Trend of robot-assisted surgery system in gastrointestinal and liver surgery: A bibliometric analysis.

BACKGROUND: Robot-assisted gastrointestinal and liver surgery has been an important development direction in the field of surgery in recent years and it is also one of the fastest developing and most concerning fields in surgical operations. AIM: To illustrate the major areas of research and forward-looking directions over the past twenty-six years. METHODS: Using the Web of Science Core Collection database, a comprehensive review of scholarly articles pertaining to robot-assisted gastrointestinal and liver surgery was researched out between 2000 and 2023. We used Citespace (Version 6.2.4) and Bibliometrix package (Version 4.3.0) to visualize the analysis of all publications including country, institutional affiliations, authors, and keywords. RESULTS: In total, 346 articles were retrieved. Surgical Endoscopy had with the largest number of publications and was cited in this field. The United States was a core research country in this field. Yonsei University was the most productive institution. The current focus of this field is on rectal surgery, long-term prognosis, perioperative management, previous surgical experience, and the learning curve. CONCLUSION: The scientific interest in robot-assisted gastrointestinal and liver surgery has experienced a significant rise since 1997. This study provides new perspectives and ideas for future research in this field.

Periodontal health and oral hygiene of children with orofacial clefts in Eastern China.

To comparatively assess the periodontal condition and oral hygiene of children and adolescents at different ages presenting with different types of orofacial clefts (OFCs). A total of 1608 patients aged 6-18 years who had not previously undergone periodontal treatment were enrolled in this study. Participants were categorized into two age groups: 6-12 years (Group I) and 13-18 years (Group II). Participants in both age groups were further classified into one of the three OFC-type subgroups: cleft lip only (without or with alveolar cleft), cleft lip and cleft palate, and cleft palate only. Periodontal health was determined by evaluating plaque formation and gingival status with reference to the Silness and Loe plaque index (PI), Loe gingival index (GI), and community periodontal index (CPI). Periodontal health and oral hygiene were not significantly different between Groups I and II for cleft type (p > 0.05). A significant difference was not observed in PI for cleft type among the groups (p > 0.05). In Group II, GI and CPI were significantly higher than in Group I (p < 0.05). According to our results, cleft type does not influence periodontal health of children and adolescents with OFCs. Age, however, influences periodontal diseases' prevalence and severity.

Major specialized natural products from the endangered plant Heptacodium miconioides, potential medicinal uses and insights into its longstanding unresolved systematic classification.

A comprehensive phytochemical investigation of the flower buds and leaves/twigs of Heptacodium miconioides, a cultivated ornamental plant native to China and categorized as 'vulnerable', has led to the isolation of 45 structurally diverse compounds, which comprise 18 phenylpropanoids (1-4, 7-20), 11 pentacyclic triterpenoids (5, 6, 21-29), eight secoiridoid glycosides (30-37), three quinic acid derivatives (38-40), and a few miscellaneous components (41-45). Among them, (+)-α-intermedianol (1), (+)-holophyllol A (2), and (-)-pseudolarkaemin A (3) represent previously unreported enantiomeric lignans, while (+)-7'(R)-hydroxymatairesinol (4) is an undescribed naturally occurring lignan. Heptacoacids A (5) and B (6) are undescribed 24-nor-urs-28-oic acid derivatives. Their chemical structures were determined by 2D-NMR, supplemented by evidence from specific rotations and circular dichroism spectra. Given the uncertainty surrounding the systematic position of Heptacodium, integrative taxonomy (ITA), a method utilized to define contentious species, is applied. Chemotaxonomy, a vital aspect of ITA, becomes significant. By employing hierarchical clustering analysis (HCA) and syntenic pattern analysis methods, a taxonomic examination based on the major specialized natural products from the flower buds of H. miconioides and two other Caprifoliaceae plants (i.e., Lonicera japonica and Abelia × grandiflora) could offer enhanced understanding of the systematic placement of Heptacodium. Additionally, compounds 39 and 40 displayed remarkable inhibitory activities against ATP-citrate lyase (ACL), with IC50 values of 0.11 and 1.10 µM, respectively. In summary, the discovery of medical properties and refining systematic classification can establish a sturdy groundwork for conservation efforts aimed at mitigating species diversity loss while addressing human diseases.

Reason and control strategy for denitrification and anammox sludge flotation in nitrogen removal process: Mechanisms, strategies and perspectives.

Anaerobic biological treatment technology, especially denitrification and anaerobic ammonia oxidation (anammox) technology as mainstream process, played dominant role in the field of biological wastewater treatment. However, the above process was prone to sludge floating during high load operation and thereby affecting the efficient and stable operation of the system. Excessive production of extracellular polymeric substance (EPS) was considered to be the main reason for anaerobic granular sludge flotation, but the summaries in this area were not comprehensive enough. In this review, the potential mechanisms of denitrification and anammox sludge floatation were discussed from the perspective of granular sludge structural characteristics, nutrient transfer, and microbial flora change respectively, and the corresponding control strategies were also summarized. Finally, this paper indicated that future research on sludge flotation should focus on reducing the negative effects of EPS in sludge particles.

Refining the phylogeny and taxonomy of the apple tribe Maleae (Rosaceae): insights from phylogenomic analyses of 563 plastomes and a taxonomic synopsis of Photinia and its allies in the Old World.

This study addresses the longstanding absence of a comprehensive phylogenetic backbone for the apple tribe Maleae, a deficiency attributed to limited taxon and marker sampling. We conducted an extensive taxon sampling, incorporating 563 plastomes from a diverse range of 370 species encompassing 26 presently recognized genera. Employing a range of phylogenetic inference methods, including RAxML and IQ-TREE2 for Maximum Likelihood (ML) analyses, we established a robust phylogenetic framework for the Maleae tribe. Our phylogenomic investigations provided compelling support for three major clades within Maleae. By integrating nuclear phylogenetic data with morphological and chromosomal evidence, we propose an updated infra-tribal taxonomic system, comprising subtribe Malinae Reveal, subtribe Lindleyinae Reveal, and subtribe Vauqueliniinae B.B.Liu (subtr. nov.). Plastid phylogenetic analysis also confirmed the monophyly of most genera, except for Amelanchier, Malus, Sorbus sensu lato, and Stranvaesia. In addition, we present a comprehensive taxonomic synopsis of Photinia and its morphological allies in the Old World, recognizing 27 species and ten varieties within Photinia, three species and two varieties within Stranvaesia, and two species and three varieties within Weniomeles. Furthermore, we also lectotypified 12 names and made two new combinations, Photiniamicrophylla (J.E.Vidal) B.B.Liu and Weniomelesatropurpurea (P.L.Chiu ex Z.H.Chen & X.F.Jin) B.B.Liu.

A new mountain pitviper of the genus Ovophis Burger in Hoge & Romano-Hoge, 1981 (Serpentes, Viperidae) from Yunnan, China.

Based on a molecular phylogenetic analysis and morphological comparison, a new species of mountain pitviper, Ovophisjenkinsi sp. nov., is described. The new species was collected in Yingjiang County, Yunnan Province, China. It can be distinguished from congeneric species by the following characters: (1) internasals in contact or separated by one small scale; (2) second supralabial entire and bordering the loreal pit; (3) dorsal scales in 23 (25)-21 (23, 25)-19 (17, 21) rows; (4) 134-142 ventrals; (5) 40-52 pairs of subcaudals; (6) third supralabial larger than fourth in all examined specimens of Ovophisjenkinsi sp. nov.; (7) deep orange-brown or dark brownish-grey markings on dorsal head surface; (8) background color of dorsal surface deep orange-brown or dark brownish-grey; (9) both sides of dorsum display dark brown trapezoidal patches; (10) scattered small white spots on dorsal surface of tail.

Causal association of sarcopenia with hepatocellular carcinoma risk in European population: a Mendelian randomization study.

Background: The causal association of sarcopenia with the incidence risk of hepatocellular carcinoma (HCC) in the European population, and the potential mediating role of C-reactive protein (CRP), remains unclear. This study employed a bidirectional two-sample, two-step Mendelian randomization (MR) analysis to investigate the causality and identify the mediator. Methods: Summary statistics for HCC, CRP, and sarcopenia-related traits, including appendicular lean mass (ALM), hand grip strength (HGS), and walking pace (WP), were acquired from publicly available databases. We conducted bidirectional MR and Steiger tests of directionality to check the presence of reverse causality. Additionally, a two-step MR analysis was used to assess the mediating effect of CRP in the causality between sarcopenia and HCC. Tests for heterogeneity and horizontal pleiotropy were performed. Results: As ALM increases, the risk of HCC occurrence decreases [odds ratio (OR), 95% confidence interval (CI): 0.703, 0.524-0.943; P = 0.019]. And, genetically predicted low-HGS (OR, 95%CI: 2.287, 1.013-5.164; P = 0.047) was associated with an increased incidence risk of HCC, with no reverse causality. However, we found no evidence supporting a causality between WP and HCC. CRP was identified as the mediator of the causal effect of ALM and low-HGS on HCC, with corresponding mediating effects of 9.1% and 7.4%. Conclusions: This MR study effectively demonstrates that lower ALM and low-HGS are linked to an elevated risk of HCC within the European population, and the causality was not bidirectional. Furthermore, CRP serves as a mediator in the associations. These findings may help mitigate HCC risk among individuals with sarcopenia.

Nontoxigenic Bacteroides fragilis: A double-edged sword.

The contribution of commensal microbes to human health and disease is unknown. Bacteroides fragilis (B. fragilis) is an opportunistic pathogen and a common colonizer of the human gut. Nontoxigenic B. fragilis (NTBF) and enterotoxigenic B. fragilis (ETBF) are two kinds of B. fragilis. NTBF has been shown to affect the host immune system and interact with gut microbes and pathogenic microbes. Previous studies indicated that certain strains of B. fragilis have the potential to serve as probiotics, based on their observed relationship with the immune system. However, several recent studies have shown detrimental effects on the host when beneficial gut bacteria are found in the digestive system or elsewhere. In some pathological conditions, NTBF may have adverse reactions. This paper presents a comprehensive analysis of NTBF ecology from the host-microbe perspective, encompassing molecular disease mechanisms analysis, bacteria-bacteria interaction, bacteria-host interaction, and the intricate ecological context of the gut. Our review provides much-needed insights into the precise application of NTBF.

Plant-derived exosome-like nanovesicles: A novel nanotool for disease therapy.

Exosomes are extracellular vesicles comprising bilayer phospholipid membranes and are secreted by eukaryotic cells. They are released via cellular exocytosis, contain DNA, RNA, proteins, and other substances, and participate in various cellular communications between tissues and organs. Since the discovery of exosomes in 1983, animal-derived exosomes have become a research focus for small-molecule drug delivery in biology, medicine, and other fields owing to their good biocompatibility and homing effects. Recent studies have found that plant-derived exosome-like nanovesicles (PELNVs) exhibit certain biological effects, such as anti-inflammatory and anti-tumor abilities, and have minimal toxic side effects. Because they are rich in active lipid molecules with certain pharmacological effects, PELNVs could be novel carriers for drug delivery. In this review, the biological formation and effects, isolation, and extraction of PELNVs, as well as characteristics of transporting drugs as carriers are summarized to provide new ideas and methods for future research on plant-derived exosome-like nanovesicles.

High-resolution vasomotion analysis reveals novel arteriole physiological features and progressive modulation of cerebral vascular networks by stroke.

Spontaneous cerebral vasomotion, characterized by ∼0.1 Hz rhythmic contractility, is crucial for brain homeostasis. However, our understanding of vasomotion is limited due to a lack of high-precision analytical methods to determine single vasomotion events at basal levels. Here, we developed a novel strategy that integrates a baseline smoothing algorithm, allowing precise measurements of vasodynamics and concomitant Ca2+ dynamics in mouse cerebral vasculature imaged by two-photon microscopy. We identified several previously unrecognized vasomotion properties under different physiological and pathological conditions, especially in ischemic stroke, which is a highly harmful brain disease that results from vessel occlusion. First, the dynamic characteristics between SMCs Ca2+ and corresponding arteriolar vasomotion are correlated. Second, compared to previous diameter-based estimations, our radius-based measurements reveal anisotropic vascular movements, enabling a more precise determination of the latency between smooth muscle cell (SMC) Ca2+ activity and vasoconstriction. Third, we characterized single vasomotion event kinetics at scales of less than 4 seconds. Finally, following pathological vasoconstrictions induced by ischemic stroke, vasoactive arterioles entered an inert state and persisted despite recanalization. In summary, we developed a highly accurate technique for analyzing spontaneous vasomotion, and our data suggested a potential strategy to reduce stroke damage by promoting vasomotion recovery.

Fecal Microbiota Transplantation Attenuates Frailty via Gut-Muscle Axis in Old Mice.

Targeting adverse pathogenic gut microbiota regulation through fecal microbiota transplantation (FMT) may restore health and has been validated in some aging-related diseases. However, the mechanisms of the gut microbiota's role in frailty and whether modulation of the gut microbiota can treat age-related frailty remain largely unknown. To assess the effects of FMT on frailty, we used bidirectional fecal microbiota transplantation in young and old mice. We demonstrated that fecal bacteria transplanted from old mice into young mice reduced body weight and grip strength (p=0.002), and led to elevated inflammatory factors in young mice, but had no significant effect on intestinal barrier function. Notably, FMT treatment in older mice not only improved frailty (grip strength: p=0.036, low physical activity: p=0.020, running speed: p=0.048, running time: p=0.058, frailty score: p=0.027) and muscle mass, but also improved intestinal ecological imbalances, intestinal barrier function, and systemic inflammation (serum TNF-α: p=0.002, and IL-6: p<0.001). KEGG enrichment analysis of fecal metabolites showed that FMT may ameliorate frailty through the sphingolipid metabolism pathway. In addition, aged mice given FMT treatment showed a significant increase in the abundance of SCFA-producing bacteria and increased levels of short-chain fatty acids (butyric acid: p=0.084, propionic acid: p=0.028). Subsequent further verification found that FMT ameliorating frailty may be achieved through SCFAs metabolism. Another mechanism study found that FMT reduces lipopolysaccharide levels (p<0.001), thereby inhibiting the TLR4/NF-κB signaling pathway and its downstream pro-inflammatory products. Therefore, regulating SCFAs metabolism by altering gut microbial composition and targeting the gut-muscle axis with LPS/TLR4 pathways may be potential strategies to treat frailty in older adults.

Microalgae-loaded biocompatible alginate microspheres for tissue repair.

Hydrogel-based microcarriers have demonstrated effectiveness in wound repair treatments. The current research focus is creating and optimizing active microcarriers containing natural ingredients capable of conforming to diverse wound shapes and depths. Here, microalgae (MA)-loaded living alginate hydrogel microspheres were successfully fabricated via microfluidic electrospray technology, to enhance the effectiveness of wound healing. The stable living alginate hydrogel microspheres loaded with photoautotrophic MA were formed by cross-linking alginate with calcium ions. The combination of MA-loaded living alginate microspheres ensures high biocompatibility and efficient oxygen release, providing strong support for wound healing. Concurrently, vascular endothelial growth factor (VEGF) has been successfully introduced into the microspheres, further enhancing the comprehensive effectiveness of wound treatment. Covering the rat's wound with these MA-VEGF-loaded alginate microspheres further substantiated their significant role in promoting collagen deposition and vascular generation during the wound closure processes. These results confirm the outstanding value of microalgae-loaded live alginate hydrogel microspheres in wound healing, paving the way for new prospects in future clinical treatment methods.

Extracellular vesicles derived from immune cells: Role in tumor therapy.

Extracellular vesicles (EVs), which have a lipid nano-sized structure, are known to contain the active components of parental cells and play a crucial role in intercellular communication. The progression and metastasis of tumors are influenced by EVs derived from immune cells, which can simultaneously stimulate and suppress immune responses. In the past few decades, there has been a considerable focus on EVs due to their potential in various areas such as the development of vaccines, delivering drugs, making engineered modifications, and serving as biomarkers for diagnosis and prognosis. This review focuses on the substance information present in EVs derived from innate and adaptive immune cells, their effects on the immune system, and their applications in cancer treatment. While there are still challenges to overcome, it is important to explore the composition of immune cells released vesicles and their potential therapeutic role in tumor therapy. The review also highlights the current limitations and future prospects in utilizing EVs for treatment purposes.

CA1 Modulates the Osteogenic Differentiation of Dental Follicle Stem Cells by Activating the BMP Signaling Pathway In Vitro.

BACKGROUND: Carbonic anhydrase 1 (CA1) has been found to be involved in osteogenesis and osteoclast in various human diseases, but the molecular mechanisms are not completely understood. In this study, we aim to use siRNA and lentivirus to reduce or increase the expression of CA1 in Dental follicle stem cells (DFSCs), in order to further elucidate the role and mechanism of CA1 in osteogenesis, and provide better osteogenic growth factors and stem cell selection for the application of bone tissue engineering in alveolar bone fracture transplantation. METHODS: The study used RNA interference and lentiviral vectors to manipulate the expression of the CA1 gene in DFSCs during in vitro osteogenic induction. The expression of osteogenic marker genes was evaluated and changes in CA1, alkaline phosphatase (ALP), Runt-related transcription factor 2 (RUNX2), and Bone morphogenetic proteins (BMP2) were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB). The osteogenic effect was assessed through Alizarin Red staining. RESULTS: The mRNA and protein expression levels of CA1, ALP, RUNX2, and BMP2 decreased distinctly in the si-CA1 group than other groups (p < 0.05). In the Lentivirus-CA1 (LV-CA1) group, the mRNA and protein expressions of CA1, ALP, RUNX2, and BMP2 were amplified to varying degrees than other groups (p < 0.05). Apart from CA1, BMP2 (43.01%) and ALP (36.69%) showed significant upregulation (p < 0.05). Alizarin red staining indicated that the LV-CA1 group produced more calcified nodules than other groups, with a higher optical density (p < 0.05), and the osteogenic effect was superior. CONCLUSIONS: CA1 can impact osteogenic differentiation via BMP related signaling pathways, positioning itself upstream in osteogenic signaling pathways, and closely linked to osteoblast calcification and ossification processes.

Lactobacillus rhamnosus GG ameliorates hyperuricemia in a novel model.

Hyperuricemia (HUA) is a metabolic syndrome caused by abnormal purine metabolism. Although recent studies have noted a relationship between the gut microbiota and gout, whether the microbiota could ameliorate HUA-associated systemic purine metabolism remains unclear. In this study, we constructed a novel model of HUA in geese and investigated the mechanism by which Lactobacillus rhamnosus GG (LGG) could have beneficial effects on HUA. The administration of antibiotics and fecal microbiota transplantation (FMT) experiments were used in this HUA goose model. The effects of LGG and its metabolites on HUA were evaluated in vivo and in vitro. Heterogeneous expression and gene knockout of LGG revealed the mechanism of LGG. Multi-omics analysis revealed that the Lactobacillus genus is associated with changes in purine metabolism in HUA. This study showed that LGG and its metabolites could alleviate HUA through the gut-liver-kidney axis. Whole-genome analysis, heterogeneous expression, and gene knockout of LGG enzymes ABC-type multidrug transport system (ABCT), inosine-uridine nucleoside N-ribohydrolase (iunH), and xanthine permease (pbuX) demonstrated the function of nucleoside degradation in LGG. Multi-omics and a correlation analysis in HUA patients and this goose model revealed that a serum proline deficiency, as well as changes in Collinsella and Lactobacillus, may be associated with the occurrence of HUA. Our findings demonstrated the potential of a goose model of diet-induced HUA, and LGG and proline could be promising therapies for HUA.

Lipid metabolism-related long noncoding RNA RP11-817I4.1 promotes fatty acid synthesis and tumor progression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of tumors. The influence of lipid metabolism disruption on the development of HCC has been demonstrated in published studies. AIM: To establish an HCC prognostic model for lipid metabolism-related long non-coding RNAs (LMR-lncRNAs) and conduct in-depth research on the specific role of novel LMR-lncRNAs in HCC. METHODS: Correlation and differential expression analyses of The Cancer Genome Atlas data were used to identify differentially expressed LMR-lncRNAs. Quantitative real-time polymerase chain reaction analysis was used to evaluate the expression of LMR-lncRNAs. Nile red staining was employed to observe intracellular lipid levels. The interaction between RP11-817I4.1, miR-3120-3p, and ATP citrate lyase (ACLY) was validated through the performance of dual-luciferase reporter gene and RIP assays. RESULTS: Three LMR-lncRNAs (negative regulator of antiviral response, RNA transmembrane and coiled-coil domain family 1 antisense RNA 1, and RP11-817I4.1) were identified as predictive markers for HCC patients and were utilized in the construction of risk models. Additionally, proliferation, migration, and invasion were reduced by RP11-817I4.1 knockdown. An increase in lipid levels in HCC cells was significantly induced by RP11-817I4.1 through the miR-3120-3p/ACLY axis. CONCLUSION: LMR-lncRNAs have the capacity to predict the clinical characteristics and prognoses of HCC patients, and the discovery of a novel LMR-lncRNAs, RP11-817I4.1, revealed its role in promoting lipid accumulation, thereby accelerating the onset and progression of HCC.

Sequential surgery for the treatment of type I knee ankylosis: a series of 62 cases.

BACKGROUNDS: The lack of systematic classification and standard treatment principles for knee ankylosis prevents optimal treatments. This study explored treatments for type I (mild) knee joint ankylosis. METHOD: This retrospective study analysed patients with knee joint ankylosis admitted from March 2013 to January 2018 who underwent sequential arthroscopic release. RESULT: The 62 patients had 12-36 (average, 18) months of follow-up. Thirty-eight patients were released; of these, 18 were assisted by limited incision with partial quadriceps femoris expansion myotomy and released according to arthroscopy. Six patients underwent lengthening and release of the quadriceps femoris. All surgeries combined with full-course rehabilitation resulted in improved joint mobility. The range of motion (ROM) of the knee joint recovered to a range of 0° to 85°-140° (mean: 118.32 ± 9.42°) from the preoperative range of 30°-70° (mean: 45° ± 15.50°). The clinical effect was evaluated according to the Judet criteria at the final follow-up. The outcomes at the last follow-up (at least for 1 year) were excellent in 55 cases, good in six cases, and fair in one case. CONCLUSION: Sequential arthroscopic release, minimal selective invasion of limited incision of partial quadriceps femoris expansion myotomy, assisted by pie-crusting technique to release, or quadriceps femoris lengthening, and release surgery for type I knee joint ankylosis, accompanied by early rehabilitation training provided satisfactory results without significant complications.

Anti- and pro-fibrillatory effects of pulmonary vein isolation gaps in human atrial fibrillation digital twins.

Although pulmonary vein isolation (PVI) gaps and extrapulmonary vein triggers contribute to recurrence after atrial fibrillation (AF) ablation, their precise mechanisms remain unproven. Our study assessed the impact of PVI gaps on rhythm outcomes using a human AF digital twin. We included 50 patients (76.0% with persistent AF) who underwent catheter ablation with a realistic AF digital twin by integrating computed tomography and electroanatomical mapping. We evaluated the final rhythm status, including AF and atrial tachycardia (AT), across 600 AF episodes, considering factors including PVI level, PVI gap number, and pacing locations. Our findings revealed that antral PVI had a significantly lower ratio of AF at the final rhythm (28% vs. 56%, p = 0.002) than ostial PVI. Increasing PVI gap numbers correlated with an increased ratio of AF at the final rhythm (p < 0.001). Extra-PV induction yielded a higher ratio of AF at the final rhythm than internal PV induction (77.5% vs. 59.0%, p < 0.001). In conclusion, our human AF digital twin model helped assess AF maintenance mechanisms. Clinical trial registration: https://www.clinicaltrials.gov ; Unique identifier: NCT02138695.

Advances in tumor vascular growth inhibition.

Tumor growth and metastasis require neovascularization, which is dependent on a complex array of factors, such as the production of various pro-angiogenic factors by tumor cells, intercellular signaling, and stromal remodeling. The hypoxic, acidic tumor microenvironment is not only conducive to tumor cell proliferation, but also disrupts the equilibrium of angiogenic factors, leading to vascular heterogeneity, which further promotes tumor development and metastasis. Anti-angiogenic strategies to inhibit tumor angiogenesis has, therefore, become an important focus for anti-tumor therapy. The traditional approach involves the use of anti-angiogenic drugs to inhibit tumor neovascularization by targeting upstream and downstream angiogenesis-related pathways or pro-angiogenic factors, thereby inhibiting tumor growth and metastasis. This review explores the mechanisms involved in tumor angiogenesis and summarizes currently used anti-angiogenic drugs, including monoclonal antibody, and small-molecule inhibitors, as well as the progress and challenges associated with their use in anti-tumor therapy. It also outlines the opportunities and challenges of treating tumors using more advanced anti-angiogenic strategies, such as immunotherapy and nanomaterials.