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Background: Lymphatic filariasis is a pervasive and life-threatening disease for human beings. Currently, 893 million people in 49 countries worldwide affected by lymphatic filariasis as per WHO statistics. The concealed aspects of lymphatic diseases such as delayed disease detection, inappropriate disease imaging, the geographical outbreak of infection, and lack of preventive chemotherapy have brought this epidemic to the edge of Neglected Tropical Diseases. Many medications and natural bioactive substances have seen to promote filaricidal activity against the target parasitic species. However, the majority of failures have occurred in pharmaceutical and pharmacokinetic issues. Objective: The purpose of the study is to focus on the challenges and therapeutic issues in the treatment of filariasis. The review brings novel techniques and therapeutic approaches for combating lymphatic filariasis. It also offers significant developments and opportunities for such therapeutic interventions. Conclusion: Through this review, an attempt has made to critically evaluate the avenues of innovative pharmaceuticals and molecular targeting approaches to bring an integrated solution to combat lymphatic filariasis.

Japan officially introduced cost-effectiveness analysis (CEA) in 2019, whereas some countries, such as England, Sweden, Canada, and Australia, have experience with health technology assessment (HTA). Therefore, there are few reports that comprehensively examine the situation of health economic evaluation in Japan. In this paper, we review the health economic evaluation systems among those countries. We also conducted a case study that investigated the time-trend of cost, effectiveness, and incremental cost-effectiveness ratio (ICER) for anticancer drug regimens in Japan. We found a time-trend ICER for breast cancer (BC). Additionally, molecular targeting drugs for BC had a positive effect on the ICER, and both small molecular-targeting drugs and monoclonal antibodies (mAb) had a higher ICER for BC compared with conventional drugs. Finally, we discuss a possible way to implement a health economic evaluation system in Japan.

Molecular imaging techniques have rapidly progressed over recent decades providing unprecedented in vivo characterization of metabolic pathways and molecular biomarkers. Many of these new techniques have been successfully applied in the field of neuro-oncological imaging to probe tumor biology. Targeting specific signaling or metabolic pathways could help to address several unmet clinical needs that hamper the management of patients with brain tumors. This review aims to provide an overview of the recent advances in brain tumor imaging using molecular targeting with positron emission tomography and magnetic resonance imaging, as well as the role in patient management and possible therapeutic implications.

PURPOSE: Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices (TI). To overcome these challenges we developed a novel multimerization platform that rapidly removed tumor targeting proteins from the blood to substantially improve TI. EXPERIMENTAL DESIGN: The platform was designed as a fusion of a Self-Assembling and DisAssembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 x anti-DOTA). SADA-BsAbs were assessed with multiple in vivo tumor models using 2-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry and anti-tumor responses. RESULTS: SADA-BsAbs self-assembled into stable tetramers (220 kDa) but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA-BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, 2-step SADA-PRIT safely delivered massive doses of alpha-emitting ((225)Ac, 1.48 MBq/kg) or beta-emitting ((177)Lu, 6,660 MBq/kg) DOTA payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver. CONCLUSIONS: The SADA-BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys or liver. Due to its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve TI and maximize the delivered dose.

The use of nanomedicine for cancer treatment takes advantage of its preferential accumulation in tumors owing to the enhanced permeability and retention (EPR) effect. The development of cancer nanomedicine has promised highly effective treatment options unprecedented by standard therapeutics. However, the therapeutic efficacy of passively targeted nanomedicine is not always satisfactory because it is largely influenced by the heterogeneity of the intensity of the EPR effect exhibited within a tumor, at different stages of a tumor, and among individual tumors. In addition, limited data on EPR effectiveness in human hinders further clinical translation of nanomedicine. This unsatisfactory therapeutic outcome in mice and humans necessitates novel approaches to improve the EPR effect. This review focuses on current attempts at overcoming the limitations of traditional EPR-dependent nanomedicine by incorporating supplementary strategies, such as additional molecular targeting, physical alteration, or physiological remodeling of the tumor microenvironment. This review will provide valuable insight to researchers who seek to overcome the limitations of relying on the EPR effect alone in cancer nanomedicine and go "beyond the EPR effect".

Aim: The negative impact of tumour hypoxia on cancer treatment outcome has been long-known, yet there has been little success combating it. This paper investigates the potential role of in silico modelling to help test emerging hypoxia-targeting treatments in cancer therapy. Methods: A Medline search was undertaken on the current landscape of in silico models that simulate cancer therapy and evaluate their ability to test hypoxia-targeting treatments. Techniques and treatments to combat tumour hypoxia and their current challenges are also presented. Results: Hypoxia-targeting treatments include tumour reoxygenation, hypoxic cell radiosensitization with nitroimidazoles, hypoxia-activated prodrugs and molecular targeting. Their main challenges are toxicity and not achieving adequate delivery to hypoxic regions of the tumour. There is promising research toward combining two or more of these techniques. Different types of in silico therapy models have been developed ranging from temporal to spatial and from stochastic to deterministic models. Numerous models have compared the effectiveness of different radiotherapy fractionation schedules for controlling hypoxic tumours. Similarly, models could help identify and optimize new treatments for overcoming hypoxia that utilize novel hypoxia-targeting technology. Conclusion: Current therapy models should attempt to incorporate more sophisticated modelling of tumour angiogenesis/vasculature and vessel perfusion in order to become more useful for testing hypoxia-targeting treatments, which typically rely upon the tumour vasculature for delivery of additional oxygen, (pro)drugs and nanoparticles Refereed/Peer-reviewed

Nuclear Receptors (NRs) are multi-domain proteins, whose natural regulation occurs via ligands for a classical, orthosteric, binding pocket and via intra- and inter-domain allosteric mechanisms. Allosteric modulation of NRs via synthetic small molecules has recently emerged as an interesting entry to address the need for small molecules targeting NRs in pathology, via novel modes of action and with beneficial profiles. In this review the general concept of allosteric modulation in drug discovery is first discussed, serving as a background and inspiration for NRs. Subsequently, the review focuses on examples of small molecules that allosterically modulate NRs, with a strong focus on structural information and the ligand binding domain. Recently discovered nanomolar potent allosteric site NR modulators are catapulting allosteric targeting of NRs to the center of attention. The obtained insights serve as a basis for recommendations for the next steps to take in allosteric small molecular targeting of NRs.

Cancer cell resistance to chemotherapeutics (chemoresistance) poses a significant clinical challenge that oncology research seeks to understand and overcome. Multiple anticancer drugs and targeting agents can be incorporated in nanomedicines, in addition to different treatment modalities, forming a single nanoplatform that can be used to address tumor chemoresistance. Nanomedicine-driven molecular assemblies using nucleic acids, small interfering (si)RNAs, miRNAs, and aptamers in combination with stimuli-responsive therapy improve the pharmacokinetic (PK) profile of the drugs and enhance their accumulation in tumors and, thus, therapeutic outcomes. In this review, we highlight nanomedicine-driven molecular targeting and therapy combination used to improve the 3Rs (right place, right time, and right dose) for chemoresistant tumor therapies.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with nearly one million new cases and deaths every year. Owing to the complex pathogenesis, hidden early symptoms, rapidly developing processes, and poor prognosis, the morbidity and mortality of HCC are increasing yearly. With the progress being made in modern medicine, the treatment of HCC is no longer limited to traditional methods. Targeted therapy and immunotherapy have emerged to treat advanced and metastatic HCC in recent years. Since Sorafenib is the first molecular targeting drug against angiogenesis, targeted drugs for HCC are continually emerging. Moreover, immunotherapy plays a vital role in clinical trials. In particular, the application of immune checkpoint inhibitors, which have received increasing attention in the field of cancer treatment, is a possible research path. Interestingly, these two therapies generally complement each other at some stages of HCC, bringing new hope for patients with advanced HCC. In this paper, we discuss the research progress of targeted therapy and immunotherapy for HCC in recent years, which will provide a reference for the further development of drugs for HCC.

Introduction Since June 2005, the University Hospital Medical Information Network-Clinical Trial Registry (UMIN-CTR) has been an International Committee of Medical Journal Editors (ICMJE)-approved clinical trial registry in Japan. The number of clinical trials registered in the UMIN-CTR has increased annually. To date, no report exists regarding the publishing of clinical trials registered in the UMIN-CTR. Therefore, we evaluated the publication frequency of clinical trials registered in the UMIN-CTR in Japan. Methods We targeted trials that assessed the treatment effect of chemotherapy or molecular targeting drugs for lung cancer. We included trials registered between June 2005 and January 2010, and identified published trials through a computer-based search of MEDLINE and Google Scholar. The cumulative publication rate of the trials was calculated using Kaplan-Meier analysis. Results In our study, 179 trials met the inclusion criteria. Of these, 46.4% (83/179) trials were published by the end of the cut-off period. With regard to publication, differences existed between the information recorded in the UMIN-CTR database and the actual searched results. The publication rate between groups was insignificantly different; however, whether a clinical study group did or did not conduct a trial differed significantly (53.3% vs. 36.1%; P = 0.024). Phase II studies with positive results were more likely to be published (84.4%); however, the overall publication rate was low (41.8%), which may reflect publication bias. Conclusions The UMIN-CTR fundamentally functions as the unique ICMJE-approved clinical trial registry in Japan. However, it seems insufficient to require it as the official clinical database.

Introduction: The global incidence of hepatocellular carcinoma (HCC) is not expected to decline significantly over the next 30 years. And although the latest gene sequencing studies have established its genetic map, the potentially targetable drivers of HCC are, so far, difficult to identify. To date, only seven drugs have been approved by the FDA for unresectable HCC treatment; thus, effective therapeutic breakthroughs are still needed urgently.Areas covered: In this review, the authors discuss both genetic and epigenetic alterations in HCC and introduce the current progress with some of the representative molecular targeting inhibitors, listing some of the approved drugs for the targets of HCC. The structure-activity relationship of molecules (e.g. thalidomide, bortezomil) used for HCC is also discussed.Expert opinion: Effective therapeutic targets and effective drugs for HCC treatment are an urgent unmet need. Better understanding and characterization of genetic and epigenetic alterations, which are important to hepatocarcinogenesis, may help to understand the molecular pathogenesis of HCC, as well as provide novel therapeutic lead compounds for HCC treatment.

Extensive experimental, clinical, and epidemiological evidence has explained and proven that products of natural origin are significantly important in preventing and/or ameliorating various disorders, including different types of cancer that researchers are extremely focused on. Among these studies on natural active substances, one can distinguish the emphasis on resveratrol and its properties, especially the potential anticancer role. Resveratrol is a natural product proven for its therapeutic activity, with remarkable anti-inflammatory properties. Various other benefits/actions have also been reported, such as cardioprotective, anti-ageing, antioxidant, etc. and its rapid digestion/absorption as well. This review aims to collect and present the latest published studies on resveratrol and its impact on cancer prevention, molecular signals (especially p53 protein participation), and its therapeutic prospects. The most recent information regarding the healing action of resveratrol is presented and concentrated to create an updated database focused on this topic presented above.

The optimum selection of the appropriate radiolabelled probe for the right target and the right patient is the foundation of theranostics in personalised medicine. In nuclear medicine, this process is realised through the appropriate choice of radiopharmaceuticals based on molecular biomarkers regarding molecular imaging. Theranostics is developing a strategy that can be used to implement accepted tools for individual molecular targeting, including diagnostics, and advances in genomic molecular knowledge, which has led to identifying theranostics biomaterials that have the potency to diagnose and treat malignancies. Today, numerous studies have reported on the discovery and execution of these radiotracers in personalised medicine. In this review, we presented our point of view of the most important theranostics agents that can be used to treat several types of malignancies. Molecular targeted radionuclide treatment methods based on theranostics are excellent paradigms of the relationship between molecular imaging and therapy that has been used to provide individualised or personalised patient care. Toward that end, a precise planned prospective examination of theranostics must be done to compare this approach to more standard therapies.

Encapsulation of the therapeutic monoclonal antibody rituximab, and its molecular targeting to brain metastases of B-cell lymphoma, significantly boosts the antibody’s therapeutic effectiveness in mice.

Background/Aim: Lenvatinib (LEN) has been developed for the treatment of unresectable hepatocellular carcinoma (u-HCC). We aimed to elucidate the relative change in hepatic reserve function early following LEN treatment in affected patients. Materials/Methods: From March 2018 to April 2019, 123 u-HCC patients (median age 71 years; male:female ratio 95:28; Child-Pugh score 5:6:7 = 65:50:8; modified albumin-bilirubin [mALBI] grade 1:2a:2b:3 = 44:28:50:1, Barcelona Clinic Liver Cancer stage A:B:C = 1:49:73) were enrolled. Relative changes in hepatic reserve function at 2 and 4 weeks after starting LEN were retrospectively evaluated. Results: The median survival was 11.3 months. The Child-Pugh score declined from the start to 4 weeks after commencing LEN (score 5:6:7:8:9:≥10 = 65:50:8:0:0:0 vs. 50:39:22:8:0:4, p < 0.001). A comparison among ALBI scores at the start of LEN and those at 2 and 4 weeks revealed significant relative changes (–2.36 ± 0.45 to –2.20 ± 0.49 at 2 weeks, –2.15 ± 0.50 at 4 weeks, p < 0.001, Bonferroni method), while there was no significant difference between those at 2 and 4 weeks (p= 0.210, Bonferroni method). Assessments of relative changes of ALBI score in patients divided by mALBI grade 1, 2a, and 2b or more showed a significant decline in score regardless of grade (–2.82 ± 0.17 to –2.53 ± 0.34, p < 0.001; –2.46 ± 0.10 to –2.31 ± 0.33, p = 0.017; and –1.90 ± 0.26 to –1.75 ± 0.42, p= 0.009, respectively). Conclusion: Decline in hepatic function is common in the early stage (≤4 weeks, especially within 2 weeks) after introducing LEN. It is important to introduce molecular targeting agent drugs for u-HCC in patients with better hepatic function, who show transarterial catheter chemoembolization failure, as much as possible, along with consideration of the negative influence of LEN on the early response of hepatic function.

Genetic alterations in signaling pathways that control cell cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in 10 canonical pathways: cell cycle, Hippo, Myc, Notch, NRF2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, P53 and β-catenin/WNT. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.

More than half of cancer patients receive radiotherapy as a part of their cancer treatment. DNA double-strand breaks (DSBs) are considered as the most lethal form of DNA damage and a primary cause of cell death and are induced by ionizing radiation (IR) during radiotherapy. Many malignant cells carry multiple genetic and epigenetic aberrations that may interfere with essential DSB repair pathways. Additionally, exposure to IR induces the activation of a multicomponent signal transduction network known as DNA damage response (DDR). DDR initiates cell cycle checkpoints and induces DSB repair in the nucleus by non-homologous end joining (NHEJ) or homologous recombination (HR). The canonical DSB repair pathways function in both normal and tumor cells. Thus, normal-tissue toxicity may limit the targeting of the components of these two pathways as a therapeutic approach in combination with radiotherapy. The DSB repair pathways are also stimulated through cytoplasmic signaling pathways. These signaling cascades are often upregulated in tumor cells harboring mutations or the overexpression of certain cellular oncogenes, e.g., receptor tyrosine kinases, PIK3CA and RAS. Targeting such cytoplasmic signaling pathways seems to be a more specific approach to blocking DSB repair in tumor cells. In this review, a brief overview of cytoplasmic signaling pathways that have been reported to stimulate DSB repair is provided. The state of the art of targeting these pathways will be discussed. A greater understanding of the underlying signaling pathways involved in DSB repair may provide valuable insights that will help to design new strategies to improve treatment outcomes in combination with radiotherapy.

The advent of genomic, proteomic, and high-throughput screening technologies has made available many new targets for brain tumor imaging; however, target availability and accessibility need to be carefully considered when designing imaging probes. Nanoparticles, although largely still only used in preclinical studies, are a versatile tool for targeted imaging of physiologic and molecular aspects of brain tumors through many clinically used modalities. Liposomes can be used to transport diverse payloads in vivo, including contrast agents and drugs, and may be functionalized to increase circulation half-life and achieve targeting specificity. Polymeric, gold, and iron oxide nanoparticles have been used for diverse applications in preclinical studies; however, the utility of other methods, such as quantum dots and self-assembling DNA molecules, is yet to be established.

// Sara Ferluga 1 , Carla Maria Lema Tome 2 , Denise Mazess Herpai 1 , Ralph D’Agostino 3 , Waldemar Debinski 1 1 Department of Cancer Biology, Radiation Oncology and Neurosurgery, Brain Tumor Center of Excellence, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA 2 Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA 3 Department of Biostatistical Sciences, Section on Biostatistics, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA Correspondence to: Waldemar Debinski, email: debinski@wakehealth.edu Keywords: Eph receptors, ephrin-A5, glioblastoma, cytotoxin, molecular targeting Received: October 12, 2015 Accepted: July 16, 2016 Published: August 1, 2016 ABSTRACT Eph tyrosine kinase receptors are frequently overexpressed and functional in many cancers, and they are attractive candidates for targeted therapy. Here, we analyzed the expression of Eph receptor A3, one of the most up-regulated factors in glioblastoma cells cultured under tumorsphere-forming conditions, together with EphA2 and EphB2 receptors. EphA3 was overexpressed in up to 60% of glioblastoma tumors tested, but not in normal brain. EphA3 was localized in scattered areas of the tumor, the invasive ring, and niches near tumor vessels. EphA3 co-localized with macrophage/leukocyte markers, suggesting EphA3 expression on tumor-infiltrating cells of bone marrow origin. We took advantage of the fact that ephrinA5 (eA5) is a ligand that binds EphA3, EphA2 and EphB2 receptors, and used it to construct a novel targeted anti-glioblastoma cytotoxin. The eA5-based cytotoxin potently and specifically killed glioblastoma cells with an IC 50 of at least 10 -11 M. This and similar cytotoxins will simultaneously target different compartments of glioblastoma tumors while mitigating tumor heterogeneity.

Targeted and sustained delivery of biologicals to improve neovascularization has been focused on stimulation angiogenesis. The formation of collaterals however is hemodynamically much more efficient, but as a target of therapy has been under-utilized. Although there is good understanding of the molecular processes involving collateral formation and there are interesting drugable candidates, the need for targeting and sustained delivery is still an obstacle towards safe and effective treatment. Molecular targeting with nanoparticles of liposomes is promising and so are peri-vascularly delivered polymer-based protein reservoirs. These developments will lead to future arteriogenesis strategies that are adjunct to current revascularization.

Cancer is a complex system. Tumor complexity is determined not only by genetic and epigenetic heterogeneity, but also by a huge number of interactions between cancer and normal cells. The heterogeneity and complexity of a tumor causes failure of molecular targeting therapy as a tool for fighting cancer. This review considers the concepts of malignant tumors as organisms that have common characteristics despite all heterogeneity. This leads to the idea that one of the most promising strategies for fighting cancer is the use of the patient's immune system.

// Victor M. Blanco 1 , Zhengtao Chu 1, 2 , Kathleen LaSance 3 , Brian D. Gray 4 , Koon Yan Pak 4 , Therese Rider 5 , Kenneth D. Greis 5 , Xiaoyang Qi 1, 2 1 Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA 2 Division of Human Genetics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA 3 Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA 4 Molecular Targeting Technologies, Inc., West Chester, Pennsylvania 19380, USA 5 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA Correspondence to: Xiaoyang Qi, email: xiaoyang.qi@uc.edu Keywords: glioblastoma, liposome, PET, optical imaging, SapC-DOPS Abbreviations: SapC, Saposin C; DOPS, dioleylphosphatidylserine; PS, phosphatidylserine Received: June 25, 2015 Accepted: March 28, 2016 Published: April 16, 2016 ABSTRACT Multimodal tumor imaging with targeted nanoparticles potentially offers both enhanced specificity and sensitivity, leading to more precise cancer diagnosis and monitoring. We describe the synthesis and characterization of phenol-substituted, lipophilic orange and far-red fluorescent dyes and a simple radioiodination procedure to generate a dual (optical and nuclear) imaging probe. MALDI-ToF analyses revealed high iodination efficiency of the lipophilic reporters, achieved by electrophilic aromatic substitution using the chloramide 1,3,4,6-tetrachloro-3α,6α-diphenyl glycoluril (Iodogen) as the oxidizing agent in an organic/aqueous co-solvent mixture. Upon conjugation of iodine-127 or iodine-124-labeled reporters to tumor-targeting SapC-DOPS nanovesicles, optical (fluorescent) and PET imaging was performed in mice bearing intracranial glioblastomas. In addition, tumor vs non-tumor (normal brain) uptake was compared using iodine-125. These data provide proof-of-principle for the potential value of SapC-DOPS for multimodal imaging of glioblastoma, the most aggressive primary brain tumor.

Despite aggressive chemoradiation (CRT) protocols in the treatment of patients with head and neck squamous cell carcinomas (HNSCC), the outcome is still unfavorable. To improve therapy efficacy we had already successfully tested the multikinase inhibitor sorafenib in combination with irradiation (IR) in previous studies on HNSCC cell lines. In this study we investigated its effect on combined CRT treatment using cisplatin.Radio- and chemosensitivity with and without sorafenib was measured in four HNSCC cell lines and normal fibroblasts (NF) by colony formation assay. Apoptosis and cell cycle analysis were performed by flow cytometry. In HNSCC cells, sorafenib enhanced the antiproliferative effect of cisplatin without affecting apoptosis induction and with only minor effects on cell inactivation. Sorafenib added prior to irradiation enhanced cellular radiosensitivity in three of the tested HNSCC cell lines and caused massive overall cell inactivation when combined with CRT. In contrast, sorafenib did not radiosensitize NF and reduced cisplatin-induced cell inactivation. Cell inactivation by IR and cisplatin is further increased by the addition of sorafenib in HNSCC, but not in NF cells. Therefore, sorafenib is a promising candidate to improve therapy efficacy for HNSCC.

A synergistic-healing strategy that combines molecular targeting within a system-wide perspective is presented as the Multiple Integrated Complementary Healing Approaches: Energetics And Light (MICHAEL). The basis of the MICHAEL approach is the realization that environmental, nutritional and electromagnetic factors form a regulatory framework involved in bone and nerve healing. The interactions of light, energy, and nutrition with neural, hormonal and cellular pathways will be presented. Energetic therapies including electrical, low-intensity pulsed ultrasound and light based treatments affect growth, differentiation and proliferation of bone and nerve and can be utilized for their healing benefits. However, the benefits of these therapies can be impaired by the absence of nutritional, hormonal and organismal factors. For example, lack of sleep, disrupted circadian rhythms and vitamin-D deficiency can impair healing. Molecular targets, such as the Wnt pathway, protein kinase B and glucocorticoid signaling systems can be modulated by nutritional components, including quercetin, curcumin and Mg(2+) to enhance the healing process. The importance of water and water-regulation will be presented as an integral component. The effects of exercise and acupuncture on bone healing will also be discussed within the context of the MICHAEL approach.

Degenerative diseases of eye like Age-related macular degeneration (AMD), that affects the central portion of the retina (macula), is one of the leading causes of blindness worldwide especially in the elderly population. It is classified mainly as wet and dry form. With expanding knowledge about the underlying pathophysiology of the disease, various treatment strategies are being employed to halt the course of the disease progression. Hitherto, there is no ideal therapy which can cure the disease completely, and targeting the posterior segment of the eye is yet another challenge. The purpose of this review is to summarize the recent advances in the management and treatment stratagems (therapies, delivery systems and diagnostic tools) pertaining to AMD viz. molecular targeting, stem cell therapy, nanotechnology and exosomes with special reference to newer technologies like artificial intelligence and 3D printing. Furthermore, the role of diet and nutritional supplements in the prevention and treatment of the disease has also been highlighted. The alarming increase in the said disorder around the globe demands exhaustive research and investigations in the treatment zone. This review thus additionally directs the attention towards the challenges and future perspectives of different treatment approaches for AMD.

Mixed-lineage leukemia (MLL) fuses with a variety of partners to produce a functionally altered MLL complex that is not expressed in normal cells, which transforms normal hematopoietic progenitors into leukemia cells. Because more than 80 fusion partners have been identified to date, the molecular functions of MLL fusion protein complexes appear diverse. However, over the past decade, the common functions utilized for leukemic transformation have begun to be elucidated. It appears that most (if not all) MLL fusion protein complexes utilize the AF4/ENL/P-TEFb and DOT1L complexes to some extent. Based on an understanding of the underlying molecular mechanisms, several molecular targeting drugs are being developed, opening paths to novel therapies. Here, we review the recent progress made in identifying the molecular functions of various MLL fusions and categorize the numerous fusion partners into several functionally-distinct groups to help discern commonalities and differences among various MLL fusion protein complexes.

Successful molecular targeting of nanoparticle drug carriers can enhance therapeutic specificity and reduce systemic toxicity. Typically, ligands specific for cognate receptors expressed on the intended target cell type are conjugated to the nanoparticle surface. This approach, often called active targeting, seems to imply that the conjugated ligand imbues the nanoparticle with homing specificity. However, ligand-receptor interactions are mediated by short-range forces and cannot produce magnetic-like attraction over larger distances. Successful targeting actually involves two key characteristics: contact of the nanoparticle with the intended target cell and subsequent ligand-mediated retention at the site. Here we propose a conceptual framework, based on recent literature combined with basic principles of molecular interactions, to guide rational design of nanoparticle targeting strategies.

Progress toward identifying an effective chemopreventive agent to reduce the incidence of head and neck squamous cell carcinoma (HNSCC) has been limited by poor efficacy and intolerable toxicity profiles. In this review, we summarize the biological basis of HNSCC chemoprevention, and outline challenges associated with identifying appropriate high-risk HNSCC populations for chemoprevention studies. We discuss findings and lessons learned from clinical trials that have investigated micronutrient and molecular targeting interventions. Finally, we introduce the concept of green chemoprevention, interventions based upon whole plant foods or simple extracts that may represent a safe and cost-conscious option for the next generation of studies. As our scientific understanding of HNSCC reaches new levels, the field is poised to develop chemoprevention studies based on rigorous biological validation with accessibility to all affected individuals regardless of socioeconomic barriers.

Accumulating studies have provided concrete evidence that p90 ribosomal S6 kinase 2 (RSK2) is a key signaling molecule involved in cell proliferation, transformation, and cancer development. RSK2 is known to be an etiological gene of Coffin-Lowry Syndrome (CLS). Recently, signaling analysis and molecular biological approaches have provided concrete evidence that RSK2 plays an essential role in human cancers. Here, we will extensively discuss signaling pathways regulating RSK2 activity, the role of RSK2 in human cancer development, inhibitors suppressing RSK2 activity, and why RSK2 is an important target to develop drugs for human cancers.

With the development of molecular targeting therapy, several treatment options for advanced hepatocellular carcinoma (HCC) have become available in cases where curative and other palliative treatments, such as radiofrequency ablation, surgical resection, and transarterial chemoembolization, are not applicable. However, with the detection of a variety of mutations in cancer-related genes in a single tumor, molecular heterogeneity is commonly observed in HCC. Therefore, mutations in the major cellular signaling pathways underlie the development of resistance to molecular targeting agents. On the contrary, immune checkpoint inhibitors have proven effective in patients who are refractory to conventional treatments and molecular targeting therapy. Several clinical trials are currently investigating the efficacy of immune checkpoint inhibitors both individually and in combination with other types of anticancer agents. In this review, we focus on the potential of immune checkpoint blockade in the treatment of human HCC.

Background The plant Nardostachys jatamansi from Valerianaceae family is a well known antidepressant plant and has historically been used in traditional medicine. As N. jatamansi contains many different compounds, to identify its mechanisms of action, we need a network-based study. Network-based studies are becoming an increasingly important tool in understanding the mechanisms of actions of drugs. Systems pharmacology (SP) and bioinformatics are two emerging tools that use computation to develop an understanding of drug actions in molecular and cellular levels. SP can provide mechanistic understanding of protein-protein (drug-target) interaction involved in a common biological pathway. The present study was undertaken to identify unknown targets and mechanisms of antidepressant activity of N. jatamansi according to a systems pharmacology approach. Method First of all a list of all the targets (receptors and metabolites) involved in depression process were provided based on KEGG database. The 3D structures of protein targets were collected as PDB files and their active sites coordinates were found. In the next step the structures of known compounds of N. jatamansi were collected. For identifying the protein-lagand interactions, a docking process was run in AutoDock and an output was received. To complete our study, the similarity between antidepressant conventional drugs and N. jatamansi compounds was analyzed. A SP map figured by Cytoscape Software, shows the relations between herbal compounds, molecular targets and depression. Results According to the docking results, we can suggest several important targets that we have no drugs for, or several natural compounds that play an important role in depression process. According to the similarity results we can suggest several molecules for extraction or synthesis that need more researches for their therapeutic effects. This study shows that how N. jatamansi can effect on depression by multiple molecular targeting with multiple compounds.

// Takashi Murakami 1, 2, 3 , Kentaro Igarashi 1 , Kei Kawaguchi 1 , Tasuku Kiyuna 1 , Yong Zhang 1 , Ming Zhao 1 , Yukihiko Hiroshima 3 , Scott D. Nelson 5 , Sarah M. Dry 5 , Yunfeng Li 5 , Jane Yanagawa 6 , Tara Russell 6 , Noah Federman 7 , Arun Singh 4 , Irmina Elliott 6 , Ryusei Matsuyama 3 , Takashi Chishima 3 , Kuniya Tanaka 3 , Itaru Endo 3 , Fritz C. Eilber 6 , Robert M. Hoffman 1, 2 1 AntiCancer, Inc., San Diego, California, USA 2 Department of Surgery, University of California, San Diego, California, USA 3 Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan 4 Division of Hematology-Oncology, University of California, Los Angeles, California, USA 5 Department of Pathology, University of California Los Angeles, California, USA 6 Division of Surgical Oncology, University of California, Los Angeles, California, USA 7 Department of Pediatrics and Department of Orthopaedics, David Geffen School of Medicine, Mattel Children’s Hospital, UCLA’s Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA Correspondence to: Robert M. Hoffman, email: all@anticancer.com Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: osteosarcoma, nude mouse, patient-derived xenograft, Salmonella typhimurium A1-R, tumor-targeting Received: October 20, 2016 Accepted: November 16, 2016 Published: December 20, 2016 ABSTRACT Osteosarcoma occurs mostly in children and young adults, who are treated with multiple agents in combination with limb-salvage surgery. However, the overall 5-year survival rate for patients with recurrent or metastatic osteosarcoma is 20-30% which has not improved significantly over 30 years. Refractory patients would benefit from precise individualized therapy. We report here that a patient-derived osteosarcoma growing in a subcutaneous nude-mouse model was regressed by tumor-targeting Salmonella typhimurium A1-R ( S. typhimurium A1-R, p

The present review briefly describes the nature, type and pathogenesis of ulcerative colitis, and explores the potential use of peptides and proteins in the treatment of inflammatory bowel disease, especially ulcerative colitis. Intestinal absorption and the barrier mechanism of peptide and protein drugs are also discussed, with special emphasis on various strategies which make these drugs better therapeutics having high specificity, potency and molecular targeting ability. However, the limitation of such therapeutics are oral administration, poor pharmacokinetic profile and decreased bioavailability. The recent findings illustrated in this review will be helpful in designing the peptide/protein drugs as a promising treatment of choice for ulcerative colitis.

Focal adhesion kinase (FAK) plays a vital role in tumor cell proliferation, survival and migration. Altered metabolic pathways fuel rapid tumor growth by accelerating glucose, lipid and glutamine processing. Besides the mitogenic effects of FAK, evidence is accumulating supporting the association between hyper-activated FAK and aberrant metabolism in tumorigenesis. FAK can promote glucose consumption, lipogenesis, and glutamine dependency to promote cancer cell proliferation, motility, and survival. Clinical studies demonstrate that FAK-related alterations of tumor metabolism are associated with increased risk of developing solid tumors. Since FAK contributes to the malignant phenotype, small molecule inhibition of FAK-stimulated bioenergetic and biosynthetic processes can provide a novel approach for therapeutic intervention in tumor growth and invasion.

Ligand-based molecular imaging probes have been designed with high affinity and specificity for monitoring biological process and responses. Single-target recognition by traditional probes can limit their applicability for disease detection and therapy because synergistic action between disease mediators and different receptors is often involved in disease progression. Consequently, probes that can recognize multiple targets should demonstrate higher targeting efficacy and specificity than their monospecific peers. This concept has been validated by multiple bispecific heterodimer-based imaging probes that have demonstrated promising results in several animal models. This review summarizes the design strategies for bispecific peptide- and antibody-based heterodimers and their applications in molecular targeting and imaging. The design and application of bispecific heterodimer-conjugated nanomaterials are also discussed.

The majority of human sarcomas, particularly soft tissue sarcomas, are relatively resistant to traditional cytotoxic therapies. The proof-of-concept study by Ray-Coquard et al., using the Nutlin human double minute (HDM)2-binding antagonist RG7112, has recently opened a new chapter in the molecular targeting of human sarcomas.In this review, the authors discuss the challenges and prospective remedies for minimizing the significant haematological toxicities of the cis-imidazole Nutlin HDM2-binding antagonists. Furthermore, they also chart the future direction of the development of p53-reactivating (p53-RA) drugs in 12q13-15 amplicon sarcomas and as potential chemopreventative therapies against sarcomagenesis in germ line mutated TP53 carriers. Drawing lessons from the therapeutic use of Imatinib in gastrointestinal tumours, the authors predict the potential pitfalls, which may lie in ahead for the future clinical development of p53-RA agents, as well as discussing potential non-invasive methods to identify the development of drug resistance.Medicinal chemistry strategies, based on structure-based drug design, are required to re-engineer cis-imidazoline Nutlin HDM2-binding antagonists into less haematologically toxic drugs. In silico modelling is also required to predict toxicities of other p53-RA drugs at a much earlier stage in drug development. Whether p53-RA drugs will be therapeutically effective as a monotherapy remains to be determined.

The present report describes the synthesis and biological evaluation of a molecular imaging platform based on gold nanoparticles directly labeled with indium 111. The direct labeling approach facilitated radiolabeling with high activities while maintaining excellent stability within the biological environment. The resulting imaging platform exhibited low interference of the radiolabel with targeting molecules which is highly desirable for in vivo probe tracking and molecular targeted tumor imaging. The indium 111 labeled gold nanoparticles were synthesized using a simple procedure that allowed stable labeling of the nanoparticle core with various indium 111 activities. Subsequent surface modification of the particle cores with RGD based ligands at various densities allowed for molecular targeting of the avß3 integrin in vitro and for molecular targeted imaging in human melanoma and glioblastoma models in vivo. The results demonstrate the vast potential of direct labeling with radioisotopes for tracking gold nanoparticles within biological systems.

Osteoarthritis (OA) is a degenerative joint disease and a leading cause of adult disability. There is no cure for OA, and no effective treatments which arrest or slow its progression. Current pharmacologic treatments such as analgesics may improve pain relief but do not alter OA disease progression. Prolonged consumption of these drugs can result in severe adverse effects. Given the nature of OA, life-long treatment will likely be required to arrest or slow its progression. Consequently, there is an urgent need for OA disease-modifying therapies which also improve symptoms and are safe for clinical use over long periods of time. Nutraceuticals—food or food products that provide medical or health benefits, including the prevention and/or treatment of a disease—offer not only favorable safety profiles, but may exert disease- and symptom-modification effects in OA. Forty-seven percent of OA patients use alternative medications, including nutraceuticals. This review will overview the efficacy and mechanism of action of commonly used nutraceuticals, discuss recent experimental and clinical data on the effects of select nutraceuticals, such as phytoflavonoids, polyphenols, and bioflavonoids on OA, and highlight their known molecular actions and limitations of their current use. We will conclude with a proposed novel nutraceutical-based molecular targeting strategy for chondroprotection and OA treatment.

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies.

Hypoxia (low O2) is an essential microenvironmental driver of phenotypic diversity in human solid cancers. Hypoxic cancer cells hijack evolutionarily conserved, O2- sensitive pathways eliciting molecular adaptations that impact responses to radiotherapy, tumor recurrence and patient survival. In this review, we summarize the radiobiological, genetic, epigenetic and metabolic mechanisms orchestrating oncogenic responses to hypoxia. In addition, we outline emerging hypoxia- targeting strategies that hold promise for individualized cancer therapy in the context of radiotherapy and drug delivery.

OncoTarget : open access impact journal 7(34), 54925-54936 (2016). doi:10.18632/oncotarget.10705, Published by Impact Journals LLC, [S.l.]

Fluorescence-enhanced optical imaging using near-infrared (NIR) light developed forin vivomolecular targeting and reporting of cancer provides promising opportunities for diagnostic imaging. The current state of the art of NIR fluorescence-enhanced optical tomography is reviewed in the context of the principle of fluorescence, the different measurement schemes employed, and the mathematical tools established to tomographically reconstruct the fluorescence optical properties in various tissue domains. Finally, we discuss the recent advances in forward modeling and distributed memory parallel computation to provide robust, accurate, and fast fluorescence-enhanced optical tomography.

Despite recent advancements in multidisciplinary treatments, the overall survival and quality of life of patients with advanced head and neck squamous cell carcinoma (HNSCC) have not improved significantly over the past decade. Molecular targeted therapies, which have been addressed and advanced by the concept of “oncogene addiction”, have demonstrated only limited successes so far. To explore a novel clue for clinically effective targeted therapies, we analyzed the molecular circuitry of HNSCC through the lens that HNSCC is an evolving system. In the trajectory of this somatic evolution, HNSCC acquires biological robustness under a variety of selective pressures including genetic, epigenetic, micro‐environmental and metabolic stressors, which well explains the major mechanism of “escaping from oncogene addiction”. On the other hand, this systemic view appears to instruct us approaches to target latent vulnerability of HNSCC that is masked behind the plasticity and evolvability of this complex adaptive system., Highlights ► There is an urgent need to develop a novel conceptual framework for the treatment of HNSCC.► The biological robustness of HNSCC was analyzed through a somatic evolution model.► This model well explains the mechanism of “escaping from oncogene addiction”.► We discuss about the possible approaches to target vulnerability of evolving HNSCC.

The inception of targeted agents has revolutionized the cancer therapy paradigm, both for physicians and patients. A large number of molecular targeted agents for cancer therapy are currently available for clinical use today. Many more are in making, but there are issues that remain to be resolved for the scientific as well as social community before the recommendation of their widespread use in may clinical scenarios can be done, one such issue being cost and cost effectiveness, others being resistance and lack of sustained efficacy. With the current knowledge about available targeted agents, the growing knowledge of intricate molecular pathways and unfolding of wider spectrum of molecular targets that can really matter in the disease control, calls for only the just use of the agents available now, drug companies need to make a serious attempt to reduce the cost of the agents. Research should focus on agents that show sustained responses in preclinical data. More needs to be done in laboratories and by the pharmaceutical industries, before we can truly claim to have entered a new era of targeted therapy in cancer care.

Oncogenic activations by mutations in key cancer genes such as EGFR and KRAS are frequently associated with human cancers. Molecular targeting of specific oncogenic mutations in human cancer is a major therapeutic inroad for anti-cancer drug therapy. In addition, progressive developments of oncogene mutations lead to drug resistance. Therefore, the ability to detect and continuously monitor key actionable oncogenic mutations is important to guide the use of targeted molecular therapies to improve long-term clinical outcomes in cancer patients. Current oncogenic mutation detection is based on direct sampling of cancer tissue by surgical resection or biopsy. Oncogenic mutations were recently shown to be detectable in circulating bodily fluids of cancer patients. This field of investigation, termed liquid biopsy, permits a less invasive means of assessing the oncogenic mutation profile of a patient. This paper will review the analytical strategies used to assess oncogenic mutations from biofluid samples. Clinical applications will also be discussed.

T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy that presents with poor prognosis. Treatment relies on the application of aggressive therapies that produce deleterious side-effects, justifying the quest for novel, more efficient and selective molecular targeting agents. Mutations leading to abnormal Notch-1 activity are present in more than half of the T-ALL patients, underscoring the potential therapeutic relevance of targeting Notch-1 inhibition and further reinforcing the need to better comprehend the mechanisms by which Notch-1 drives T cell leukemogenesis. Clinical application of γ-secretase inhibitors to block Notch signaling in T-ALL revealed new challenges that involve improvement of the therapeutic benefit and reduction of intestinal toxicity. Here, we review the latest advances in the development and use of Notch antagonists and summarize the current knowledge on Notch function in T-ALL to understand how it may translate into novel therapeutic strategies that increment the efficiency of Notch inhibition.

Meningiomas are slow-growing benign tumors believed to originate from arachnoidal cap cells. This article discusses the surgical approaches for resection, especially the transnasal endoscopic approach. Alternative treatment options are primarily used where patients are not surgical candidates or location of recurrence precludes additional surgery. These options include radiotherapy, stereotactic radiosurgery, and chemotherapy. In addition, we discuss the current on going research in molecular targeting agents for meningioma treatment.

Despite advances in treatment for glioblastoma multiforme (GBM), patient prognosis remains poor. Although there is growing evidence that molecular targeting could translate into better survival for GBM, current clinical data show limited impact on survival. Recent progress in GBM genomics implicate several activated pathways and numerous mutated genes. This molecular diversity can partially explain therapeutic resistance and several approaches have been postulated to target molecular changes. Furthermore, most drugs are unable to reach effective concentrations within the tumor owing to elevated intratumoral pressure, restrictive vasculature and other limiting factors. Here, we describe the preclinical and clinical developments in treatment strategies of GBM. We review the current clinical trials for GBM and discuss the challenges and future directions of targeted therapies.