Clonal evolution from B-cell acute lymphoblastic leukemia with BCR::ABL1 multilineage involvement to acute myeloid leukemia after multiple anti-CD19 chimeric antigen receptor T-cell therapy.

Not available.

Effects of perioperative magnesium on postoperative analgesia following thoracic surgery: a meta-analysis of randomised controlled trials.

To evaluate the analgesic effects of intravenous magnesium in patients undergoing thoracic surgery. Randomised clinical trials (RCTs) were systematically identified from MEDLINE, EMBASE, Google Scholar and the Cochrane Library from inception to May 1st, 2023. The primary outcome was the effect of intravenous magnesium on the severity of postoperative pain at 24 hours following surgery, while the secondary outcomes included association between intravenous magnesium and pain severity at other time points, morphine consumption, and haemodynamic changes. Meta-analysis of seven RCTs published between 2007 and 2019, involving 549 adults, showed no correlation between magnesium and pain scores at 1-4 (standardized mean difference [SMD]=-0.06; p=0.58), 8-12 (SMD=-0.09; p=0.58), 24 (SMD=-0.16; p=0.42), and 48 (SMD=-0.27; p=0.09) hours post-surgery. Perioperative magnesium resulted in lower equivalent morphine consumption at 24 hours post-surgery (mean difference [MD]=-25.22 mg; p=0.04) and no effect at 48 hours (MD=-4.46 mg; p=0.19). Magnesium decreased heart rate (MD = -5.31 beats/min; p=0.0002) after tracheal intubation or after surgery, but had no effect on postoperative blood pressure (MD=-6.25 mmHg; p=0.11). There was a significantly higher concentration of magnesium in the magnesium group compared with that in the placebo group (MD = 0.91 mg/dL; p<0.00001). This meta-analysis provides evidence supporting perioperative magnesium as an analgesic adjuvant at 24 hours following thoracic surgery, but no opioid-sparing effect at 48 hours post-surgery. The severity of postoperative pain did not significantly differ between any of the postoperative time points, irrespective of magnesium. Further research on perioperative magnesium in various surgical settings is needed.

Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators.

BACKGROUND: Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment. AIM: To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model. METHODS: The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1ß, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice. RESULTS: Transforming growth factor (TGF)-ß1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1ß, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF. CONCLUSION: MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses.

Genomics and resequencing of Fagopyrum dibotrys from different geographic regions reveals species evolution and genetic diversity.

Fagopyrum dibotrys, belonging to the family Polygonaceae and genus Fagopyrum, is used in traditional Chinese medicine and is rich in beneficial components, such as flavonoids. As its abundant medicinal value has become increasingly recognized, its excessive development poses a considerable challenge to wild germplasm resources, necessitating artificial cultivation and domestication. Considering these factors, a high-quality genome of F. dibotrys was assembled and the evolutionary relationships within Caryophyllales were compared, based on which 58 individual samples of F. dibotrys were re-sequenced. We found that the samples could be categorized into three purebred populations and regions distributed at distinct elevations. Our varieties were cultivated from the parental populations of the subpopulation in central Yunnan. F. dibotrys is speculated to have originated in the high-altitude Tibetan Plateau region, and that its combination with flavonoids can protect plants against ultraviolet radiation; this infers a subpopulation with a high accumulation of flavonoids. This study assembled a high-quality genome and provided a theoretical foundation for the future introduction, domestication, and development of cultivated varieties of F. dibotrys.

Synergistic Construction of Sub-Nanometer Channel Membranes through MOF-Polymer Composites: Strategies and Nanofiltration Applications.

The selective separation of small molecules at the sub-nanometer scale has broad application prospects in the field, such as energy, catalysis, and separation. Conventional polymeric membrane materials (e.g., nanofiltration membranes) for sub-nanometer scale separations face challenges, such as inhomogeneous channel sizes and unstable pore structures. Combining polymers with metal-organic frameworks (MOFs), which possess uniform and intrinsic pore structures, may overcome this limitation. This combination has resulted in three distinct types of membranes: MOF polycrystalline membranes, mixed-matrix membranes (MMMs), and thin-film nanocomposite (TFN) membranes. However, their effectiveness is hindered by the limited regulation of the surface properties and growth of MOFs and their poor interfacial compatibility. The main issues in preparing MOF polycrystalline membranes are the uncontrollable growth of MOFs and the poor adhesion between MOFs and the substrate. Here, polymers could serve as a simple and precise tool for regulating the growth and surface functionalities of MOFs while enhancing their adhesion to the substrate. For MOF mixed-matrix membranes, the primary challenge is the poor interfacial compatibility between polymers and MOFs. Strategies for the mutual modification of MOFs and polymers to enhance their interfacial compatibility are introduced. For TFN membranes, the challenges include the difficulty in controlling the growth of the polymer selective layer and the performance limitations caused by the "trade-off" effect. MOFs can modulate the formation process of the polymer selective layer and establish transport channels within the polymer matrix to overcome the "trade-off" effect limitations. This review focuses on the mechanisms of synergistic construction of polymer-MOF membranes and their structure-nanofiltration performance relationships, which have not been sufficiently addressed in the past.

Uncovering the ferroptosis related mechanism of laduviglusib in the cell-type-specific targets of the striatum in Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder featured by abnormal movements, arising from the extensive neuronal loss and glial dysfunction in the striatum. Although the causes and pathogenetic mechanisms of HD are well established, the development of disease-modifying pharmacological therapies for HD remains a formidable challenge. Laduviglusib has demonstrated neuroprotective effects through the enhancement of mitochondrial function in the striatum of HD animal models. Ferroptosis is a nonapoptotic form of cell death that occurs as a consequence of lethal iron-dependent lipid peroxidation and mitochondrial dysfunction. However, the ferroptosis-related mechanisms underlying the neuroprotective effects of laduviglusib in the striatum of HD patients remain largely uncharted. In this study, we leveraged single-nucleus RNA sequencing data obtained from the striatum of HD patients in stages 2-4 to identify differentially expressed genes within distinct cell-type. We subsequently integrated these differentially expressed genes of HD, laduviglusib target genes and ferroptosis-related genes to predict the ferroptosis-related mechanisms underpinning the neuroprotective effects of laduviglusib in HD patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses unveiled that the effects of laduviglusib on direct pathway striatal projection neurons (dSPNs) is mainly associated with Th17 cell differentiation pathways. Conversely, its impact on indirect pathway striatal projection neurons (iSPNs) extends to the Neurotrophin signaling pathway, FoxO signaling pathway, and reactive oxygen species pathway. In microglia, laduviglusib appears to contribute to HD pathology via mechanisms related to Th17 cell differentiation and the FoxO signaling pathway. Further, molecular docking results indicated favorable binding of laduviglusib with PARP1 (associated with dSPNs and iSPNs), SCD (associated with astrocytes), ALOX5 (associated with microglia), and HIF1A (associated with dSPNs, iSPNs, and microglia). In addition, the KEGG results suggest that laduviglusib may enhance mitochondrial function and protect against neuronal loss by targeting ferroptosis-related signaling pathways, particularly mediated by ALOX5 in microglia. These findings provide valuable insights into the potential mechanisms through which laduviglusib exerts its effects on distinct cell-types within the HD striatum.

[Characteristics of soil moisture limitation and non-limitation in the response of sap flow to transpiration driving factors]. / æ ‘å¹²æ¶²æµå¯¹è’¸è ¾é©±åŠ¨å› å­å“åº”çš„åœŸå£¤æ°´åˆ†é™åˆ¶ä¸Žéžé™åˆ¶ç‰¹å¾.

Transpiration is a significant part of water cycle in forest ecosystems, influenced by meteorological factors and potentially constrained by soil moisture. We used Granier-type thermal dissipation probes to monitor xylem sap flow dynamics of three tree species (Quercus liaotungensis, Platycladus orientalis, and Robinia pseudoacacia) in a semi-arid loess hilly region, and to continuously monitor the key meteorological factors and soil water content (SWC). We established the SWC thresholds delineating soil moisture-limited and -unlimited sap flow responses to transpiration drivers. The results showed that mean sap flux density (Js) of Q. liaotungensis and R. pseudoacacia was significantly higher during period with higher soil moisture compared to lower soil moisture, while the difference in Js for P. orientalis between the two periods was not significant. We used an exponential saturation function to fit the relationship between the Js of each tree species and the integrated transpiration variable (VT) which reflected solar radiation and vapor pressure deficit. The difference in the fitting curve parameters indicated that there were distinct response patterns between Js and VT under different soil moisture conditions. There was a threshold in soil moisture limitation on sap flow for each species, which was identified as 0.129 m3·m-3 for Q. liaotungensis, 0.116 m3·m-3 for P. orientalis, and 0.108 m3·m-3 for R. pseudoacacia. Below the thresholds, Js was limited by soil moisture. Above these points, the normalized sensitivity index (NSI) for Q. liaotungensis and P. orientalis reached saturation, while that of R. pseudoacacia did not reach saturation but exhibited a significant reduction in moisture limitation. Among the three species, P. orientalis was the most capable of overcoming soil moisture constraints.

Tranexamic acid may benefit patients with preexisting thromboembolic risk undergoing total joint arthroplasty: a systematic review and meta-analysis.

Purpose: This study sought to determine if the use of tranexamic acid (TXA) in preexisting thromboembolic risk patients undergoing total joint arthroplasty (TJA) was linked to an increased risk of death or postoperative complications. Methods: We conducted a comprehensive search for studies up to May 2023 in PubMed, Web of Science, EMBASE, and the Cochrane Library. We included randomized clinical trials, cohort studies, and case-control studies examining the use of TXA during TJA surgeries on high-risk patients. The Cochrane Risk of Bias instrument was used to gauge the excellence of RCTs, while the MINORS index was implemented to evaluate cohort studies. We used mean difference (MD) and relative risk (RR) as effect size indices for continuous and binary data, respectively, along with 95% CIs. Results: Our comprehensive study, incorporating data from 11 diverse studies involving 812 993 patients, conducted a meta-analysis demonstrating significant positive outcomes associated with TXA administration. The findings revealed substantial reductions in critical parameters, including overall blood loss (MD = -237.33; 95% CI (-425.44, -49.23)), transfusion rates (RR = 0.45; 95% CI (0.34, 0.60)), and 90-day unplanned readmission rates (RR = 0.86; 95% CI (0.76, 0.97)). Moreover, TXA administration exhibited a protective effect against adverse events, showing decreased risks of pulmonary embolism (RR = 0.73; 95% CI (0.61, 0.87)), myocardial infarction (RR = 0.47; 95% CI (0.40-0.56)), and stroke (RR = 0.73; 95% CI (0.59-0.90)). Importantly, no increased risk was observed for mortality (RR = 0.53; 95% CI (0.24, 1.13)), deep vein thrombosis (RR = 0.69; 95% CI (0.44, 1.09)), or any of the evaluated complications associated with TXA use. Conclusion: The results of this study indicate that the use of TXA in TJA patients with preexisting thromboembolic risk does not exacerbate complications, including reducing mortality, deep vein thrombosis, and pulmonary embolism. Existing evidence strongly supports the potential benefits of TXA in TJA patients with thromboembolic risk, including lowering blood loss, transfusion, and readmission rates.

miR-221-3p as a potential biomarker of chronic periodontitis and its regulatory effect on inflammatory response.

PURPOSE: To explore the function of miR-221-3p in the development and course of chronic periodontitis (CP) and offer a fresh avenue for CP diagnosis and management. METHODS: miR-221-3p expression was detected by RT-qPCR. The clinical diagnostic value of miR-221-3p in CP patients was analyzed by receiver operating characteristic (ROC). ELISA was used to determine the IL-1ß and IL-6 in CP subjects and healthy controls. Pearson correlation analysis was performed with miR-221-3p. PDLCs were induced by LPS, transfected with miR-221-3p mimics, and their expression was analyzed for the effects of IL-1ß, and IL-6. RESULTS: The miR-221-3p expression was lower in the gingival sulcus fluid GCF of CP subjects compared to healthy controls. miR-221-3p showed high potential for clinical diagnosis in CP patients by ROC analysis, with high specificity and sensitivity. miR-221-3p was negatively correlated with Probing pocket depth (PD), Attachment loss (AL), Plaque index (PI), and Bleeding index (BI), and negatively correlated with inflammatory factors IL-1ß and IL-6. In LPS-induced PDLCs, IL-1ß and IL-6 were significantly increased, whereas miR-221-3p was significantly downregulated. Overexpression of miR-221-3p inhibited the production of inflammatory factors IL-1ß and IL-6 in LPS-induced PDLCs. CLINICAL SIGNIFICANCE: miR-221-3p expression may be a potential biological marker for the diagnosis of chronic periodontitis and provide a new direction for its treatment of chronic periodontitis.

GIP attenuates neuronal oxidative stress by regulating glucose uptake in spinal cord injury of rat.

AIM: Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GIP has been regarded as a hormone-like peptide to regulate the local metabolic environment. In this study, we investigated the antioxidant role of GIP on the neuron and explored the possible mechanism. METHODS: Cell counting Kit-8 (CCK-8) was used to measure cell survival. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect apoptosis in vitro and in vivo. Reactive oxygen species (ROS) levels were probed with 2', 7'-Dichloro dihydrofluorescein diacetate (DCFH-DA), and glucose intake was detected with 2-NBDG. Immunofluorescence staining and western blot were used to evaluate the protein level in cells and tissues. Hematoxylin-eosin (HE) staining, immunofluorescence staining and tract-tracing were used to observe the morphology of the injured spinal cord. Basso-Beattie-Bresnahan (BBB) assay was used to evaluate functional recovery after spinal cord injury. RESULTS: GIP reduced the ROS level and protected cells from apoptosis in cultured neurons and injured spinal cord. GIP facilitated wound healing and functional recovery of the injured spinal cord. GIP significantly improved the glucose uptake of cultured neurons. Meanwhile, inhibition of glucose uptake significantly attenuated the antioxidant effect of GIP. GIP increased glucose transporter 3 (GLUT3) expression via up-regulating the level of hypoxia-inducible factor 1α (HIF-1α) in an Akt-dependent manner. CONCLUSION: GIP increases GLUT3 expression and promotes glucose intake in neurons, which exerts an antioxidant effect and protects neuronal cells from oxidative stress both in vitro and in vivo.

Circadian rhythm disruption-mediated downregulation of Bmal1 exacerbates DSS-induced colitis by impairing intestinal barrier.

Background: Circadian rhythm disruption (CRD) is thought to increase the risk of inflammatory bowel disease. The deletion of Bmal1, a core transcription factor, leads to a complete loss of the circadian rhythm and exacerbates the severity of dextran sodium sulfate (DSS)-induced colitis in mice. However, the underlying mechanisms by which CRD and Bmal1 mediate IBD are still unclear. Methods: We used a CRD mouse model, a mouse colitis model, and an in vitro model of colonic epithelial cell monolayers. We also knocked down and overexpressed Bmal1 in Caco-2 cells by transfecting lentivirus in vitro. The collected colon tissue and treated cells were assessed and analyzed using immunohistochemistry, immunofluorescence staining, quantitative reverse transcription-polymerase chain reaction, western blot, flow cytometry, transmission electron microscopy, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling staining. Results: We found that CRD mice with downregulated Bmal1 expression were more sensitive to DSS-induced colitis and had more severely impaired intestinal barrier function than wild-type mice. Bmal1-/- mice exhibited more severe colitis, accompanied by decreased tight junction protein levels and increased apoptosis of intestinal epithelial cells compared with wild-type mice, which were alleviated by using the autophagy agonist rapamycin. Bmal1 overexpression attenuated Lipopolysaccharide-induced apoptosis of intestinal epithelial cells and impaired intestinal epithelial cells barrier function in vitro, while inhibition of autophagy reversed this protective effect. Conclusion: This study suggests that CRD leads to the downregulation of Bmal1 expression in the colon, which may exacerbate DSS-induced colitis in mice, and that Bmal1 may serve as a novel target for treating inflammatory bowel disease.

Modulation of Salmonella virulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex.

The injectisome encoded by Salmonella pathogenicity island 2 (SPI-2) had been thought to translocate 28 effectors. Here, we used a proteomic approach to characterize the secretome of a clinical strain of invasive non-typhoidal Salmonella enterica serovar Enteritidis that had been mutated to cause hyper-secretion of the SPI-2 injectisome effectors. Along with many known effectors, we discovered the novel SseM protein. sseM is widely distributed among the five subspecies of Salmonella enterica, is found in many clinically relevant serovars, and is co-transcribed with pipB2, a SPI-2 effector gene. The translocation of SseM required a functional SPI-2 injectisome. Following expression in human cells, SseM interacted with five components of the dystrophin-associated protein complex (DAPC), namely, ß-2-syntrophin, utrophin/dystrophin, α-catulin, α-dystrobrevin, and ß-dystrobrevin. The interaction between SseM and ß-2-syntrophin and α-dystrobrevin was verified in Salmonella Typhimurium-infected cells and relied on the postsynaptic density-95/discs large/zonula occludens-1 (PDZ) domain of ß-2-syntrophin and a sequence corresponding to a PDZ-binding motif (PBM) in SseM. A ΔsseM mutant strain had a small competitive advantage over the wild-type strain in the S. Typhimurium/mouse model of systemic disease. This phenotype was complemented by a plasmid expressing wild-type SseM from S. Typhimurium or S. Enteritidis and was dependent on the PBM of SseM. Therefore, a PBM within a Salmonella effector mediates interactions with the DAPC and modulates the systemic growth of bacteria in mice. Furthermore, the ΔsseM mutant strain displayed enhanced replication in bone marrow-derived macrophages, demonstrating that SseM restrains intracellular bacterial growth to modulate Salmonella virulence. IMPORTANCE: In Salmonella enterica, the injectisome machinery encoded by Salmonella pathogenicity island 2 (SPI-2) is conserved among the five subspecies and delivers proteins (effectors) into host cells, which are required for Salmonella virulence. The identification and functional characterization of SPI-2 injectisome effectors advance our understanding of the interplay between Salmonella and its host(s). Using an optimized method for preparing secreted proteins and a clinical isolate of the invasive non-typhoidal Salmonella enterica serovar Enteritidis strain D24359, we identified 22 known SPI-2 injectisome effectors and one new effector-SseM. SseM modulates bacterial growth during murine infection and has a sequence corresponding to a postsynaptic density-95/discs large/zonula occludens-1 (PDZ)-binding motif that is essential for interaction with the PDZ-containing host protein ß-2-syntrophin and other components of the dystrophin-associated protein complex (DAPC). To our knowledge, SseM is unique among Salmonella effectors in containing a functional PDZ-binding motif and is the first bacterial protein to target the DAPC.

Exploring the potential of isorhapontigenin: attenuating Staphylococcus aureus virulence through MgrA-mediated regulation.

The emerging prevalence of drug-resistant Staphylococcus aureus isolates underscores the urgent need for alternative therapeutic strategies due to the declining effectiveness of traditional antibiotics in clinical settings. MgrA, a key virulence regulator in S. aureus, orchestrates the expression of numerous virulence factors. Here, we report the discovery of isorhapontigenin, a methoxylated analog of resveratrol, as a potential anti-virulence agent against S. aureus. Isorhapontigenin effectively inhibits the hemolytic activity of S. aureus in a non-bactericidal manner. Additionally, it significantly reduces the cytotoxicity of S. aureus and impairs its ability to survive in macrophages. Mechanistically, isorhapontigenin modulates the expression of virulence factors, dose-dependently downregulating hla and upregulating the MgrA-regulated gene spa. Electrophoretic mobility shift assays demonstrated that isorhapontigenin inhibits the binding of MgrA to the hla promoter in a dose-dependent manner. Thermal shift assays confirmed the direct interaction between isorhapontigenin and the MgrA protein. The in vivo experiments demonstrated that isorhapontigenin significantly reduced the area of skin abscesses and improved survival in a pneumonia model while decreasing bacterial burden and inflammation in the lungs. In conclusion, isorhapontigenin holds potential as a candidate drug for further development as an anti-virulence agent for treating S. aureus infections. IMPORTANCE: The emergence of antibiotic-resistant Staphylococcus aureus strains presents a formidable challenge to public health, necessitating novel approaches in combating these pathogens. Traditional antibiotics are becoming increasingly ineffective, leading to a pressing need for innovative therapeutic strategies. In this study, targeting virulence factors that play a crucial role in the pathogenesis of bacterial infections offers a promising alternative to circumvent resistance mechanisms. The discovery of isorhapontigenin as an inhibitor of S. aureus virulence represents a significant advance in anti-virulence therapy.

DNA mismatch and damage patterns revealed by single-molecule sequencing.

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases1,2. Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired3,4. However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination-a common type of DNA damage-with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing.

Plain language summary of the FOENIX-CCA2 study: futibatinib for people with advanced bile duct cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. WHAT WERE THE RESULTS?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. WHAT DO THE RESULTS MEAN?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

Tumor-Derived Exosomal miR-143-3p Induces Macrophage M2 Polarization to Cause Radiation Resistance in Locally Advanced Esophageal Squamous Cell Carcinoma.

We aimed to determine whether monitoring tumor-derived exosomal microRNAs (miRNAs) could be used to assess radiotherapeutic sensitivity in patients with locally advanced esophageal squamous cell carcinoma (ESCC). RNA sequencing was employed to conduct a comparative analysis of miRNA expression levels during radiotherapy, focusing on identifying miRNAs associated with progression. Electron microscopy confirmed the existence of exosomes, and co-cultivation assays and immunofluorescence validated their capacity to infiltrate macrophages. To determine the mechanism by which exosomal miR-143-3p regulates the interplay between ESCC cells and M2 macrophages, ESCC cell-derived exosomes were co-cultured with macrophages. Serum miR-143-3p and miR-223-3p were elevated during radiotherapy, suggesting resistance to radiation and an unfavorable prognosis for ESCC. Increased levels of both miRNAs independently predicted shorter progression-free survival (p = 0.015). We developed a diagnostic model for ESCC using serum microRNAs, resulting in an area under the curve of 0.751. Radiotherapy enhanced the release of miR-143-3p from ESCC cell-derived exosomes. Immune cell infiltration analysis at the Cancer Genome Atlas (TCGA) database revealed that ESCC cell-derived miR-143-3p triggered M2 macrophage polarization. Mechanistically, miR-143-3p upregulation affected chemokine activity and cytokine signaling pathways. Furthermore, ESCC cell exosomal miR-143-3p could be transferred to macrophages, thereby promoting their polarization. Serum miR-143-3p and miR-223-3p could represent diagnostic and prognostic markers for patients with ESCC undergoing radiotherapy. Unfavorable prognosis could be linked to the increased levels of ESCC cell-derived exosomal miR-143-3p, which might promote tumor progression by interacting with macrophages.

Current Applications of Colorectal Cancer Organoids: A Review.

Colorectal cancer is a prevalent malignancy, with advanced and metastatic forms exhibiting poor treatment outcomes and high relapse rates. To enhance patient outcomes, a comprehensive understanding of the pathophysiological processes and the development of targeted therapies are imperative. The high heterogeneity of colorectal cancer demands precise and personalized treatment strategies. Colorectal cancer organoids, a three-dimensional in vitro model, have emerged as a valuable tool for replicating tumor biology and exhibit promise in scientific research, disease modeling, drug screening, and personalized medicine. In this review, we present an overview of colorectal cancer organoids and explore their applications in research and personalized medicine, while also discussing potential future developments in this field.

Integration of food raw materials, food microbiology, and food additives: systematic research and comprehensive insights into sweet sorghum juice, Clostridium tyrobutyricum TGL-A236 and bio-butyric acid.

Introduction: Sweet sorghum juice is a typical production feedstock for natural, eco-friendly sweeteners and beverages. Clostridium tyrobutyricum is one of the widely used microorganisms in the food industry, and its principal product, bio-butyric acid is an important food additive. There are no published reports of Clostridium tyrobutyricum producing butyric acid using SSJ as the sole substrate without adding exogenous substances, which could reach a food-additive grade. This study focuses on tailoring a cost-effective, safe, and sustainable process and strategy for their production and application. Methods: This study modeled the enzymolysis of non-reducing sugars via the first/second-order kinetics and added food-grade diatomite to the hydrolysate. Qualitative and quantitative analysis were performed using high-performance liquid chromatography, gas chromatography-mass spectrometer, full-scale laser diffraction method, ultra-performance liquid chromatography-tandem mass spectrometry, the cell double-staining assay, transmission electron microscopy, and Oxford nanopore technology sequencing. Quantitative real-time polymerase chain reaction, pathway and process enrichment analysis, and homology modeling were conducted for mutant genes. Results: The treated sweet sorghum juice showed promising results, containing 70.60 g/L glucose and 63.09 g/L fructose, with a sucrose hydrolysis rate of 98.29% and a minimal sucrose loss rate of 0.87%. Furthermore, 99.62% of the colloidal particles and 82.13% of the starch particles were removed, and the concentrations of hazardous substances were effectively reduced. A food microorganism Clostridium tyrobutyricum TGL-A236 with deep utilization value was developed, which showed superior performance by converting 30.65% glucose and 37.22% fructose to 24.1364 g/L bio-butyric acid in a treated sweet sorghum juice (1:1 dilution) fermentation broth. This titer was 2.12 times higher than that of the original strain, with a butyric acid selectivity of 86.36%. Finally, the Genome atlas view, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and evolutionary genealogy of genes: Non-supervised Orthologous (eggNOG) functional annotations, three-dimensional structure and protein cavity prediction of five non-synonymous variant genes were obtained. Conclusion: This study not only includes a systematic process flow and in-depth elucidation of relevant mechanisms but also provides a new strategy for green processing of food raw materials, improving food microbial performance, and ensuring the safe production of food additives.