Genetic modification of mesenchymal stem cells to enhance their anti-tumor efficacy

Non-hematopoietic mesenchymal stem cells (MSCs) are widely used in regenerative medicine and tissue engineering as they possess multilineage differentiation potential and self-renewal properties. MSCs can be easily isolated from several tissues and expanded following standard cell culture procedures. MSCs have the capability of mobilization to the tumor site; so, they can automatically relocate to the tumor sites through their chemokine receptors following intravenous transplantation. In this respect, they can be used for MSC-based gene therapy. In this therapeutic technique, beneficial genes are inserted by viral and non-viral methods into MSCs that lead to transgene expression in them. Genetic modifications of MSCs have been widely studied and thoroughly investigated to further enhance their therapeutic efficacy. The current strategies of MSC-based therapies emphasize the incorporation of beneficial genes, which will enhance the therapeutic ability of MSCs and have better homing efficiency. Non-viral methods produce less toxicity and immunogenicity compared to viral gene delivery methods and thus represent a promising and efficient tool for the genetic engineering of MSCs. Several non-viral gene delivery strategies have been developed in recent decades, and some of them have been used for MSCs modification. This mini review provides an overview of current gene delivery approaches used for the genetic modification of MSCs with beneficial genes including viral and non-viral vectors.

Fabrication and bioactivity evaluation of curcumin and paclitaxel loaded lipid nanoparticles of pH-sensitive histidinylated cationic amphiphile

Drug resistance, inefficient cellular uptake and the subservient drug release to increase the intracellular drug concentration inside the tumor cells are the key reasons for low therapeutic efficacy of drug-loaded lipid nanoparticles in cancer therapy. Herein, we report on the design, synthesis and bioactivity evaluation of Curcumin & Paclitaxel (PTX) encapsulated endosomal pH-Sensitive lipid nanoparticles of histidinylated cationic amphiphile (16-GH; 2 in 1 system) to overcome these challenges. Findings in fluorescence resonance energy transfer (FRET) assay and in vitro drug release studies showed a controlled pH dependent fusogenic and drug release properties of the lipid nanoparticles of cationic amphiphile 16-GH respectively. Further in vitro studies revealed that Curcumin & PTX encapsulated nanoparticles of lipid 16-GH significantly inhibited proliferation of tumor cells than healthy cells. These lipid nanoparticles were further analyzed for their effect on 5-bromo-2'-deoxyuridine (BrdU) incorporation, Annexin V-FITC and cell cycle arrest (Sub-G1 phase). Further studies also confirmed that nanoparticles of lipid 16-GH containing Curcumin & PTX displayed significantly enhanced the caspase3/9 activity. Remarkably, nanoparticles of lipid 16-GH containing Curcumin & PTX are efficient in inducing apoptosis. The results in our initial mechanistic studies support the notion that the tumor cell selective cytotoxic capability of the lipid nanoparticles of the presently described endosomal pH-sensitive lipid probably instigates from depolarization of mitochondrial membrane potential and subsequent activation of caspases 3 and 9. The distinguishing feature of the currently described endosomal pH-sensitive system is that it not only efficiently delivers highly potent anti-cancer agents (Curcumin & PTX) to tumor cells, but the lipid nanoparticle drug carrier itself also contributes to inhibiting tumor cell growth. In summary, the presently described lipid nanoparticles are expected to simultaneously delivering combination of drugs to various types of tumor models.

Crossmark Policy of Asian Medical Press Ltd.

Crossmark Policy of Asian Medical Press Ltd.

Crossmark Policy of Asian Medical Press Ltd.

Crossmark policy of Asian Medical Press Ltd.

Crossmark policy

Crossmark policy of Asian Medical Press Ltd.

Navigating in the labyrinth of thrombotic and bleeding risks in patients with malignancies – how to make the most reasonable choices for personalized anticoagulation?

Venous thromboembolism (VTE) frequently occurs among patients with malignancies and poses an important cause of morbidity and mortality in this population. Therefore, effective and safe thromboprophylaxis for oncology patients at the increased risk of VTE is of utmost importance. Commonly used anticancer treatments, including hormonal therapy (HT), chemotherapy (CHT), targeted therapy (TT), immune therapy (IT), radiotherapy (RT), and anti-angiogenesis monoclonal antibodies, as well as surgical procedures have been associated with VTE. For this reason, risk stratification scores, including tumor site, laboratory parameters, and patient’s clinical characteristics can help most accurately identify those patients, who will take the greatest advantage of a personalized approach to VTE. This mini-review discusses cancer-related VTE risk stratification scores (e.g., the Khorana, Vienna Cancer and Thrombosis (CATS), and PROTECHT) that have been very useful for the detection of patients at the highest risk of VTE, who require an individual choice of the anticoagulant. This article briefly summarizes the updated American Society of Clinical Oncology (ASCO) clinical guidelines for the prevention and treatment of VTE in patients with cancer. In particular, it presents the direct oral anticoagulants (DOACs) as a new opportunity for both the preventive and therapeutic approach to VTE in this population. Furthermore, this overview provides some practical implications of the ASCO recommendations to the decision-making regarding safe and effective, personalized anticoagulant selection in various clinical setting. Hopefully, blending the patient’s medical context and personal preferences into VTE risk stratification scores will contribute to progress in the management of cancer-related VTE.

Implication of expression of MMR proteins and clinicopathological characteristics in gastric cancer

Introduction Microsatellite instability (MSI), referred to as variations at microsatellite loci, at mismatch repair (MMR) genes leads to the formation of an aberrant MMR system that fails to rectify errors occurring during DNA replication. MMR deficiency can be assessed by immunohistochemical analysis of the expression of mismatch repair proteins in the target tissues. Methods We investigated the expression of four key MMR proteins (MLH1, MSH2, MSH6, and PMS2) in formalin-fixed paraffin-embedded (FFPE) tumor and normal tissues obtained from thirty gastric cancer (GC) patients. The association of clinicopathological features with MMR status was also analyzed. Results A total of 12 (40%) GC patients exhibited loss of expression of MMR proteins, including loss of MLH1 and PMS2 in 3 cases and loss of MSH2 and MSH6 in 4 cases. Univariate analysis showed an association of loss of MMR protein expression with moderately differentiated GC. However, there was no statistically significant association between loss of MMR protein expression with gender, tumor location, depth of invasion, lymph node metastasis, WHO classification, lympho-vascular invasion, and infection with H. pylori. Conclusion Our results implicate the role of mismatch repair proteins in gastric tumorigenesis. The MMR protein status is an important aspect of tumorigenesis and can be prescribed for the screening of GC.

Whole-exome Sequencing Reveals Genetic Underpinnings of Tongue Carcinoma in Chinese Population

Oral tongue squamous cell carcinoma (OTSCC) is a common malignancy, of which the incidence has increased in China in the last decade. Surprisingly, while multiple studies have revealed the mutational features of OTSCC in Western populations, limited data was shown in Asian patients. Herein, we utilized whole-exome sequencing to profile the genetic alterations in 13 Chinese OTSCC and compared them to those from 40 Western patients published in Cancer Discovery. In result, some key driver mutations were observed in both Chinese and Western cohorts, such as TP53 (Chinese 60.0% vs Western 60.0%), FAT1 (Chinese 7.7% vs Western 30.0%), CASP8 (Chinese 7.7% vs Western 10.0%) and NOTCH1 (Chinese 15.4% vs Western 10.0%), while mutations in CDKN2A (23.1%) and NTRK3 (23.1%) were only observed in Chinese patients, indicating these two novel mutations might play vital roles in OTSCC tumorigenesis specifically in Asian population. Mutational signatures depicted both common and distinct features across cohorts. In addition, significant copy number loss was found in 7q22.1, 9q13.1, and focal regions spanning CDKN2A and CDKN2B. FOXP1-TEX261 (2p13.3:3p13) fusion, reported in various cancer types, was firstly observed in OTSCC. Also, we identified numerous actionable mutations with FDA approved targeted. Taken together, our study revealed the mutational features of Chinese OTSCC patients, either similar or distinct to those of Caucasian patients. CDKN2A and NTRK3 were observed as two novel drivers that might play essential roles in tumorigenesis in Chinese patients, and were found as two potential therapeutic targets, rendering it promising to develop novel therapies.

Temporal trends and geographic differences of insurance coverage for cancer drug trials in mainland China

Background Data on insurance coverage of cancer drug trials in mainland China was of paucity, especially for its time trend and regional difference. Methods Based on the national authoritative database, time trend analysis of insurance coverage of cancer drug trials was conducted, from both the perspectives of trials and participants. Meanwhile, group comparisons by region, drug type and study phase, were also performed. Mann-Kendall test was used for trend analysis, and chi-square test was used to conduct group comparisons. Results A total of 1889 clinical trials were included, with 333 being international trials. In average, the insurance rate of trials was 79.8%, and it was steadily increased by 6.8% annually from 2010 to 2019. While the insurance coverage of Chinese participants was 67.6%, and it showed a wavy upward trend. Compared with international trials (91.9%), insurance rate of domestic trials (77.2%) was significantly lower (P < 0.001), but the rate gap decreased gradually. The comparisons by region showed that, the insurance rate in Northeast China (86.6%) was the highest, while that for Northwest China (40.0%) was lowest. Additionally, traditional Chinese medicine trials, and BE studies had significantly lower rate of insurance. Conclusion The insurance coverage of cancer drug trials in mainland China has been increasing steadily over the past decade. However, the regional differences are significant. To promote insurance coverage emphatically in underdeveloped areas could be our work emphasis. Although this study specially included cancer drug trials, the results could also provide reference for trials in all other fields.

Labeling of ethylenediamine tetramethylene phosphonate with 153Sm and 177Lu,Comparison Study

Background 177Lu and 153Sm are perspective radionuclides in terms of applying to nuclear medicine. High-energy beta particles and the relative half-life of the radionuclide are used to achieve an effective palliative treatment of bone metastases. Materials and methods The absorbed doses in different organs and tissues of 177Lu and 153Sm in ionic form and labeled with EDTMP are determined by IDAC-Dose 2.1 (Internal Dose Assessment by Computer) software and WinAct software which used to calculate cumulative activity. 177Lu and 153Sm are lanthanide radionuclide which actively accumulates in liver and bone when used in ionic form. In the case of labeling with EDTMP, the distribution and elimination of the drug occur according to the kinetics of a carrier, EDTMP. The using of osteotropic (Describing any drug etc. that is attracted to, and targets bone) complex allows creating a large dose in the pathological areas and minimizing damages in healthy organs and tissues. Results The effective dose per administered activity is 0.189 mSv/MBq for 177Lu-ionic form, 0.232 mSv/MBq for 153Sm-ionic form and 0.242 mSv/MBq for 177Lu-EDTMP and 0.139 mSv/MBq for 153sm-EDTMP. Conclusion 177Lu and 153Sm labeled with EDTMP are decreasing the liver dose absorption and increasing the bone surface absorption for more effective treatment and minimize side effects.