Comparison of propofol-esketamine versus propofol-sufentanil for deep sedation and analgesia in children with autism: A randomized double-blind clinical trial.

Propofol sedation, routinely used for endoscopic procedures, is safe and acceptable for children. Adjuvants, such as esketamine or sufentanil, are commonly added to improve the efficacy and safety of propofol sedation. This study aimed to compare the clinical efficacy and safety of propofol-esketamine (PE) versus propofol-sufentanil (PS) for deep sedation and analgesia in children with autism undergoing colonoscopy procedure. One hundred and twenty-four children with autism undergoing colonoscopy procedure were included in the study. Patients were randomly assigned to receive one of the two adjuvants: esketamine (0.3 mg/kg) or sufentanil (0.2 µg/kg), subsequently administered propofol 2.0 mg/kg to induce anesthesia. Additional doses of propofol (0.5-1.0 mg/kg) were administered as needed to ensure patient tolerance for the remaining duration of the procedure. Movement during the procedure, hemodynamic variables, the total dose of propofol, recovery time, and adverse events were recorded. The PE group exhibited a significantly lower incidence of severe movement during the procedure compared with the PS group (14.52% vs. 32.26%, p = 0.020). The PE group showed significantly lower incidence of respiratory depression, hypotension, and severe injection pain of propofol than the PS group during the procedure (all p < 0.05). The mean arterial pressure (MAP) decreased significantly after anesthesia induction in the PS group and remained lower than baseline (all p < 0.05). Compared with the combination of low-dose sufentanil (0.2 µg/mg) with propofol, the low-dose esketamine (0.3 mg/kg) combined with propofol provided more stable hemodynamics, higher quality of sedation, and fewer adverse events in children with autism undergoing colonoscopy procedure.

Enhanced Recovery After Surgery Management for Neonatal Congenital Malformations to Accelerate the Postoperative Recovery of Children.

Objective: The purpose of this study was to investigate the clinical benefits of implementing enhanced recovery after surgery (ERAS) protocols in managing congenital malformations in newborns. Methods: Sixty infants diagnosed with congenital malformations admitted to the Anqing Municipal Hospital between October 2020 and April 2022 were selected for this study. They were randomly assigned to either the observation group, receiving ERAS management, or the control group, receiving routine management, or the control group, receiving routine management. Each group consisted of 30 patients. Outcome measures included operative duration, intraoperative bleeding volume, intravenous nutrition maintenance duration, length of hospital stay, and hospital costs, complications, and readmission. Results: The duration of the procedure did not show any notable variances, and there were no reports of bleeding during or after surgery in relation to the operative time, intraoperative bleeding, postoperative complications, or readmission. The implementation of ERAS management resulted in notably shorter periods of intravenous nutrition maintenance and hospitalization and reduced costs compared to standard management. Furthermore, ERAS management resulted in significantly lower scores on the Modified Faces, Legs, Activity, Cry, and Consolability Scale at 2, 12, and 24 hours after surgery. However, this difference became insignificant after 48 hours. All study participants experienced elevated levels of cortisol and C-peptide following interventions, with lower levels observed in the observation group. Additionally, all study participants exhibited increased levels of susceptible C-reactive protein and interleukin (IL)-6 and decreased serum albumin levels after interventions, with lower serum IL-6 levels observed in the observation group. Conclusion: Implementing ERAS management for neonatal congenital malformations is safe and feasible, and it can potentially accelerate postoperative recovery in children. It shows promise for wider clinical adoption.

Washed microbiota transplantation for Crohn's disease: A metagenomic, metatranscriptomic, and metabolomic-based study.

BACKGROUND: Fecal microbiota transplantation (FMT) is a promising therapeutic approach for treating Crohn's disease (CD). The new method of FMT, based on the automatic washing process, was named as washed microbiota transplantation (WMT). Most existing studies have focused on observing the clinical phenomena. However, the mechanism of action of FMT for the effective management of CD-particularly in-depth multi-omics analysis involving the metagenome, metatranscriptome, and metabolome-has not yet been reported. AIM: To assess the efficacy of WMT for CD and explore alterations in the microbiome and metabolome in response to WMT. METHODS: We conducted a prospective, open-label, single-center clinical study. Eleven CD patients underwent WMT. Their clinical responses (defined as a decrease in their CD Activity Index score of > 100 points) and their microbiome (metagenome, metatranscriptome) and metabolome profiles were evaluated three months after the procedure. RESULTS: Seven of the 11 patients (63.6%) showed an optimal clinical response three months post-WMT. Gut microbiome diversity significantly increased after WMT, consistent with improved clinical symptoms. Comparison of the metagenome and metatranscriptome analyses revealed consistent alterations in certain strains, such as Faecalibacterium prausnitzii, Roseburia intestinalis, and Escherichia coli. In addition, metabolomics analyses demonstrated that CD patients had elevated levels of various amino acids before treatment compared to the donors. However, levels of vital amino acids that may be associated with disease progression (e.g., L-glutamic acid, gamma-glutamyl-leucine, and prolyl-glutamine) were reduced after WMT. CONCLUSION: WMT demonstrated therapeutic efficacy in CD treatment, likely due to the effective reconstruction of the patient's microbiome. Multi-omics techniques can effectively help decipher the potential mechanisms of WMT in treating CD.

Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models.

CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301's high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50 < 1.5 µM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD/CSF1Rmed) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1Rhi/wild-type FLT3) growth, likely due to the inhibition of CSF1R ("a putative driver"); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3/CSF1Rlo). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

Endoclip combined with colonic transendoscopic enteral tubing: a new approach for managing iatrogenic colonoscopy perforation.

BACKGROUND: Iatrogenic colonoscopy perforation (ICP) is a rare but most serious complication during colonoscopy investigation. However, endoscopic closure plays an important role in the dealing with ICP with the development of endoscopic techniques presently, there are still some portion of patients transferred to surgery. METHODS: Once a perforation was detected, endoclips were used to closed the defect of the colon. Then a colonic TET was planted inside the colon. The terminal end of the TET was put proximally to or near the location of the perforation. Then gas and fluid was sucked out through the TET with a syringe every 4 h. RESULTS: Three cases were treated with endoclip closure and colonic TET drainage. Case 1 was caused by urgent immediate perforation during routine colonoscopy, case 2 was delayed perforation after snare resection, and case 3 was ESD-related perforation. All patients got healed, no one transferred to surgery. CONCLUSIONS: A combination of endoclip closure and colonic TET drainage might be an easy and potential method in the dealing with different types of ICP. This study may offer a novel paradigm for addressing endoscopy-related intestinal perforations.

Radiation injury and gut microbiota-based treatment.

The exposure to either medical sources or accidental radiation can cause varying degrees of radiation injury (RI). RI is a common disease involving multiple human body parts and organs, yet effective treatments are currently limited. Accumulating evidence suggests gut microbiota are closely associated with the development and prevention of various RI. This article summarizes 10 common types of RI and their possible mechanisms. It also highlights the changes and potential microbiota-based treatments for RI, including probiotics, metabolites, and microbiota transplantation. Additionally, a 5P-Framework is proposed to provide a comprehensive strategy for managing RI.

Fecal microbiota transplantation through transendoscopic enteral tubing for inflammatory bowel disease: High acceptance and high satisfaction.

BACKGROUND AND AIM: Fecal microbiota transplantation (FMT) has been shown to positively affect the treatment of inflammatory bowel disease (IBD). However, the safety and efficacy of FMT may depend on the route of microbiota delivery. This study investigates the acceptance, satisfaction, and selection preference of a new delivery route, transendoscopic enteral tubing (TET), for treating IBD. METHODS: A survey was conducted among patients with IBD from five medical centers across China. The objective was to assess their acceptance, subjective feelings, and major concerns regarding two types of TET: colonic TET and mid-gut TET. In addition, the survey also analyzed the factors affecting the selection of TET and TET types among these patients. RESULTS: The final analysis included 351 questionnaires. Up to 76.6% of patients were willing to accept TET and preferred to choose colonic TET when they first learned about TET. Patients with longer disease duration, history of enema therapy, or enteral nutrition were more open to considering TET among IBD patients. After treatment, 95.6% of patients were satisfied with TET, including colonic TET (95.9%) and mid-gut TET (95.1%). Patients with a history of enema therapy and ulcerative colitis preferred colonic TET. In contrast, those with a history of enteral nutrition and Crohn's disease were willing to choose mid-gut TET. However, some patients hesitated to accept TET due to concerns about efficacy, safety, and cost. CONCLUSIONS: TET was highly accepted and satisfied patients with IBD. Disease type and combination therapy influenced the choice of colonic or mid-gut TET.

HX009, a novel BsAb dual targeting PD1 x CD47, demonstrates potent anti-lymphoma activity in preclinical models.

Both PD1/PD-L1 and CD47 blockades have demonstrated limited activity in most subtypes of NHL save NK/T-cell lymphoma. The hemotoxicity with anti-CD47 agents in the clinic has been speculated to account for their limitations. Herein we describe a first-in-class and rationally designed bispecific antibody (BsAb), HX009, targeting PD1 and CD47 but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD1 interaction, potentially reducing toxicity. In vitro characterization confirmed: (1) Both receptor binding/ligand blockade, with lowered CD47 affinity; (2) functional PD1/CD47 blockades by reporter assays; (3) T-cell activation in Staphylococcal-enterotoxin-B-pretreated PBMC and mixed-lymphocyte-reaction. In vivo modeling demonstrated antitumor activity in Raji-B and Karpass-229-T xenograft lymphomas. In the humanized mouse syngeneic A20 B-lymphoma (huCD47-A20) HuGEMM model, which has quadruple knocked-in hPD1xhPD-L1xhCD47xhSIRPα genes and an intact autologous immune-system, a contribution of effect is demonstrated for each targeted biologic (HX008 targeting PD1 and SIRPα-Fc targeting CD47), which is clearly augmented by the dual targeting with HX009. Lastly, the expression of the immune-checkpoints PD-L1/L2 and CD47 seemed co-regulated among a panel of lymphoma-derived-xenografts, where HX009 maybe more effective in those with upregulated CD47. Our data warrants HX009's further clinical development for treating NHLs.

Encyclopedia of fecal microbiota transplantation: a review of effectiveness in the treatment of 85 diseases.

ABSTRACT: Fecal microbiota transplantation (FMT) has been used as a core therapy for treating dysbiosis-related diseases by remodeling gut microbiota. The methodology and technology for improving FMT are stepping forward, mainly including washed microbiota transplantation (WMT), colonic transendoscopic enteral tubing (TET) for microbiota delivery, and purified Firmicutes spores from fecal matter. To improve the understanding of the clinical applications of FMT, we performed a systematic literature review on FMT published from 2011 to 2021. Here, we provided an overview of the reported clinical benefits of FMT, the methodology of processing FMT, the strategy of using FMT, and the regulations on FMT from a global perspective. A total of 782 studies were included for the final analysis. The present review profiled the effectiveness from all clinical FMT uses in 85 specific diseases as eight categories, including infections, gut diseases, microbiota-gut-liver axis, microbiota-gut-brain axis, metabolic diseases, oncology, hematological diseases, and other diseases. Although many further controlled trials will be needed, the dramatic increasing reports have shown the promising future of FMT for dysbiosis-related diseases in the gut or beyond the gut.

Instant messaging client gives the opportunity to recognize gut microbiota and dysbiosis-related disease: An investigation study on WeChat APP.

Objectives: Gut microbiota and dysbiosis are closely related to the occurrence and development of various diseases. It is necessary to popularize gut microbiota-related knowledge to the public. And the instant messaging client on smartphones supplies a perfect tool to achieve this goal. Hence, we will describe the current status of gut microbiota education spread by WeChat official accounts. Methods: The keywords of "gut microbiota," "fecal microbiota transplantation (FMT)," and "probiotics" were searched in the articles published from January 2015 to August 2020 on the WeChat official accounts. And the data were analyzed based on the 10 common gut dysbiosis-related diseases. Results: A total of 3061 WeChat official accounts have published 11,239 articles on gut microbiota dysbiosis-related diseases, with a rising trend in the total article numbers and the total pageviews. The keywords of "gut microbiota" dominate 50.61%, and the articles on inflammatory bowel disease had the largest proportion. Additionally, articles on the keyword "gut microbiota" also included cancer and obesity, articles on the keyword "FMT" mainly consist of Clostridium difficile infection and psychological disease, and the keyword "probiotics" was mainly related to obesity and irritable bowel syndrome disease. The top three total pageviews were on inflammatory bowel disease, obesity, and cancer. Conclusion: This study indicates the current research hotspots and public concerns on the gut microbiota, and WeChat as an instant messaging client plays an important role in promoting the scientific popularization of gut microbiota.

The Gut Microbiome and Sex Hormone-Related Diseases.

The role of the gut microbiome has been a hot topic in recent years. One aim of this review is to shed light on the crosstalk between sex hormones and the gut microbiome. Researchers have observed a sex bias of the composition of the gut microbiome in mice and have proved that sex differences influence the composition of the gut microbiome, although the influence is usually obscured by genetic variations. Via cell studies, animal studies and some observational studies in humans, researchers have confirmed that the gut microbiome can be shaped by the hormonal environment. On other hand, some theories suggest that the gut microbiota regulates the levels of sex hormones via interactions among its metabolites, the immune system, chronic inflammation and some nerve-endocrine axes, such as the gut-brain axis. In addition, bidirectional interactions between the microbiome and the hormonal system have also been observed, and the mechanisms of these interactions are being explored. We further describe the role of the gut microbiome in sex hormone-related diseases, such as ovarian cancer, postmenopausal osteoporosis (PMOP), polycystic ovary syndrome and type 1 diabetes. Among these diseases, PMOP is described in detail. Finally, we discuss the treatments of these diseases and the application prospects of microbial intervention.

Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor.

Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor" was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.

The potential of Akkermansia muciniphila in inflammatory bowel disease.

Akkermansia muciniphila is a next-generation probiotic with significant application prospects. The role of A. muciniphila in metabolic diseases and tumor immunotherapy has been widely recognized. Recent clinical trials further confirmed its safety and therapeutic value in human metabolic diseases. A. muciniphila also shows potential in the treatment of intestinal inflammatory diseases, especially for inflammatory bowel disease (IBD). The improvement in the efficacy of washed microbiota transplantation (WMT) in treating IBD is closely related to the increase in the abundance of A. muciniphila in patients' gut. However, there is still controversy regarding the pro-inflammatory or anti-inflammatory effect of A. muciniphila on IBD. Currently, several studies targeting the correlation between A. muciniphila and IBD have demonstrated opposite conclusions. Similarly, the interventional studies exploring causality between them also come to conflicting results. This article therefore aims to review the relationship between A. muciniphila and IBD, the effect of intervention of A. muciniphila on IBD, and the possible reasons for the contradictory role of A. muciniphila in the treatment of IBD. KEY POINTS: The effect of A. muciniphila on inflammatory bowel disease is controversy. A. muciniphila shows anti-inflammatory potential in IBD. The colitogenicity of A. muciniphila is context dependent.

Fecal Microbiota Transplantation is a Promising Switch Therapy for Patients with Prior Failure of Infliximab in Crohn's Disease.

Background: How to handle patients with anti-tumor necrosis factor (anti-TNF) failure was a common challenge to clinicians in Crohn's disease (CD). The present study is dedicated to clarifying whether fecal microbiota transplantation (FMT) could be a switch therapy for patients with prior failure of infiiximab (IFX) in CD in a long-term observation. Methods: Thirty-six patients with CD who had prior failure of IFX were recruited from January 2013 to December 2019. The "one-hour FMT protocol" was followed in all patients. All patients received the first course of FMT through gastroscopy or mid-gut transendoscopic enteral tubing. After April 2014, the methodology of FMT was coined as washed microbiota transplantation (WMT), substituting for the manual methods, which is dependent on the automatic microbiota purification system and the washing process. The primary endpoint of this study was the clinical remission at one month and one year after FMT. The secondary endpoint was the safety of FMT in the short and long term, and clinical factors as predictors for long-term efficacy of FMT. Clinical factors as independent predictors of efficacy from FMT were isolated using univariable and multivariable logistic regression analysis. Results: There was no significant difference in the rates of clinical response and remission between IFX treatment stage and FMT treatment stage (at one month, three months and six months after administration) (p > 0.05). Compared with those of 19 patients who achieved clinical remission at one month after FMT, the rates of clinical relapse were significantly higher in 18 patients who achieved clinical remission at one month after IFX [log-rank test p = 0.0009 HR = 3.081 (95% CI 1.43-6.639)]. Multivariate analysis revealed that the gender of donor (95% CI: 0.001-0.72; p = 0.031) was an independent predictor of efficacy at one year after FMT. No serious adverse events (AEs) associated with FMT were observed during and after FMT. The rate of AEs was significantly lower in group FMT than that in group IFX (p = 0.002). Conclusion: The present findings first time provided the evidence for clinicians to consider FMT into practice as an alternative switch therapy for patients with prior loss of response or intolerance to IFX in CD. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT01793831.

Impact of cap-assisted colonoscopy during transendoscopic enteral tubing: A randomized controlled trial.

BACKGROUND: Colonic transendoscopic enteral tubing (TET) requires double cecal intubation, raising a common concern of how to save cecal intubation time and make the tube stable. We hypothesized that cap-assisted colonoscopy (CC) might reduce the second cecal intubation time and bring potential benefits during the TET procedure. AIM: To investigate if CC can decrease the second cecal intubation time compared with regular colonoscopy (RC). METHODS: This prospective multicenter, randomized controlled trial was performed at four centers. Subjects ≥ 7 years needing colonic TET were recruited from August 2018 to January 2020. All subjects were randomly assigned to two groups. The primary outcome was the second cecal intubation time. Secondary outcomes included success rate, insertion pain score, single clip fixation time, purpose and retention time of TET tube, length of TET tube inserted into the colon, and all procedure-related (serious) adverse events. RESULTS: A total of 331 subjects were randomized to the RC (n = 165) or CC (n = 166) group. The median time of the second cecal intubation was significantly shorter for CC than RC (2.2 min vs 2.8 min, P < 0.001). In patients with constipation, the median time of second cecal intubation in the CC group (n = 50) was shorter than that in the RC group (n = 43) (2.6 min vs 3.8 min, P = 0.004). However, no difference was observed in the CC (n = 42) and RC (n = 46) groups of ulcerative colitis patients (2.0 min vs 2.5 min, P = 0.152). The insertion pain score during the procedure in CC (n = 14) was lower than that in RC (n = 19) in unsedated colonoscopy (3.8 ± 1.7 vs 5.4 ± 1.9; P = 0.015). Multivariate analysis revealed that only CC (odds ratio [OR]: 2.250, 95% confidence interval [CI]: 1.161-4.360; P = 0.016) was an independent factor affecting the second cecal intubation time in difficult colonoscopy. CC did not affect the colonic TET tube's retention time and length of the tube inserted into the colon. Moreover, multivariate analysis found that only endoscopic clip number (OR: 2.201, 95%CI: 1.541-3.143; P < 0.001) was an independent factor affecting the retention time. Multiple regression analysis showed that height (OR: 1.144, 95%CI: 1.027-1.275; P = 0.014) was the only independent factor influencing the length of TET tube inserted into the colon in adults. CONCLUSION: CC for colonic TET procedure is a safe and less painful technique, which can reduce cecal intubation time.

Cap-assisted endoscopic sclerotherapy for internal hemorrhoids: technique protocol and study design for a multi-center randomized controlled trial.

BACKGROUND: Cap-assisted endoscopic sclerotherapy is a new interventional therapy for internal hemorrhoids and rectal prolapse under colonoscopy. The proper length of the endoscopic injection needle is the core for performing cap-assisted endoscopic sclerotherapy well with more benefits and less complications. However, no data are currently available to guide endoscopists to consider the length of injection needle before cap-assisted endoscopic sclerotherapy. This study is designed to evaluate the efficacy and safety of cap-assisted endoscopic sclerotherapy with long or short injection needle in the treatment of internal hemorrhoids. METHODS: This is a nationwide multi-center, prospective, single-blind and randomized controlled trial. Patients with grade I-II internal hemorrhoids who have failed to conservative treatments and grade III internal hemorrhoids who are not suitable for surgery or refuse surgery will be included. Participants will be randomized 1:1 into either long or short injection needle group. The primary outcome is the recurrence rate of internal hemorrhoids 24 weeks after cap-assisted endoscopic sclerotherapy. The secondary outcomes are as follows: (1) symptom severity score, (2) three-level EuroQoL five dimensions health scale scores, (3) occurrence of adverse events and severe adverse events, and (4) patients' attitudes toward cap-assisted endoscopic sclerotherapy. Data collection will be conducted before and during operation, the 1st day, 1st week, 2nd week, and 24th week after cap-assisted endoscopic sclerotherapy. DISCUSSION: The outcome of this study is expected to provide a practical clinical protocol of cap-assisted endoscopic sclerotherapy for patients with internal hemorrhoids and promote the use of this new endoscopic technique. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03917056. Registered on 12 April 2019.

Colonic transendoscopic tube-delivered enteral therapy (with video): a prospective study.

BACKGROUND: Colonic transendoscopic enteral tubing (TET) refers to colonic transendoscopic tube-delivered enteral therapy. Colonic TET has been successfully used for frequent colonic administration of drugs or multiple fecal microbiota transplantations (FMTs). This prospective observational study aimed to evaluate possible factors affecting methodology, feasibility and safety of colonic TET. METHODS: Patients who underwent colonic TET at our center from October 2014 to November 2018 were included. The feasibility, efficacy, and safety of TET were evaluated. RESULTS: In total, 224 patients were analyzed. The success rate of TET was 100%. The median retention time of TET tube within the colonic lumen was 8.5 (IQR 7-11) days in 158 patients with tube falling out spontaneously, and the maximum retention time was up to 28 days. These patients were divided into the short-retention group (≤ 8.5 days) and the long-retention group (> 8.5 days). Univariate and multivariate analysis demonstrated that the type of endoscopic clip (p = 0.001) was an independent factor for the retention time. The larger clips as well as a greater number of clips significantly affected the retention time (p = 0.013). No severe adverse event was observed during and after TET. CONCLUSIONS: Colonic TET is a feasible, practical, and safe colon-targeted drug delivery technique with a high degree of patients' satisfaction. Two to four large endoscopic clips are recommended to maintain stability of the TET tube within the colon for over 7 days.

HX008: a humanized PD-1 blocking antibody with potent antitumor activity and superior pharmacologic properties.

Through reactivating tumor-infiltrating lymphocytes, therapeutics targeting programmed cell death protein 1 (PD-1) demonstrate impressive clinical efficacy in the treatment of multiple cancers. In this report, we characterize HX008, a humanized IgG4S228P anti-PD-1 monoclonal antibody with an engineered Fc domain, in a series of in vitro assays and in vivo studies. In vitro, HX008 binds to human PD-1 with high affinity and potently suppresses the interaction of PD-1 with PD-L1 and PD-L2. The lack of detectable binding to complement C1q and Fc gamma receptor III-a (FcγRIIIa) suggested that HX008 maintained reduced antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. A comparable enhancement of cytokine production and NFAT-driven luciferase expression in cell-based assays confirmed that HX008 could promote T-cell function as effectively as Nivolumab. In vivo antitumor activity studies were carried out within two special tumor models: 1) the MiXeno model with an adoptive transfer of human peripheral blood mononuclear cells into HCC827 xenograft mice; and 2) HuGEMM with human PD-1 gene knock-in syngeneic MC38-bearing mice. In both models, HX008 significantly inhibits tumor growth and shows an effective antitumor response comparable to approved anti-PD-1 drugs. Furthermore, in a pharmacokinetics study performed in cynomolgus monkeys, HX008 induced no immune-related adverse events when administered at 10 mg/kg. Although some anti-drug antibody effects were observed in the primate PK study, the safety and favorable pharmacokinetics demonstrated in human clinical trials validate HX008 as a suitable candidate for cancer immunotherapy. Taken together, our studies provide a fairly thorough characterization of HX008 and strong support for its further clinical research and application.