Rule Abstraction Is Facilitated by Auditory Cuing in REM Sleep.

Sleep facilitates abstraction, but the exact mechanisms underpinning this are unknown. Here, we aimed to determine whether triggering reactivation in sleep could facilitate this process. We paired abstraction problems with sounds, then replayed these during either slow-wave sleep (SWS) or rapid eye movement (REM) sleep to trigger memory reactivation in 27 human participants (19 female). This revealed performance improvements on abstraction problems that were cued in REM, but not problems cued in SWS. Interestingly, the cue-related improvement was not significant until a follow-up retest 1 week after the manipulation, suggesting that REM may initiate a sequence of plasticity events that requires more time to be implemented. Furthermore, memory-linked trigger sounds evoked distinct neural responses in REM, but not SWS. Overall, our findings suggest that targeted memory reactivation in REM can facilitate visual rule abstraction, although this effect takes time to unfold.SIGNIFICANCE STATEMENT The ability to abstract rules from a corpus of experiences is a building block of human reasoning. Sleep is known to facilitate rule abstraction, but it remains unclear whether we can manipulate this process actively and which stage of sleep is most important. Targeted memory reactivation (TMR) is a technique that uses re-exposure to learning-related sensory cues during sleep to enhance memory consolidation. Here, we show that TMR, when applied during REM sleep, can facilitate the complex recombining of information needed for rule abstraction. Furthermore, we show that this qualitative REM-related benefit emerges over the course of a week after learning, suggesting that memory integration may require a slower form of plasticity.

Structural and thermodynamic properties of conserved water molecules in Mpro native: A combined approach by MD simulation and Grid Inhomogeneous Solvation Theory.

The new viral strains of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are continuously rising, becoming more virulent, and transmissible. Therefore, the development of new antiviral drugs is essential. Due to its significant role in the viral life cycle of SARS-CoV-2, the main protease (Mpro) enzyme is a leading target for antiviral drug design. The Mpro monomer consists of domain DI, DII, and DI-DII interface. Twenty-one conserved water molecules (W4-W24) are occupied at these domains according to multiple crystal structure analyses. The crystal and MD structures reveal the presence of eight conserved water sites in domain DI, DII and remaining in the DI-DII interface. Grid-based inhomogeneous fluid solvation theory (GIST) was employed on MD structures of Mpro native to predict structural and thermodynamic properties of each conserved water site for focusing to identify the specific conserved water molecules that can easily be displaced by proposed ligands. Finally, MD water W13 is emerged as a promising candidate for water mimic drug design due to its low mean interaction energy, loose binding character with the protein, and its involvement in a water-mediated H-bond with catalytic His41 via the interaction Thr25(OG)---W13---W---His41(NE2). In this context, water occupancy, relative interaction energy, entropy, and topologies of W13 are thermodynamically acceptable for the water displacement method. Therefore, the strategic use of W13's geometrical position in the DI domain may be implemented for drug discovery against COVID disease by designing new ligands with appropriately oriented chemical groups to mimic its structural, electronic, and thermodynamic properties.

Thermodynamic consequences of stapling side-chains on a peptide ligand using a lactam-bridge: A theoretical study on anti-angiogenic peptides targeting VEGF.

Peptides are promising therapeutic agents for various biological targets due to their high efficacy and low toxicity, and the design of peptide ligands with high binding affinity to the target of interest is of utmost importance in peptide-based drug design. Introducing a conformational constraint to a flexible peptide ligand using a side-chain lactam-bridge is a convenient and efficient method to improve its binding affinity to the target. However, in general, such a small structural modification to a flexible ligand made with the intent of lowering the configurational entropic penalty for binding may have unintended consequences in different components of the binding enthalpy and entropy, including the configurational entropy component, which are still not clearly understood. Toward probing this, we examine different components of the binding enthalpy and entropy as well as the underlying structure and dynamics, for a side-chain lactam-bridged peptide inhibitor and its flexible analog forming complexes with vascular endothelial growth factor (VEGF), using all-atom molecular dynamics simulations. It is found that introducing a side-chain lactam-bridge constraint into the flexible peptide analog led to a gain in configurational entropy change but losses in solvation entropy, solute internal energy, and solvation energy changes upon binding, pinpointing the opportunities and challenges in drug design. The present study features an interplay between configurational and solvation entropy changes, as well as the one between binding enthalpy and entropy, in ligand-target binding upon imposing a conformational constraint into a flexible ligand.

KIT/PDGFRA Variant Allele Frequency as Prognostic Factor in Gastrointestinal Stromal Tumors (GISTs): Results From a Multi-Institutional Cohort Study.

BACKGROUND: The patient selection for optimal adjuvant therapy in gastrointestinal stromal tumors (GISTs) is provided by nomogram based on tumor size, mitotic index, tumor location, and tumor rupture. Although mutational status is not currently used to risk assessment, tumor genotype showed a prognostic influence on natural history and tumor relapse. Innovative measures, such as KIT/PDGFRA-mutant-specific variant allele frequency (VAF) levels detection from next-generation sequencing (NGS), may act as a surrogate of tumor burden and correlate with prognosis and overall survival of patients with GIST, helping the choice for adjuvant treatment. PATIENTS AND METHODS: This was a multicenter, hospital-based, retrospective/prospective cohort study to investigate the prognostic role of KIT or PDGFRA-VAF of GIST in patients with radically resected localized disease. In the current manuscript, we present the results from the retrospective phase of the study. RESULTS: Two-hundred (200) patients with GIST between 2015 and 2022 afferent to 6 Italian Oncologic Centers in the EURACAN Network were included in the study. The receiver operating characteristic (ROC) curves analysis was used to classify "low" vs. "high" VAF values, further normalized on neoplastic cellularity (nVAF). When RFS between the low and high nVAF groups were compared, patients with GIST with KIT/PDGFRA nVAF > 50% showed less favorable RFS than patients in the group of nVAF ≤ 50% (2-year RFS, 72.6% vs. 93%, respectively; P = .003). The multivariable Cox regression model confirmed these results. In the homogeneous sub-population of intermediate-risk, patients with KIT-mutated GIST, the presence of nVAF >50% was statistically associated with higher disease recurrence. CONCLUSION: In our study, we demonstrated that higher nVAF levels were independent predictors of GIST prognosis and survival in localized GIST patients with tumors harboring KIT or PDGFRA mutations. In the cohort of intermediate-risk patients, nVAF could be helpful to improve prognostication and the use of adjuvant imatinib.

A diagnostic challenge of KIT p.V559D and BRAF p.G469A mutations in a paragastric mass.

A patient with gastrointestinal stroma tumor (GIST) and KIT p.V559D and BRAF p.G469A alterations was referred to our institutional molecular tumor board (MTB) to discuss therapeutic implications. The patient had been diagnosed with B-cell chronic lymphocytic leukemia (CLL) years prior to the MTB presentation. GIST had been diagnosed 1 month earlier. After structured clinical annotation of the molecular alterations and interdisciplinary discussion, we considered BRAF/KIT co-mutation unlikely in a treatment-naïve GIST. Discordant variant allele frequencies furthermore suggested a second malignancy. NGS of a CLL sample revealed the identical class 2 BRAF alteration, thus supporting admixture of CLL cells in the paragastric mass, leading to the detection of 2 alterations. Following the MTB recommendation, the patient received imatinib and had a radiographic response. Structured annotation and interdisciplinary discussion in specialized tumor boards facilitate the clinical management of complex molecular findings. Coexisting malignancies and clonal hematopoiesis warrant consideration in case of complex and uncommon molecular findings.

MPI-parallelization of the grid inhomogeneous solvation theory calculation.

The grid inhomogeneous solvation theory (GIST) method requires the often time-consuming calculation of water-water and water-solute energy on a grid. Previous efforts to speed up this calculation include using OpenMP, GPUs, and particle mesh Ewald. This article details how the speed of this calculation can be increased by parallelizing it with MPI, where trajectory frames are divided among multiple processors. This requires very little communication between individual processes during trajectory processing, meaning the calculation scales well to large processor counts. This article also details how the entropy calculation, which must happen after trajectory processing since it requires information from all trajectory frames, is parallelized via MPI. This parallelized GIST method has been implemented in the freely-available CPPTRAJ analysis software.

Four and a half LIM domains 2 (FHL2) attenuates tumorigenesis of gastrointestinal stromal tumors (GISTs) by negatively regulating KIT signaling.

Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.

Manipulated overlapping reactivation of multiple memories promotes explicit gist abstraction.

Sleep is considered to promote gist abstraction on the basis of spontaneous memory reactivation. As speculated in the theory of 'information overlap to abstract (iOtA)', 'overlap' between reactivated memories, beyond reactivation, is crucial to gist abstraction. Yet so far, empirical research has not tested this theory by manipulating the factor of 'overlap'. In the current study, 'overlap' itself was manipulated by targeted memory reactivation (TMR), through simultaneously reactivating multiple memories that either contain or do not contain spatially overlapped gist information, to investigate the effect of overlapping reactivation on gist abstraction. This study had a factorial design of 2 factors with 2 levels respectively (spatial overlap/no spatial overlap, TMR/no-TMR). Accordingly, 82 healthy college students (aged 19 âˆ¼ 25, 57 females) were randomized into four groups. After learning 16 pictures, paired with 4 auditory cues (4 pictures - 1 cue) according to the grouping, participants were given a 90-minute nap opportunity. Then TMR cueing was conducted during N2 and slow wave sleep of the nap. Performance in memory task was used to measure gist abstraction. The results showed a significant main effect of TMR on both implicit and explicit gist abstraction, and a marginally significant interaction effect on explicit gist abstraction. Further analyses showed that explicit gist abstraction in the spatial overlap & TMR group was significantly better than in the control group. Moreover, explicit gist abstraction was positively correlated with spindle density. The current study thus indicates that TMR facilitates gist abstraction, and explicit gist abstraction may benefit more from overlapping reactivation.

Recurrence of fusocellular subtype GIST with SDHB mutation: A case of SDHB-loss and therapeutic challenges.

Gastrointestinal stromal tumors (GISTs) are sarcomas affecting the stomach and small intestine, with a rare subtype characterized by succinate dehydrogenase B (SDHB)-loss posing significant diagnostic and therapeutic challenges. A 62-year-old man with weight loss and abdominal pain was diagnosed with a gastric GIST showing SDHB-loss. Initial treatment with Imatinib reduced the tumor size, but surgery revealed no residual tumor. Despite adjuvant Imatinib, recurrence occurred, necessitating further surgical intervention. While GISTs typically benefit from surgery and tyrosine kinase inhibitors (TKIs), those with SDHB-loss are resistant to TKIs, requiring a different management approach. This case emphasizes the importance of surgical intervention for SDHB-deficient GISTs and the need for ongoing research into effective treatments for this subtype.

Gastric gastrointestinal stromal tumors: therapeutic strategies and long-term prognosis.

OBJECTIVES: This study aimed to evaluate the clinical and prognostic characteristics of primary gastric gastrointestinal stromal tumors (GIST). METHODS: Patients who underwent resection for primary gastric GIST between January 2002 and December 2017 were included. Recurrence-free survival (RFS) was calculated by Kaplan-Meier analysis, and Cox proportional hazards model was used to identify independent prognostic factors. RESULTS: Altogether, 653 patients were enrolled. The median patient age was 59 years (range 15-86 years). Open, laparoscopic, and endoscopic resections were performed in 394 (60.3%), 105 (16.1%), and 154 (23.6%) patients, respectively. According to the modified NIH consensus classification, 132 (20.2%), 245 (37.5%), 166 (25.4%), and 88 (13.5%) patients were categorized into very low-, low-, intermediate-, and high-risk, respectively. A total of 136 (20.8%) patients received adjuvant imatinib treatment. The median follow-up time was 78 months (range 4-219 months), and the estimated 5-year RFS rate was 93.0%. In all patients, tumor size and rupture, mitotic counts, and adjuvant imatinib treatment were independent prognostic factors. The prognosis of gastric GIST treated with endoscopic resection was not significantly different from that of laparoscopic or open resection after adjusting for covariates using propensity score matching (log-rank p = .558). Adjuvant imatinib treatment (HR = 0.151, 95%CI 0.055-0.417, p < .001) was a favorable prognostic factor for high-risk patients, but was not associated with prognosis in intermediate-risk patients. CONCLUSION: Patients with small gastric GISTs who successfully underwent endoscopic resection may have a favorable prognosis. Adjuvant imatinib treatment improve the prognosis of high-risk gastric GISTs, however, its use in intermediate-risk patients remains controversial.

Cell-permeable PI3 kinase competitive peptide inhibits KIT mutant mediated tumorigenesis of gastrointestinal stromal tumor (GIST).

BACKGROUND: Mutations in the receptor tyrosine kinase KIT are the main cause of gastrointestinal stromal tumor (GIST), and the KIT mutants mediated PI3 kinase activation plays a key role in the tumorigenesis of GIST. In this study, we aimed to block PI3 kinase activation by cell-permeable peptide and investigate its possible application in the treatment of GIST. METHODS AND RESULTS: We designed cell-permeable peptides based on the binding domain of PI3 kinase subunit p85 to KIT or PI3 kinase subunit p110, respectively, in order to compete for the binding between p85 and KIT or p110 and therefore inhibit the activation of PI3 kinases mediated by KIT. The results showed that the peptide can penetrate the cells, and inhibit the activation of PI3 kinases, leading to reduced cell survival and cell proliferation mediated by KIT mutants in vitro. Treatment of mice carrying germline KIT/V558A mutation, which can develop GIST, with the peptide that can compete for the binding between p85 and p110, led to reduced tumorigenesis of GIST. The peptide can further enhance the inhibition of the tumor growth by imatinib which is used as the first line targeted therapy of GIST. CONCLUSIONS: Our results showed that cell-permeable PI3 kinase competitive peptide can inhibit KIT-mediated PI3 kinase activation and tumorigenesis of GIST, providing a rationale to further test the peptide in the treatment of GIST and even other tumors with over-activation of PI3 kinases.

Precutting Endoscopic Band Ligation-Assisted Resection Is Safe and Effective for Treating Gastric Submucosal Tumors from the Muscularis Propria.

BACKGROUND: We previously treated small gastric submucosal tumors originating from the muscularis propria layer by precutting endoscopic band ligation but lacked precise pathological results. Then, precutting endoscopic band ligation was modified by additional snare resection after ligation to obtain tumor specimens, termed precutting endoscopic band ligation-assisted resection. AIMS: In this study, we aimed to explore the safety, feasibility, and efficacy of precutting endoscopic band ligation-assisted resection. METHODS: From 2021 to 2022, a total of 16 consecutive patients underwent precutting endoscopic band ligation-assisted resection to treat small gastric submucosal tumors originating from the muscularis propria. The clinical demography, perioperative data, and follow-up outcomes were retrospectively collected. RESULTS: With a mean operative time of 21.3 min, all lesions were successfully and completely resected, and no severe adverse events or local recurrences occurred postoperatively. More importantly, en bloc and R0 resection were achieved in all 16 patients. CONCLUSION: Precutting endoscopic band ligation-assisted resection is a safe, effective, and time-saving endoscopic technique for managing gastric small gastric submucosal tumors originating from the muscularis propria for both diagnosis and eradication.

Development and validation of a preoperative risk nomogram prediction model for gastric gastrointestinal stromal tumors.

BACKGROUND AND STUDY AIMS: Gastrointestinal stromal tumors (GIST) carry a potential risk of malignancy, and the treatment of GIST varies for different risk levels. However, there is no systematic preoperative assessment protocol to predict the malignant potential of GIST. The aim of this study was to develop a reliable and clinically applicable preoperative nomogram prediction model to predict the malignant potential of gastric GIST. PATIENTS AND METHODS: Patients with a pathological diagnosis of gastric GIST from January 2015 to December 2021 were screened retrospectively. Univariate and multivariate logistic analyses were used to identify independent risk factors for gastric GIST with high malignancy potential. Based on these independent risk factors, a nomogram model predicting the malignant potential of gastric GIST was developed and the model was validated in the validation group. RESULTS: A total of 494 gastric GIST patients were included in this study and allocated to a development group (n = 345) and a validation group (n = 149). In the development group, multivariate logistic regression analysis revealed that tumor size, tumor ulceration, CT growth pattern and monocyte-to- lymphocyte ratio (MLR) were independent risk factors for gastric GIST with high malignancy potential. The AUC of the model were 0.932 (95% CI 0.890-0.974) and 0.922 (95% CI 0.868-0.977) in the development and validation groups, respectively. The best cutoff value for the development group was 0.184, and the sensitivity and specificity at this value were 0.895 and 0.875, respectively. The calibration curves indicated good agreement between predicted and actual observed outcomes, while the DCA indicated that the nomogram model had clinical application. CONCLUSIONS: Tumor size, tumor ulceration, CT growth pattern and MLR are independent risk factors for high malignancy potential gastric GIST, and a nomogram model developed based on these factors has a high ability to predict the malignant potential of gastric GIST.

Is laparoscopic approach as treatment of large gastric GIST acceptable?

AIM: Laparoscopic surgery is widely used for small gastric gastrointestinal stromal tumors (GISTs) (≤ 5 cm) but remains a controversial approach for larger gastric GISTs (> 5 cm). This study aims to compare short- and long-term outcomes of laparoscopic resection in comparison with open resection for gastric GISTs measuring over 5 cm. METHOD: All patients receiving surgery for gastric GIST > 5 cm between 2000 and 2021 in a single tertiary hospital were included. Data were collected from prospectively maintained records. Kaplan-Meier method and log rank test were used to compare survival outcomes. RESULTS: Among 108 included patients, 59 patients had minimally invasive (MI) surgery (54.6%) whereas 49 patients had open surgery (46.4%). The rate of overall postoperative morbidity was 14.8% and the median length was significantly shorter in the MI group [4 (range 2-30) vs. 7 (range 4-33) days; P = 0.007]. The overall R0 resection rate was 98.2% and the rate of tumor rupture was 13%, not different between the two groups. Recurrence occurred in 24% of the whole population without any difference between groups (20.3% vs. 28.7%, p = 0.31). Minimally invasive surgery was not found as a negative prognostic disease-free survival factor. CONCLUSION: Laparoscopic surgery could be a safe and feasible alternative to open surgery in large gastric GIST, bringing the benefits of minimally invasive surgery without compromising oncologic results.

The GIST of it all: management of gastrointestinal stromal tumors (GIST) from the first steps to tailored therapy. A bibliometric analysis.

PURPOSE: Improvement of patient care is associated with increasing publication numbers in biomedical research. However, such increasing numbers of publications make it challenging for physicians and scientists to screen and process the literature of their respective fields. In this study, we present a comprehensive bibliometric analysis of the evolution of gastrointestinal stromal tumor (GIST) research, analyzing the current state of the field and identifying key open questions going beyond the recent advantages for future studies to assess. METHODS: Using the Web of Science Core Collection, 5040 GIST-associated publications in the years 1984-2022 were identified and analyzed regarding key bibliometric variables using the Bibliometrix R package and VOSviewer software. RESULTS: GIST-associated publication numbers substantially increased over time, accentuated from year 2000 onwards, and being characterized by multinational collaborations. The main topic clusters comprise surgical management, tyrosine kinase inhibitor (TKI) development/treatment, diagnostic workup, and molecular pathophysiology. Within all main topic clusters, a significant progress is reflected by the literature over the years. This progress ranges from conventional open surgical techniques over minimally invasive, including robotic and endoscopic, resection techniques to increasing identification of specific functional genetic aberrations sensitizing for newly developed TKIs being extensively investigated in clinical studies and implemented in GIST treatment guidelines. However, especially in locally advanced, recurrent, and metastatic disease stages, surgery-related questions and certain specific questions concerning (further-line) TKI treatment resistance were infrequently addressed. CONCLUSION: Increasing GIST-related publication numbers reflect a continuous progress in the major topic clusters of the GIST research field. Especially in advanced disease stages, questions related to the interplay between surgical approaches and TKI treatment sensitivity should be addressed in future studies.

English version of Japanese Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) issued by the Japan Society of Clinical Oncology.

The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients' wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries.

Working memory limitations constrain visual episodic long-term memory at both specific and gist levels of representation.

Limitations in one's capacity to encode information in working memory (WM) constrain later access to that information in long-term memory (LTM). The present study examined whether these WM constraints on episodic LTM are limited to specific representations of past episodes or also extend to gist representations. Across three experiments, young adult participants (n = 40 per experiment) studied objects in set sizes of two or six items, either sequentially (Experiments 1a and 1b) or simultaneously (Experiment 2). They then completed old/new recognition tests immediately after each sequence (WM tests). After a long study phase, participants completed LTM conjoint recognition tests, featuring old but untested items from the WM phase, lures that were similar to studied items at gist but not specific levels of representation, and new items unrelated to studied items at both specific and gist levels of representation. Results showed that LTM estimates of specific and gist memory representations from a multinomial-processing-tree model were reduced for items encoded under supra-capacity set sizes (six items) relative to within-capacity set sizes (two items). These results suggest that WM encoding capacity limitations constrain episodic LTM at both specific and gist levels of representation, at least for visual objects. The ability to retrieve from LTM each type of representation for a visual item is contingent on the degree to which the item could be encoded in WM.

A scientific theory of gist communication and misinformation resistance, with implications for health, education, and policy.

A framework is presented for understanding how misinformation shapes decision-making, which has cognitive representations of gist at its core. I discuss how the framework goes beyond prior work, and how it can be implemented so that valid scientific messages are more likely to be effective, remembered, and shared through social media, while misinformation is resisted. The distinction between mental representations of the rote facts of a message-its verbatim representation-and its gist explains several paradoxes, including the frequent disconnect between knowing facts and, yet, making decisions that seem contrary to those facts. Decision makers can falsely remember the gist as seen or heard even when they remember verbatim facts. Indeed, misinformation can be more compelling than information when it provides an interpretation of reality that makes better sense than the facts. Consequently, for many issues, scientific information and misinformation are in a battle for the gist. A fuzzy-processing preference for simple gist explains expectations for antibiotics, the spread of misinformation about vaccination, and responses to messages about global warming, nuclear proliferation, and natural disasters. The gist, which reflects knowledge and experience, induces emotions and brings to mind social values. However, changing mental representations is not sufficient by itself; gist representations must be connected to values. The policy choice is not simply between constraining behavior or persuasion-there is another option. Science communication needs to shift from an emphasis on disseminating rote facts to achieving insight, retaining its integrity but without shying away from emotions and values.

Pharmacokinetics and pharmacodynamic evaluation of hyaluronic acid-modified imatinib-loaded PEGylated liposomes in CD44-positive Gist882 tumor-bearing mice.

To develop a PEGylated and CD44-targeted liposomes, enabled by surface coating with hyaluronic acid (HA) via amide bond to improve the efficacy of imatinib mesylate (IM), for tumor-targeted cytoplasmic drug delivery. HA was covalently grafted on DSPE-PEG2000-NH2 polymer. HA-modified or unmodified PEGylated liposomes were prepared with ethanol injection method, and the stability, drug release, and cytotoxicity of these liposomes were studied. Meanwhile, intracellular drug delivery efficiency, antitumor efficacy, and pharmacokinetics were also investigated. Ex vivo fluorescence biodistribution was also detected by small animal imaging. In addition, endocytosis mechanism was also explored HA-coated PEGylated liposomes (137.5 nm ± 10.24) had a negative zeta potential (-29.3 mV ± 5.44) and high drug loading (27.8%, w/w). The liposomes were stable with cumulative drug leakage (<60%) under physiological conditions. Blank liposomes were nontoxic to Gist882 cells, and IM-loaded liposomes had higher cytotoxicity to Gist882 cells. HA-modified PEGylated liposomes were internalized more effectively than non-HA coating via CD44-mediated endocytosis. Besides, the cellular uptake of HA-modified liposomes also partly depends on caveolin-medicated endocytosis and micropinocytosis. In rats, both liposomes produced a prolonged half-life of IM (HA/Lp/IM: 14.97h; Lp/IM: 11.15h) by 3- to 4.5-folds compared with the IM solution (3.61h). HA-decorated PEGylated liposomes encapsulated IM exhibited strong inhibitory effect on tumor growth in Gist882 cell-bearing nude mice and formation of 2D/3D tumor spheroids. The Ki67 immunohistochemistry result was consistent with the above results. IM-loaded PEGylated liposomes modified with HA exerted the excellent anti-tumor effect on tumor-bearing mice and more drugs accumulated into the tumor site.

Short-term and long-term outcomes after robotic radical surgery for rectal gastrointestinal stromal tumor.

BACKGROUND: The optimal approach for ensuring both complete resection and preservation of anal function in rectal gastrointestinal stromal tumor (GIST) remains unknown. The aim of this study was to clarify short-term and long-term outcomes after robotic radical surgery for rectal GIST. METHODS: A total of 13 patients who underwent robotic radical surgery for rectal GIST between December 2011 and April 2022 were included. All robotic procedures were performed using a systematic approach. A supplemental video of robotic radical surgery for rectal GIST is attached. The short-term outcome was the incidence of postoperative complications during the first 30 days after surgery. Surgical outcomes were retrieved from a prospective database. Long-term outcomes, including overall survival and recurrence-free survival, were determined in all patients. RESULTS: Median distance from the tumor to the anal verge was 4.0 cm. Surgical margins were negative in all patients. Two patients underwent neoadjuvant imatinib therapy. All patients underwent sphincter-preserving surgery. None underwent conversion to open or laparoscopic surgery. The incidence of postoperative Clavien-Dindo grade II and grade ≥ III complications was 7.7% and 0%, respectively. The median postoperative hospital stay was 7 days. Twelve patients (92.3%) underwent stoma closure within 5 months of the initial surgery. Median follow-up time was 76 months. The 5-year overall survival and recurrence-free survival rates were both 100%. None of the patients had recurrence. CONCLUSION: Short-term and long-term outcomes after radical robotic surgery for rectal GIST were favorable. Robotic surgery might be a useful surgical approach for rectal GIST.