The SRC family kinases are the largest family of norreceptor tyrosine kinases and one of the best-studied targets for cancer therapy. SRC, arguably the oldest oncogene, has been implicated in ...pathways regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. More recently, researchers have proposed that the transforming ability of SRC is linked to its ability to activate key signaling molecules in these pathways, rather than through direct activity. It has been hypothesized that blocking SRC activation may inhibit these pathways, resulting in antitumor activity. However, successfully targeting SRC in a clinical setting remains a challenge, and SRC inhibitors have only recently begun to move through clinical development. Preclinical studies have identified specific molecular “subgroups” and histologies that may be more sensitive to SRC inhibition. In addition, other studies have demonstrated synergistic interactions between SRC inhibitors and other targeted therapies and cytotoxics. In this review, we summarize SRC biology and how it has been applied to the clinical development of SRC inhibitors. The status of SRC inhibitors, including dasatinib, saracatinib, and bosutinib, which are in phase 1, 2, and 3 trials, is highlighted.
At the three-loop level we analyze, how the NSVZ relation appears for N=1 SQED regularized by the dimensional reduction. This is done by the method analogous to the one which was earlier used for the ...theories regularized by higher derivatives. Within the dimensional technique, the loop integrals cannot be written as integrals of double total derivatives. However, similar structures can be written in the considered approximation and are taken as a starting point. Then we demonstrate that, unlike the higher derivative regularization, the NSVZ relation is not valid for the renormalization group functions defined in terms of the bare coupling constant. However, for the renormalization group functions defined in terms of the renormalized coupling constant, it is possible to impose boundary conditions to the renormalization constants giving the NSVZ scheme in the three-loop order. They are similar to the all-loop ones defining the NSVZ scheme obtained with the higher derivative regularization, but are more complicated. The NSVZ schemes constructed with the dimensional reduction and with the higher derivative regularization are related by a finite renormalization in the considered approximation.
In this study, we focus on carbon quantum dots (CQDs) derived from L-Lysine using a microwave-assisted technique, which offers a rapid and straightforward route to generate CQDs smaller than 10 nm on ...average. We present a method for procuring dry CQDs powder, capable of dissolving in various solvents. To examine the influence of CQDs on the properties of organic–inorganic perovskite and the potential impact of DMA solvent on CQDs, we investigated the optical and electrical characteristics of both pure CQDs and CQDs combined with MAPbBr3 films within a temperature range from 89 to 293 K. Our findings reveal the presence of a positive temperature coefficient of resistivity in the temperature range of 90–290 K. Subsequently, we discuss the plausible mechanism responsible for charge carrier transport in these types of composites.
This study identifies similarities and differences in the structural organization and cultural attitudes expressed in Swedish and Russian proverbs of comparative semantics on poverty and wealth. It ...provides a classification of linguistic units (35 Swedish and 60 Russian proverbs) based on their expression of identity, comparison, contrast, and syntactic organization. The research reveals that in the Swedish language, proverbs expressing comparison with adjectives in the comparative degree have quantitative advantages, while in the Russian language, proverbs expressing contrast prevail. Similar cultural attitudes in Swedish and Russian proverbs of comparative semantics on poverty and wealth include: (1) The wealthy person’s material status is incomparably higher than that of the poor, but the poor person surpasses the wealthy in moral terms. (2) The wealthy always desire more, being unsatisfied with their wealth. (3) Laws operate differently for the rich and the poor. (4) Wealth is fleeting if not used wisely. Differences lie in specific cultural attitudes. For instance, Swedish proverbs focus on the wealthy person’s daughter as a coveted prize for those seeking easy enrichment, while Russian proverbs intensify certain qualities of individuals based on their degree of poverty / wealth (the poorer a person is, the more generous, wise, intelligent, brave, cunning they are, etc.).
Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited ...data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.
Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. ...Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer.
Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (
= 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X).
Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5-24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling.
This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.
Transcriptional factor p53 is a master regulator of energy metabolism. Energy metabolism strongly depends on thiamine (vitamin B1) and/or its natural derivatives. Thiamine diphosphate (ThDP), which ...is a major thiamine derivative, affects p53 binding to DNA. In order to elucidate the mechanism of regulation of thiamine-dependent metabolism by p53, we assessed putative p53-binding sites near transcription starting points in genes coding for transporters and enzymes, whose function is associated with thiamine and/or its derivatives. The predictions were validated by studying cell metabolic response to the p53 inducer cisplatin. Expression of p53 and its known target, p21, has been evaluated in cisplatin-treated and control human lung adenocarcinoma A549 cells that possess functional p53 pathway. We also investigated the activity of enzymes involved in the thiamine-dependent energy metabolism. Along with upregulating the expression of p53 and p21, cisplatin affected the activities of metabolic enzymes, whose genes were predicted as carrying the p53-binding sites. The activity of glutamate dehydrogenase GDH2 isoenzyme strongly decreased, while the activities of NADP
+
-dependent isocitrate dehydrogenase (IDH) and malic enzymes, as well as the activity of 2-oxoglutarate dehydrogenase complex at its endogenous ThDP level, were elevated. Simultaneously, the activities of NAD
+
-dependent IDH, mitochondrial aspartate aminotransferase, and two malate dehydrogenase isoenzymes, whose genes were not predicted to have the p53-binding sequences near the transcription starting points, were upregulated by cisplatin. The p53-dependent regulation of the assayed metabolic enzymes correlated with induction of p21 by p53 rather than induction of p53 itself.
Despite significant advances in early detection and treatment, breast cancer still remains a major cause of morbidity and mortality for women. Our understanding of the molecular heterogeneity of the ...disease has significantly expanded over the past decade and the role of cell cycle signaling in both breast cancer oncogenesis and anti-estrogen resistance has gained increasing attention. The mammalian cell cycle is driven by a complex interplay between cyclins and their associated cyclin-dependent kinase (CDK) partners, and dysregulation of this process is one of the hallmarks of cancer. Despite this, initial results with broadly acting CDK inhibitors were largely disappointing. However, recent preclinical and phase I/II clinical studies using a novel, oral, reversible CDK4/6 inhibitor, palbociclib (PD-0332991), have validated the role of CDK4/6 as a potential target in estrogen receptor-positive (ER+) breast cancers. This review highlights our current understanding of CDK signaling in both normal and malignant breast tissues, with special attention placed on recent clinical advances in inhibition of CDK4/6 in ER+ disease.
Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for ...predicting pCR and risk of metastatic recurrence.
Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years.
At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5).
Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.
•Lack of ctDNA clearance early during NAC portends poor response.•Detectable ctDNA during NAC is associated with poor outcomes.•Failure to clear ctDNA after NAC is associated with inferior distant disease-free recurrence survival.•Clearance of ctDNA is associated with improved survival even in patients who did not achieve pCR.
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