Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

Non-small-cell lung cancer(NSCLC)remains the leading cause of cancer-related death in both men and women in the United States.Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease.Improvements in overall survival and quality of life have been modest.Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics,thus changing the treatment paradigm for many NSCLC patients.In this review,we present a summary of many of the currently investigated biologic targets in NSCLC,discuss their current clinical trial status,and also discuss the potential for development of other targeted agents.

WJH 6^(th) Anniversary Special Issues(2): Hepatocellular carcinoma Mammalian target of rapamycin inhibition in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.

Hepatocellular carcinoma: Therapeutic advances in signaling,epigenetic and immune targets

Hepatocellular carcinoma(HCC)remains a global medical burden with rising incidence due to chronic viral hepatitis and non-alcoholic fatty liver diseases.Treatment of advanced disease stages is still unsatisfying.Besides first and second generation tyrosine kinase inhibitors,immune checkpoint inhibitors have become central for the treatment of HCC.New modalities like epigenetic therapy using histone deacetylase inhibitors(HDACi)and cell therapy approaches with chimeric antigen receptor T cells(CAR-T cells)are currently under investigation in clinical trials.Development of such novel drugs is closely linked to the availability and improvement of novel preclinical and animal models and the identification of predictive biomarkers.The current status of treatment options for advanced HCC,emerging novel therapeutic approaches and different preclinical models for HCC drug discovery and development are reviewed here.

Review: Plant Genome Editing Targeted by RNA-Guided DNA Endonuclease CRISPR/Cas9

This review chronicles the development of the research on CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR associated protein 9) during the last 30 years from the discovery of CRISPR sequence, of biological significance and of the molecular mechanism for adaptive bacterial immunity. It describes recent works on structural and functional diversity of CRISPR/Cas systems, and on three-dimensional structure-based improvements of on-target specificity of CRISPR/Cas9 and Cpf1 endonucleases. The review ends with the application of CRISPR/Cas9 to targeted editing of plant genomes. Importantly, plant commodities modified by CRISPR-Cas9 have not been considered as genetically modified organisms (GMO) as long as foreign DNAs from plant pests were not introduced, according to the recent determination by the USDA.

Searching for a Target Traveling between a Hiding Area and an Operating Area over Multiple Routes

We consider the problem of searching for a target that moves between a hiding area and an operating area over multiple fixed routes. The search is carried out with one or more cookie-cutter sensors, which can detect the target instantly once the target comes within the detection radius of the sensor. In the hiding area, the target is shielded from being detected. The residence times of the target, respectively, in the hiding area and in the operating area, are exponentially distributed. These dwell times are mathematically described by Markov transition rates. The decision of which route the target will take on each travel to and back from the operating area is governed by a probability distribution. We study the mathematical formulation of this search problem and analytically solve for the mean time to detection. Based on the mean time to capture, we evaluate the performance of placing the searcher(s) to monitor various travel route(s) or to scan the operating area. The optimal search design is the one that minimizes the mean time to detection. We find that in many situations the optimal search design is not the one suggested by the straightforward intuition. Our analytical results can provide operational guidances to homeland security, military, and law enforcement applications.

Personalizing therapies for gastric cancer: Molecular mechanisms and novel targeted therapies

Globally,gastric cancer is the 4thmost frequently diagnosed cancer and the 2ndleading cause of death from cancer,with an estimated 990000 new cases and738000 deaths registered in 2008.In the advanced setting,standard chemotherapies protocols acquired an important role since last decades in prolong survival.Moreover,recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2(HER2)therapies.Trastuzumab,an anti-HER2 monoclonal antibody,was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based chemotherapy.Further,HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this field.Thus,we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer,providing a comprehensive overview of molecular mechanisms and novel trials involved.

Effects of Dietary Soy Protein Concentrate on Growth, Digestive Enzymes Activities and Target of Rapamycin Signaling Pathway Regulation in Juvenile Soft-Shelled Turtle, <i>Pelodiscus sinensis</i>

Soft-shelled turtle, Pelodiscus sinensis is important aquatic species in China, and searching for alternatives protein resources to fish meal (FM)-based feeds in feed has become urgent and important for its sustainability development. The present study was conducted to assess the effects of dietary soy protein concentrate (SPC) on growth, digestive enzymes and target of rapamycin (TOR) signaling pathway of juvenile P. sinensis (4.56 ± 0.09 g). SPC was applied to replace FM protein at 0%, 15%, 30% and 60% (designated as T0, T15, T30 and T60, respectively), and each diet was fed to triplicate groups. The results showed that there was no significant difference in growth performance and feed utilization except of the turtles fed with T60 diet, of which showed poorer daily weight gain and feed conversion rate. The pepsin/trypsin and Na+-K+ ATP-ase activities decreased dramatically when SPC level increased, and lipase activities in liver and intestinal tract also showed decline tendency. However, amylase activities were unaffected. No significant differences were observed in TOR, S6K1 and 4E-BP1 genes mRNA expression level of TOR signaling pathway among the treatments. However, the relative phosphorylated level of these proteins decreased significantly when SPC level increased. The present study indicated that high SPC substitution level would suppress digestive enzymes and TOR signaling pathway proteins phosphorylated level and eventually result in growth reduction of P. sinensis.

Partial and Full Arc Volumetric Modulated Arc Therapy in Lung Cancer Stereotactic Body Radiotherapy with Different Definitions of Internal Target Volume Based on 4D CT

Purpose: To investigate the feasibility of partial arc volumetric modulated arc therapy (VMAT) in lung cancer stereotactic body radiotherapy (SBRT), as well the volumetric and dosimetric effects of different internal target volume (ITV) definitions with 4D CT. Methods: Fourteen patients with primary and metastatic lung cancer underwent SBRT were enrolled. Full and partial arc VMAT plans were generated with four different ITVs: ITVall, ITVMIP, ITVAIP and ITV2phases, representing ITVs generated from all 10 respiratory phases, maximum intensity projection (MIP), average intensity projection (AIP), and 2 extreme respiratory phases. Volumetric and dosimetric differences, as well as MU and delivery time were investigated. Results: Partial arc VMAT irradiated more dose at 2 cm away from planning target volume (PTV) (P = 0.002), however, it achieved better protection on mean lung dose , lung V5, spinal cord, heart and esophagus compared with full arc VMAT. The average MU and delivery time of partial arc VMAT were 240 and 1.6 min less than those of full arc VMAT. There were no significant differences on target coverage and organ at risks (OARs) sparing among four ITVs. The average percent volume differences of ITVMIP, ITVAIP and ITV2phases to ITVall were 8.6%, 13.4%, and 25.2%, respectively. Conclusions: Although partial arc VMAT delivered more dose 2 cm out of PTV, it decreases the dose to lung, spinal cord, and esophagus, as well decreased the total MU and delivery time compared with full arc VMAT without sacrificing target coverage. Partial arc VMAT was feasible and more efficient for lung SBRT.

Angiographic and volumetric effects of mammalian target of rapamycin inhibitors on angiomyolipomas in tuberous sclerosis

AIM: To investigate the angiographic and volumetric effects of mammalian target of rapamycin(m TOR) inhibitors on angiomyolipomas(AMLs) in a case series of patients with tuberous sclerosis complex.METHODS: All patients who underwent catheter angiography prior to and following m TOR inhibitor therapy(n = 3) were evaluated. All cross-sectional imaging studies were analyzed with three-dimensional volumetrics, and tumor volume curves for all three tissue compartments(soft tissue, vascular, and fat) were generated. Segmentation analysis tools were used to automatically create a region of interest(ROI) circumscribing the AML. On magnetic resonance images, the "fat only" map calculated from the in- and opposed-phase gradient recalled echo sequences was used to quantify fat volume within tumors. Tumor vascularity was measured by applying a thresholding toolwithin the ROI on post-contrast subtraction images. On computed tomography images, volume histogram analysis of Hounsfield unit was performed to quantify tumor tissue composition. The angiography procedures were also reviewed, and tumor vascularity based on pre-embolization angiography was characterized in a semi-quantitative manner. RESULTS: Patient 1 presented at the age of 15 with a 6.8 cm right lower pole AML and a 4.0 cm right upper pole AML. Embolization was performed of both tumors, and after a few years of size control, the tumors began to grow, and the patient was initiated on m TOR inhibitor therapy. There was an immediate reduction in the size of both lesions. The patient then underwent repeat embolization and discontinuation of m TOR inhibition, after which point there was a substantial regrowth in both tumors across all tissue compartments. Patient 2 presented at the age of 18 with a right renal AML. Following a brief period of tumor reduction after embolization, she was initiated on m TOR inhibitor therapy, with successful reduction in tumor size across all tissue compartments. As with patient 1, however, there was immediate rebound growth following discontinuation of inhibitor therapy, without sustained control despite repeat embolization. patient 3 presented at the age of 5 with a left renal AML and underwent two embolization procedures without lasting effect prior to starting m TOR inhibition. As with patients 1 and 2, following discontinuation of therapy, there was immediate rebound growth of the tumor. Repeat embolization, however, was notable for a substantial reduction in intratumoral aneurysms and vascularity.CONCLUSION: AML volume reduction as well as posttreatment rebound growth due to m TOR inhibitors involves all three tissue components of the tumor.

Evolution of breast cancer therapeutics: Breast tumour kinase's role in breast cancer and hope for breast tumour kinase targeted therapy

There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients' overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase(Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current "state of play" with respect to targeted therapy for breast cancer, as well as discussing Brk's role in the processes underlying tumour development and metas-tasis and its potential as a therapeutic target in breast cancer.

Joint resource allocation scheme for target tracking in distributed MIMO radar systems

A joint resource allocation scheme concerned with the sensor subset,power and bandwidth for range-only target tracking in multiple-input multiple-output(MIMO)radar systems is proposed.By selecting an optimal subset of sensors with the predetermined size and implementing the power allocation and bandwidth strategies among them,this algorithm can help achieving a better performance within the same resource constraints.Firstly,the Bayesian Cramer-Rao bound(BCRB)is derived from it.Secondly,a criterion for minimizing the BCRB at the target location among all targets tracking in a certain range is derived.Thirdly,the optimization problem involved with three variable vectors is formulated,which can be simplified by deriving the relationship between the optimal power allocation vector and the bandwidth allocation vector.Then,the simplified optimization problem is solved by the cyclic minimization algorithm incorporated with the sequential parametric convex approximation(SPCA)algorithm.Finally,the validity of the proposed method is demonstrated with simulation results.

Prospective Development of Small Molecule Targets to Oncogenic Ras Proteins

Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediate cell transformtion. Yet, there has been very little development of therapies to help tackle Ras-related diseased states. The development of small molecules to target Ras proteins to potentially inhibit abnormal Ras-stimulated cell signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies characterizing Ras protein-small molecule interactions to show the importance and potential that these small molecules may have for Ras-related drug discovery. We summarize recent results, highlighting small molecules that can be directly targeted to Ras using Structure-Based Drug Design (SBDD) and Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic signaling in vitro by small molecules is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this regard, important features of previously characterized properties of small molecule Ras targets, as well as a current understanding of conformational and dynamics changes seen for Ras-related mutants, relative to wild type, must be taken into account as newer small molecule design strategies towards Ras are developed.

Antineoplastic effects of mammalian target of rapamycine inhibitors

Cancer after transplantation is the third cause of death and one of the more relevant comorbidities. Aim of this review is to verify the role of different pathogenetic mechanisms in cancer development in transplant patients and in general population as well. In particular has been outlined the different role exerted by two different families of drug as calcineurin inhibitor and mammalian target of rapamycin(m TOR) inhibitor. The role of m TOR pathways in cell homeostasis is complex but enough clear. As a consequence the m TOR pathway deregulation is involved in the genesis of several cancers. Hence the relevant role of m TOR inhibitors. The authors review the complex mechanism of action of m TOR inhibitors, not only for what concerns the immune system but also other cells as endothelial, smooth muscle and epithelial cells. The mechanism of action is still now not completely defined and understood. It implies the inhibition of m TOR pathway at different levels, but mainly at level of the phosphorylation of several intracellular kinases that contribute to activate m TOR complex. Many prospective and retrospective studies in transplant patients document the antineoplastic role of m TOR inhibition. More recently m TOR inhibitors proven to be effective in the treatment of some cancers also in general population. Kidney cancers, neuroendocrine tumors and liver cancers seem to be the most sensitive to these drugs. Best results are obtained with a combination treatment, targeting the m TOR pathway at different levels.

Review of the current targeted therapies for non-small-cell lung cancer

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer(NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor(EGFR), and crizotinib which targets anaplastic lymphoma kinase(ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790 Mtargeted agents CO-1686 and AZD9291, and the ALKtargeted agents ceritinib(LDK378), AP26113, alectinib(CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

Reflections on China’s Targeted Poverty Alleviation Strategy from the Perspective of Drawing on Advantages and Avoiding Disadvantages in the New Era

The new era has put forward new requirements for targeted poverty alleviation.Coordinating disaster prevention,mitigation and relief and ecological civilization construction to assist targeted poverty alleviation has become an important direction for alleviating poverty from the perspective of drawing on advantages and avoiding disadvantages.The Outline of the 13th Five-Year Plan for National Economic and Social Development of the People's Republic of China has planned and deployed to fully implement the task of poverty alleviation.The current poverty alleviation is extending from fixed-point poverty alleviation to collaborative poverty alleviation and targeted poverty alleviation.Combining the needs of disaster response,climate adaptation,resource utilization,ecological construction,and information utilization in poverty-stricken areas,the role of disaster risk monitoring,forecasting and early warning services is displayed.The disaster prevention,mitigation and relief and poverty alleviation in the new era should be integrated into the national poverty alleviation pattern,actively serve poverty alleviation projects of industry development,relocation and ecological protection,deeply explore the value of disaster risk information and improve the effective supply of disaster prevention,mitigation and relief services,letting disaster prevention,mitigation and relief and ecological civilization construction help the implementation of targeted poverty alleviation.

Land Use Regionalization in Poor Counties in Mountainous Areas Based on Targeted Poverty Alleviation

Land use regionalization is a strategic measure for the rational use,management and protection of land resources based on local conditions.Based on the needs of targeted poverty alleviation and rural revitalization strategy and the analysis on the natural and socioeconomic conditions,characteristics of land resources,and the current status of land use in Luquan County,corresponding regionalization indices were selected from four aspects:economic environment conditions,socioeconomic conditions,land resources and land use structure,and poverty alleviation and development level,a scientific and feasible index system for land use regionalization was constructed,and land use in Luquan County was regionalized by using systematic cluster analysis method.The results show that the 16 townships(towns)of Luquan County were divided into four land use regions,poverty alleviation region for development of new town and characteristic industries in the southwest(I),agricultural development and ecological poverty alleviation region in central mountainous area(II),poverty alleviation region for development of characteristic agriculture and tourism towns in eastern plateau mountainous area(III),and poverty alleviation region for development of characteristic industries and protection of land economy in the northern alpine valley area(IV).In addition,suggestions were put forward for the rational use of land in each region.

Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas

Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cellbased therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transforma-tion of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-Raf V600 E and N-RasQ 61 R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor(EGFR), stem cell-like factor(SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1(SDF-1)/CXC chemokine receptor-4(CXCR4) and vascular endothelial growth factor(VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition(EMT)-associated molecules, including phosphatidylinositol 3'-kinase(PI3K)/Akt/ molecular target of rapamycin(mT OR), nuclear factor-kappaB(NF-κB), macrophage inhibitory cytokine-1(MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.

Fast density peak-based clustering algorithm for multiple extended target tracking

The key challenge of the extended target probability hypothesis density (ET-PHD) filter is to reduce the computational complexity by using a subset to approximate the full set of partitions. In this paper, the influence for the tracking results of different partitions is analyzed, and the form of the most informative partition is obtained. Then, a fast density peak-based clustering (FDPC) partitioning algorithm is applied to the measurement set partitioning. Since only one partition of the measurement set is used, the ET-PHD filter based on FDPC partitioning has lower computational complexity than the other ET-PHD filters. As FDPC partitioning is able to remove the spatially close clutter-generated measurements, the ET-PHD filter based on FDPC partitioning has good tracking performance in the scenario with more clutter-generated measurements. The simulation results show that the proposed algorithm can get the most informative partition and obviously reduce computational burden without losing tracking performance. As the number of clutter-generated measurements increased, the ET-PHD filter based on FDPC partitioning has better tracking performance than other ET-PHD filters. The FDPC algorithm will play an important role in the engineering realization of the multiple extended target tracking filter.

Work Effectiveness,Problems and Countermeasures of Third-Party Assessment Teams from Colleges and Universities for Targeted Poverty Alleviation

Conducting a third-party assessment on targeted poverty alleviation can effectively avoid the disadvantage that local government plays as both athlete(i.e.performer of poverty alleviation work)and referee(i.e.referee for poverty alleviation effect)in poverty alleviation to ensure the truth of poverty alleviation,and therefore,it is an important part of the work to win the battle against poverty.Since 2016,the thirdparty assessment teams from colleges and universities for targeted poverty alleviation have achieved good results and performance in the assessment on both the effectiveness of targeted poverty alleviation work and the exit of poor counties in China,and they have made due contributions to the cause of poverty alleviation.However,as a new thing,third-party assessment obviously has some problems,mainly including the following:subjective understanding on the long-term nature of rural poverty alleviation is insufficient,and there is a lack of long-term considerations and related mechanism for third-party assessment;affected by policies and institutions,most of the existing third-party assessment teams from colleges and universities have not regarded third-party assessment of targeted poverty alleviation as a cause,and they lack the motivation to actively study the assessment business;and the third-party assessment staff from colleges and universities for targeted poverty alleviation have low stability and high mobility,not conducive to the long-term construction of assessment teams.In order to establish long-term poverty alleviation and prevention mechanisms,these issues must be addressed squarely and relevant countermeasures need to be taken actively to effectively build a long-term mechanism for building third-party assessment teams from colleges and universities for targeted poverty alleviation.

A Modified Four Path Method for Calculating Coupling Field of Super-Low Altitude Aircraft Target

A novel modified four path method (FPM) is presented for calculating coupling field of super-low altitude aircraft target. Based on the hybrid method PO + MEC (Physical Optics and Method of Equivalent Currents), the antenna radiation pattern is introduced to consider the multipath interference from side lobe of seeker. The modified FPM is used to calculate the coupling field from super-low altitude aircraft target above different terrestrial environments. The curves of scattering coefficient are analyzed. The influences of height of target, root mean square (RMS), and incident angle on coupling field characteristics are discussed. The simulation results can be used for reference in detection for super-low altitude target and optimization for radar system.