A molecular subtyping associated with the cGAS-STING pathway provides novel perspectives on the treatment of ulcerative colitis.

Ulcerative colitis (UC) is characterized by an abnormal immune response, and the pathogenesis lacks clear understanding. The cGAS-STING pathway is an innate immune signaling pathway that plays a significant role in various pathophysiological processes. However, the role of the cGAS-STING pathway in UC remains largely unclear. In this study, we obtained transcriptome sequencing data from multiple publicly available databases. cGAS-STING related genes were obtained through literature search, and differentially expressed genes (DEGs) were analyzed using R package limma. Hub genes were identified through protein-protein interaction (PPI) network analysis and module construction. The ConsensuClusterPlus package was utilized to identify molecular subtypes based on hub genes. The therapeutic response, immune microenvironment, and biological pathways of subtypes were further investigated. A total of 18 DEGs were found in UC patients. We further identified IFI16, MB21D1 (CGAS), TMEM173 (STING) and TBK1 as the hub genes. These genes are highly expressed in UC. IFI16 exhibited the highest diagnostic value and predictive value for response to anti-TNF therapy. The expression level of IFI16 was higher in non-responders to anti-TNF therapy. Furthermore, a cluster analysis based on genes related to the cGAS-STING pathway revealed that patients with higher gene expression exhibited elevated immune burden and inflammation levels. This study is a pioneering analysis of cGAS-STING pathway-related genes in UC. These findings provide new insights for the diagnosis of UC and the prediction of therapeutic response.

All-in-one nanotheranostic platform based on tumor microenvironment: new strategies in multimodal imaging and therapeutic protocol.

Conventional tumor diagnosis and treatment approaches have significant limitations in clinical application, whereas personalized theranostistic nanoplatforms can ensure advanced diagnosis, precise treatment, and even a good prognosis in cancer. Tumor microenvironment (TME)-targeted therapeutic strategies offer absolute advantages in all aspects compared to tumor cell-targeted therapeutic strategies. It is essential to create a TME-responsive all-in-one nanotheranostic platform to facilitate individualized tumor treatment. Based on the TME-responsive multifunctional nanotheranostic platform, we focus on the combined use of multimodal imaging and therapeutic protocols and summary and outlooks on the latest advanced nanomaterials and structures for creating the integrated nanotheranostic system based on material science, which provide insights and reflections on the development of innovative TME-targeting tools for cancer theranostics.

Novel multi-target angiogenesis inhibitors as potential anticancer agents: Design, synthesis and preliminary activity evaluation.

Based on the crucial role of histone deacetylase (HDAC) and receptor tyrosine kinase in angiogenesis, in situ assembly, skeletal transition, molecular hybridization, and pharmacophore fusion were employed to yield seventy-six multi-target angiogenesis inhibitors. Biological evaluation indicated that most of the compounds exhibited potent proliferation inhibitory activity on MCF-7 cells, with the TH series having the highest inhibitory activity on MCF-7 cells. In addition, the IC50 values of TA11 and TH3 against HT-29 cellswere 0.078 µmol/L and 0.068 µmol/L, respectively. The cytotoxicity evaluation indicated that TC9, TA11, TM4, and TH3 displayed good safety against HEK293T cells. TH2 and TH3 could induce apoptosis of MCF-7 cells. Molecular modeling and ADMET prediction results indicated that most of target compounds showed promising medicinal properties, which was consistent with the experimental results. Our findings provided new lead compounds for the structural optimization of multi-target angiogenesis inhibitors.

Transmembrane modification of tumor vascular targeting peptide A7R as molecular cargo delivery tool.

In recent years, targeting tumor angiogenesis has emerged as a prominent research focus in the treatment and prevention of tumor expansion. A7R (ATWLPPR) exhibits high affinity and specificity for VEGFR-2, which is overexpressed in various tumors. To enhance the tumor tissue and cell penetration capabilities of A7R, we substituted its non-critical amino acid with Arginine (R) and Glutamic acid (E), cyclized the mutant peptide, and linked it to the membrane permeation sequence using coordination principles. We designed and synthesized fifteen novel penetrating peptides that target tumor blood vessels and cells, followed by conducting various biological evaluations and cell imaging experiments. The results demonstrated that Cyclo-A7R-RRR and A7R-RLLRLLR exhibited excellent permeability towards tumor cells, with Cyclo-A7R-RRR showing superior serum stability compared to A7R. Furthermore, the modified peptides showed no toxicity towards HeLa cells, U251 cells, HuH-7 cells, and HEK293 cells under 10 µmol/L. Utilizing Cyclo-A7R-RRR or A7R-RLLRLLR for transmembrane delivery of drug molecules could significantly improve their efficacy. Our findings broaden the potential application scenarios of A7R in targeted tumor angiogenesis.

An ambulatory dental treatment of a child with Rett syndrome and limited mouth opening under muscle relaxant-free general anesthesia: a case report.

BACKGROUND: Rett Syndrome (RTT) is a rare, severe, and progressive developmental disorder with intellectual disability. Anesthesia in RTT patients presents a range of challenges. We report a child with RTT who received dental treatment under muscle relaxant-free general anesthesia in our ambulatory center. CASE PRESENTATION: A 15-year-old girl with RTT was admitted to our dental clinic with multiple dental caries and residual roots. Dental treatment was scheduled under ambulatory general anesthesia. After anesthesia induction, a nasal tube was initiated under the guidance of a fiberoptic bronchoscope. Multimodal analgesia, body temperature monitoring, and postoperative nausea and vomiting prevention were applied. No muscle relaxants were used throughout the process. The endotracheal tube was successfully removed after the operation and the patient was discharged home the same day. CONCLUSION: An individualized anesthesia strategy enabled a quick and safe recovery for this RTT patient after dental treatment under muscle relaxant-free general anesthesia.

A patent perspective of antiangiogenic agents.

INTRODUCTION: Angiogenesis plays a crucial role in the development of numerous vascular structures and is involved in a variety of physiologic and pathologic processes, including psoriasis, diabetic retinopathy, and especially cancer. By obstructing the process of angiogenesis, these therapies effectively inhibit the progression of the disease. Consequently, anti-angiogenic agents were subsequently developed. AREAS COVERED: This review provides a comprehensive summary of the anti-angiogenic inhibitors developed in the past five years in terms of chemical structure, biochemical/pharmacological activity and potential clinical applications. A literature search was conducted using utilizing the databases Web of Science, SciFinder and PubMed with the key word 'anti-angiogenic agents' and 'angiogenesis inhibitor.' EXPERT OPINION: This is despite the fact that the concept of antiangiogenesis has been proposed for more than 50 years and angiogenesis inhibitors are extensively employed in clinical practice. However, significant challenges continue to confront them. In recent years, there has been a significant increase in the number of patents focusing on angiogenesis inhibitors. These patents aim to enhance the selectivity of drugs against VEGF/VEGFR, explore new targets to overcome drug resistance, and explore potential drug combinations, thereby expanding the therapeutic possibilities in this field.

Pyroptosis burden is associated with anti-TNF treatment outcome in inflammatory bowel disease: new insights from bioinformatics analysis.

Biological agents known as anti-tumor necrosis factor (TNF) drugs are frequently utilized in the treatment of inflammatory bowel disease (IBD). In this study, we analyzed the shared processes of pyroptosis in Ulcerative colitis (UC) and Crohn's disease (CD), as well as explored the correlation between the burden of pyroptosis and the results of anti-TNF treatment based on bioinformatics analyses. We identified CAPS1, CASP5, GSDMD, AIM2, and NLRP3 as the hub genes, with AIM2 being the most effective indicator for predicting the response to anti-TNF therapy. We also noticed that non-responders received anti-TNF therapy exhibited elevated AIM2 protein expression. Subsequently, we conducted a cluster analysis based on AIM2-inflammasome-related genes and discovered that patients with a higher burden of AIM2 inflammasome displayed stronger immune function and a poor response to anti-TNF therapy. Overall, our study elucidates the pathway of pyroptosis in IBD and reveals AIM2 expression level as a potential biomarker for predicting the effectiveness of anti-TNF therapy.

Giant calcifying epithelial odontogenic tumor after I-125 seed implantation: A case report.

Calcifying Epithelial Odontogenic Tumor (CEOT), also known as Pindborg tumor, is a rare odontogenic benign tumor. It was first reported by Thoma and Goldman in 1946 and defined as an independent tumor by Pindborg in 1957. Herein, we reported a CEOT case involving most of the mandible after I-125 implantation in a 53-year-old man. We cooperated with governmental and hospital departments to resect the tumors, reconstruct the mandible with a fibular flap graft, and properly dispose of the radioactive particles.

Response of nitrite accumulation to elevated C/NO- 3-N ratio during partial denitrification process: Insights of extracellular polymeric substance, microbial community and metabolic function.

This study investigated the response of nitrite accumulation to elevated COD/NO3--N ratio (C/N) during partial denitrification (PD). Results indicated nitrite was gradually accumulated and remained stable (C/N = 1.5 âˆ¼ 3.0), while that rapidly declined after reaching the peak (C/N = 4.0 âˆ¼ 5.0). The polysaccharide (PS) and protein (PN) content of tightly-bound extracellular polymeric substances (TB-EPS) reached the maximum at C/N of 2.5 âˆ¼ 3.0, which might be stimulated by high level of nitrite. Illumina MiSeq sequencing showed Thauera and OLB8 were dominated denitrifying genera at C/N of 1.5 âˆ¼ 3.0, while Thauera was further enriched with fading OLB8 at C/N of 4.0 âˆ¼ 5.0. Meanwhile, the highly-enriched Thauera might enhance the activity of nitrite reductase (nirK) promoting further nitrite reduction. Redundancy analysis (RDA) showed positive correlations between nitrite production and PN content of TB-EPS, denitrifying bacteria (Thauera and OLB8) and nitrate reductases (narG/H/I) in low C/N. Finally, their synergistic effects for driving nitrite accumulation were comprehensively elucidated.

Discovery of novel antibody-drug conjugates bearing tissue protease specific linker with both anti-angiogenic and strong cytotoxic effects.

Bevacizumab is an FDA-approved class of monoclonal antibodies used to inhibit angiogenesis and promote normalization of blood vessels. It is usually combined with chemotherapeutic agents to treat a variety of solid tumors. However, the whole-body toxicities and toxicity associated with chemotherapy greatly limit the clinical use of this combination therapy. Antibody-drug conjugates (ADCs) couple monoclonal antibodies to cytotoxic molecules via a linker, utilizing the high specificity of monoclonal antibodies to tumor surface antigens to act as a "biological missile" to deliver chemotherapeutic drugs to the tumor site. Herein, we designed a bevacizumab-based ADC, Bevacizumab Vedotin, conjugating bevacizumab to the microtubulin inhibitor MMAE via a tissue protease-specific linker. Biological studies showed strong stability and good tumor cell targeting of our constructed ADCs; rapid drug release was achieved in the presence of exogenous histone protease B. In addition, Bevacizumab Vedotin exhibited good anti-proliferative, apoptosis-promoting and cell cycle-stalling effects on glioma (U87), hepatocellular carcinoma (HepG2), and breast cancer (MCF-7) cell lines. Further in vitro assays demonstrated the enhanced anti-migration activity against MCF-7, potent anti-angiogenic effects, and blockade of the VEGF/VEGFR pathway of Bevacizumab Vedotin.

Discovery of intracellular self-assembly protein degraders driven by tumor-specific activatable bioorthogonal reaction.

Proteolysis Targeting Chimera (PROTAC) is a type of bifunctional chimeric molecule that can directly degrade the binding proteins through the ubiquitin-proteasome pathway. PROTAC has shown great potential in overcoming drug resistance and targeting undruggable targets. However, there are still many shortcomings that need to be solved urgently, including worse membrane permeability and bioavailability induced by their large molecular weight. Herein, we used intracellular self-assembly strategy to construct tumor-specific PROTACs via small molecular precursors. We developed two types of precursors incorporated with azide and alkyne as biorthogonal groups, respectively. These small precursors with improved membrane permeability could react facilely with each other under the catalysis of copper ions with high concentration in tumor tissues, affording novel PROTACs. These novel intracellular self-assembled PROTACs could effectly induce degradation of VEGFR-2 and EphB4 in U87 cells. Meanwhile, they could also promote apoptosis and block cells in S phase. These tumor-specific intracellular self-assembled PROTACs exhibited high selectivity due to the high concentration of copper content in tumor tissue. Moreover, this new strategy could reduce the molecular weight of PROTACs, as well as improve the membrane permeability. These results will greatly expand the applications of bioorthogonal reaction in discovery of novel PROTACs.

Characteristics and Risk Factors of Ultra-High-Risk Patients with Newly Diagnosed Multiple Myeloma.

OBJECTIVE: To investigate the clinical characteristics and risk factors of ultra-high-risk (UHR) patients with newly diagnosed multiple myeloma (MM). METHODS: We screened UHR patients with a survival of less than 24 months and we selected patients with a concurrent survival of more than 24 months as a control group. We retrospectively analyzed the clinical characteristics of UHR patients with newly diagnosed MM and screened related risk factors. RESULTS: In total we analyzed 477 patients, which included 121 (25.4%) UHR patients and 356 (74.6%) control patients. Median overall survival (OS) and progression-free survival (PFS) of UHR patients was 10.5 months (7.5-13.5 months) and 6.3 months (5.4-7.2 months), respectively. Univariate logistic regression analysis showed that age > 65 years, hemoglobin (HGB) < 100 g/L, lactate dehydrogenase (LDH) > 250 U/L, serum creatinine (SCr) > 2 mg/dL, corrected serum calcium (CsCa) > 2.75 mmol/L, B-type natriuretic peptide (BNP) or N-terminal prohormone BNP (NT-proBNP) > 2 upper limit of normal (ULN), high-risk cytogenetics, Barthel index score, and International Staging System (ISS) stage III were associated with UHR MM. In a multivariate analysis, age > 65 years, LDH > 250 U/L, CsCa > 2.75 mmol/L, BNP or NT-proBNP > 2 ULN, high-risk cytogenetics, and Barthel index score were independent risk factors for UHR MM. Moreover, UHR patients had a worse response rate than control patients. CONCLUSION: Our study highlighted the characteristics of UHR MM patients and suggested that the combination of organ insufficiency and highly malignant myeloma cells resulted in poor outcomes of patients with UHR MM.

Prognostic nomogram for multiple myeloma early relapse after autologous stem cell transplant in the novel agent era.

BACKGROUND: The present study intended to establish a predictive nomogram for early relapse (ER) (<12 months) after autologous stem cell transplantation (ASCT) in the novel drug era for multiple myeloma (MM). PATIENTS AND METHODS: The nomogram was designed and constructed to a retrospective clinical data of newly diagnosed MM patients received novel agent induction therapy and subsequent ASCT at three centers in China from July 2007 to December 2018. The retrospective study was conducted among 294 patients in the training cohort and 126 in the validation cohort. The nomogram's predictive accuracy was evaluated by the concordance index, calibration curve and decision clinical curve. RESULTS: The study cohort included 420 newly diagnosed MM patients, and 100 (23.8%) were identified as having ER, including 74 in the training cohort and 26 in the validation cohort. According to the result of multivariate regression in the training cohort, the prognostic variables included in the nomogram were high-risk cytogenetics, LDH > UNL, and response less than very good partial response (VGPR) after ASCT. The calibration curve showed good fitness between the nomogram predictions and the actual observations and the nomogram was further validated by a clinical decision curve. The nomogram's C-index achieved 0.75 (95% CI, 0.70-0.80), which was higher than that of the Revised International Staging System (R-ISS) (0.62), ISS (0.59), and Durie-Salmon (DS) staging system (0.52). The discrimination ability of the nomogram in the validation cohort was superior to that of the other staging systems (C-index: 0.73 vs. R-ISS (0.54), ISS (0.55), and DS staging system (0.53)). DCA showed the prediction nomogram adds much more clinical utility. Different scores of the nomogram draw a distinction of OS. CONCLUSION: The present nomogram could serve as a feasible and accurate prediction of ER in novel drug induction transplantation-eligible MM patients, which could help modify the post-ASCT strategy for patients at high risk of ER.

Discovery of novel protein degraders based on bioorthogonal reaction-driven intracellular self-assembly strategy.

Proteolysis targeting chimera (PROTAC) is a promising therapeutic modality capable of degrading undruggable proteins and overcoming the shortcomings of traditional inhibitors. However, the molecular weight and pharmaceutical properties of PROTACs fall outside of a reasonable range. To overcome the inherent poor druggability of PROTACs, an intracellular self-assembly strategy based on bio-orthogonal reaction was proposed and applied in this study. Herein, two novel classes of intracellular precursors that can self-assemble into protein degraders through bio-orthogonal reactions were explored, including a novel class of E3 ubiquitin ligase ligands bearing tetrazine (E3L-Tz) and target protein ligands incorporated with norbornene (TPL-Nb). These two types of precursors could spontaneously undergo bio-orthogonal reactions in living cells, affording novel PROTACs. Among these precursors, the biological activities of PROTACs formed by target protein ligand with norbornene group (S4N-1) were more potent than others and degrade VEGFR-2, PDGFR-ß and EphB4. The results demonstrated that a highly specific bio-orthogonal reaction driven intracellular self-assembly strategy in living cells could be utilized to improve the degradation activity of PROTACs.

Large-scale phage cultivation for commensal human gut bacteria.

Phages are highly abundant in the human gut, yet most of them remain uncultured. Here, we present a gut phage isolate collection (GPIC) containing 209 phages for 42 commensal human gut bacterial species. Genome analysis of the phages identified 34 undescribed genera. We discovered 22 phages from the Salasmaviridae family that have small genomes (∼10-20 kbp) and infect Gram-positive bacteria. Two phages from a candidate family, Paboviridae, with high prevalence in the human gut were also identified. Infection assays showed that Bacteroides and Parabacteroides phages are specific to a bacterial species, and strains of the same species also exhibit substantial variations in phage susceptibility. A cocktail of 8 phages with a broad host range for Bacteroides fragilis strains effectively reduced their abundance in complex host-derived communities in vitro. Our study expands the diversity of cultured human gut bacterial phages and provides a valuable resource for human microbiome engineering.

Discovery of novel PROTACs based on multi-targeted angiogenesis inhibitors.

Anti-angiogenesis has been proved to be an effective strategy for the treatment of tumors. Anti-angiogenic drugs had achieved certain therapeutic effects. However, drug resistance also gradually emerged and limited the application of angiogenesis inhibitors. Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules capable of degrading proteins through the ubiquitin-proteasome system (UPS). Compared with traditional inhibitors, they displayed advantages of less dosage, lower toxicity and less resistance. In this study, we designed and synthesized a series of novel PROTACs based on our recently reported multi-targeted angiogenesis inhibitor S5. Preliminary biological evaluation of title PROTACs was carried out in various cell lines. The results indicated that these novel bifunctional PROTACs displayed potential in degrading BRAF protein. Their degradation mechanism showed that the degradation of BRAF by PROTAC-1 was dependent on binding to target proteins and E3 ubiquitin ligase. Our findings provided further evidence that these novel PROTACs could be considered in further application in overcome of clinical resistance of traditional angiogenesis inhibitors.

[Clinical study of bilateral axillo-breast approach robot in obese women with thyroid cancer].

Objective:To explore the safety and feasibility of bilateral axillo-breast approach （BABA） robot in the operation of thyroid cancer in obese women. Methods:The clinical data of 81 obese female patients who underwent da Vinci robotic thyroid cancer surgery（robotic group） at the Department of Thyroid and Breast Surgery, PLA 960 Hospital from May 2018 to December 2021 were retrospectively analyzed and compared with the clinical data of 106 obese female thyroid cancer patients who underwent open surgery（open group） during the same period. The age, body mass index（BMI）, mean time of surgery, mean postoperative drainage, tumor diameter, postoperative tumor stage, number of lymph node dissection in the central and lateral cervical regions, number of positive lymph nodes in the central and lateral cervical regions, postoperative cosmetic outcome satisfaction score, mean postoperative hospital stay and postoperative complications of all patients were counted. The results were analyzed using SPSS 26.0 statistical software, and the count data were compared using the χ² test, and the measurement data were compared using the t test. Results:All patients completed the operation successfully, and there was no conversion in the robot group, postoperative pathological results were all composed of papillary thyroid carcinoma. The operation time in the robot group was（144.62±36.38） min, which was longer than that in the open group（117.06±18.72） min（P<0.05）. The average age of the robot group was（40.25±9.27） years, which was lower than that of the open group（49.59±8.70） years（P<0.05）. The satisfactory score of cosmetic effect in the robot group（9.44±0.65） was higher than that in the open group（5.23±1.07）（P<0.05）. There was no significant difference in tumor diameter, BMI, average postoperative drainage, temporary hypoparathyroidism and recurrent laryngeal nerve injury, number of central and lateral cervical lymph node dissection, number of positive lymph nodes in the central and lateral cervical regions, and average postoperative hospital stay between the two groups. There was no permanent hypoparathyroidism and recurrent laryngeal nerve injury in both groups. Conclusion:The application of BABA pathway robot in thyroid cancer surgery in obese women is safe and feasible, and the cosmetic effect is better after operation.

Advanced nitrogen removal from low carbon nitrogen ratio domestic sewage via continuous plug-flow anaerobic/oxic/anoxic system: Enhanced by endogenous denitrification.

An anaerobic/oxic/anoxic continuous plug-flow biorereactor was established to derive stable advanced nitrogen removal of oligotrophic domestic wastewater by setting a sludge dual-reflux system and a mixed liquid cross-flow system, while extending the hydraulic retention time in anoxic section. The effluent total inorganic nitrogen was 7.9 ± 2.2 mg N/L, with removal efficiency of 84 ± 3.9%. Results of nitrogen balance calculations indicated that the contribution of simultaneous nitrification and denitrification to total inorganic nitrogen loss in oxic region was 15% during stable stage, and the total inorganic nitrogen removal by endogenous-denitrification and enhanced exogenous-denitrification in the anoxic region was 39.9%. Prolongation of hydraulic retention time in anoxic segment is the critical reason for enhancing endogenous-denitrification, and cross-flow system is an important measure to improve exogenous-denitrification. This study provides new insights into bridging the gap between energy-saving and high-level nitrogen removal from municipal wastewater with low carbon to nitrogen ratios.

Design, synthesis and bioactivity evaluation of self-assembled PROTACs based on multi-target kinase inhibitors.

Proteolysis targeting chimera (PROTAC) is a heterobifunctional molecule with enormous potential for its ability to overcome the limitations of traditional inhibitors. However, its inherent disadvantages have been increasingly revealed, such as poor cell permeability caused by large molecule weight. Herein, to overcome the inherent shortcomings, intracellular self-assembly was proposed based on bioorthogonal reaction and molecular fragments, affording a novel type of self-assembled PROTACs. Two types of precursors incorporated with tetrazine and norbornene as bioorthogonal groups were designed and synthesized, and they could subsequently be conjugated in cells to generate novel PROTACs. Fortunately, ultrafast HRMS and HPLC assays indicated that self-assembled PROTACs driven by the bio-orthogonal reaction were detected in living U87 cells. Biological evaluation suggested that the precursor molecule LN-1 could degrade PDGFR-ß protein in a concentration-dependent manner, while cancer cells were co-treated with another precursor molecule, TzB. Our findings verified the feasibility of a self-assembly strategy in future development of novel PROTACs.

Impact of Gamification on Consumers' Favorability in Cause-Related Marketing Programs: Between-Subjects Experiments.

BACKGROUND: Successful cause-related marketing (CRM) campaigns can help companies stand out from their competitors; however, CRM may not have pleasant outcomes, even if it receives substantial investment. OBJECTIVE: This research aimed to investigate how gamified CRM projects influence consumers' favorability. METHODS: We introduced 3 different CRM projects in 3 different studies. Every project had 2 versions according to the level of gamification, and participants were randomly assigned into these 2 groups. Additionally, we used a 2 (gamification: lower, higher) 2 (rules presentation: without visual cues, with visual cues) between-subjects design to test the moderation role of rules presentation in gamified CRM projects. RESULTS: In Study 1, we identified that the highly gamified CRM program induces more enjoyment (F1,139=21.11, P<.001) and higher favorability (F1,139=14.57, P<.001). Moreover, we found that enjoyment played a mediation role between gamification and favorability (P<.001) in Study 2. In addition, the results of Study 3 indicated rules presentation in a gamified CRM program can moderate the indirect effect of gamification on favorability via enjoyment (index of the moderated mediation: 95% CI -1.12 to -0.10; for rules presentation with visual cues: 95% CI 0.69 to 1.40; for rules presentation without visual cues: 95% CI 0.08 to 0.83). CONCLUSIONS: Overall, this research contributes to the CRM literature and suggests gamification is an effective way of managing CRM campaigns.