Leaky gut, circulating immune complexes, arthralgia, and arthritis in IBD: coincidence or inevitability?

Most host-microbiota interactions occur within the intestinal barrier, which is essential for separating the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. Gut inflammation allows pathogenic bacteria to enter the blood stream, forming immune complexes which may deposit on organs. Despite increased circulating immune complexes (CICs) in patients with inflammatory bowel disease (IBD) and discussions among IBD experts regarding their potential pathogenic role in extra-intestinal manifestations, this phenomenon is overlooked because definitive evidence demonstrating CIC-induced extra-intestinal manifestations in IBD animal models is lacking. However, clinical observations of elevated CICs in newly diagnosed, untreated patients with IBD have reignited research into their potential pathogenic implications. Musculoskeletal symptoms are the most prevalent extra-intestinal IBD manifestations. CICs are pivotal in various arthritis forms, including reactive, rheumatoid, and Lyme arthritis and systemic lupus erythematosus. Research indicates that intestinal barrier restoration during the pre-phase of arthritis could inhibit arthritis development. In the absence of animal models supporting extra-intestinal IBD manifestations, this paper aims to comprehensively explore the relationship between CICs and arthritis onset via a multifaceted analysis to offer a fresh perspective for further investigation and provide novel insights into the interplay between CICs and arthritis development in IBD.

Integrative Multi-omics Analysis Identifies Genetic Variants Contributing to Non-syndromic Cleft Lip with or without Cleft Palate.

OBJECTIVE: To provide novel insights into the aetiology of non-syndromic cleft lip with or without cleft palate (NSCL/P) by integrating multi-omics data and exploring susceptibility genes associated with NSCL/P. METHODS: A two-stage genome-wide association study (GWAS) of NSCL/P was performed, involving a total of 1,069 cases and 1,724 controls. Using promoter capture Hi-C (pCHi-C) datasets in human embryonic stem cells (hESC) and chromatin immunoprecipitation sequencing (ChIP-seq) in craniofacial tissues, we filtered out single nucleotide polymorphisms (SNPs) with active cis-regulation and their target genes. Additionally, we employed expression quantitative trait loci (eQTL) analysis to identify candidate genes. RESULTS: Thirteen SNPs were identified as cis-regulation units associated with the risk of NSCL/P. Five of these were proven to be active in chromatin states in early human craniofacial development (rs7218002: odds ratio [OR] 1.50, P = 8.14E-08; rs835367: OR 0.78, P = 3.48E- 05; rs77022994: OR 0.55, P = 1.05E-04; rs961470: OR 0.73, P = 1.38E-04; rs17314727: OR 0.73, P = 1.85E-04). Additionally, pCHi-C and eQTL analysis prioritised three candidate genes (rs7218002: NTN1, rs835367: FGGY, LINC01135). NTN1 and FGGY were expressed in mouse orofacial development. Deficiencies in NTN1, FGGY and LINC01135 were associated with cleft palate and cleft lip, abnormal facial shape and bifid uvula, and abnormality of the face, respectively. CONCLUSION: Our study identified five SNPs (rs7218002, rs835367, rs77022994, rs961470 and rs17314727) and three susceptibility genes (NTN1, FGGY and LINC01135) associated with NSCL/P. These findings contribute to a better understanding of the genetic factors involved.

Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment.

BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

Engineering Escherichia coli for high-yielding 2,5-Dimethylpyrazine synthesis from L-Threonine by reconstructing metabolic pathways and enhancing cofactors regeneration.

2,5-Dimethylpyrazine (2,5-DMP) is important pharmaceutical raw material and food flavoring agent. Recently, engineering microbes to produce 2,5-DMP has become an attractive alternative to chemical synthesis approach. In this study, metabolic engineering strategies were used to optimize the modified Escherichia coli BL21 (DE3) strain for efficient synthesis of 2,5-DMP using L-threonine dehydrogenase (EcTDH) from Escherichia coli BL21, NADH oxidase (EhNOX) from Enterococcus hirae, aminoacetone oxidase (ScAAO) from Streptococcus cristatus and L-threonine transporter protein (EcSstT) from Escherichia coli BL21, respectively. We further optimized the reaction conditions for synthesizing 2,5-DMP. In optimized conditions, the modified strain can convert L-threonine to obtain 2,5-DMP with a yield of 2897.30 mg/L. Therefore, the strategies used in this study contribute to the development of high-level cell factories for 2,5-DMP.

GDPF: a data resource for the distribution of prokaryotic protein families across the global biosphere.

Microorganisms encode most of the functions of life on Earth. However, conventional research has primarily focused on specific environments such as humans, soil and oceans, leaving the distribution of functional families throughout the global biosphere poorly comprehended. Here, we present the database of the global distribution of prokaryotic protein families (GDPF, http://bioinfo.qd.sdu.edu.cn/GDPF/), a data resource on the distribution of functional families across the global biosphere. GDPF provides global distribution information for 36 334 protein families, 19 734 superfamilies and 12 089 KEGG (Kyoto Encyclopedia of Genes and Genomes) orthologs from multiple source databases, covering typical environments such as soil, oceans, animals, plants and sediments. Users can browse, search and download the distribution data of each entry in 10 000 global microbial communities, as well as conduct comparative analysis of distribution disparities among multiple entries across various environments. The GDPF data resource contributes to uncovering the geographical distribution patterns, key influencing factors and macroecological principles of microbial functions at a global level, thereby promoting research in Earth ecology and human health.

Discordant patterns between nitrogen-cycling functional traits and taxa in distant coastal sediments reveal important community assembly mechanisms.

A central question in microbial ecology is how immense microbes are assembled in changing natural environments while executing critical ecosystem functions. Over the past decade, effort has been made to unravel the contribution of stochasticity and determinism to the compositional of microbial communities. However, most studies focus on microbial taxa, ignoring the importance of functional traits. By employing shotgun metagenomic sequencing and state-of-the-art bioinformatics approaches, this study comprehensively investigated the microbially mediated nitrogen (N) cycling processes in two geographically distant coastal locations. Both shotgun and 16S rRNA gene amplicon sequencing demonstrated significantly differed taxonomic compositions between the two sites. The relative abundance of major microbial phyla, such as Pseudomonadota, Thaumarchaeota, and Bacteroidota, significantly differed. In contrast, high homogeneity was observed for N-cycling functional traits. Statistical analyses suggested that N-cycling taxonomic groups were more related to geographic distance, whereas microbial functional traits were more influenced by environmental factors. Multiple community assembly models demonstrated that determinism strongly governed the microbial N-cycling functional traits, whereas their carrying taxonomic groups were highly stochastic. Such discordant patterns between N-cycling functional traits and taxa demonstrated an important mechanism in microbial ecology in which essential ecosystem functions are stably maintained despite geographic distance and stochastic community assembly.

Effect of environmental level of methomyl on hatching, morphology, immunity and development related genes expression in zebrafish (Danio rerio) embryo.

The extensive use of carbamate pesticides has led to a range of environmental and health problems, such as surface and groundwater contamination, and endocrine disorders in organisms. In this study, we focused on examining the effects of toxic exposure to the carbamate pesticide methomyl on the hatching, morphology, immunity and developmental gene expression levels in zebrafish embryos. Four concentrations of methomyl (0, 2, 20, and 200 µg/L) were administered to zebrafish embryos for a period of 96 h. The study found that exposure to methomyl accelerated the hatching process of zebrafish embryos, with the strongest effect recorded at the concentration of 2 µg/L. Methomyl exposure also trigged significantly reductions in heart rate and caused abnormalities in larvae morphology, and it also stimulated the synthesis and release of several inflammatory factors such as IL-1ß, IL-6, TNF-α and INF-α, lowered the IgM contents, ultimately enhancing inflammatory response and interfering with immune function. All of these showed the significant effects on exposure time, concentration and their interaction (Time × Concentration). Furthermore, the body length of zebrafish exposed to methomyl for 96 h was significantly shorter, particularly at higher concentrations (200 µg/L). Methomyl also affected the expression levels of genes associated with development (down-regulated igf1, bmp2b, vasa, dazl and piwi genes), demonstrating strong developmental toxicity and disruption of the endocrine system, with the most observed at the concentration of 200 µg/L and 96 h exposure to methomyl. The results of this study provide valuable reference information on the potential damage of methomyl concentrations in the environment on fish embryo development, while also supplementing present research on the immunotoxicity of methomyl.

Synergistic mediating effect of edible fungal polysaccharides (Auricularia and Tremellan) and Crataegus flavonoids in hyperlipidemic rats.

Both edible fungal polysaccharides (Auricularia and Tremellan) and Crataegus flavonoids promote the balance of dyslipidemia, which have a positive biological regulating effect on intestinal flora. In this study, the extraction of water-soluble polysaccharides from Auricularia and Tremellan was investigated and optimized firstly. Polysaccharides and flavonoids were then combined to study the effects on the mediating role of abnormal blood lipid concentration and intestinal flora in vivo. The rats were divided into 10 groups, the NC (normal control), HM (model), PCI (Simvastatin control), PCII (Fenofibrate control), AAP (Auricularia auricular Polysaccharide), TFP (Tremella fuciformis Polysaccharide), HF (Crataegus Flavonoid), LDC (Low-dose combination), MDC (Medium dose combination), and HDC (High-dose combination), used to explore the impact of polysaccharides and flavonoids complex on state of blood lipid, liver, and intestinal flora of dyslipidemia rats. The results showed that the combination of polysaccharides and flavonoids could significantly decrease the levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), and increase the level of high-density lipoprotein cholesterol (HDL-C). It also significantly decreased the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and improved liver morphology. What is more, the HDC favorably alters the intestinal microflora balance, promotes intestinal integrity and mobility, and inhibits the growth of harmful bacteria such as Escherichia coli/Shigella and Clostridium compared with HM group. In brief, the combination of polysaccharides and flavonoids had a synergistic effect on the remission of dyslipidemia, and promoted health by improving lipid metabolism, protecting liver tissue, and regulating the intestinal flora in hyperlipidemia rats.

Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients.

BACKGROUND: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. METHODS: LS patients with CRC who had evaluable tumours and received at least 2 cycles of PD-1 inhibitors were retrospectively included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies, including anticytotoxic T-lymphocyte-associated antigen-4 treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analysed. RESULTS: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3-71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses and 42.7% (n = 32) partial responses. Four of five cases of LS CRCs displaying proficient MMR (pMMR) or microsatellite stable (MSS) were not responsive. Mucinous/signet-ring cell differentiation was associated with a lower ORR (P = 0.013). The 3-year overall survival and progression-free survival were 91.2% and 82.2%, respectively. A polyp was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment, and they were all larger than 7 mm. CONCLUSION: PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC. Large LS adenomas may also be eliminated by anti-PD-1 treatment. DATA AVAILABILITY STATEMENT: Due to the privacy of patients, the related data cannot be available for public access but can be obtained from Pei-Rong Ding (dingpr@sysucc.org.cn) upon reasonable request. The key raw data have been uploaded to the Research Data Deposit public platform (www.researchdata.org.cn).

Peroxisome Proliferator Activated Receptor-γ Agonistic Compounds from the Jellyfish-Derived Fungus Cladosporium oxysporum.

In our search for peroxisome proliferator-activated receptor (PPAR) agonists, five undescribed compounds, namely two acyclic diterpenes (1 and 2; cladopsol A and cladopsol B), two sesquiterpenes (3 and 4; cladopsol C and cladopsol D), and one C21-ecdysteroid (5; cladopsol E), and 15 known compounds were isolated from the jellyfish-derived fungus - Cladosporium oxysporum. The structures of the undescribed compounds were defined using UV, NMR, HR-ESI-MS, and electronic circular dichroism (ECD) spectroscopy and a modified Mosher's method. Luciferase reporter assay and docking analysis suggested that cladopsol B may function as a PPAR-γ partial agonist with a potential antidiabetic lead which may evade the side effects of full agonists. Moreover, cladopsol B stimulated glucose uptake in HepG2 cells with an efficacy comparable to that of rosiglitazone, but with less side effect induced by lipid accumulation in 3T3-L1 cells. Therefore, cladopsol B could serve as a molecular skeleton in a study of advanced antidiabetic lead with less side effect.

Evaluation of metoprolol standard dosing pathway in Chinese patients with acute coronary syndrome: a prospective multicenter single-arm interventional study.

OBJECTIVE: To evaluate the feasibility and tolerability of metoprolol standard dosing pathway (MSDP) in Chinese patients with acute coronary syndrome (ACS). METHODS: In this multicenter, prospective, open label, single-arm and interventional study that was conducted from February 2018 to April 2019 in fifteen Chinese hospitals. A total of 998 hospitalized patients aged ≥ 18 years and diagnosed with ACS were included. The MSDP was applied to all eligible ACS patients based on the standard treatment recommended by international guidelines. The primary endpoint was the percentage of patients achieving the target dose at discharge (V2). The secondary endpoints included the heart rate and blood pressure at V2 and four weeks after discharge (V4), and percentage of patients experiencing bradycardia (heart rate < 50 beats/min), hypotension (blood pressure < 90/60 mmHg) and transient cardiac dysfunction at V2 and V4. RESULTS: Of the 998 patients, 29.46% of patients achieved the target dose (≥ 95 mg/d) at V2. The total population was divided into two groups: target group (patients achieving the target dose at V2) and non-target group (patients not achieving the target dose at V2). There was significant difference in the reduction of heart rate from baseline to discharge in the two groups (-4.97 ± 11.90 beats/min vs. -2.70 ± 9.47 beats/min, P = 0.034). There was no significant difference in the proportion of bradycardia that occurred in the two groups at V2 (0 vs. 0, P = 1.000) and V4 (0.81% vs. 0.33%, P = 0.715). There was no significant difference in the proportion of hypotension between the two groups at V2 (0.004% vs. 0.004%, P = 1.000) and V4 (0 vs. 0.005%, P = 0.560). No transient cardiac dysfunction occurred in two groups during the study. A total of five adverse events (1.70%) and one serious adverse event (0.34%) were related to the pathway in target group. CONCLUSIONS: In Chinese ACS patients, the feasibility and tolerability of the MSDP have been proved to be acceptable.

A molecular network-based pharmacological study on the protective effect of Panax notoginseng rhizomes against renal ischemia-reperfusion injury.

Objective: We aimed to explore the protective effect of Panax notoginseng rhizomes (PNR) on renal ischemia and reperfusion injury (RIRI) and the underlying molecular network mechanism based on network pharmacology and combined systemic experimental validation. Methods: A bilateral RIRI model was established, and Cr, SCr, and BUN levels were detected. Then, the PNR was pretreated 1 week before the RIRI model was prepared. To determine the effects of the PNR in RIRI, histopathological damage and the effect of PNRs to the kidney was assessed, using TTC, HE, and TUNEL staining. Furthermore, the underlying network pharmacology mechanism was detected by screening drug-disease intersection targets from PPI protein interactions and GO and KEGG analysis, and the hub genes were screened for molecular docking based on the Degree value. Finally, the expression of hub genes in kidney tissues was verified by qPCR, and the protein expression of related genes was further detected by Western blot (WB). Results: PNR pretreatment could effectively increase Cr level, decrease SCr and BUN levels, reduce renal infarct areas and renal tubular cell injury areas, and inhibit renal cell apoptosis. By using network pharmacology combined with bioinformatics, we screened co-targets both Panax notoginseng (Sanchi) and RIRI, acquired ten hub genes, and successfully performed molecular docking. Of these, pretreatment with the PNR reduced the mRNA levels of IL6 and MMP9 at postoperative day 1 and TP53 at postoperative day 7, and the protein expression of MMP9 at postoperative day 1 in IRI rats. These results showed that the PNR could decrease kidney pathological injury in IRI rats and inhibit apoptotic reaction and cell inflammation so as to improve renal injury effectively, and the core network mechanism is involved in the inhibition of MMP9, TP53, and IL-6. Conclusion: The PNR has a marked protective effect for RIRI, and the underlying mechanism is involved in inhibiting the expression of MMP9, TP53, and IL-6. This striking discovery not only provides fruitful evidence for the protective effect of the PNR in RIRI rats but also provides a novel mechanic explanation.

Compounds That Have an Anti-Biofilm Effect against Common Bacteria at Very Low Concentrations and Their Antibiotic Combination Effect.

Two synthetic compounds, MHY1383, azo-resveratrol and MHY1387, 5-[4-hydroxy-3,5-methoxybenzy]-2-thioxodihydropyrimidine-4,6[1H,5H]-dione have been reported to have an anti-biofilm effect on Pseudomonas aeruginosa at very low concentrations (1-10 pM). Here, we investigated the anti-biofilm effects of these compounds in various bacteria. We found that MHY1383 significantly inhibited Escherichia coli, Bacillus subtilis, and Staphylococcus aureus biofilm formation at 1 pM, 1 nM, and 10 nM, respectively. MHY1387 also inhibited the biofilm formation of E. coli, B. subtilis, and S. aureus at 1 pM, 10 nM, and 100 pM, respectively. Both MHY1383 and MHY1387 showed medium-dependent anti-biofilm effects on Salmonella enterica at high concentrations (10 µM). We also tested the susceptibility to antibiotics by measuring the minimum inhibitory concentration (MIC) in various bacteria. When P. aeruginosa, E. coli, B. subtilis, S. enterica, and S. aureus were treated with MHY1383 or MHY1387 in combination with four different antibiotics, the MICs of carbenicillin against B. subtilis and S. aureus were lowered more than two-fold by the combination with MHY1387. However, in all other combinations, the MIC changed within two-fold. The results of this study suggest that MHY1383 and MHY1387 are effective anti-biofilm agents and can be used at very low concentrations against biofilms formed by various types of bacteria. We also suggest that even if a substance that inhibits biofilm is used together with antibiotics, it does not necessarily have the effect of lowering the MIC of the antibiotics.

Efficacy of granulocyte colony-stimulating factor for infertility undergoing IVF: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the effectiveness of granulocyte colony-stimulating factor (G-CSF) for infertility and recurrent spontaneous abortion. METHODS: Existing research was searched in PubMed, Embase and Cochrane Library till Dec 2021. Randomized control trials (RCTs) that compared G-CSF administration with the control group in infertility women undergoing IVF were included. The primary outcomes included clinical pregnancy rate; the secondary outcomes included live birth rate, abortion ratebiochemical pregnancy rate, embryo implantation rate, as well as endometrial thickness. RESULT(S): 20 RCTs were included in this study. G-CSF increased the clinical pregnancy rate (RR = 1.85; 95% CI: 1.07, 3.18) and the endometrial thickness (MD = 2.25; 95% CI: 1.58,2.92;) in patients with thin endometrium undergoing IVF. G-CSF increased the biochemical pregnancy rate (RR = 2.12; 95% CI: 1.54, 2.93), the embryo implantation rate (RR = 2.51; 95% CI: 1.82, 3.47) and the clinical pregnancy rate (RR = 1.93; 95% CI: 1.63, 2.29) in patients with a history of repeated implantation failure undergoing IVF. No differences were found in pregnancy outcomes of general IVF patients. CONCLUSIONS: Granulocyte colony-stimulating factor is likely to be a potential option for infertility women undergoing IVF with thin endometrium or recurrent implantation failure . TRIAL REGISTRATION: Retrospectively registered (The PROSPERO registration number: CRD42022360161).

The combined formulation of brassinolide and pyraclostrobin increases biomass and seed yield by improving photosynthetic capacity in Arabidopsis thaliana.

In the context of global food crisis, applying the phytohormone-brassinosteroids (BRs) in combination with the fungicide-pyraclostrobin (Pyr) was beneficial for plant quality and productivity in several field trials. However, in addition to the benefits of disease control due to the innate fungicidal activity of Pyr, it remains to be understood whether the coapplication of BL+ Pyr exerts additional growth-promoting effects. For this purpose, the effects of BL treatment, Pyr treatment, and BL+ Pyr treatment in Arabidopsis thaliana were compared. The results showed that the yield increased at a rate of 25.6% in the BL+Pyr group and 9.7% in the BL group, but no significant change was observed in the Pyr group. Furthermore, the BL+Pyr treatment increased the fresh weight of both the leaves and the inflorescences. In contrast, the Pyr and BL treatments only increased the fresh weight of leaves and inflorescences, respectively. Additionally, the BL + Pyr treatment increased the Pn, Gs, Tr, Vc, max, Jmax, VTPU, ETR, Fv'/Fm', ΦPSII, Rd, AYE and Rubisco enzyme activity by 26%, 38%, 40%, 16%, 19%, 15%, 9%, 10%, 17%, 179%, 18% and 32%, respectively. While, these paraments did not change significantly by the BL or Pyr treatments. Treatment with BL + Pyr and Pyr, rather than BL, improved the chlorophyll a and chlorophyll b contents by upregulating genes related to chlorophyll biosynthesis and downregulating genes related to chlorophyll degradation. Additionally, according to transcriptomic and metabolomic analysis, the BL+ Pyr treatment outperformed the individual BL or Pyr treatments in activating the transcription of genes involved in photosynthesis and increasing sugar accumulation. Our results first validated that the combined usage of BL and Pyr exerted striking synergistic effects on enhancing plant biomass and yield by increasing photosynthetic efficiency. These results might provide new understanding for the agricultural effects by the co-application of BL and Pyr, and it might stimulate the efforts to develop new environment-friendly replacement for Pyr to minimize the ecotoxicology of Pyr.

Correction: Synergistic effect of polysaccharides and flavonoids on lipid and gut microbiota in hyperlipidemic rats.

Correction for 'Synergistic effect of polysaccharides and flavonoids on lipid and gut microbiota in hyperlipidemic rats' by Yun-fei Bai et al., Food Funct., 2023, 14, 921-933, https://doi.org/10.1039/D2FO03031D.

Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments.

Colorectal cancer (CRC) is one of the most lethal and common malignancies in the world. Chemotherapy has been the conventional treatment for metastatic CRC (mCRC) patients. However, the effects of chemotherapy have been unsatisfactory. With the advent of targeted therapy, the survival of patients with CRC have been prolonged. Over the past 20 years, targeted therapy for CRC has achieved substantial progress. However, targeted therapy has the same challenge of drug resistance as chemotherapy. Consequently, exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy, along with searching for novel effective regimens, is a constant challenge in the mCRC treatment, and it is also a hot research topic. In this review, we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.

Challenges and exploration for immunotherapies targeting cold colorectal cancer.

In recent years, immune checkpoint inhibitors (ICIs) have made significant breakthroughs in the treatment of various tumors, greatly improving clinical efficacy. As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery, chemotherapy, radiotherapy and targeted therapy, the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells, features that are also important when distinguishing malignant tumors from "cold tumors" or "hot tumors". At present, only a small proportion of colorectal cancer (CRC) patients with deficient mismatch repair (dMMR) or who are microsatellite instability-high (MSI-H) can benefit from ICI treatments because these patients have the characteristics of a "hot tumor", with a high tumor mutational burden (TMB) and massive immune cell infiltration, making the tumor more easily recognized by the immune system. In contrast, a majority of CRC patients with proficient MMR (pMMR) or who are microsatellite stable (MSS) have a low TMB, lack immune cell infiltration, and have almost no response to immune monotherapy; thus, these tumors are "cold". The greatest challenge today is how to improve the immunotherapy response of "cold tumor" patients. With the development of clinical research, immunotherapies combined with other treatment strategies (such as targeted therapy, chemotherapy, and radiotherapy) have now become potentially effective clinical strategies and research hotspots. Therefore, the question of how to promote the transformation of "cold tumors" to "hot tumors" and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration. Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.

Collaboration of two-star nanomaterials: The applications of nanocellulose-based metal organic frameworks composites.

Nanocellulose, as the star nanomaterial in carbohydrate polymers, has excellent mechanical properties, biodegradability, and easy chemical modification. However, further practical applications of nanocellulose are limited by their inadequate functionalization. Metal-organic frameworks (MOFs), as the star nanomaterial in functional polymers, have a large surface area, high porosity, and adjustable structure. The collaboration of nanocellulose and MOFs is a desirable strategy to make composites especially interesting for multifunctional and multi-field applications. What sparks will be produced by the collaboration of two-star nanomaterials? In this review article, we highlight an up-to-date overview of nanocellulose-based MOFs composites. The sewage treatment, gas separation, energy storage, and biomedical applications are mainly summarized. Finally, the challenges and research trends of nanocellulose-based MOFs composites are prospected. We hope this review may provide a valuable reference for the development and applications of carbohydrate polymer composites soon.