human malignancies, ...including breast cancer.
Here, we evaluated lncRNAs differentially expressed in triple-negative breast cancer (TNBC) from a cDNA microarray data set obtained in a previous study from our group. Using in silico analyses in combination with a review of the current literature, we identify three lncRNAs as potential prognostic factors for TNBC patients.
We found that the expression of WDFY3-AS2, BDNF-AS, and AFAP1-AS1 was associated with poor survival in patients with TNBCs. WDFY3-AS2 and BDNF-AS are lncRNAs known to play an important role in tumor suppression of different types of cancer, while AFAP1-AS1 exerts oncogenic activity.
Our findings provided evidence that WDFY3-AS2, BDNF-AS, and AFAP1-AS1 may be potential prognostic factors in TNBC development.
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