Tumor Mutational Burden Associated With Response to Hyperthermic Intraperitoneal Chemotherapy.

Background: Gastric cancer (GC) is one of the most common cancer types, especially in Asian countries. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to improve the progression-free survival among gastric cancer patients with peritoneal metastases; however, not all patients demonstrate response to HIPEC. Methods: Biomarkers are needed to select patients for effective treatment of HIPEC. Here, we performed whole-exome sequencing on tumor samples from 18 gastric cancer patients who received HIPEC treatment and assessed the association between genomic mutation features and progression-free survival. Exome sequencing was further conducted on tumor samples from additional 15 gastric cancer patients as a replication study. Results: The tumor mutational burden (TMB) was significantly higher in the group of patients with a better response to HIPEC treatment than that of the others. Kaplan-Meier survival curve showed that patients with high TMB had a significantly longer survival time than that in patients with low TMB. This discovery was validated in the replication cohort. Genes bearing mutations recurrently and selectively in patients with better response to HIPEC were found in the two cohorts. Conclusion: We found that higher TMB is significantly associated with better response to HIPEC. Our results provide useful hints for prognostic stratification of HIPEC treatment.

Noncoding RNAs and hyperthermic intraperitoneal chemotherapy in advanced gastric cancer.

Gastric cancer (GC) is one of the most common malignant tumors globally. About 20-30% of patients with gastric cancer show peritoneal implantation metastasis at the first diagnosis. Peritoneal metastasis is responsible for 70% of deaths of patients with advanced gastric cancer. Although there are many ways to treat advanced gastric cancer, the prognosis of patients with recurrence is unsatisfactory. An auxiliary treatment with hyperthermic intraperitoneal chemotherapy (HIPEC), is an internationally recognized recommended treatment for advanced gastric cancer. A series of clinical trials have shown that HIPEC significantly improves the overall survival of patients with cancer. Compared with the cytoreductive surgery (CRS) alone, HIPEC combined with CRS markedly reduced the rate of peritoneal metastasis in patients with ovarian cancer and colorectal cancer. It has been demonstrated that HIPEC alters transcription of many genes by affecting non-coding RNAs, which may contribute to the suppressive effect of HIPEC on the synthesis of nucleic acids and proteins in cancer cells. This paper reviews the recent advances in understanding the role of non-coding RNAs in tumor invasion and metastasis of advanced gastric cancer. We also consider changes in noncoding RNA levels and other molecules in advanced gastric cancer cases treated with HIPEC. We hope that our review will provide a reference for future research on molecular epidemiology and etiology of advanced gastric cancer and promote precise treatment of this malignancy using HIPEC.

Multifunctional Non-Coding RNAs Mediate Latent Infection and Recurrence of Herpes Simplex Viruses.

Herpes simplex viruses (HSVs) often cause latent infection for a lifetime, leading to repeated recurrence. HSVs have been engineered as oncolytic HSVs. The mechanism of the latent infection and recurrence remains largely unknown, which brings great challenges and limitations to eliminate HSVs in clinic and engineer safe oHSVs. Here, we systematically reviewed the latest development of the multi-step complex process of HSV latency and reactivation. Significantly, we first summarized the three HSV latent infection pathways, analyzed the structure and expression of the LAT1 and LAT2 of HSV-1 and HSV-2, proposed the regulation of LAT expression by four pathways, and dissected the function of LAT mediated by five LAT products of miRNAs, sRNAs, lncRNAs, sncRNAs and ORFs. We further analyzed that application of HSV LAT deletion mutants in HSV vaccines and oHSVs. Our review showed that deleting LAT significantly reduced the latency and reactivation of HSV, providing new ideas for the future development of safe and effective HSV therapeutics, vaccines and oHSVs. In addition, we proposed that RNA silencing or RNA interference may play an important role in HSV latency and reactivation, which is worth validating in future.

Raltitrexed as a synergistic hyperthermia chemotherapy drug screened in patient-derived colorectal cancer organoids.

OBJECTIVE: Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer. Our research aimed to establish a library of patient-derived colorectal cancer organoids to evaluate synergism between chemotherapy drugs and hyperthermia; validate an index of the hyperthermia chemotherapy sensitization enhancement ratio (HCSER) to identify the chemotherapeutics most enhanced by hyperthermia; and recommend chemotherapy drugs for hyperthermic intraperitoneal treatment. METHODS: Organoids were grown from cells extracted from colorectal cancer patient samples or colorectal cancer cell lines. Cells from both sources were encapsulated in 3D Matrigel droplets, which were formulated in microfluidics and phase-transferred into identical cell-laden Matrigel microspheres. The microspheres were seeded in 96-well plates, with each well containing a single microsphere that developed into an organoid after 7 days. The organoids were used to evaluate the efficacy of chemotherapy drugs at both 37°C as a control and 43°C for 90 min to examine hyperthermia synergism. Cell viability was counted with 10% CCK8. RESULTS: We successfully established a library of colorectal cancer organoids from 22 patient parental tumors. We examined the hyperthermia synergism of 7 commonly used hyperthermic intraperitoneal chemotherapy drugs. In 11 of the 22 patient organoids, raltitrexed had significant hyperthermia synergism, which was indexed as the highest HCSER score within each patient group. CONCLUSIONS: Our results primarily demonstrated the use of patient-derived colorectal cancer organoids as in vitro models to evaluate hyperthermia synergistic chemotherapeutics. We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.

Non-radioactive and sensitive tracking of neutrophils towards inflammation using antibody functionalized magnetic particle imaging tracers.

White blood cells (WBCs) are a key component of the mammalian immune system and play an essential role in surveillance, defense, and adaptation against foreign pathogens. Apart from their roles in the active combat of infection and the development of adaptive immunity, immune cells are also involved in tumor development and metastasis. Antibody-based therapeutics have been developed to regulate (i.e. selectively activate or inhibit immune function) and harness immune cells to fight malignancy. Alternatively, non-invasive tracking of WBC distribution can diagnose inflammation, infection, fevers of unknown origin (FUOs), and cancer. Magnetic Particle Imaging (MPI) is a non-invasive, non-radioactive, and sensitive medical imaging technique that uses safe superparamagnetic iron oxide nanoparticles (SPIOs) as tracers. MPI has previously been shown to track therapeutic stem cells for over 87 days with a ~200 cell detection limit. In the current work, we utilized antibody-conjugated SPIOs specific to neutrophils for in situ labeling, and non-invasive and radiation-free tracking of these inflammatory cells to sites of infection and inflammation in an in vivo murine model of lipopolysaccharide-induced myositis. MPI showed sensitive detection of inflammation with a contrast-to-noise ratio of ~8-13.

Inheritance and QTL mapping of related root traits in soybean at the seedling stage.

KEY MESSAGE: This study provides a foundation for further research on root genetic regulation and molecular breeding with emphasis on correlations among root traits to ensure robust root growth and well-developed root systems. A set of 447 recombinant inbred lines (RILs) derived from a cross between Jingdou23 (cultivar, female parent) and ZDD2315 (semi-wild, male parent) were used to analyze inheritance and detect QTLs related to root traits at the seedling stage using major gene plus polygene mixed inheritance analysis and composite interval mapping. The results showed that maximum root length (MRL) was controlled by three equivalent major genes, lateral root number (LRN) was controlled by two overlapping major genes, root weight (RW) and volume (RV) were controlled by four equivalent major genes. Hypocotyl length (HL) was controlled by four additive main genes, and hypocotyl weight (HW) was controlled by four additive and additive × additive epistatic, major genes; however, polygene effects were not detected in these traits. Shoot weight (SW) was controlled by multi-gene effects, but major gene effects were not detected. Twenty-four QTLs for MRL, LRN, RW, RV, SW, HL, HW were mapped on LG A1 (chromosome 5), LG A2 (chromosome 8), LG B1 (chromosome 11), LG B2 (chromosome 14), LG C2 (chromosome 6), LG D1b (chromosome 2), LG F_1 (chromosome 13), LG G (chromosome 18), LG H_1 (chromosome 12), LG H_2 (chromosome 12), LG I (chromosome 20), LG K_2 (chromosome 9), LG L (chromosome 19), LG M (chromosome 7), LG N (chromosome 3), LG O (chromosome 10), separately. Root traits were shown to have complex genetic mechanisms at the seedling stage, SW was controlled by multi-gene effects, and the other six traits were controlled by major gene effects. It is concluded that correlations among root traits must be considered to improve the development of beneficial root traits.