Prognostic value of body mass index for first-line chemoimmunotherapy combinations in advanced non-small cell lung cancer in Chinese population.

Background: Few studies have examined the correlation between body mass index (BMI) and effectiveness of first-line chemoimmunotherapy in patients with advanced non-small cell lung cancer (NSCLC); moreover, the conclusion remains elusive and no such studies have been conducted in the Chinese population. Our study aimed to validate the predictive significance of BMI in Chinese patients with advanced NSCLC receiving first-line chemoimmunotherapy combinations. Methods: Data of patients with advanced NSCLC treated with first-line chemoimmunotherapy between June 2018 and February 2022 at three centers were retrieved retrospectively. The association between baseline BMI with progression-free survival (PFS) and overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression models. BMI was categorized according to the World Health Organization criteria. Results: Of the included 805 patients, 5.3 % were underweight, 63.4 % had normal weight, 27.8 % were overweight, and 3.5 % were obese. Survival analysis showed that patients in the high BMI group had significantly better PFS (p = 0.012) and OS (p = 0.014) than those in the low BMI group. Further, patients in the overweight subgroup had better PFS (p = 0.036) and OS (p = 0.043) compared to the normal weight population. The results of Cox regression analysis confirmed the correlations between BMI and prognosis of advanced NSCLC patients receiving first-line chemoimmunotherapy combinations. Conclusions: Baseline BMI affected the clinical outcomes of first-line chemoimmunotherapy combinations in patients with advanced NSCLC, and was especially favorable for the overweight subgroup.

Correlation between immune-related adverse events and efficacy of PD-(L)1 inhibitors in small cell lung cancer: a multi-center retrospective study.

BACKGROUND: Patients receiving PD-(L)1 inhibitors frequently encounter unusual side effects known as immune-related adverse events (irAEs). However, the correlation of irAEs development with clinical response in small cell lung cancer (SCLC) is unknown. METHOD: This retrospective study enrolled 244 stage IV SCLC patients who receiving PD-(L)1 inhibitors from 3 cancer centers. The correlation of irAEs with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: 140 in 244 (57%) patients experienced irAEs, with 122 (87.1%) experiencing one and 18 (12.9%) experiencing two or more. Compared to patient without irAEs, those developing irAEs had higher ORR (73.6% vs. 52.9%, P < 0.001) and DCR (97.9% vs. 79.8%, P < 0.001), as well as prolonged median PFS (8.8 vs. 4.5 months, P < 0.001) and OS (23.2 vs. 21.6 months, P < 0.05). Among the different spectra of irAEs, thyroid dysfunction, rash, and pneumonitis were the most powerful indicator for improved PFS. When analyzed as a time-dependent covariate, the occurrence of irAEs was associated with significant improvement in PFS rather than in OS. Furthermore, patients experiencing multisystem irAEs displayed a longer PFS and OS compared with single-system irAEs and the irAE-free ones. IrAEs grade and steroid use did not impact the predictive value of irAEs on PFS. CONCLUSION: The presence of irAEs predicts superior clinical benefit in SCLC. Patients who develop multi-system irAEs may have an improved survival than those developed single-system irAEs and no-irAEs. This association persists even when systemic corticosteroids were used for irAEs management.

A General Strategy toward Self-assembled Nanovaccine Based on Cationic Lentinan to Induce Potent Humoral and Cellular Immune Responses.

Adjuvants play a critical role in the induction of effective immune responses by vaccines. Here, a self-assembling nanovaccine platform that integrates adjuvant functions into the delivery vehicle is prepared. Cationic Lentinan (CLNT) is mixed with ovalbumin (OVA) to obtain a self-assembling nanovaccine (CLNTO nanovaccine), which induces the uptake and maturation of bone marrow dendritic cells (BMDCs) via the toll-like receptors 2/4 (TLR2/4) to produce effective antigen cross-presentation. CLNTO nanovaccines target lymph nodes (LNs) and induce a robust OVA-specific immune response via TLR and tumor necrosis factor (TNF) signaling pathways, retinoic acid-inducible gene I (RIG-I) receptor, and cytokine-cytokine receptor interactions. In addition, CLNTO nanovaccines are found that promote the activation of follicular helper T (Tfh) cells and induce the differentiation of germinal center (GC) B cells into memory B cells and plasma cells, thereby enhancing the immune response. Vaccination with CLNTO nanovaccine significantly inhibits the growth of ovalbumin (OVA)-expressing B16 melanoma cell (B16-OVA) tumors, indicating its great potential for cancer immunotherapy. Therefore, this study presents a simple, safe, and effective self-assembling nanovaccine that induces helper T cell 1 (Th1) and helper T cell (Th2) immune responses, making it an effective vaccine delivery system.

Controlling the speed of antigens transport in dendritic cells improves humoral and cellular immunity for vaccine.

Vaccines are an effective intervention for preventing infectious diseases. Currently many vaccine strategies are designed to improve vaccine efficacy by controlling antigen release, typically involving various approaches at the injection site. Yet, strategies for intracellular slow-release of antigens in vaccines are still unexplored. Our study showed that controlling the degradation of antigens in dendritic cells and slowing their transport from early endosomes to lysosomes markedly enhances both antigen-specific T-cell immune responses and germinal center B cell responses. This leads to the establishment of sustained humoral and cellular immunity in vivo imaging and flow cytometry indicated this method not only prolongs antigen retention at the injection site but also enhances antigen concentration in lymph nodes, surpassing traditional Aluminium (Alum) adjuvants. Additionally, we demonstrated that the slow antigen degradation induces stronger follicular helper T cell responses and increases proportions of long-lived plasma cells and memory B cells. Overall, these findings propose that controlling the speed of antigens transport in dendritic cells can significantly boost vaccine efficacy, offering an innovative avenue for developing highly immunogenic next-generation vaccines.

Exosomal circPOLQ promotes macrophage M2 polarization via activating IL-10/STAT3 axis in a colorectal cancer model.

BACKGROUND: Accumulating evidence demonstrates that an increased tumor-associated macrophage abundance is often associated with poor prognosis in colorectal cancer (CRC). The mechanism underlying the effect of tumor-derived exosomes on M2 macrophage polarization remains elusive. RESULTS: The novel circular RNA circPOLQ exhibited significantly higher expression in CRC tissues than in paired normal tissues. Higher circPOLQ expression was associated with poorer prognosis in patients with CRC. In vitro and in vivo experiments showed that tumor-derived exosomal circPOLQ did not directly regulate CRC cell development but promoted CRC metastatic nodule formation by enhancing M2 macrophage polarization. circPOLQ activated the interleukin-10/signal transducer and activator of transcription 3 axis by targeting miR-379-3 p to promote M2 macrophage polarization. CONCLUSION: circPOLQ can enter macrophages via CRC cell-derived exosomes and promote CRC metastatic nodule formation by enhancing M2 macrophage polarization. These findings reveal a tumor-derived exosome-mediated tumor-macrophage interaction potentially affecting CRC metastatic nodule formation.

Switchable Skeletal Rearrangement of Hexahydro-4H-indol-4-ones: Divergent Synthesis of Dihydroxy-4H-cyclopenta[b]pyridin-4-ones and 8-Alkenyl Oxepane-2,6-diones.

An unprecedented base-controlled selective skeletal rearrangement reaction of hexahydro-4H-indol-4-ones has been developed. In this protocol, highly functionalized dihydroxy-4H-cyclopenta[b]pyridin-4-ones and 8-alkenyl oxepane-2,6-diones were prepared with a broad substrate scope and high chemoselectivity in moderate to excellent yields selectively by modulating LiOH and Et3N. In addition, the newly formed 8-alkenyl oxepane-2,6-dione scaffolds could be easily further derivatized to 5-(pyrrol-2-yl)dihydrofuran-2(3H)-ones through a rare intramolecular rearrangement reaction.

Ursonic acid from medicinal herbs inhibits PRRSV replication through activation of the innate immune response by targeting the phosphatase PTPN1.

Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), has caused substantial economic losses to the global swine industry due to the lack of effective commercial vaccines and drugs. There is an urgent need to develop alternative strategies for PRRS prevention and control, such as antiviral drugs. In this study, we identified ursonic acid (UNA), a natural pentacyclic triterpenoid from medicinal herbs, as a novel drug with anti-PRRSV activity in vitro. Mechanistically, a time-of-addition assay revealed that UNA inhibited PRRSV replication when it was added before, at the same time as, and after PRRSV infection was induced. Compound target prediction and molecular docking analysis suggested that UNA interacts with the active pocket of PTPN1, which was further confirmed by a target protein interference assay and phosphatase activity assay. Furthermore, UNA inhibited PRRSV replication by targeting PTPN1, which inhibited IFN-ß production. In addition, UNA displayed antiviral activity against porcine epidemic diarrhoea virus (PEDV) and Seneca virus A (SVA) replication in vitro. These findings will be helpful for developing novel prophylactic and therapeutic agents against PRRS and other swine virus infections.

Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery.

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of -31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake.

Identification of B-cell epitopes located on the surface in the PB2 protein of the H9N2 subtype avian influenza virus.

Avian influenza (AI), caused by H9N2 subtype avian influenza virus (AIV), poses a serious threat to poultry farming and public health due to its transmissibility and pathogenicity. The PB2 protein is a major component of the viral RNA polymerase complex. It is of great importance to identify the antigenic determinants of the PB2 protein to explore the function of the PB2 protein. In this study, the PB2 sequence of H9N2 subtype AIV, from 1090 to 1689 bp, was cloned and expressed. The recombinant PB2 protein with cutting gel was used to immunize BALB/c mice. After cell fusion, the hybridoma cell lines secreting monoclonal antibodies (mAbs) targeting the PB2 protein were screened by indirect ELISA and western blotting, and the antigenic epitopes of mAbs were identified by constructing truncated overlapping fragments in the PB2 protein of H9N2 subtype AIV. The results showed that three hybridoma cell lines (4B7, 4D10, and 5H1) that stably secreted mAbs specific to the PB2 protein were screened; the heavy chain of 4B7 was IgG2α, those of 4D10 and 5H1 were IgG1, and all three mAbs had kappa light chain. Also, the minimum B-cell epitope recognized was 475LRGVRVSK482 and 528TITYSSPMMW537. Homology analysis showed that these two epitopes were conserved among the different subtypes of AIV strains and located on the surface of the PB2 protein. The above findings provide an experimental foundation for further investigation of the function of the PB2 protein and developing monoclonal antibody-based diagnostic kits.

Multi-objective and multi-solution source mask optimization using NSGA-II for more direct process window enhancement.

Source and mask optimization (SMO) technology is increasingly relied upon for resolution enhancement of photolithography as critical dimension (CD) shrinks. In advanced CD technology nodes, little process variation can impose a huge impact on the fidelity of lithography. However, traditional source and mask optimization (SMO) methods only evaluate the imaging quality in the focal plane, neglecting the process window (PW) that reflects the robustness of the lithography process. PW includes depth of focus (DOF) and exposure latitude (EL), which are computationally intensive and unfriendly to gradient-based SMO algorithms. In this study, we propose what we believe to be a novel process window enhancement SMO method based on the Nondominated Sorting Genetic Algorithm II (NSGA-II), which is a multi-objective optimization algorithm that can provide multiple solutions. By employing the variational lithography model (VLIM), a fast focus-variation aerial image model, our method, NSGA-SMO, can directly optimize the PW performance and improve the robustness of SMO results while maintaining the in-focus image quality. Referring to the simulations of two typical patterns, NSGA-SMO showcases an improvement of more than 20% in terms of DOF and EL compared to conventional multi-objective SMO, and even four times superior to single-objective SMO for complicated patterns.

The effect of lentinan on dexamethasone-induced immunosuppression in mice.

The immune system acts as a vital defense barrier against pathogenic invasions, and its stable operation is crucial for maintaining body health. Nevertheless, various natural or artificial factors can compromise the body's immune function, leading to immunosuppression, which may interfere with the efficacy of vaccination and increase the susceptibility of the body to disease-causing pathogens. In an effort to ensure successful vaccinations and improve overall physical well-being, the search for appropriate immune regulators to enhance immunity is of paramount importance. Lentinan (LNT) has a significant role in immune regulation and vaccine adjuvants. In the present study, we constructed an immunosuppressive model using dexamethasone (DEX) and demonstrated that LNT could significantly improved antibody levels in immunosuppressive mice and stimulated T-lymphocyte proliferation and differentiation in intestinal Peyer's patches. LNT also increased the production of secretory immunoglobulin A (sIgA) in the duodenal fluid, the number of goblet cells, and the proportion of mucin area. Moreover, LNT modulated the intestinal microbiota and increased the production of short-chain fatty acids. Additionally, LNT promoted the proliferation, differentiation, and pro-inflammatory cytokines production of DEX-treated splenic T lymphocytes in vitro. Thus, the present study highlights the potential of LNT in reversing immunosuppression and avoiding the failure of vaccination.

Mechanism of Peppermint Extract-Induced Delay of 'Packham's Triumph' Pear (Pyrus communis L.) Postharvest Ripening.

Postharvest ripening is correlated to the quality and shelf life of European pear fruit. In this study, the effects of peppermint extract on fruit phenotype, related physiological activities, and aroma components during postharvest ripening of the European pear variety 'Packham's Triumph' were examined. Fruit treated with 2.0 g L-1 peppermint extract for 12 h showed delayed softening by 4 d compared with that of the untreated control group. The peak values of ethylene and respiratory rate in fruit were reduced to a certain extent after peppermint extract treatment; however, the peppermint extract did not delay the occurrence of the respiratory climacteric peak. Peppermint extract treatment also did not significantly increase the content of the characteristic peppermint aroma in pear fruit. Further, widely targeted metabolome analysis revealed 298 significantly different metabolites, with flavonoids (40%) and lipid compounds (15%) accounting for the highest proportion on the first day after treatment. The Kyoto Encyclopedia of Genes and Genomes pathway result showed significant enrichment in the metabolic pathways of biosynthesis of flavonoid, isoflavonoid, flavone and flavonol, linoleic acid, and alpha-linolenic acid metabolism following peppermint extract treatment. The combined analysis of transcriptome and metabolome data showed significant enrichment in linoleic acid metabolism and alpha-linolenic acid metabolism on the first, third, and fifth days after peppermint extract treatment. This study indicates that peppermint extract mainly affects the pear fruit softening process in the early stage after treatment.

Mask-Moving-Lithography-Based High-Precision Surface Fabrication Method for Microlens Arrays.

Microlens arrays, as typical micro-optical elements, effectively enhance the integration and performance of optical systems. The surface shape errors and surface roughness of microlens arrays are the main indicators of their optical characteristics and determine their optical performance. In this study, a mask-moving-projection-lithography-based high-precision surface fabrication method for microlens arrays is proposed, which effectively reduces the surface shape errors and surface roughness of microlens arrays. The pre-exposure technology is used to reduce the development threshold of the photoresist, thus eliminating the impact of the exposure threshold on the surface shape of the microlens. After development, the inverted air bath reflux method is used to bring the microlens array surface to a molten state, effectively eliminating surface protrusions. Experimental results show that the microlens arrays fabricated using this method had a root mean square error of less than 2.8%, and their surface roughness could reach the nanometer level, which effectively improves the fabrication precision for microlens arrays.

First Report of Alternaria alternata Causing Leaf Blight on Elsholtzia ciliata in China.

Elsholtzia ciliata is an annual medicinal plant characterized to the family Lamiaceae Martinov. It is grown in most parts of China and has high economic value as a traditional Chinese medicine. In September of 2022, E. ciliata plants located at the planting base of traditional Chinses medicine in Daying county (30°35'40″N, 105°14 12″E), Sichuan Province, China, were recorded with leaf blight. The incidence of symptomatic plants was 15% (30 infected plants out of 200 surveyed). The symptoms included an irregular necrotic lesion at the tip of the leaf, which gradually expanded across the entire leaf. To elucidate the cause of the symptoms, 12 symptomatic leaves were sampled from four different plants and 5×5 mm section, including symptomatic and non-symptomatic tissue was excised. Tissue samples were disinfected in 75% ethanol for 30s, and 7% sodium hypochlorite for 1 min, and then rinsed three times with sterile distilled water (Sun et al. 2022). The sampled tissues were placed onto potato dextrose agar (PDA) and incubated at 25℃ in the dark. Seven days later, single spores were recovered onto fresh PDA (Zhu et al. 1992). Colonies on PDA initially appeared white, developing grayish-green conidia with white margins. Conidia (n=150) were collected and observed under the microscope. The conidia were smooth walled and dark brown, with pear-shaped, 12.1-31.4 × 5.0-9.4µm, with 3-5 transverse septa, 1-3 longitudinal or oblique septa. Conidiophores were thick, dark brown, simple with multiple conidial scars, 5.0-75.5 × 2.5.0-5.0µm. Based on morphological observations the 12 isolates were most similar to Alternaria alternata (Simmons 2007). The internal transcribed spacer (ITS) rDNA regions, glyceraldehyde-3-phosphate dehydrogenase (gpd), Alternaria major allergen (Alt a 1), RNA polymerase second largest subunit gene (RPB2) and translation elongation factor 1-alpha (TEF 1) were amplified and sequenced using the primers ITS4/ITS5, RPB2-5F/RPB2-7CR, gpd1/gpd2, EF1-728F/EF1-986R, and Alt-for/Alt-rev respectively (Woudenberg et al. 2015). The sequences of representative isolate (XR) were uploaded in GenBank (ITS: OM319521, RPB2: OM849248, gpd: OM296240, TEF1: OM238122, and Alt a 1: OM649814). The bootstrap value of the isolate and the type strain CBS 595.93 (ITS: KP124320, RPB2: KP124788, gpd: KP124175, TEF1: KP125096, and Alt a 1: JQ646399) on the phylogenetic tree was 99%. Therefore, based on morphology and phylogenetic analysis the fungus was identified as A. alternata. To verify pathogenicity, a spore suspension (1 × 106 conidia/ml) of the representative isolate XR was misted onto the foliage of six twenty-day-old non-symptomatic plants. Six additional plants were sprayed with distilled water and used as controls. The plants were covered with plastic bags for 48 h and incubated at a temperature of 28℃ in the dark. Eight days later, all inoculated plants demonstrated similar symptoms as recorded on the original source, while the control plants were symptomless. The experiment was repeated three times with similar results. A. alternata was re-isolated from the artificially inoculated plants, hence fulfilling Koch's postulates. To our best knowledge this is the first report of leaf blight caused by A. alternata in China on E. ciliate. The disease may be an economic threat and should be further monitored and studied.

First Report of Alternaria alternata Causing Leaf Spot on Oenothera biennis in China.

Oenothera biennis is a versatile plant that can be used for both ornamental and medicinal purposes. Its potential in treating a range of diseases is noteworthy and has been studied extensively (Bayles et al. 2009). In September 2022, leaf spot on O. biennis was first observed in a 0.2 ha plant experimental demonstration land in Libo County (25°23'24″N, 108°4'22″E), Guizhou Province, China. The incidence of all O. biennis was about 60% over the 0.2 ha surveyed. Initially, red round or irregular spots appeared on the leaves, which then gradually turned dry yellow. To identify the cause, diseased tissues (5 mm2) from the margin of the lesions were surface disinfected by immersion in 75% ethanol for 30 sec, and 7% sodium hypochlorite for 1 min, and then rinsed three times with sterile distilled water (Sun et al. 2022). The tissues were cultured in potato dextrose agar (PDA) at 25℃. After 7 days, further purification was performed by transferring onto the new PDA and potato carrot agar (PCA) by single-spore isolation. After 8 days, the colonies on PDA were 80 mm in diameter, cotton-like in texture, dark green in color and nearly circular in shape with a white edge. The conidia on the PCA were short-chains, pear-shaped or oval, pale brown, smooth surface, 15.3-30.8 × 8.3-12.6µm (n = 150). Beaks were columnar or conical, 0-6.0 × 0-4.0µm (n = 100). Conidiophores were solitary straight or flexuous less branched, dark brown, and measured 14.0-60.5 × 3.0-4.5µm. Based upon morphological observations, all these characteristics were consistent with those of Alternaria alternata (Simmons 2007). To further identify the fungal species, internal transcribed spacer (ITS) rDNA regions, glyceraldehyde-3-phosphate dehydrogenase (gpd), Alternaria major allergen (Alt a 1), RNA polymerase second largest subunit gene (RPB2) and translation elongation factor 1-alpha (TEF 1) were amplified and sequenced using the primers ITS4/ITS5, RPB2-5F/RPB2-7CR, gpd1/gpd2, EF1-728F/EF1-986R, and Alt-for/Alt-rev (Woudenberg et al. 2015). Sequences were deposited in GenBank (ITS: OM319523; RPB2: OM849249; gpd: OM296248; TEF1: OM238124; Alt a 1: OM649813). The similarity of the representative isolate YJC and the type strain CBS 595.93 (ITS: KP124320; RPB2: KP124788; gpd: KP124175; TEF1: KP125096; Alt a 1: JQ646399) on the phylogenetic tree was 98%. Therefore, the fungus was identified as A. alternata by morphology and phylogenetic analysis. To confirm pathogenicity, a spore suspension (1 × 106 conidia/ml) of the representative isolate YJC was sprayed on the leaves of six healthy plants and six plants sprayed with distilled water as controls. The plants used in the experiment were covered with plastic bags for 48 h (Luo et al. 2012). After 8 days, all inoculated plants exhibited symptoms of the disease, while the control plants remained symptom-free. The experiment was conducted twice using the same approach. The fungus that has been inoculated was reisolated from the leaves of the infected plants and identified as A. alternata through morphological observation, thus fulfilling Koch's postulates. To the best of our knowledge, this is the first documented case of O. biennis leaf spot caused by A. alternata. This pathogen could pose a threat to O. biennis yield and result in economic losses. For further development of specific control measures, it is important to confirm the identity.

Role of HOXA1-4 in the development of genetic and malignant diseases.

The HOXA genes, belonging to the HOX family, encompass 11 members (HOXA1-11) and exert critical functions in early embryonic development, as well as various adult processes. Furthermore, dysregulation of HOXA genes is implicated in genetic diseases, heart disease, and various cancers. In this comprehensive overview, we primarily focused on the HOXA1-4 genes and their associated functions and diseases. Emphasis was placed on elucidating the impact of abnormal expression of these genes and highlighting their significance in maintaining optimal health and their involvement in the development of genetic and malignant diseases. Furthermore, we delved into their regulatory mechanisms, functional roles, and underlying biology and explored the therapeutic potential of targeting HOXA1-4 genes for the treatment of malignancies. Additionally, we explored the utility of HOXA1-4 genes as biomarkers for monitoring cancer recurrence and metastasis.

An assessment system for clinical and biological interpretability in ulcerative colitis.

Ulcerative colitis (UC) is a serious inflammatory bowel disease (IBD) with high morbidity and mortality worldwide. As the traditional diagnostic techniques have various limitations in the practice and diagnosis of early ulcerative colitis, it is necessary to develop new diagnostic models from molecular biology to supplement the existing methods. In this study, we developed a machine learning-based synthesis to construct an artificial intelligence diagnostic model for ulcerative colitis, and the correctness of the model is verified using an external independent dataset. According to the significantly expressed genes related to the occurrence of UC in the model, an unsupervised quantitative ulcerative colitis related score (UCRScore) based on principal coordinate analysis was established. The UCRScore is not only highly generalizable across UC bulk cohorts at different stages, but also highly generalizable across single-cell datasets, with the same effect in terms of cell numbers, activation pathways and mechanisms. As an important role of screening genes in disease occurrence, based on connectivity map analysis, 5 potential targeting molecular compounds were identified, which can be used as an additional supplement to the therapeutic of UC. Overall, this study provides a potential tool for differential diagnosis and assessment of bio-pathological changes in UC at the macroscopic level, providing an opportunity to optimize the diagnosis and treatment of UC.

Roles of exosomes in immunotherapy for solid cancers.

Although immunotherapy has made breakthrough progress, its efficacy in solid tumours remains unsatisfactory. Exosomes are the main type of extracellular vesicles that can deliver various intracellular molecules to adjacent or distant cells and organs, mediating various biological functions. Studies have found that exosomes can both activate the immune system and inhibit the immune system. The antigen and major histocompatibility complex (MHC) carried in exosomes make it possible to develop them as anticancer vaccines. Exosomes derived from blood, urine, saliva and cerebrospinal fluid can be used as ideal biomarkers in cancer diagnosis and prognosis. In recent years, exosome-based therapy has made great progress in the fields of drug transportation and immunotherapy. Here, we review the composition and sources of exosomes in the solid cancer immune microenvironment and further elaborate on the potential mechanisms and pathways by which exosomes influence immunotherapy for solid cancers. Moreover, we summarize the potential clinical application prospects of engineered exosomes and exosome vaccines in immunotherapy for solid cancers. Eventually, these findings may open up avenues for determining the potential of exosomes for diagnosis, treatment, and prognosis in solid cancer immunotherapy.

Efficacy of first-line treatment options beyond RET-TKIs in advanced RET-rearranged non-small cell lung cancer: A multi-center real-world study.

BACKGROUND: Although RET-tyrosine kinase inhibitors (RET-TKIs) are the preferred first-line therapy for advanced RET-arranged NSCLC, most patients cannot afford them. In this population, bevacizumab, immunotherapy, and chemotherapy are the most commonly used regimens. However, the optimal scheme beyond RET-TKIs has not been defined in the first-line setting. METHODS: This retrospective study included 86 stage IV NSCLC patients harboring RET rearrangement from six cancer centers between May 2017 and October 2022. RET-TKIs, chemotherapy, or one of the combination therapies (including immune checkpoint inhibitor (ICI) combined with chemotherapy (I + C), bevacizumab combined with chemotherapy (B + C), ICI and bevacizumab combined with chemotherapy (I + B + C)), were used as the first-line therapeutics. The clinical outcomes and safety were evaluated. RESULTS: Fourteen of the 86 patients received RET-TKIs, 57 received combination therapies, and 15 received chemotherapy alone. Their medium PFS (mPFS) were 16.92 months (95% CI: 5.9-27.9 months), 8.7 months (95% CI: 6.5-11.0 months), and 5.55 months (95% CI: 2.4-8.7 months) respectively. Among all the combination schemes, B + C (p = 0.007) or I + B + C (p = 0.025) gave beneficial PFS compared with chemotherapy, while I + C treatment (p = 0.169) generated comparable PFS with chemotherapy. In addition, I + B + C treatment had a numerically longer mPFS (12.21 months) compared with B + C (8.74 months) or I + C (7.89 months) schemes. In terms of safety, I + B + C treatment led to the highest frequency of hematological toxicity (50%) and vomiting (75%), but no ≥G3 adverse effect was observed. CONCLUSIONS: I + B + C might be a preferred option beyond RET-TKIs in the first-line therapy of RET-arranged NSCLC. Combination with Bevacizumab rather than with ICIs offered favorable survival compared with chemotherapy alone.

YTHDF2-mediated circYAP1 drives immune escape and cancer progression through activating YAP1/TCF4-PD-L1 axis.

Immune escape is identified as one of the reasons for the poor prognosis of colorectal cancer (CRC) patients. Circular RNAs are considered to promote tumor progression by mediating tumor immune escape. We discovered that higher expression of circYAP1 was associated with a worse prognosis of CRC patients. Functional experiments in vitro and in vivo showed that circYAP1 upregulation inhibited the cytotoxicity of CD8+ T cells by upregulating programmed death ligand-1 (PD-L1). Mechanistically, we found that circYAP1 directly binds to the YAP1 protein to prevent its phosphorylation, enhancing proportion of YAP1 protein in the nucleus, and that YAP1 interacts with TCF4 to target the PD-L1 promoter and initiate PD-L1 transcription in CRC cells. Taken together, circYAP1 promotes CRC immune escape and tumor progression by activating the YAP1/TCF4-PD-L1 axis and may provide a new strategy for combination immunotherapy of CRC patients.