Molecular-targeted Drugs Research Articles

Angiogenesis inhibition in metastatic colorectal cancer continuum of care

Current treatment for most patients with metastatic colorectal cancer consists of sequential lines of different systemic therapies, including chemotherapy combinations (5-fluorouracil plus irinotecan or oxaliplatin) with the addition of molecular-targeted drugs, such as anti-angiogenic drugs (independently of the molecular characterisation of the tumour) or anti-epidermal growth factor receptor drugs (for patients whose tumours are wild type for KRAS and NRAS genes). More recently, for the subgroup of patients with high microsatellite instable or mismatch repair deficient tumours (approximately 5% of patients), immune checkpoint inhibitors (pembrolizumab or nivolumab plus ipilimumab) have been shown to be highly effective as first-line or second-line therapies. 1 Ciardiello F Ciardiello D Martini G Napolitano S Tabernero J Cervantes A Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022; 72: 372-401 Crossref PubMed Scopus (49) Google Scholar , 2 Cervantes A Adam R Roselló S et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34: 10-32 Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar Furthermore, in patients whose tumours show HER2 gene amplification, BRAFV600E mutation, or KRASG12C mutation, current treatment options also incorporate the corresponding appropriate molecular-targeted drugs. 1 Ciardiello F Ciardiello D Martini G Napolitano S Tabernero J Cervantes A Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022; 72: 372-401 Crossref PubMed Scopus (49) Google Scholar , 2 Cervantes A Adam R Roselló S et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34: 10-32 Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 studyFruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. Full-Text PDF

A Case of Successful Lenvatinib Re-challenge following Atezolizumab Plus Bevacizumab Combination Therapy Failure for Unresectable Hepatocellular Carcinoma.

To our knowledge, there have been no reports of first-line lenvatinib (LEN) and LEN re-challenge following atezolizumab/bevacizumab (Atezo-Bev) failure in the same patient. We herein report a patient with advanced hepatocellular carcinoma who failed either 1st line LEN and 2nd line Atezo-Bev, and successfully achieved complete response to LEN rechallenge with sequencial TACE. This patient had a poor response to TACE before immunotherapy and introduction of molecular-targeted drugs but showed a good response to selective TACE after LEN rechallenge. Our findings suggest the need to reconsider the use of molecular-targeted drugs and TACE with advances in immunotherapy.

Shared gene expression signatures between visceral adipose and skeletal muscle tissues are associated with cardiometabolic traits in children with obesity

Obesity in children is related to the development of cardiometabolic complications later in life, where molecular changes of visceral adipose tissue (VAT) and skeletal muscle tissue (SMT) have been proven to be fundamental. The aim of this study is to unveil the gene expression architecture of both tissues in a cohort of Spanish boys with obesity, using a clustering method known as weighted gene co-expression network analysis. For this purpose, we have followed a multi-objective analytic pipeline consisting of three main approaches; identification of gene co-expression clusters associated with childhood obesity, individually in VAT and SMT (intra-tissue, approach I); identification of gene co-expression clusters associated with obesity-metabolic alterations, individually in VAT and SMT (intra-tissue, approach II); and identification of gene co-expression clusters associated with obesity-metabolic alterations simultaneously in VAT and SMT (inter-tissue, approach III). In both tissues, we identified independent and inter-tissue gene co-expression signatures associated with obesity and cardiovascular risk, some of which exceeded multiple-test correction filters. In these signatures, we could identify some central hub genes (e.g., NDUFB8, GUCY1B1, KCNMA1, NPR2, PPP3CC) participating in relevant metabolic pathways exceeding multiple-testing correction filters. We identified the central hub genes PIK3R2, PPP3C and PTPN5 associated with MAPK signaling and insulin resistance terms. This is the first time that these genes have been associated with childhood obesity in both tissues. Therefore, they could be potential novel molecular targets for drugs and health interventions, opening new lines of research on the personalized care in this pathology. This work generates interesting hypotheses about the transcriptomics alterations underlying metabolic health alterations in obesity in the pediatric population.

BRAFV600E Metastatic Colorectal Cancer: Perspective from a Patient, a Caregiver, and an Oncologist.

This article has been co-authored by a patient with right-sided BRAFV600E metastatic colorectal cancer (mCRC), his caregiver, and an oncologist. Here the patient and caregiver discuss their personal experiences struggling with cancer, including their fears, expectations, and attitudes as the disease progresses. The oncologist describes how patients with BRAFV600E mCRC are treated and how the management strategy can be balanced to mitigate any side effects. Improved diagnostic techniques and the availability of numerous treatment options, including various chemotherapy schemes and molecular-targeted drugs, can aid rapid implementation of treatment algorithms. The pivotal roles of patients' associations in the general support of patients and those close to them, and in facilitating the link with healthcare professionals, are highlighted in this perspective piece.

Dupilumab aggravates Sézary syndrome: The importance of accurate pathological diagnosis

We report a case of Sézary syndrome aggravated by dupilumab. Although a diagnosis of atopic dermatitis was made previously, our retrospective diagnosis was cutaneous T-cell lymphoma. A 72-year-old woman was referred for evaluation of erythema over her entire body. She had received a diagnosis of atopic dermatitis (AD) based on skin biopsy elsewhere 7 years earlier. Since her symptoms were resistant to topical corticosteroids and oral antihistamines, dupilumab was started. She noticed peripheral lymph node enlargement 11 months after the commencement of dupilumab. Physical examination revealed generalized erythroderma with desquamation (Figure 1A,B) and lymphadenopathy in the neck, axilla, and inguinal region. A biopsy from her abdomen showed dense infiltrations of atypical lymphoid cells in the upper dermis with epidermotropism (Figure 1C,D). Immunohistochemically, the infiltrating cells were positive for CD3 and CD4; CD8 was almost negative. There was a 50% deletion of CD7 (Figure 1E–H). Her peripheral blood (PB) white blood cell count was 7660/μL, with 35% abnormal lymphocytes (2681/μL). Although CD4+/CD26− or CD4+/CD7− cells were not assessed, CD4/CD8 ratio was 10.59.1, 2 Human T-lymphotropic virus-1 antibody was negative. Monoclonal gene rearrangement of T-cell receptor β-chain was identified in her PB by Southern blot analysis. Inguinal lymph node biopsy showed partial effacement by atypical lymphocytes. The diagnosis was Sézary syndrome (SS), stage IVA2 (T4N3MXB2). Taking into account the risk of tumor lysis syndrome due to high tumor burden, we selected conventional multiagent chemotherapy as an initial therapy before using a molecular-targeted drug. Dupilumab was discontinued; cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) were started. After two cycles of CHOP, biweekly intravenous mogamulizumab was introduced. Her skin lesions gradually improved. The PB abnormal lymphocyte count decreased. Her disease was well controlled with mogamulizumab for 17 months. We reviewed the previous biopsy specimen. Dense dermal infiltrates with atypical cells and epidermotropism were seen (Figure 1I,J). These infiltrates were positive for CD3 and CD4. CD8-positive cells were sparse. There was a 30% deletion of CD7 (Figure 1K–N). The atypical cells were CCR4+ and CD68−. Although a diagnosis of AD was made previously, our retrospective diagnosis was cutaneous T-cell lymphoma (CTCL). Dupilumab is a monoclonal antibody which inhibits both IL-4 and IL-13 signaling pathways by binding specifically to the α subunit of the IL-4 receptor. Several cases of CTCL that developed or worsened after dupilumab use have been reported. A proposed mechanism of CTCL due to dupilumab is the involvement of IL-13 receptor α2 (IL-13Rα2), which is expressed on CTCL cells and promotes tumor progression. When dupilumab blocks IL-4 and IL-13 receptors, serum IL-13 levels increase. Because dupilumab inhibits IL-13Rα1 but not IL-13Rα2 signaling, increased IL-13 levels due to dupilumab stimulate IL-13Rα2, leading to the activation and proliferation of lymphoma cells.3 To our knowledge, there are 36 cases3-19 of CTCL worsened by dupilumab based on the diagnosis of AD or eczema have been reported. Of these 36 patients, 18 underwent skin biopsy prior to dupilumab therapy; no evidence of CTCL was described in 16 patients.3-10 In one remaining patient, the authors re-evaluated the biopsy specimen taken before dupilumab treatment and revised the diagnosis to early CTCL-not otherwise specified.10 In another patient, the first skin biopsy taken before dupilumab was compatible with AD; however, the diagnosis of mycosis fungoides was made by the second biopsy taken on the first day of dupilumab treatment. After 6 months of dupilumab treatment, the third biopsy turned out CD30-positive anaplastic large-cell lymphoma.11 When using dupilumab for AD, clinicians should be alert to the development or worsening of CTCL. Skin biopsy with immunohistochemical examination is strongly recommended before dupilumab therapy, especially in patients with erythroderma and elderly patients. The authors declare no conflict of interest. Approval of the research protocol: N/A. Informed Consent: N/A. Registry and the Registration No.: N/A. Animal Studies: N/A.

Heterocyclic Molecular Targeted Drugs and Nanomedicines for Cancer: Recent Advances and Challenges.

Cancer is a top global public health concern. At present, molecular targeted therapy has emerged as one of the main therapies for cancer, with high efficacy and safety. The medical world continues to struggle with the development of efficient, extremely selective, and low-toxicity anticancer medications. Heterocyclic scaffolds based on the molecular structure of tumor therapeutic targets are widely used in anticancer drug design. In addition, a revolution in medicine has been brought on by the quick advancement of nanotechnology. Many nanomedicines have taken targeted cancer therapy to a new level. In this review, we highlight heterocyclic molecular-targeted drugs as well as heterocyclic-associated nanomedicines in cancer.

Sorafenib-Based Drug Delivery Systems: Applications and Perspectives.

As a Food and Drug Administration (FDA)-approved molecular-targeted chemotherapeutic drug, sorafenib (SF) can inhibit angiogenesis and tumor cell proliferation, leading to improved patient overall survival of hepatocellular carcinoma (HCC). In addition, SF is an oral multikinase inhibitor as a single-agent therapy in renal cell carcinoma. However, the poor aqueous solubility, low bioavailability, unfavorable pharmacokinetic properties and undesirable side effects (anorexia, gastrointestinal bleeding, and severe skin toxicity, etc.) seriously limit its clinical application. To overcome these drawbacks, the entrapment of SF into nanocarriers by nanoformulations is an effective strategy, which delivers SF in a target tumor with decreased adverse effects and improved treatment efficacy. In this review, significant advances and design strategies of SF nanodelivery systems from 2012 to 2023 are summarized. The review is organized by type of carriers including natural biomacromolecule (lipid, chitosan, cyclodextrin, etc.); synthetic polymer (poly(lactic-co-glycolic acid), polyethyleneimine, brush copolymer, etc.); mesoporous silica; gold nanoparticles; and others. Co-delivery of SF and other active agents (glypican-3, hyaluronic acid, apolipoprotein peptide, folate, and superparamagnetic iron oxide nanoparticles) for targeted SF nanosystems and synergistic drug combinations are also highlighted. All these studies showed promising results for targeted treatment of HCC and other cancers by SF-based nanomedicines. The outlook, challenges and future opportunities for the development of SF-based drug delivery are presented.

Immune Phenotype as a Biomarker for Systemic Lupus Erythematosus.

The treatment of rheumatoid arthritis was revolutionized with the use of molecular-targeted drugs that target immunoregulatory molecules. The success of treatment with these drugs prompted the development of molecular-targeted drugs for systemic lupus erythematosus. However, systemic lupus erythematosus is a disease with high heterogeneous immune abnormalities, and diverse cells or molecules can be treatment targets. Thus, the identification of subpopulations based on immune abnormalities is essential for the development of effective treatment. One analytical method used to identify subpopulations is the immunophenotyping of peripheral blood samples of patients. This analysis evaluates the validity of target molecules for peripheral blood immune cell subsets, which are expected to be developed as biomarkers for precision medicine in which appropriate treatment targets are set for each subpopulation.

Exploration of the potential common pathogenic mechanisms in COVID-19 and silicosis by using bioinformatics and system biology

Silicosis is an occupational lung disease that is common worldwide. In recent years, coronavirus disease 2019 (COVID-19) has provided daunting challenges to public healthcare systems globally. Although multiple studies have shown a close link between COVID-19 and other respiratory diseases, the inter-relational mechanisms between COVID-19 and silicosis remain unclear. This study aimed to explore the shared molecular mechanisms and drug targets of COVID-19 and silicosis. Gene expression profiling identified four modules that were most closely associated with both diseases. Furthermore, we performed functional analysis and constructed a protein–protein interaction network. Seven hub genes (budding uninhibited by benzimidazoles 1 [BUB1], protein regulator of cytokinesis 1 [PRC1], kinesin family member C1 [KIFC1], ribonucleotide reductase regulatory subunit M2 [RRM2], cyclin-dependent kinase inhibitor 3 [CDKN3], Cyclin B2 [CCNB2], and minichromosome maintenance complex component 6 [MCM6]) were involved in the interaction between COVID-19 and silicosis. We investigated how diverse microRNAs and transcription factors regulate these seven genes. Subsequently, the correlation between the hub genes and infiltrating immune cells was explored. Further in-depth analyses were performed based on single-cell transcriptomic data from COVID-19, and the expression of hub-shared genes was characterized and located in multiple cell clusters. Finally, molecular docking results reveal small molecular compounds that may improve COVID-19 and silicosis. The current study reveals the common pathogenesis of COVID-19 and silicosis, which may provide a novel reference for further research.

Treatment Settings and Outcomes with Regorafenib and Trifluridine/Tipiracil at Third-Line Treatment and beyond in Metastatic Colorectal Cancer: A Real-World Multicenter Retrospective Study.

Patients with refractory mCRC rarely undergo third-line or subsequent treatment. This strategy could negatively impact their survival. In this setting, regorafenib (R) and trifluridine/tipiracil (T) are two key new treatment options with statistically significant improvements in overall survival (OS), progression-free survival (PFS), and disease control with different tolerance profiles. This study aimed to retrospectively evaluate the efficacy and safety profiles of these agents in real-world practice. In 2012-2022, 866 patients diagnosed with mCRC who received sequential R and T (T/R, n = 146; R/T, n = 116]) or T (n = 325]) or R (n = 279) only were retrospectively recruited from 13 Italian cancer institutes. The median OS is significantly longer in the R/T group (15.9 months) than in the T/R group (13.9 months) (p = 0.0194). The R/T sequence had a statistically significant advantage in the mPFS, which was 8.8 months with T/R vs. 11.2 months with R/T (p = 0.0005). We did not find significant differences in outcomes between groups receiving T or R only. A total of 582 grade 3/4 toxicities were recorded. The frequency of grade 3/4 hand-foot skin reactions was higher in the R/T sequence compared to the reverse sequence (37.3% vs. 7.4%) (p = 0.01), while grade 3/4 neutropenia was slightly lower in the R/T group than in the T/R group (66.2% vs. 78.2%) (p = 0.13). Toxicities in the non-sequential groups were similar and in line with previous studies. The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

High throughput LC/ESI-MS/MS method for simultaneous analysis of 20 oral molecular-targeted anticancer drugs and the active metabolite of sunitinib in human plasma

Many types of oral molecular-targeted anticancer drugs are clinically used in cancer genomic medicine. Combinations of multiple molecular-targeted anticancer drugs are also being investigated, expecting to prolong the survival of patients with cancer. Therapeutic drug monitoring of oral molecular-targeted drugs is important to ensure efficacy and safety. A liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) has been used for simultaneous determination of these drugs in human plasma. However, the sensitivity of mass spectrometers and differences in the therapeutic range of drugs have rendered the development of simultaneous LC/ESI-MS/MS methods difficult. In this study, a simultaneous quantitative method for 20 oral molecular-targeted anticancer drugs and the active metabolite of sunitinib was developed based on the results of linear range shifts of the calibration curves using four ion abundance adjustment techniques (collision energy defects, in-source collision-induced dissociation, secondary product ion selected reaction monitoring, and isotopologue selected reaction monitoring). The saturation of the detector for the seven analytes was resolved by incorporating optimal ion abundance adjustment techniques. Furthermore, the reproducibility of this method was confirmed in validation tests, and plasma from patients was measured by this method to demonstrate its usefulness in actual clinical practice. This analytical method is expected to make a substantial contribution to the promotion of personalized medicine in the future.

Erianin as a Promising Novel Agent in the Treatment of Neuroblastoma: The Anticancer Effects and Underlying Molecular Mechanisms.

Erianin is an active dibenzyl compound isolated from Dendrobium officinale and Dendrobium chrysotoxum and there are very few studies on molecular mechanisms and drug targets of erianin. In addition, there is no study investigating the anti-cancer effect of erianin on neuroblastoma cells. The aim of the study is to investigate the anticancer effect of erianin and the underlying mechanism of this effect on SH-SY5Y cells. The effects of erianin on cell viability, invasion and migration were determined by XTT, matrigel chamber and wound healing evaluation, respectively. Expression changes of miRNAs (microRNA) and apoptosis-related genes were evaluated by RT-PCR, and the apoptosis rate was supported by Annexin V evaluation. Erianin significantly decreased cell proliferation, invasion and migration. Erianin administration caused apoptosis by significantly increasing caspase-7, FADD (Fas-associated protein with death domain), BID (BH3 Interacting Domain Death Agonist) and DR5 (Death receptor 5) gene expressions. While the rate of total apoptotic cells was 45.35 ± 6.80% in SH-SY5Y cells treated with erianin, it was 0.133 ± 0.05% in the control group (p = 0.000). In addition, erianin administration significantly decreased the expressions of hsa-miR-155-5p (p = 0.014) and hsa-miR-223-3p (p = 0.004). Also, our study demonstrated for the first time the relationship between erianin and mi-RNAs in a cancer cell. Our study suggests that erianin may be a natural, safe and easily accessible drug candidate that can be used in the treatment of neuroblastoma.

Anlotinib: A Novel Molecular-Targeted Drug for Tumours

Anlotinib is a tyrosine kinase inhibitor. It inhibits tumour growth by inhibiting the phosphorylation of angiogenesis-related receptors and attenuating the expression of related signals downstream of this pathway. Anlotinib has shown good antitumour activity and tolerability in patients with tumours, and multitargeted inhibition of angiogenesis does not lead to drug resistance due to excessive bypass activation. Moreover, its antitumour activity is superior to that of sunitinib, a conventional angiogenesis inhibitor. Results from several clinical studies have indicated that anlotinib improves progression-free survival and overall survival. Most adverse effects of anlotinib treatment were found to be alleviated by dose adjustment and symptomatic supportive therapy in several clinical trials. Therefore, anlotinib is a promising drug for oncology patients that is safe, effective, and tolerable, allowing patients with advanced cancer to benefit from drug therapy. This article reviews the basic information, antitumour mechanisms, clinical applications, clinical trial findings, and adverse effects of anlotinib and describes the problems in anlotinib research. It concludes with an outlook on future work.

Research progress of targeted therapy combined with immunotherapy for hepatocellular carcinoma.

Hepatocellular carcinoma is a common gastrointestinal malignancy with a high mortality rate and limited treatment options. Molecularly targeted drugs combined with immune checkpoint inhibitors have shown unique advantages over single-agent applications, significantly prolonging patient survival. This paper reviews the research progress of molecular-targeted drugs combined with immune checkpoint inhibitors in the treatment of hepatocellular carcinoma and discusses the effectiveness and safety of the combination of the two drugs to provide a reference for the further application of molecular-targeted drugs combined with immune checkpoint inhibitors in clinical practice.

Transcriptomic analysis of benznidazole-resistant and susceptible Trypanosoma cruzi populations

BackgroundChagas disease (CD), caused by the parasite Trypanosoma cruzi, is a serious public health concern in Latin America. Nifurtimox and benznidazole (BZ), the only two drugs currently approved for the treatment of CD, have very low efficacies in the chronic phase of the disease and several toxic side effects. Trypanosoma cruzi strains that are naturally resistant to both drugs have been reported. We performed a comparative transcriptomic analysis of wild-type and BZ-resistant T. cruzi populations using high-throughput RNA sequencing to elucidate the metabolic pathways related to clinical drug resistance and identify promising molecular targets for the development of new drugs for treating CD.MethodsAll complementary DNA (cDNA) libraries were constructed from the epimastigote forms of each line, sequenced and analysed using the Prinseq and Trimmomatic tools for the quality analysis, STAR as the aligner for mapping the reads against the reference genome (T. cruzi Dm28c—2018), the Bioconductor package EdgeR for statistical analysis of differential expression and the Python-based library GOATools for the functional enrichment analysis.ResultsThe analytical pipeline with an adjusted P-value of < 0.05 and fold-change > 1.5 identified 1819 transcripts that were differentially expressed (DE) between wild-type and BZ-resistant T. cruzi populations. Of these, 1522 (83.7%) presented functional annotations and 297 (16.2%) were assigned as hypothetical proteins. In total, 1067 transcripts were upregulated and 752 were downregulated in the BZ-resistant T. cruzi population. Functional enrichment analysis of the DE transcripts identified 10 and 111 functional categories enriched for the up- and downregulated transcripts, respectively. Through functional analysis we identified several biological processes potentially associated with the BZ-resistant phenotype: cellular amino acid metabolic processes, translation, proteolysis, protein phosphorylation, RNA modification, DNA repair, generation of precursor metabolites and energy, oxidation–reduction processes, protein folding, purine nucleotide metabolic processes and lipid biosynthetic processes.ConclusionsThe transcriptomic profile of T. cruzi revealed a robust set of genes from different metabolic pathways associated with the BZ-resistant phenotype, proving that T. cruzi resistance mechanisms are multifactorial and complex. Biological processes associated with parasite drug resistance include antioxidant defenses and RNA processing. The identified transcripts, such as ascorbate peroxidase (APX) and iron superoxide dismutase (Fe-SOD), provide important information on the resistant phenotype. These DE transcripts can be further evaluated as molecular targets for new drugs against CD.Graphical

Identification of a new gibberellin receptor agonist, diphegaractin, by a cell-free chemical screening system

Gibberellin (GA) is a phytohormone that regulates various developmental processes during the plant life cycle. In this study, we identify a new GA agonist, diphegaractin, using a wheat cell-free based drug screening system with grape GA receptor. A GA-dependent interaction assay system using GA receptors and DELLA proteins from Vitis vinifera was constructed using AlphaScreen technology and cell-free produced proteins. From the chemical compound library, diphegaractin was found to enhance the interactions between GA receptors and DELLA proteins from grape in vitro. In grapes, we found that diphegaractin induces elongation of the bunch and increases the sugar concentration of grape berries. Furthermore, diphegaractin shows GA-like activity, including promotion of root elongation in lettuce and Arabidopsis, as well as reducing peel pigmentation and suppressing peel puffing in citrus fruit. To the best of our knowledge, this study is the first to successfully identify a GA receptor agonist showing GA-like activity in agricultural plants using an in vitro molecular-targeted drug screening system.

Synergy of Combining Methionine Restriction and Chemotherapy: The Disruptive Next Generation of Cancer Treatment.

All cancer cell types are methionine-addicted, which is termed the Hoffman effect. Cancer cells, unlike normal cells, cannot survive without large amount of methionine. In general, when methionine is depleted, both normal cells and cancer cells synthesize methionine from homocysteine, but cancer cells consume large amounts of methionine and they cannot survive without exogenous methionine. For this reason, methionine restriction has been shown to be effective against many cancers in vitro and in vivo. Methionine restriction arrests cancer cells in the S/G2-phase of the cell cycle. Cytotoxic agents that act in the S/G2-phase are highly effective when used in combination with methionine restriction due to the cancer cells being trapped in S/G2-phase, unlike normal cells which arrest in G1/G0-phase. Combining methionine restriction and chemotherapeutic drugs for cancer treatment is termed the Hoffman protocol. The efficacy of many cytotoxic agents and molecular-targeted drugs in combination with methionine restriction has been demonstrated. The most effective method of methionine restriction is the administration of recombinant methioninase (rMETase), which degrades methionine. The efficacy of rMETase has been reported in mice and human patients by oral administration. The present review describes studies on anticancer drugs that showed synergistic efficacy in combination with methionine restriction, including rMETase administration. It is proposed that the next disruptive generation of cancer chemotherapy should employ current therapy in combination with methionine restriction for all cancer types.

Medical Treatments for Malignant Brain Tumor

Treatment of brain tumors, particularly malignant gliomas, is challenging using only surgical resection and radiation therapy, and medical treatment plays an important role in the management of these malignancies. Temozolomide has been mainly used for the treatment of malignant gliomas over a decade. However, novel therapeutic options, such as molecular-targeted drugs and oncolytic virus therapeutic agents have been introduced in recent years. Classical anticancer medications, such as nitrosoureas and platinum-based drugs, continue to be administered for treatment of some types of malignant brain tumors.

A strategy for low-cost portable monitoring of plasma drug concentrations using a sustainable boron-doped-diamond chip

On-site monitoring of plasma drug concentrations is required for effective therapies. Recently developed handy biosensors are not yet popular owing to insufficient evaluation of accuracy on clinical samples and the necessity of complicated costly fabrication processes. Here, we approached these bottlenecks via a strategy involving engineeringly unmodified boron-doped diamond (BDD), a sustainable electrochemical material. A sensing system based on a ∼1 cm2 BDD chip, when analysing rat plasma spiked with a molecular-targeting anticancer drug, pazopanib, detected clinically relevant concentrations. The response was stable in 60 sequential measurements on the same chip. In a clinical study, data obtained with a BDD chip were consistent with liquid chromatography–mass spectrometry results. Finally, the portable system with a palm-sized sensor containing the chip analysed ∼40 μL of whole blood from dosed rats within ∼10 min. This approach with the ‘reusable’ sensor may improve point-of-monitoring systems and personalised medicine while reducing medical costs.

Latest Findings on the Pathogenic Mechanisms of Thoracic Aortic Dissection

Thoracic aortic dissection (TAD) is a cardiovascular disease entailing a high lethality between 65% and 85%. Surgery-assissed implant/interventional stenting is the prevailing treatment of TAD. However, surgical treatment can cause severe postoperative complications and patients incur a relatively higher risk of postoperative mortality. Since the pathogenic mechanism underlying TAD is not clear, effective medication therapies are still not available. In recent years, along with advances in single-cell sequencing and other molecular biological technologies, there have been prelimiary findings suggesting the special role of dysfunctional vascular smooth muscle cells (VSMCs) in the pathogenesis and development of TAD. Furthermore, the molecular mechanisms regulating the dysfunction of VSMCs have been initially explored. It is expected that these new findings will contribute to the development of new strategies to prevent TAD and lead to new ideas for the identifiction of potential drug therapeutic targets. Herein, we summarized the critical role of dysfunctional VSMCs in the pathogenesis and development of TAD and presented in detail the biological factors and the related molecular mechanisms that regulate the dysfunction of VSMCs. We hope this review will provide a reference for further investigation into the central role of dysfunctional VSMCs in the pathogenesis and development of TAD and exploration for effective molecular drug targets for TAD.