Emerging Insights of Tumor Heterogeneity and Drug Resistance Mechanisms in Lung Cancer Targeted Therapy

Abstract The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells’ ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity—the driving force behind minimal residual disease—is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells

Marginalisation of the Dan Fishing Community and Relocation of Sanya Fishing Port, Hainan Island, China

When marginal groups face social transformation, they risk being unable to adapt and acquire equal developmental opportunities, slipping into ‘further marginalisation’. This paper explores the case of the Dan fishing community of Sanya City, Hainan, China. Efforts to transform Sanya City into an international island tourism destination involve plans to relocate Sanya fishing port and to clear the adjacent neighbourhood inhabited by the Dan people, traditionally a boat-dwelling people, who have long been marginalised relative to China’s land-oriented society. As their natural and social resources dwindle, the Dan of Sanya City must cope with the loss of their homes and livelihoods, as they are forced into the city’s suburbs and as the port relocation complicates the economics and practicalities of making a living from the fishing industry. This paper argues for greater attention to be given to local needs in the formulation of urban development strategies in island cities

6-Allyl-3-(6-chloro-3-pyridylmeth­yl)-6,7-dihydro-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-imine

The title compound, C13H12ClN7, crystallizes with two independent mol­ecules in the asymmetric unit, each with similar geometries. The dihedral angles between the triazole and pyrimidine rings are 0.45 (9) and 1.00 (10)° in the two mol­ecules. A number of N—H⋯N hydrogen bonds co-operate with C–H⋯N contacts, forming a supra­molecular array in the ab plane. C—H⋯π inter­actions are also present. One of the vinyl groups was found to be disordered so that the C(H)=CH2 atoms were resolved over two positions with the major component having a site occupancy factor of 0.539 (4)

2,2′-Bis(4-fluoro­anilino)-3,3′-(3,6-dioxa­octane-1,8-di­yl)diquinazolin-4(3H)-one

In the centrosymmetric title compound, C34H30F2N6O4, the dihedral angle between the quinazolinone and fluorobenzene ring planes are 71.00 (2) and 74.94 (2)° and an intra­molecular N—H⋯O interaction stabilizes the conformation. In the crystal, C—H⋯F and C—H⋯O links help to establish the packing

6-Butyl-5-(4-methoxy­phen­oxy)-3-phenyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7(6H)-one

The asymmetric unit of the title compound, C21H21N5O3, consists of two geometrically similar mol­ecules. The fused rings of the triazolo[4,5-d]pyrimidine system are nearly coplanar, making dihedral angels of 1.48 (18) and 1.34 (16)°, and the phenyl rings are twisted by 12.3 (1) and 8.7 (1)° with respect to the triazolopyrimidine plane. The ethyl groups of the n-butyl side chains are disordered over two sites in each of the independent mol­ecules, the ratios of occupancies being 0.60:0.40 and 0.61:0.39

Ethyl 1-[(2-chloro-1,3-thia­zol-5-yl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylate

In the title compound, C10H11ClN4O2S, the triazole ring carries methyl and ethoxy­carbonyl groups and is bound via a methyl­ene bridge to a chloro­thia­zole unit. There is also evidence for significant electron delocalization in the triazolyl system. Intra- and inter­molecular C—H⋯O hydrogen bonds together with strong π–π stacking inter­actions [centroid–centroid distance 3.620 (1) Å] stabilize the structure

3-(2-Hydroxy­ethyl)-2-(p-tolyl­amino)­quinazolin-4(3H)-one

In the title compound, C17H17N3O2, the quinazolinone ring system is essentially planar. The benzene ring is twisted with respect to it by a dihedral angle of 32.7 (5)°. The mol­ecular conformation is stabilized by an N—H⋯O hydrogen bond, and the crystal structure is stabilized by inter­molecular O—H⋯N inter­actions

Bayesian optimization - LSTM modeling and time frequency correlation mapping based probabilistic forecasting of ultra-short-term photovoltaic power outputs

Due to the fluctuation and randomness of photovoltaic power over time, accurate and reliable ultra-short-term photovoltaic power forecasting is significant for real-time dispatch and frequency regulation of power grids. In this paper, the improved BO-LSTM forecasting frame considering frequency correlation mapping is proposed. Firstly, the features of photovoltaic power are extracted and resolved according to power series frequency segments. Then, the established BO-LSTM forecasting model is adjusted based on the above extracted features in separate segment, and the results of deterministic forecasting are obtained. Furthermore, in order to obtain the reliable performance, the time-correlation algorithm is employed into the above deterministic forecasting model, which offers the base for probabilistic power forecasting. Finally, the above algorithms and forecasting framework are applied to the measurement data from a commercial photovoltaic power station in North China. Compared to the benchmark models, the Power Interval Normalized Average Width (PINAW) error of the proposed ultra-short-term forecasting algorithm has shown satisfied improvements. The PINAW has reduced by 8.4% (v.s. Adam-LSTM), 48.9% (v.s. Sgd-LSTM), 52.8% (v.s. Adagrad-LSTM), 9.1% (v.s. Rmsprop-LSTM), 97.2% (v.s. Adadelta-LSTM), 86.8% (v.s. Adam-mlp), 87.4% (v.s. Sgd-mlp), 90.9% (v.s. Adagrad-mlp), 86.5% (v.s. Rmsprop-mlp), and 99.7% (v.s. Adadelta-mlp)

DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: A comprehensive profiling approach

10.1186/1471-230X-14-55BMC Gastroenterology141-BGMA