Regulating the valence and size of the active center of Co/Al2O3 catalyst improved the performance and selectivity of NH3-SCO.

To improve the activity of Co/Al2O3 catalysts in selective catalytic oxidation of ammonia (NH3-SCO), valence state and size of active centers of Al2O3-supported Co catalysts were adjusted by conducting H2 reduction pretreatment. The NH3-SCO activity of the adjusted 2Co/Al2O3 catalyst was substantially improved, outperforming other catalysts with higher Co-loading. Fresh Co/Al2O3 catalysts exhibited multitemperature reduction processes, enabling the control of the valence state of the Co-active centers by adjusting the reduction temperature. Changes in the state of the Co-active centers also led to differences in redox capacity of the catalysts, resulting in different reaction mechanisms for NH3-SCO. However, in situ diffuse reflectance infrared Fourier transform spectra revealed that an excessive O2 activation capacity caused overoxidation of NH3 to NO and NO2. The NH3-SCO activity of the 2Co/Al2O3 catalyst with low redox capacity was successfully increased while controlling and optimizing the N2 selectivity by modulating the active centers via H2 pretreatment, which is a universal method used for enhancing the redox properties of catalysts. Thus, this method has great potential for application in the design of inexpensive and highly active catalysts.

Cu/TiO2 adsorbents modified by air plasma for adsorption-oxidation of H2S.

In this study, non-thermal plasma (NTP) was employed to modify the Cu/TiO2 adsorbent to efficiently purify H2S in low-temperature and micro-oxygen environments. The effects of Cu loading amounts and atmospheres of NTP treatment on the adsorption-oxidation performance of the adsorbents were investigated. The NTP modification successfully boosted the H2S removal capacity to varying degrees, and the optimized adsorbent treated by air plasma (Cu/TiO2-Air) attained the best H2S breakthrough capacity of 113.29 mg H2S/gadsorbent, which was almost 5 times higher than that of the adsorbent without NTP modification. Further studies demonstrated that the superior performance of Cu/TiO2-Air was attributed to increased mesoporous volume, more exposure of active sites (CuO) and functional groups (amino groups and hydroxyl groups), enhanced Ti-O-Cu interaction, and the favorable ratio of active oxygen species. Additionally, the X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) results indicated the main reason for the deactivation was the consumption of the active components (CuO) and the agglomeration of reaction products (CuS and SO42-) occupying the active sites on the surface and the inner pores of the adsorbents.

Surgical Treatment Strategies for Ankylosing Spondylitis with "Folded Man" Deformity: A Single-Center Retrospective Case Series Study.

OBJECTIVE: Ankylosing spondylitis (AS) combined with severe kyphotic deformity can cause the trunk to collapse, pressing tightly against the front of the thighs and forming a "folded man" deformity. The purpose of this article is to evaluate the effectiveness and safety of a treatment strategy for correcting the "folded man" deformity. METHODS: A retrospective study was conducted to analyze 12 AS patients with "folded man" deformity treated at our hospital with staged kyphosis correction in the lateral position, followed by total hip arthroplasty, from May 2018 to July 2021. Global kyphosis (GK), thoracic kyphosis, lumbar lordosis, sagittal vertical axis, chin-brow vertical angle, and Scoliosis Research Society-22 Patient Questionnaire scores were compared preoperation and postoperation. Surgical duration, positioning time, blood loss, and complications were also recorded and analyzed. RESULTS: All patients demonstrated a correction of the "folded man" deformity, achieving sagittal balance and horizontal gaze with mild complications. Postoperatively, there were significant improvements in spinal sagittal parameters (GK, thoracic kyphosis, lumbar lordosis, and sagittal vertical axis) and chin-brow vertical angle compared to preoperative values (P < 0.05). The preoperative GK of 139.6 ± 9.1° was corrected to 55.3 ± 5.7° postoperatively, with a mean correction of 84.3°. CONCLUSIONS: The standardized treatment strategy involving staged correction of spinal kyphosis in a lateral position, followed by subsequent total hip arthroplasty, offers a safe and effective solution for managing AS with "folded man" deformity.

Uterine arteriovenous malformation: a case report with proposal for pathogenesis.

Uterine arteriovenous malformation (UAM) is a rare medical condition. Even though UAM can cause abnormal and life-threatening uterine hemorrhage, there is no consensus on the clinical guideline on its treatments, most likely due to its low incidence, unknown etiology, and distinct fertility demands by different patients. Here, we present one elderly woman with uncommon UAM. We first discuss our experience regarding the diagnoses and treatments of UAM and then propose a hypothesis for the pathogenesis of UAM.

Nuclear receptor TLX functions to promote cancer stemness and EMT in prostate cancer via its direct transactivation of CD44 and stem cell-regulatory transcription factors.

BACKGROUND: Prostate cancer stem cells (PCSCs) play crucial roles in therapy-resistance and metastasis in castration-resistant prostate cancer (CRPC). Certain functional link between cancer stemness and epithelial-mesenchymal transition (EMT) is involved in CRPC. However, up-stream regulators controlling these two processes in PCSCs are still poorly understood. Recently, we have shown that orphan nuclear receptor TLX can promote tumour initiation and progression in CRPC by repressing androgen receptor and oncogene-induced senescence. METHODS: PCSCs were isolated from various prostate cancer cell lines and clinical tumour tissues using multiple methods for various in vitro and in vivo oncogenic growth analyses. Direct targets of TLX involved in stemness and EMT regulation were determined by specific reporter gene assays and ligand-driven modulation of TLX activity. RESULTS: PCSCs isolated from various sources exhibited increased expression of TLX. Functional and molecular characterisation showed that TLX could function to promote cancer stemness and EMT in prostate cancer cells via its direct transactivation of CD44, SOX2, POU5F1 and NANOG, which share certain functional crosstalk in these two cellular processes. CONCLUSIONS: TLX could act as a key up-stream regulator in transcriptional control of stemness and EMT in PCSCs, which contribute to their tumorigenicity, castration-resistance and metastasis potentials in advanced prostate cancer.

Effect and mechanism of GPR75 in metabolic dysfunction-related steatosis liver disease.

Research on G protein-coupled receptor 75 (GPR75) in metabolic dysfunction-related steatosis liver disease (MASLD) reveals its potential role in regulating body weight and energy balance. Loss-of-function mutations in the GPR75 gene are significantly associated with lower body mass index and reduced body weight. Studies demonstrate that GPR75 knockout mice exhibit lower fasting blood glucose levels, improved glucose homeostasis, and significant prevention of high-fat diet-induced MASLD. The absence of GPR75 reduces fat accumulation by beneficially altering energy balance rather than restricting adipose tissue expansion. Moreover, female GPR75 knockout mice show greater protection against lipid accumulation on a high-fat diet compared to males, potentially attributed to higher physical activity and energy expenditure. However, current research primarily relies on mouse models, and its applicability to humans requires further validation. Future studies should explore the role of GPR75 across diverse populations, its clinical potential, and delve into its specific mechanisms and interactions with other metabolic pathways. Ultimately, targeted therapies based on GPR75 could offer novel strategies for the prevention and treatment of MASLD and other metabolic disorders.

Structural and mechanistic insights into a mesophilic prokaryotic Argonaute.

Argonaute (Ago) proteins are programmable nucleases found in all domains of life, playing a crucial role in biological processes like DNA/RNA interference and gene regulation. Mesophilic prokaryotic Agos (pAgos) have gained increasing research interest due to their broad range of potential applications, yet their molecular mechanisms remain poorly understood. Here, we present seven cryo-electron microscopy structures of Kurthia massiliensis Ago (KmAgo) in various states. These structures encompass the steps of apo-form, guide binding, target recognition, cleavage, and release, revealing that KmAgo employs a unique DDD catalytic triad, instead of a DEDD tetrad, for DNA target cleavage under 5'P-DNA guide conditions. Notably, the last catalytic residue, D713, is positioned outside the catalytic pocket in the absence of guide. After guide binding, D713 enters the catalytic pocket. In contrast, the corresponding catalytic residue in other Agos has been consistently located in the catalytic pocket. Moreover, we identified several sites exhibiting enhanced catalytic activity through alanine mutagenesis. These sites have the potential to serve as engineering targets for augmenting the catalytic efficiency of KmAgo. This structural analysis of KmAgo advances the understanding of the diversity of molecular mechanisms by Agos, offering insights for developing and optimizing mesophilic pAgos-based programmable DNA and RNA manipulation tools.

Versatility of threose nucleic acids: synthesis, properties, and applications in chemical biology and biomedical advancements.

This feature article delves into the realm of α-L-threose nucleic acid (TNA), an artificial nucleic acid analog characterized by a backbone comprising an unconventional four-carbon sugar, α-L-threose, with phosphodiester linkages connecting at the 2' and 3' vicinal positions of the sugar ring. Within this article, we encapsulate the potential, progress, current state of the art, and persisting challenges within TNA research. Kicking off with a historical overview of xeno nucleic acids (XNAs), the discussion transitions to the compelling attributes and structure-property relationships of TNAs as advanced tools when contrasted with natural nucleic acids. Noteworthy aspects such as their advantageous spatial arrangements of functional groups around the sugar ring, stable Watson-Crick base pairing, high binding affinity, biostability, biocompatibility, and in vivo bio-safety are highlighted. Moreover, the narrative unfolds the latest advancements in chemical and biological methodologies for TNA synthesis, spanning from monomer and oligomer synthesis to polymerization, alongside cutting-edge developments in enzyme engineering aimed at bolstering large-scale TNA synthesis for in vitro selection initiatives. The article sheds light on the evolution of TNA aptamers over time, expounding on the tools and selection techniques engineered to unearth superior binding aptamers and TNA catalysts. Furthermore, the article accentuates the recent applications of TNAs across diverse domains such as molecular detection, immunotherapy, gene therapy, synthetic biology, and molecular computing. In conclusion, we summarize the key aspects of recent TNA research, address persisting gaps and challenges, and provide crucial insights and future perspectives in the dynamic domain of TNA research.

Genome Engineering of Primary and Pluripotent Stem Cell-Derived Hepatocytes for Modeling Liver Tumor Formation.

Genome editing has demonstrated its utility in generating isogenic cell-based disease models, enabling the precise introduction of genetic alterations into wild-type cells to mimic disease phenotypes and explore underlying mechanisms. However, its application in liver-related diseases has been limited by challenges in genetic modification of mature hepatocytes in a dish. Here, we conducted a systematic comparison of various methods for primary hepatocyte culture and gene delivery to achieve robust genome editing of hepatocytes ex vivo. Our efforts yielded editing efficiencies of up to 80% in primary murine hepatocytes cultured in monolayer and 20% in organoids. To model human hepatic tumorigenesis, we utilized hepatocytes differentiated from human pluripotent stem cells (hPSCs) as an alternative human hepatocyte source. We developed a series of cellular models by introducing various single or combined oncogenic alterations into hPSC-derived hepatocytes. Our findings demonstrated that distinct mutational patterns led to phenotypic variances, affecting both overgrowth and transcriptional profiles. Notably, we discovered that the PI3KCA E542K mutant, whether alone or in combination with exogenous c-MYC, significantly impaired hepatocyte functions and facilitated cancer metabolic reprogramming, highlighting the critical roles of these frequently mutated genes in driving liver neoplasia. In conclusion, our study demonstrates genome-engineered hepatocytes as valuable cellular models of hepatocarcinoma, providing insights into early tumorigenesis mechanisms.

Exploration of potential drug targets for Glaucoma by plasma proteome screening.

BACKGROUND: Glaucoma is the leading cause of irreversible blindness. However, the current available treatment methods are still unsatisfactory. Therefore, the exploration of new drug targets for the treatment of glaucoma is of paramount importance. METHODS: We conducted two-sample Mendelian randomization (MR) using plasma protein quantitative trait loci (pQTL) data from two datasets (n = 734, n = 4907) and their instrumental variables to investigate the causal relationship between plasma proteins and glaucoma. The analysis was validated by replacing the exposure and outcome cohorts. Additionally, we utilized protein-protein interaction networks to assess the associations between these potential drug targets and existing drug targets. RESULTS: Through two-sample Mendelian randomization analysis, we identified causal relationships between Glaucoma and the following proteins: AZU1, OBP2B, ENPP5, INPP5B, KREMEN1, LYPLAL1, and PTPRJ. External validation confirmed the protective effect of LYPLAL1 on Glaucoma, while ENPP5, KREMEN1, and PTPRJ increased the risk of Glaucoma. Reverse MR and Steiger filtering did not indicate any reverse causal associations of the aforementioned proteins with Glaucoma. CONCLUSION: Our study demonstrates a causal impact of ENPP5, KREMEN1, PTPRJ, and LYPLAL1 on the risk of Glaucoma. These findings suggest that these four proteins may serve as promising drug targets for Glaucoma treatment. SIGNIFICANCE: Currently, the pharmacological treatment of glaucoma primarily focuses on lowering intraocular pressure, which has its limitations. Targeted therapy is a personalized treatment approach that aims to inhibit or block the development and progression of diseases such as cancer and inflammation by selectively acting on specific biomolecules or signaling pathways. Our research employs a two-sample Mendelian randomization (MR) method, integrating a large amount of GWAS and pQTL data to perform MR analysis. This has enabled us to explore several plasma proteins as potential drug targets for glaucoma, providing direction and a research foundation for future investigations into glaucoma drug targets.

Genome-Wide Identification and Characterization of the HMGR Gene Family in Taraxacum kok-saghyz Provide Insights into Its Regulation in Response to Ethylene and Methyl Jsamonate Treatments.

HMGR (3-hydroxy-3-methylglutaryl-CoA reductase) plays a crucial role as the first rate-limiting enzyme in the mevalonate (MVA) pathway, which is the upstream pathway of natural rubber biosynthesis. In this study, we carried out whole-genome identification of Taraxacum kok-saghyz (TKS), a novel rubber-producing alternative plant, and obtained six members of the TkHMGR genes. Bioinformatic analyses were performed including gene structure, protein properties, chromosomal localization, evolutionary relationships, and cis-acting element analyses. The results showed that HMGR genes were highly conserved during evolution with a complete HMG-CoA reductase conserved domain and were closely related to Asteraceae plants during the evolutionary process. The α-helix is the most prominent feature of the secondary structure of the TkHMGR proteins. Collinearity analyses demonstrated that a whole-genome duplication (WGD) event and tandem duplication event play a key role in the expansion of this family and TkHMGR1 and TkHMGR6 have more homologous gene between other species. Cis-acting element analysis revealed that the TkHMGR gene family had a higher number of MYB-related, light-responsive, hormone-responsive elements. In addition, we investigated the expression patterns of family members induced by ethylene (ETH) and methyl jasmonate (MeJA), and their expression levels at different stages of T. kok-saghyz root development. Finally, subcellular localization results showed that six TkHMGR members were all located in the endoplasmic reticulum. In conclusion, the results of our study lay a certain theoretical basis for the subsequent improvement of rubber yield, molecular breeding of rubber-producing plants, and genetic improvement of T. kok-saghyz.

Temporal dynamics in psychological assessments: a novel dataset with scales and response times.

The growing prevalence of mental health issues underscores the need for innovative screening methods. Large-scale, internet-based psychological screening has emerged as a vital tool to accurately determine morbidity rates and facilitate early diagnosis of mental disorders. However, conventional psychological screening methods often struggle with non-genuine responses and lack objective metrics. To bridge this gap, we have compiled a novel dataset derived from an expansive screening initiative at Xinxiang Medical University. The study, conducted from February 27 to March 17, 2021, yielded a dataset comprising responses from 24,292 students to four well-established psychological scales-PHQ-9, GAD-7, ISI, and PSS. A distinctive feature of this dataset is the inclusion of response time data, which captures the temporal dynamics of participants' interactions with the scales, offering valuable insights into their response behaviour. The release of this dataset offers a substantial opportunity for researchers in the domains of psychology and public health to explore new insights into mental health, scale reliability, and the dynamics of psychological assessment.

DNA damage-mediated FTO downregulation promotes CRPC progression by inhibiting FOXO3a via an m6A-dependent mechanism.

Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) represent a promising novel treatment for castration-resistant prostate cancer (CRPC) with encouraging results. However, the combination targets in CRPC remain largely unexplored. N6-methyladenosine (m6A) has been shown to play a crucial role in cancer progression and DNA damage response. Here, we observed a higher overall level of m6A and a downregulation of Fat mass and obesity-associated protein (FTO), which correlated with unfavorable clinicopathological parameters in prostate cancer (PCa). Functionally, reduced FTO promotes PCa growth, while overexpression of FTO has the opposite effect. Mechanistically, FOXO3a was identified as the downstream target of FTO in PCa. FTO downregulates the expression of FOXO3a in an m6A-dependent manner, leading to the degradation of its mRNA. Importantly, DNA damage can degrade FTO through the ubiquitination pathway. Finally, we found that overexpression of FTO can enhance the effect of PARPi on PCa. Therefore, our findings may provide insight into novel therapeutic approaches for CRPC.

Association of variant vitamin statuses and tuberculosis development: a systematic review and meta-analysis.

BACKGROUND: Several studies have suggested an association between vitamin deficiency and the development of tuberculosis; however, the precise impact remains unclear. This study aimed to elucidate the relationship between distinct vitamin statuses and the occurrence of tuberculosis. MATERIALS AND METHODS: Retrieval was conducted using several databases without language restrictions to capture the eligible studies on tuberculosis and vitamin status. Pooled odds ratios (ORs), relative risks (RRs), and hazard ratios (HRs) were used with 95% confidence intervals (CIs) to clarify the relationship between the different vitamin statuses (A, B, D, and E) and the occurrence of tuberculosis. Subgroup analysis, sensitivity analysis, meta-regression analysis, and Galbraith plot were performed to determine sources of heterogeneity. Potential publication biases were detected using Begg's test, Egger's test, and the trim-and-fill test. RESULTS: We identified 10,266 original records from our database searches, and 69 eligible studies were considered in this study. The random-effect model showed that people with tuberculosis may exhibit vitamin A deficiency (OR = 10.66, 95%CI: 2.61-43.63, p = .001), while limited cohort studies showed that vitamin A supplementation may reduce tuberculosis occurrence. Additionally, vitamin D deficiency was identified as a risk factor for tuberculosis development (RR = 1.69, 95%CI: 1.06-2.67, p = .026), and people with tuberculosis generally had lower vitamin D levels (OR = 2.19, 95%CI: 1.76-2.73, p < .001) compared to other groups. No publication bias was detected. CONCLUSIONS: This meta-analysis indicated that people with tuberculosis exhibited low levels of vitamins A and D, while vitamin D deficiency was identified as a risk factor for tuberculosis. More randomized controlled interventions at the community levels should be recommended to determine the association between specific vitamin supplementation and tuberculosis onset.

Effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular and cerebrovascular diseases: a meta-analysis of controlled clinical trials.

Objective: Evaluate the effects of sodium-glucose cotransporter 2 inhibitor (SGLT2i) on cardiovascular and cerebrovascular diseases. Methods: Articles of SGLT2i on cardiovascular and cerebrovascular diseases were searched. Two authors independently screened the literature, extracted the data, assessed the quality of the study and performed statistical analyses using Review Manager 5.4. Results: Random-effect model was used to merge the OR values, and the pooled effect showed that SGLT2i had significant preventive effects on cardiovascular death (OR=0.76, 95%CI 0.64 to 0.89), myocardial infarction (OR=0.90, 95%CI 0.84 to 0.96), heart failure (OR=0.69, 95%CI 0.64 to 0.74) and all-cause mortality (OR=0.65, 95%CI 0.58 to 0.73). Empagliflozin, dapagliflozin and canagliflozin all reduced the incidence of heart failure (OR=0.72, 95%CI 0.64 to 0.82; OR=0.56, 95%CI 0.39 to 0.80; OR=0.62, 95%CI 0.53 to 0.73), but only dapagliflozin displayed a favorable effect on inhibiting stroke (OR=0.78, 95%CI 0.63 to 0.98). SGLT2i could prevent stroke (OR=0.86, 95%CI 0.75 to 0.99), heart failure (OR=0.63, 95%CI 0.56 to 0.70) and all-cause mortality (OR=0.64, 95%CI 0.57 to 0.72) compared to DPP-4i. Furthermore, SGLT2i could reduce the incidence of heart failure (OR=0.72, 95%CI 0.67 to 0.77) and cardiovascular death (OR=0.72, 95%CI 0.54 to 0.95) in patients with high-risk factors. Conclusions: SGLT2i affects cardiovascular death, myocardial infarction, heart failure and all-cause mortality. Only dapagliflozin displayed a favorable effect on inhibiting stroke. SGLT2i could prevent stroke, heart failure and all-cause mortality compared to DPP-4i. In addition, SGLT2i significantly reduced the development of heart failure and cardiovascular death in patients with high-risk factors. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42024532783.

Rosa roxburghii Tratt (Cili) has a more effective capacity in alleviating DSS-induced colitis compared to Vitamin C through B cell receptor pathway.

Rosa roxburghii Tratt (RRT), a traditional Chinese plant known as the 'King of Vitamin C (VitC; ascorbic acid, AsA)', contains a wealth of nutrients and functional components, including polysaccharides, organic acids, flavonoids, triterpenes, and high superoxide dismutase (SOD) activity. The various functional components of RRT suggest that it may theoretically have a stronger potential for alleviating colitis compared to VitC. This study aims to verify whether RRT has a stronger ability to alleviate colitis than equimolar doses of VitC and to explore the mechanisms underlying this improvement. Results showed that RRT significantly mitigated body weight loss, intestinal damage, elevated inflammation levels, and compromised barriers in mice induced by Dextran sulfate sodium (DSS). Additionally, RRT enhanced the diversity and composition of intestinal microbiota in these DSS-induced mice. Colon RNA sequencing analysis revealed that compared to VitC, RRT further downregulated multiple immune-related signaling pathways, particularly the B cell receptor (BCR) pathway, which is centered around genes like Btk and its downstream PI3K-AKT, NF-κB, and MAPK signaling pathways. Correlation analysis between microbiota and genes demonstrated a significant relationship between the taxa improved by RRT and the key genes in the BCR and its downstream signaling pathways. Overall, RRT exhibited superior capabilities in alleviating DSS-induced colitis compared to VitC by decreasing intestinal inflammation and modulating BCR and its downstream signaling pathways, potentially regulated by the improved intestinal microbiota.

Why does afforestation policy lead to a drying trend in soil moisture on the Loess Plateau?

Soil moisture is a key factor for vegetation restoration in arid and semi-arid regions. Clarifying the vertical characteristics of soil moisture in artificial forests on a regional scale and its response mechanisms can benefit for land use management in water-deficient areas such as the Loess Plateau. The study targets Robinia pseudoacacia on the Loess Plateau with a meta-analysis based on 790 soil moisture data points abstracted from 35 published papers. The results show that extensive cultivation of R pseudoacacia on the Loess Plateau leads to a significant reduction in soil moisture (P < 0.05). Soil moisture decreases significantly with growth of trees, especially between 400 and 500 cm soil layers. Soil moisture increases with the hydrothermal gradient. The results indicate that intensive afforestation activities in high temperature and rainy areas still significantly consume deep soil moisture. The main reason is that the impact of hydrothermal factors on soil moisture is significant between 0 and 200 cm soil layers and decreases with increasing soil depth. However, the continuous depletion of deep soil moisture leads to insignificant differences in soil moisture responses under different topographical conditions in the region. Therefore, neglecting the impact of forest age and hydrothermal factors on soil moisture in afforestation activities, the excessive water consumption by R pseudoacacia during growth poses potential risks to the ecological environment of the Loess Plateau. This study provides references for knowledge on water relating problems and sustainable management of artificial forests in arid and semi-arid areas.

Underlying mechanisms and management strategies for regorafenib-induced toxicity in hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) accounts for 85% of liver cancer cases and is the third leading cause of cancer death. Regorafenib is a multi-target inhibitor that dramatically prolongs progression-free survival in HCC patients who have failed sorafenib therapy. However, one of the primary factors limiting regorafenib's clinical utilization is toxicity. Using Clinical Trials.gov and PubMed, we gathered clinical data on regorafenib and conducted a extensive analysis of the medication's adverse reactions and mechanisms. Next, we suggested suitable management techniques to improve regorafenib's effectiveness. AREAS COVERED: We have reviewed the mechanisms by which regorafenib-induced toxicity occurs and general management strategies through clinical trials of regorafenib. Furthermore, by examining the literature on regorafenib and other tyrosine kinase inhibition, we summarized the mechanics of the onset of regorafenib toxicity and mechanism-based intervention strategies by reviewing the literature related to regorafenib and other tyrosine kinase inhibition. EXPERT OPINION: One of the primary factors restricting regorafenib's clinical utilization and combination therapy is its toxicity reactions. To optimize regorafenib treatment regimens, it is especially important to further understand the specific toxicity mechanisms of regorafenib as a multi-kinase inhibitor.