Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis.

GLS1 orchestrates glutaminolysis and promotes cell proliferation when glutamine is abundant by regenerating TCA cycle intermediates and supporting redox homeostasis. CB-839, an inhibitor of GLS1, is currently under clinical investigation for a variety of cancer types. Here, we show that GLS1 facilitates apoptosis when glutamine is deprived. Mechanistically, the absence of exogenous glutamine sufficiently reduces glutamate levels to convert dimeric GLS1 to a self-assembled, extremely low-Km filamentous polymer. GLS1 filaments possess an enhanced catalytic activity, which further depletes intracellular glutamine. Functionally, filamentous GLS1-dependent glutamine scarcity leads to inadequate synthesis of asparagine and mitogenome-encoded proteins, resulting in ROS-induced apoptosis that can be rescued by asparagine supplementation. Physiologically, we observed GLS1 filaments in solid tumors and validated the tumor-suppressive role of constitutively active, filamentous GLS1 mutants K320A and S482C in xenograft models. Our results change our understanding of GLS1 in cancer metabolism and suggest the therapeutic potential of promoting GLS1 filament formation.

Formation of Different Polyploids Through Disrupting Meiotic Crossover Frequencies Based on cntd1 Knockout in Zebrafish.

Polyploidy, a significant catalyst for speciation and evolutionary processes in both plant and animal kingdoms, has been recognized for a long time. However, the exact molecular mechanism that leads to polyploid formation, especially in vertebrates, is not fully understood. Our study aimed to elucidate this phenomenon using the zebrafish model. We successfully achieved an effective knockout of the cyclin N-terminal domain containing 1 (cntd1) using CRISPR/Cas9 technology. This resulted in impaired formation of meiotic crossovers, leading to cell-cycle arrest during meiotic metaphase and triggering apoptosis of spermatocytes in the testes. Despite these defects, the mutant (cntd1-/-) males were still able to produce a limited amount of sperm with normal ploidy and function. Interestingly, in the mutant females, it was the ploidy not the capacity of egg production that was altered. This resulted in the production of haploid, aneuploid, and unreduced gametes. This alteration enabled us to successfully obtain triploid and tetraploid zebrafish from cntd1-/- and cntd1-/-/- females, respectively. Furthermore, the tetraploid-heterozygous zebrafish produced reduced-diploid gametes and yielded all-triploid or all-tetraploid offspring when crossed with wild-type (WT) or tetraploid zebrafish, respectively. Collectively, our findings provide direct evidence supporting the crucial role of meiotic crossover defects in the process of polyploidization. This is particularly evident in the generation of unreduced eggs in fish and, potentially, other vertebrate species.

Decoupling Carrier-Phonon Scattering Boosts the Thermoelectric Performance of n-Type GeTe-Based Materials.

The coupled relationship between carrier and phonon scattering severely limits the thermoelectric performance of n-type GeTe materials. Here, we provide an efficient strategy to enlarge grains and induce vacancy clusters for decoupling carrier-phonon scattering through the annealing optimization of n-type GeTe-based materials. Specifically, boundary migration is used to enlarge grains by optimizing the annealing time, while vacancy clusters are induced through the aggregation of Ge vacancies during annealing. Such enlarged grains can weaken carrier scattering, while vacancy clusters can strengthen phonon scattering, leading to decoupled carrier-phonon scattering. As a result, a ratio between carrier mobility and lattice thermal conductivity of ∼492.8 cm3 V-1 s-1 W-1 K and a peak ZT of ∼0.4 at 473 K are achieved in Ge0.67Pb0.13Bi0.2Te. This work reveals the critical roles of enlarged grains and induced vacancy clusters in decoupling carrier-phonon scattering and demonstrates the viability of fabricating high-performance n-type GeTe materials via annealing optimization.

MicroRNA-196a-5p facilitates the onset and progression via targeting ITM2B in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy affecting the digestive tract, with an increasing incidence rate worldwide. Recently, numerous studies revealed that microRNAs were associated with gene expression regulation, particularly their involvement in the regulation of tumor cells, garnering widespread attention. Here, we discovered that miR-196a-5p was significantly upregulated in both ESCC tissues and cells, which was correlated with an unfavorable prognosis. Series functional in vitro investigations have confirmed that silencing miR-196a-5p obviously restrained the ESCC cells malignant phenotypes and promoted apoptosis. Bioinformatics analysis and rescue experiments revealed that miR-196a-5p directly targeted ITM2B, exerting influence on the development of ESCC cells through negative regulation of ITM2B expression. Xenograft mouse models were established for conducting in vivo experiments, providing further confirmation of the regulatory mechanism and biological significance of the miR-196a-5p/ITM2B axis in ESCC. Our research demonstrated miR-196a-5p promoted ESCC malignant progression by interacting with ITM2B, thereby providing novel clues and potential targets for the new diagnosis and thereby of ESCC.

Distribution and transformation of potentially toxic elements in cracks under coal mining disturbance in farmland.

The ground cracks resulting from coal mining activities induce alterations in the physical and chemical characteristics of soil. However, limited knowledge exists regarding the impact of subsidence caused by coal mining on the distribution of potentially toxic elements (PTEs) fractions in farmland soil. In this study, we collected 19 soil profiles at varying depths from the soil surface and at horizontal distances of 0, 1, 2, and 5 m from the vertical crack. Using BCR extraction fractionation, we determined the geochemical fractions and total concentrations of Chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), cadmium (Cd) and lead (Pb) to investigate their ecological risk, spatial fraction distribution, and main influencing factors. Results showed that the E r i values of Cd appearing in 68.7% of the samples were higher than 40 and less than 80, presented a moderate ecological risk. Chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), and lead (Pb) were mainly bound to residual fractions (> 60%) with lower mobility and Cd was dominated by F1 (acid-soluble fractions, 50%) and F2 (reducible fractions, 29%) in surface soil (0-20 cm). The geochemical fractionation revealed that the mobile fractions (F1-acid-soluble and F2-reducible) of PTEs were primarily located near the crack, influenced by available potassium. In contrast, the less mobile fractions (F3-oxidizable and F4-residual) exhibited higher concentrations at distances of 2 and 5 m from the crack, except for arsenic, influenced by the presence of clay particles and available phosphorus.

Lattice Distortions and Multiple Valence Band Convergence Contributing to High Thermoelectric Performance in MnTe.

Here, a new route is proposed for the minimization of lattice thermal conductivity in MnTe through considerable increasing phonon scattering by introducing dense lattice distortions. Dense lattice distortions can be induced by Cu and Ag dopants possessing large differences in atom radius with host elements, which causes strong phonon scattering and results in extremely low lattice thermal conductivity. Density functional theory (DFT) calculations reveal that Cu and Ag codoping enables multiple valence band convergence and produces a high density of state values in the electronic structure of MnTe, contributing to the large Seebeck coefficient. Cu and Ag codoping not only optimizes the Seebeck coefficient but also substantially increases the carrier concentration and electrical conductivity, resulting in the significant enhancement of power factor. The maximum power factor reaches 11.36 µW cm-1 K-2 in Mn0.98 Cu0.04 Ag0.04 Te. Consequently, an outstanding ZT of 1.3 is achieved for Mn0.98 Cu0.04 Ag0.04 Te by these synergistic effects. This study provides guidelines for developing high-performance thermoelectric materials through the rational design of effective dopants.

Successional Changes of Microbial Communities and Host-Microbiota Interactions Contribute to Dietary Adaptation in Allodiploid Hybrid Fish.

Host-microbiota interactions play critical roles in host development, immunity, metabolism, and behavior. However, information regarding host-microbiota interactions is limited in fishes due to their complex living environment. In the present study, an allodiploid hybrid fish derived from herbivorous Megalobrama amblycephala (♀) × carnivorous Culter alburnus (♂) was used to investigate the successional changes of the microbial communities and host-microbiota interactions during herbivorous and carnivorous dietary adaptations. The growth level was not significantly different in any developmental stage between the two diet groups of fish. The diversity and composition of the dominant microbial communities showed similar successional patterns in the early developmental stages, but significantly changed during the two dietary adaptations. A large number of bacterial communities coexisted in all developmental stages, whereas the abundance of some genera associated with metabolism, including Acinetobacter, Gemmobacter, Microbacterium, Vibrio, and Aeromonas, was higher in either diet groups of fish. Moreover, the abundance of phylum Firmicutes, Actinobacteria, and Chloroflexi was positively correlated with the host growth level. In addition, Spearman's correlation analysis revealed that the differentially expressed homologous genes in the intestine associated with cell growth, immunity, and metabolism were related to the dominant gut microbiota. Our results present evidence that host genetics-gut microbiota interactions contribute to dietary adaptation in hybrid fish, which also provides basic data for understanding the diversity of dietary adaptations and evolution in fish.

Uterus-preserving surgical management of placenta accreta spectrum disorder: a large retrospective study.

BACKGROUND: The two-child policy implemented in China resulted in a surge of high-risk pregnancies among advanced maternal aged women and presented a window of opportunity to identify a large number of placenta accreta spectrum (PAS) cases, which often invoke severe blood loss and hysterectomy. We thus had an opportunity to evaluate the surgical outcomes of a unique conservative PAS management strategy for uterus preservation, and the impacts of magnetic resonance imaging (MRI) in PAS surgical planning. METHODS: Cross-sectional study, comparing the outcomes of a new uterine artery ligation combined with clover suturing technique (UAL + CST) with the existing conservative surgical approaches in a maternal public hospital with an annual birth of more than 20,000 neonates among all placenta previa cases suspecting of PAS between January 1, 2015 and December 31, 2018. RESULTS: From a total of 89,397 live births, we identified 210 PAS cases from 400 singleton pregnancies with placenta previa. Aside from 2 self-requested natural births (low-lying placenta), all PAS cases had safe cesarean deliveries without any total hysterectomy. Compared with the existing approaches, the evaluated UAL + CST had a significant reduction in intraoperative blood loss (ß=-312 ml, P < .001), RBC transfusion (ß=-1.08 unit, P = .001), but required more surgery time (ß = 16.43 min, P = .01). MRI-measured placenta thickness, when above 50 mm, can increase blood loss (ß = 315 ml, P = .01), RBC transfusion (ß = 1.28 unit, P = .01), surgery time (ß = 48.84 min, P < .001) and hospital stay (ß = 2.58 day, P < .001). A majority of percreta patients resumed normal menstrual cycle within 12 months with normal menstrual fluid volume, without abnormal urination or defecation. CONCLUSIONS: A conservative surgical management approach of UAL + CST for PAS is safe and effective with a low complication rate. MRI might be useful for planning PAS surgery. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR2000035202.

Advances in the Structure of GGGGCC Repeat RNA Sequence and Its Interaction with Small Molecules and Protein Partners.

The aberrant expansion of GGGGCC hexanucleotide repeats within the first intron of the C9orf72 gene represent the predominant genetic etiology underlying amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The transcribed r(GGGGCC)n RNA repeats form RNA foci, which recruit RNA binding proteins and impede their normal cellular functions, ultimately resulting in fatal neurodegenerative disorders. Furthermore, the non-canonical translation of the r(GGGGCC)n sequence can generate dipeptide repeats, which have been postulated as pathological causes. Comprehensive structural analyses of r(GGGGCC)n have unveiled its polymorphic nature, exhibiting the propensity to adopt dimeric, hairpin, or G-quadruplex conformations, all of which possess the capacity to interact with RNA binding proteins. Small molecules capable of binding to r(GGGGCC)n have been discovered and proposed as potential lead compounds for the treatment of ALS and FTD. Some of these molecules function in preventing RNA-protein interactions or impeding the phase transition of r(GGGGCC)n. In this review, we present a comprehensive summary of the recent advancements in the structural characterization of r(GGGGCC)n, its propensity to form RNA foci, and its interactions with small molecules and proteins. Specifically, we emphasize the structural diversity of r(GGGGCC)n and its influence on partner binding. Given the crucial role of r(GGGGCC)n in the pathogenesis of ALS and FTD, the primary objective of this review is to facilitate the development of therapeutic interventions targeting r(GGGGCC)n RNA.

Distribution and transformation of potentially toxic elements in crack under coal mining disturbance.

In China, coal provides about 56.8% of the energy. Most of China's coal mines are shaft mines, which cause the surface to collapse and crack during the mining process. The soil near the cracks changes its physicochemical properties due to the altered stress conditions. This will affect the distribution of PTEs in the soil. We collected 18 samples from a selected crack in the abandoned land. The pH, Eh, and PTE and their fractions of the samples were determined. With the test results, we understand the distribution characteristics of pH, Eh, PTEs, and their fractions at the cracks. Meanwhile, we explored the key factors that contribute to this distribution. It was determined that crack decreases surface soil pH while increasing Eh. The total amount of 7 PTEs is higher in the bottom soil of the main crack and 2 m away from the main crack. The content of reducible fractions of PTEs increases with the increase of soil Eh. The oxidizable and residual fractions of PTEs adsorbed to the clay particles migrate to and enrich the deeper layers of the main crack. This study emphasizes the effect of crack generation on the distribution of PTEs in soil. It provides insights to describe the distribution of PTE throughout the full life cycle of crack.

A novel ferritin L (FerL) in hybrid crucian carp could participate in host defense against Aeromonas hydrophila infection and diminish inflammatory signals.

FerL, a multifunctional iron-storage polypeptide, not only exhibited a regulatory role in iron metabolism, but also participated in the regulation of fish immunity. In this study, ORF sequence of WR-FerL was 522 bp, encoding 173 amino acid residues. Tissue-specific analysis revealed that the highest expression of WR-FerL was detected in spleen. A. hydrophila challenge and LPS stimulation could sharply enhance WR-FerL mRNA expression in tissues and fish cells, respectively. Purified WR-FerL fusion peptide exhibited in vitro binding activity to A. hydrophila and endotoxin, limited bacterial dissemination to tissues as well as attenuated A. hydrophila-induced production of pro-inflammatory cytokines. Moreover, WR-FerL overexpression could abrogate NF-κB and TNFα promoter activity in fish cells. These results indicated that WR-FerL could play an important role in host defense against A. hydrophila infection.

Blood cell characterization and transcriptome analysis reveal distinct immune response and host resistance of different ploidy cyprinid fish following Aeromonas hydrophila infection.

Aeromonas hydrophila can pose a great threat to survival of freshwater fish. In this study, A. hydrophila infection could decrease blood cell numbers, promote blood cell damage as well as alter the levels of alkaline phosphatase (ALP), lysozyme (LZM), aspartate aminotransferase (AST), total antioxidant capacity (T-AOC), total superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) in immune-related tissues of red crucian carp (RCC, 2 N = 100) and triploid cyprinid fish (3 N fish, 3 N = 150). In addition, the significant alternation of antioxidant status was observed in PBMCs isolated from RCC and 3 N following LPS stimulation. The core differential expression genes (DEGs) involved in apoptosis, immunity, inflammation and cellular signals were co-expressed differentially in RCC and 3 N following A. hydrophila challenge. NOD-like receptor (NLR) signals appeared to play a critical role in A. hydrophila-infected fish. DEGs of NLR signals in RCCah vs RCCctl were enriched in caspase-1-dependent Interleukin-1ß (IL-1ß) secretion, interferon (IFN) signals as well as cytokine activation, while DEGs of NLR signals in 3Nah vs 3Nctl were enriched in caspase-1-dependent IL-1ß secretion and antibacterial autophagy. These results highlighted the differential signal regulation of different ploidy cyprinid fish to cope with bacterial infection.

Circ_SNX27 regulates hepatocellular carcinoma development via miR-637/FGFR1 axis.

BACKGROUND: Circular RNAs (circRNAs) serve as critical regulatory factors in cancer development. Nonetheless, the potential regulatory mechanism of circRNA sorting nexin 27 (circ_SNX27) in hepatocellular carcinoma (HCC) is still unknown. METHODS: The circ_SNX27, microRNA-637 (miR-637), and fibroblast growth factor receptor 1 (FGFR1) levels were quantified by quantitative real-time polymerase chain reaction and western blot analysis. Next, function experiments were conducted using in vitro assays and in vivo senograft study. The relationship between miR-637 with circ_SNX27 or FGFR1 was uncovered by dual-luciferase reporter and RNA pull-down assays. RESULTS: The circ_SNX27 and FGFR1 levels were up-regulated, but miR-637 content was reduced in HCC. Circ_SNX27 down-regulation inhibited HCC cell proliferation, motility, and invasion and promoted apoptosis in vitro, as well as weakened tumor growth in vivo. Circ_SNX27 served as a sponge of miR-637 to promote FGFR1 expression. MiR-637 reduction abolished the restrained effect of circ_SNX27 absence on HCC cell development. Moreover, miR-637 curbed HCC cell malignant phenotype by regulating FGFR1. CONCLUSION: Circ_SNX27 contributed to HCC development via miR-637/FGFR1 axis, offering a new idea for the treatment of HCC.

Calcium-Based Antimicrobial Peptide Compounds Attenuate DNFB-Induced Atopic Dermatitis-Like Skin Lesions via Th-Cells in BALB/c Mice.

Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease, characterized by severe itching and recurrent skin lesions. We hypothesized that a novel treatment involving calcium-based antimicrobial peptide compounds (CAPCS), a combination of natural calcium extracted from marine shellfish, and a variety of antimicrobial peptides, may be beneficial for AD. We established a dinitrofluorobenzene (DNFB)-induced AD model in BALB/c mice to test our hypothesis. We observed mouse behavior and conducted histopathological and immunohistochemical analyses on skin lesions before and after CAPCS treatment. We also characterized the changes in the levels of cytokines, inflammatory mediators, and Toll-like receptors (TLRs) in plasma and skin lesions. The results showed that (i) topical application of CAPCS ameliorated AD-like skin lesions and reduced scratching behavior in BALB/c mice; (ii) CAPCS suppressed infiltration of inflammatory cells and inhibited the expression of inflammatory cytokines in AD-like skin lesions; (iii) CAPCS reduced plasma levels of inflammatory cytokines; and (iv) CAPCS inhibited TLR2 and TLR4 protein expression in skin lesions. Topical application of CAPCS exhibits a therapeutic effect on AD by inhibiting inflammatory immune responses via recruiting helper T cells and engaging the TLR2 and TLR4 signaling pathways. Therefore, CAPCS may be useful for the treatment of AD.

Comparative analysis of erythrocyte hemolysis, plasma parameters and metabolic features in red crucian carp (Carassius auratus red var) and triploid hybrid fish following Aeromonas hydrophila challenge.

Aeromonas hydrophila can pose a great threat to survival of freshwater fish. In this study, A. hydrophila challenge could promote the erythrocyte hemolysis, increase free hemoglobin (FHB) level and generate malondialdehyde (MDA) production in plasma but decrease the levels of total antioxidant capacity (T-AOC), total superoxide dismutase (SOD), catalase (CAT), alkaline phosphatase (ALP) and lysozyme (LZM) of red crucian carp (RCC, 2 N = 100) and triploid hybrid fish (3 N fish, 3 N = 150) following A. hydrophila challenge. Elevated expression levels of heat shock protein 90 alpha (HSP90α), matrix metalloproteinase 9 (MMP-9), free fatty acid receptor 3 (FFAR3), paraoxonase 2 (PON2) and cytosolic phospholipase A2 (cPLA2) were observed in A. hydrophila-infected fish. In addition, A. hydrophila challenge could significantly increase expressions of cortisol, leucine, isoleucine, glutamate and polyunsaturated fatty acids (PUFAs) in RCC and 3 N, while glycolysis and tricarboxylic acid cycle appeared to be inactive. We identified differential fatty acid derivatives and their metabolic networks as crucial biomarkers from metabolic profiles of different ploidy cyprinid fish subjected to A. hydrophila infection. These results highlighted the comparative metabolic strategy of different ploidy cyprinid fish against bacterial infection.

Structure, dynamics and transport behavior of migrating corrosion inhibitors on the surface of calcium silicate hydrate: a molecular dynamics study.

The incorporation of a corrosion inhibitor into a cement-based material can enhance the durability of the reinforced concrete. In this study, molecular dynamics simulation is utilized to study the interfacial structure and dynamic behavior of a solution with three migrating corrosion inhibitors (MCI) functionalized by hydroxyl (-OH), carboxyl (-COO-), and phenyl (-PH) groups in calcium silicate hydrate (CSH) gel pores. The transport rate of inhibitors is greatly dependent on the polarity of the functional group: -PH > -OH > -COO-. The slow migration rate of the inhibitor with -OH and -COO- is attributed to the chemical bond formed between CSH and MCI. The silicate chains near the CSH surface can provide plenty of non-bridging oxygen sites to accept the H-bond from the hydroxyl group in the inhibitor molecule. The surface calcium atom can capture the -COO- by forming an ionic COO-Ca bond. Furthermore, the hydration structure of the inhibitor molecule also influences its transport properties. The inhibitor functionalized by the carboxyl group, associating with the neighboring water molecules, forms ion-water clusters, and the inhibitor molecule and its hydration shell with a long resident time retard the migration rate. Hopefully, this study is able to provide molecules for the development of a migration-type corrosion inhibitor to elongate the service life of cement-based materials.

[A new quinoline alkaloid from Scolopendra subspinipes mutilans].

Three compounds, including scolosprine C(1), uracil(2) and hypoxanthine(3), were isolated and purified from the ethyl acetate fraction of centipede by silica gel normal-phase column chromatography, reversed-phase medium pressure preparation chromatography, and high-pressure semi-preparative HPLC. The structure was elucidated through a combination of spectroscopic analyses [such as nuclear magnetic resonance(NMR) and mass spectrometry(MS)] and literature review. Among them, compound 1 was a new quinoline alkaloid. In previous reports, we have described the isolation and structure elucidation of one new and two known quinoline alkaloids. In this paper, we would report the isolation and structure elucidation of scolosprine C in detail.

The establishment of the fertile fish lineages derived from distant hybridization by overcoming the reproductive barriers.

Distant hybridization refers to the cross between two different species or higher-ranking taxa. It is very significant if the new lineages with genetic variation, fertile ability, and improved characteristics can be established through distant hybridization. However, reproductive barriers are key limitations that must be overcome to establish fertile lineages derived from distant hybridization. In the present review, we discussed how distant hybridization is an important way to form new species by overcoming reproductive barriers and summarized effective measures to overcome reproductive barriers in order to create fertile lineages of fish distant hybridization. In addition, we described the utilization of the fish lineages derived from distant hybridization. Finally, we discussed the relationship between distant hybridization and Mendel's laws, which generally apply to the inbred hybridization. We aim to provide a comprehensive reference for the establishment of fertile fish lineages by overcoming reproductive barriers and to emphasize the significance of fish distant hybridization in the fields of evolutionary biology, reproductive biology, and genetic breeding.

A prospective, single-arm, phase II clinical trial of intraoperative radiotherapy using a low-energy X-ray source for local advanced Laryngocarcinoma (ILAL): a study protocol.

BACKGROUND: Laryngocarcinoma (LC), in most cases a squamous cell carcinoma, accounts for 1 ~ 5% of the incidence of all tumors. At present, laryngocarcinoma is mainly managed with the integration of surgery and radio- and chemo-therapies. The current development trend of treatment is to improve the local control rate of tumor and the quality of life of patients. Intraoperative radiation therapy (IORT) is a radiotherapy that delivers single high dose irradiation at a close range to the tumor bed during the surgical operation process. It has particular radiobiological advantages in protecting normal surrounding tissues by directly applying the irradiation dose to the high-risk tumor bed area. Two forms of IORT, i.e., high dose rate (HDR) brachytherapy and external beam radiotherapy (EBRT, including electron and photono IORT), had been studied before the treatment of head and neck tumors (including laryngocarcinoma). However, no relevant assessment had been carried out on 50KV low-energy X-ray. We are convinced by certain arguments that the application of low-energy X-ray for intraoperative local radiotherapy of laryngocarcinoma can not only achieve the therapeutic effect of IORT but also reduce the incidence of high-energy irradiation related toxic and side effects. The purpose of this study is to observe the safety and short-term efficacy of IORT when used in conjunction with standard of care for the treatment of local advanced laryngocarcinoma (LAL). METHODS/DESIGN: In consideration of the applications of precise targeted IORT in oncosurgery and in line with the application range and reference clinical medical guidances approved by SFDA (ZEISS radiosurgical operation system has been used for the treatment of solid tumors since 31 December, 2013 with an approval from SFDA), we have preliminarily planned the tumors suitable for IORT, determined the members of MDT in our hospital, improved the MDT diagnosis and treatment processes for the tumors, established the standards, indications and contraindications for the application of IORT, determined the indicators to be observed after the treatment of tumors with surgical operations plus IORT, and carried out follow-up visits and statistical analysis. This is a single-arm, prospective Phase II clinical trial of the treatment of LAL patients with IORT + EBRT. The study subjects are followed up for statistics and information of their acute/chronic toxic reactions and local control rate, DFS, and OS etc. The safety and short-term efficacy of the application of IORT as SIB for the treatment of LAL. The sample size of the study is 125 subjects. DISCUSSION: The safety and efficacy of IORT for the treatment of head and neck cancers have been proven in studies by multiple institutions (1-3). The purpose of this study is to investigate the maximum safe dose and short-term efficacy of IORT for providing a theoretical basis for clinical trials. TRIAL REGISTRATION: Trial registration: Clinicaltrials.gov , NCT04278638. Registered 18 February 2020 - prospectively registered, https://clinicaltrials.gov/ct2/show/NCT04278638.

A Phase II Trial of Concurrent Temozolomide and Hypofractionated Stereotactic Radiotherapy for Complex Brain Metastases.

PURPOSE: Complex brain metastases (BMs), such as large lesions, lesions within or close to eloquent locations, or multiple recurrent/progressive BMs, remain the most challenging forms of brain cancer because of decreased intracranial control rates and poor survival. In the present study, we report the results from a single institutional phase II trial of concurrent temozolomide (TMZ) with hypofractionated stereotactic radiotherapy (HFSRT) in patients with complex brain metastases, including assessment of its feasibility and toxicity. PATIENTS AND METHODS: Fifty-four patients with histologically proven primary cancer and complex BMs were enrolled between 2010 and 2015. All the patients were treated with concurrent HFSRT and TMZ (administrated orally at a dosage of 75 mg/m2 per day for at least 20 days). The primary endpoint was overall survival (OS). RESULTS: The median follow-up time was 30.6 months. The local control rates at 1 and 2 years were 96% and 82%, respectively. The median OS was 17.4 months (95% confidence interval [CI], 12.6-22.2), and the OS rates at 1 and 2 years were 65% (95% CI, 52%-78%) and 33% (19%-47%). Only six patients (15.8%) died of intracranial disease. The median brain metastasis-specific survival was 46.9 months (95% CI, 35.5-58.4). Treatment-related grade 3-4 adverse events were rare and included one grade 3 hematological toxicity and two grade 3 liver dysfunctions. CONCLUSION: Treatment using HFSRT concurrent with TMZ was well tolerated and could significantly extend OS compared with historical controls in complex BMs. Large randomized clinical trials are warranted. Trial registration ID: NCT02654106. IMPLICATIONS FOR PRACTICE: The treatment using hypofractionated stereotactic radiotherapy concurrent with temozolomide appeared to be safe and could significantly extend overall survival compared with historical control in complex brain metastases. Large randomized clinical trials are warranted to verify our results.