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Abstract Organoid technology provides a transformative approach to understand human physiology and pathology, offering valuable insights for scientific research and therapeutic development. Human gastric organoids, in particular, have gained significant interest for applications in disease modeling, drug discovery, and studies of tissue regeneration and homeostasis. However, the lack of standardized quality control has limited their extensive clinical applications. The “Human Gastric Organoids” is part of a series of guidelines for human gastric organoids in China, which establishes comprehensive standards on terminology, technical specifications, testing methods, inspection rules, usage instructions, labeling, transportation, and storage, developed by experts from the Chinese Society for Cell Biology and its branch societies. Released on October 29, 2024, this guideline aims to establish standardized protocols, enhance institutional practices, and promote international standardization for clinical and research applications of human gastric organoids.

Abstract Background Agonistic monoclonal antibodies targeting 4-1BB/CD137 have shown preclinical promise, but their clinical development has been limited by severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy. Methods A novel anti-MSLN×4-1BB bispecific antibody (bsAb) was generated via antibody engineering, and its affinity and activity were detected via enzyme-linked immunosorbent assay (ELISA), flow cytometry, and T-cell activation and luciferase reporter assays. In vivo antitumour activity was assessed by establishing humanized mice bearing human MSLN-expressing MC38 (MC38/hMSLN) or CT26 (CT26/hMSLN) cells, and safety was further evaluated in cynomolgus monkeys. Results We generated two humanized anti-MSLN×4-1BB bsAbs (HK013-G1/G4) by fusing an anti-4-1BB scFv to the C-terminus of an anti-MSLN VHH with an intact Fc fragment from human IgG1 or IgG4. The two bsAbs were able to block the binding of CA125 to MSLN and stimulate 4-1BB signaling pathway, which was strictly dependent on MSLN expression. In particular, HK013-G1 retained Fc function and induced ADCC effect in tumour cells, whereas HK013-G4 did not. Strikingly, HK013-G1 showed superior antitumour activity to HK013-G4 both in vitro and in vivo and remained effective even in the presence of soluble MSLN. HK013-G1 enhanced antitumour immunity and induced durable antigen-specific immune memory to prevent rechallenged tumour growth, even at a dose as low as 1 mg/kg. Furthermore, HK013-G1 did not induce nonspecific production of proinflammatory cytokines and showed good tolerability up to the highest tested dose (30 mg/kg weekly) for 5 weeks, with no HK013-G1-related adverse effects observed in cynomolgus monkeys. In addition, the mean half-life of HK013-G1 was approximately 61 and 97 h at single doses of 3 and 30 mg/kg, respectively. Conclusion The optimal anti-MSLN×4-1BB bsAb HK013-G1 exhibited synergistic antitumour effects by inducing an ADCC effect (innate immunity) and stimulating the 4-1BB signaling pathway (adaptive immunity) upon cross-bridging with MSLN with no systemic toxicity, which may offer the promise of an improved therapeutic window relative to that of 4-1BB agonists.

Objective: Esophageal cancer (EC) ranks eighth among cancers in cancer-related deaths globally, and ~44% of new cases occur in China. We sought to describe the clinical characteristics and treatment landscape of EC in China before the approval of immunotherapy in 2020. Methods: CHANNEL was a large, retrospective study using patient-level data from 14 hospitals/cancer centers across China, including adults initiating therapy for newly diagnosed EC (January to December 2018). Demographics, clinicopathologic characteristics, and treatment patterns over 6 months were descriptively summarized. Results: Of 3,493 patients, 75.7% were men, the mean age was 64.1 years, and 75.0% had no family history of cancer. Most (92.8%) had squamous cell carcinoma, with a primary lesion in the middle esophagus (56.4%). Among patients with resectable EC, 92.9% received initial surgery, and 7.1% received neoadjuvant therapy, primarily chemotherapy (85.5% platinum-taxane). Among patients with unresectable early or locally advanced EC, 50.8% and 49.2% received palliative and radical therapy, respectively, as the initial treatment, primarily chemotherapy (66.5% platinum-taxane) and chemoradiotherapy (50.8% platinum-taxane), respectively. Adjuvant therapy was administered to 22.9% of patients undergoing initial surgery, and 2.4% receiving neoadjuvant therapy and surgery. Among patients with advanced EC, 84.6% received systemic therapy as an initial treatment, primarily chemotherapy (61.5% platinum-taxane). Conclusions: Before the approval of immunotherapy in China, most patients with resectable early or locally advanced EC underwent radical surgery without preoperative treatment, whereas most patients with advanced EC received platinum-taxane chemotherapy. These findings highlight the need for novel EC treatments before immunotherapy was introduced, and provide a baseline for evaluating the benefits of immunotherapy, now that this treatment is widely used in this setting.

Abstract Background/aim This research study was conducted to examine the clinical characteristics and post-splenectomy survival outcomes of patients diagnosed with hepatosplenic T-cell lymphoma (HSTCL). Materials and methods A total of 10 cases of HSTCL patients admitted to the Hematology Department of Fudan University Affiliated Huadong Hospital between January 2012 and December 2021 were included. In addition, we also included 30 other cases reported from domestic and international sources. All pathological specimens were stained with hematoxylin and eosin (H&E) and immunohistochemistry, with color development using DAB staining. Survival analysis was conducted using Kaplan-Meier curves and log-rank tests. Results In the 10 HSTCL patients, Epstein-Barr virus (EBV) infection was confirmed. Six patients had died, with 5 of them within 1 year of disease onset. Survival analysis showed poorer prognosis in patients with hemophagocytic syndrome and thrombocytopenia. Patients who underwent splenectomy followed by chemotherapy had a higher median and average survival time compared to those who only received chemotherapy. The study included a total of 40 HSTCL patients, with 29 males and 11 females, and an average age of onset at 42.3 years. All patients presented with fever, with some exhibiting emaciation and/or hemophagocytic syndrome. Splenomegaly, hepatomegaly, lymphadenopathy, and bone marrow involvement were found in the patients. Common laboratory findings included leukopenia, anemia, and thrombocytopenia. All patients exhibited elevated ferritin levels and decreased blood calcium levels. Conclusion Those patients suffering from hemophagocytic syndrome at the onset of this disease face greater treatment-related difficulties and a higher risk of mortality. Combined chemotherapy after splenectomy may improve HSTCL patient survival.

Abstract Gastric cancer is one of the most common malignancies with poor prognosis. The use of organoids to simulate gastric cancer has rapidly developed over the past several years. Patient-derived gastric cancer organoids serve as in vitro models that closely mimics donor characteristics, offering new opportunities for both basic and applied research. The “Human Gastric Cancer Organoid” is part of a series of guidelines for human gastric cancer organoids in China, jointly drafted by experts from the Chinese Society for Cell Biology and its branches, and initially released on October 29, 2024. This standard outlines terminology, technical requirements, assessment protocols, and applies to production, evaluation procedures, and quality control for human gastric cancer organoids. The publication of this guideline aims to assist institutions in endorsing, establishing, and applying best practices, advancing the international standardization of human gastric cancer organoids for clinical development and therapeutic application.

Abstract The pathophysiology of immune checkpoint inhibitor-related pneumonitis remains incompletely understood. We conducted single-cell and T-cell receptor transcriptomic sequencing on the bronchoalveolar lavage fluid from five patients with grade ≥2 immune checkpoint inhibitor-related pneumonitis. Our analyses revealed a prominent enrichment of T cells in the bronchoalveolar lavage fluid of patients with immune checkpoint inhibitor-related pneumonitis. Within the CD4 + T cell subset, Tfh-like T cells were highly enriched and exhibited signatures associated with inflammation and clonal expansion. Regulatory T cells were also enriched and displayed enhanced inhibitory functions. Within the CD8 + T-cell subset, effector memory/tissue-resident memory T cells with an elevated cytotoxic phenotype were highly infiltrated. Among myeloid cells, alveolar macrophages were depleted, while pro-inflammatory intermediate monocytes were elevated. Dendritic cells demonstrated enhanced antigen presentation capabilities. Cytokines CXCR4, CXCL13, TNF-α, IFN-α, IFN-γ, and TWEAK were elevated. Through a comprehensive single-cell analysis, we depicted the landscape of immune checkpoint inhibitor-related pneumonitis.

Abstract Metabolic reprogramming, a key mechanism regulating the growth and recurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), still lacks effective clinical strategies for its integration into the precise screening of primary liver cancer. This study utilized ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry to conduct a comprehensive, non-targeted metabolomics analysis, revealing significant upregulation of lipid metabolites such as phosphatidylcholine and lysophosphatidylcholine in patients with HCC and CCA, particularly within the glycerophospholipid metabolic pathway. Hematoxylin and eosin and immunohistochemical staining demonstrated marked upregulation of phospholipase A2 in tumor tissues, further emphasizing the potential of lipid metabolism as a therapeutic target and its important part in the course of cancer. This work provides a new viewpoint for addressing the clinical challenges associated with HCC and CCA, laying the groundwork for the broad application of early diagnosis and personalized treatment strategies, and ultimately aiming to provide tailored and precise therapeutic options for patients.

Abstract. Background:. While some studies have reported the impact of COVID-19 vaccines on immune recovery and human immunodeficiency virus (HIV) reservoirs in persons living with HIV (PLWH), their findings remain inconsistent. Furthermore, limited data exist on the safety of multiple COVID-19 vaccines among PLWH. This study aimed to investigate the safety of heterological COVID-19 vaccine administration in PLWH receiving antiretroviral treatment (ART) and its effects on HIV reservoirs and immune recovery. Such an investigation can help provide a basis for vaccinations against COVID-19 in PLWH. Methods:. In this cross-sectional study, PLWH receiving ART were recruited from the outpatient clinic of the Department of Infectious Diseases at the Fifth Medical Center of the Chinese PLA General Hospital from September 1, 2021 to December 31, 2021. Fifty-three PLWH receiving ART were vaccinated against COVID-19, with 35 receiving an inactivated vaccine (IN group) and 18 receiving a recombinant protein (CHO cells) vaccine (CHO group) as the third dose. We assessed the changes in liver and kidney functions, blood lipids, and other laboratory parameters at 0, 1, 2, 4, 7, 8, 10, and 13 months after the first vaccination dose. We also monitored CD4+ and CD8+ T cell counts using flow cytometry at 0, 1, 2, 4, 7, 8, 10, and 13 months after the first vaccination dose, as well as levels of cell-associated HIV DNA (CA HIV DNA) and cell-associated HIV RNA (CA HIV RNA) in peripheral blood using the corresponding quantitative detection kits at 0, 2, and 8 months after the first vaccination dose. Results:. No severe adverse events related to either type of COVID-19 vaccine were observed in HIV patients, irrespective of their CD4+ T cell levels. Both the IN and CHO groups showed significant increases in CD4+ T cell counts during follow-up, CD4+ T cells increased from 438 ± 45 cells/μL to 557 ± 48 cells/μL in the CHO group, while in the IN group, it increased from 448 ± 34 cells/μL to 572 ± 39 cells/μL (both P < 0.001). CA HIV DNA initially decreased and then increased in both groups. CA HIV RNA levels showed significantly decreased in both group after three doses of vaccination (P < 0.01 in CHO group and P < 0.001 in IN group). CD8+ T cells increased from 608 ± 77 cells/μL to 812 ± 116 cells/μL in the CHO group (P < 0.01), while in the IN group, it increased from 702 ± 71 cells/μL to 852 ± 68 cells/μL(P < 0.001) from baseline to the 13 month of following up. Conclusion:. Our data suggest that the SARS-CoV-2 booster vaccine is safe for PLWH on ART, although it may affect HIV reservoirs and CD8+ T cell counts.

Abstract Biocatalysis is an attractive approach for the synthesis of chiral pharmaceuticals and fine chemicals, but assessing and/or improving the enantioselectivity of biocatalyst towards target substrates is often time and resource intensive. Although machine learning has been used to reveal the underlying relationship between protein sequences and biocatalytic enantioselectivity, the establishment of substrate fitness space is usually disregarded by chemists and is still a challenge. Using 240 datasets collected in our previous works, we adopt chemistry and geometry descriptors and build random forest classification models for predicting the enantioselectivity of amidase towards new substrates. We further propose a heuristic strategy based on these models, by which the rational protein engineering can be efficiently performed to synthesize chiral compounds with higher ee values, and the optimized variant results in a 53-fold higher E-value comparing to the wild-type amidase. This data-driven methodology is expected to broaden the application of machine learning in biocatalysis research.

Abstract The ecological compensation mechanism is a tool for managing regional development and promoting the green economy. This paper proposes a revised model for carbon emissions and absorption based on IPCC, then analyses the spatial and temporal variations of carbon emissions, absorption, and deficit in 31 provinces of China from 2001 to 2019. A model was developed to redistribute carbon deficits and compensate for ecological imbalances, with the aim of eliminating background differences between regions. The concept of ecological compensation sensitivity was proposed, and a redundancy analysis (RDA) was conducted to detect possible influencing factors. Results indicate that: (1) The carbon deficits were relatively substantial in the centre and developed coastal regions, which were the subject regions of China’s ecological compensation. Meanwhile, the northwest and southwest regions were the object regions of ecological compensation, and the compensated object regions tended to extend towards the southeast. The majority of compensated subject areas are generally less sensitive than compensated object regions. (2) The graph of carbon deficit volume over time shows that China’s two carbon targets are closely aligned. The distribution of China’s ecological compensation amounts follows the pattern of provincial economic development levels, with higher compensation amounts concentrated in the central and coastal regions. There is a positive correlation between GDP, year, and population size with carbon emission and carbon deficit. Additionally, there is a positive correlation between year, region, and carbon absorption. (3) This compensation model can strongly incentivise the compensation subject area to proactively adjust its economic development model to cope with the significant compensation pressure. Additionally, it can fully encourage the compensation recipient area to continue adhering to the green economic development model. The conclusions of the study hold significant reference value for promoting the development of a green, low-carbon economy.

Abstract Although histological and molecular classifications have been extensively studied for gastric cancer (GC), targeted therapies for GC remain limited. CDH1 mutations (MT) are characteristic of genomically stable GC and are associated with poor prognosis, but lack effective or targeted therapies. Here, we showed the overall mutation frequency of CDH1 was 9.7% (155 of 1596). CDH1-MT GC showed significantly lower rates of PD-L1 positivity (CPS score ≥1) than CDH1-wildtype (WT) GC (56.7% vs. 73.3%, p

Abstract The immunosuppressive residual tumor microenvironment (IRTM) is a key factor in the high recurrence and metastasis rates of hepatocellular carcinoma (HCC) after microwave ablation (MWA). Cholesterol‐rich tumor fragments significantly contribute to IRTM deterioration. This study developed a cholesterol‐targeted catalytic hydrogel, DA‐COD‐OD‐HCS, to enhance the synergy between MWA and immune checkpoint inhibitors (ICIs) for HCC treatment. Cholesterol oxidase (COD), modified with dimethyl maleic anhydride (DA) for release in acidic IRTM, is used to degrade cholesterol. Oxydextran (OD) and hemin‐chitosan (HCS) formed a dual network gel, ensuring long‐term fixation of COD and hemin in the IRTM post‐MWA. In both in vitro and in vivo HCC models, DA‐COD‐OD‐HCS effectively released COD, degraded cholesterol, and induced tumor cell ferroptosis, enhancing the antitumor immune response. Combined with anti‐PD‐L1 immunotherapy, this strategy inhibited primary tumor growth and distant metastases, without side effects on adjacent tissues. This work highlights that cholesterol‐targeting catalytic hydrogels fueled by tumor debris can significantly improve the efficacy of MWA and ICIs, offering a novel therapeutic approach for HCC.

Excessive copper (Cu) has the potential risk to ecosystems and organism health, with its impact on dairy cow mammary glands being not well-defined. This study used a bovine mammary epithelial cell (MAC-T) model to explore how copper excess affects cellular oxidative stress, autophagy, ferroptosis, and protein and lipid biosynthesis in milk. Results showed the increased intracellular ROS, MDA, and CAT (P

The influence of inter-typological variations on the processing of manner information has been extensively examined in the domain of motion. Manner, however, extends to more other semantic domains, as demonstrated in the onomasiological approach to manner analysis. This study, based on this approach, analyses the influence of directionality and cognitive load (measured by interpreting performance) on the transfer of manner under high cognitive demands, using bidirectional corpus data of consecutive interpreting between Chinese (an equipollently framed language) and English (a satellite-framed language). The results indicate that (1) increased interpreting performance correlates with higher transfer rates of both manner adjuncts and verbs; (2) transfer rates for manner verbs are significantly higher when interpreting into English (CE) than into Chinese (EC), supporting previous findings on the salience of manner in English; (3) interpreting direction influences resistance to cognitive load, with manner adjuncts showing greater resistance in the EC direction due to Chinese’s more flexible locus of manner information, while manner verbs exhibit better resistance in the CE direction, reflecting English’s higher verbal codability of manner. These findings suggest the broader applicability of Talmy’s typology to semantic domains beyond motion and to processing under high cognitive loads in different language combinations and interpreting modes.

Abstract Infigratinib, an FGFR1‐3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open‐label, single‐arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a “3 weeks on, 1 week off” schedule for 28‐day cycles. Plasma PK parameters were calculated with a non‐compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean Cmax of 85.9 ng/mL and AUC0‐t of 637 h*ng/mL. After 21‐day dosing, geometric mean infigratinib Cmax,ss of 204 ng/mL was reached at a median of 4.0 h; geometric mean AUC0‐24,ss was 3060 h*ng/mL. The geometric mean Rac,Cmax (%CV) and Rac,AUC0‐24 (%CV) of infigratinib was 2.5 (113.8) and 5.1 (138.2), respectively. A steady state of infigratinib was reached after continuous dosing for 15 days. The metabolites accounting for >10% of infigratinib were BHS697 and CQM157. The PK profiles of infigratinib and its metabolites in Chinese patients with GC or GEJ were largely consistent with known PK profiles of infigratinib from global populations.

Abstract Major strike-slip faults that develop between strong and weaker regions are thought to focus along narrow shear zones at the rheological boundary. Here we present the InSAR-derived velocity field spanning almost the entire length of one such fault, the 1600 km-long Altyn Tagh Fault (ATF), and analyse the strain distribution. We find that localisation of strain is actually variable, in contrast to other major strike-slip faults that show little variation, with strain concentrated at the fault for some sections and distributed over broad (>100 km) shear zones for others. Slip rate along the ATF is also variable, decreasing along the fault from 11.6 ± 1.6 mm/yr in the west to 7.2 ± 1.4 mm/yr in the central portion, before increasing again to 11.7 ± 0.9 mm/yr over the eastern portion. We show that the variable shear zone width may be linked to geological variability and the influence of heat flow, and the results imply that sub-parallel faults play an important role in the overall deformation field. This demonstrates the significance of accurately characterising strain rates over a broad region when assessing seismic hazard.

Abstract The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.

Abstract Background FGFR genomic aberrations occur in approximately 5–10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer. Methods Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics. Results Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7–63.6); the median progression-free survival was 5.6 months (95% CI, 3.6–12.7) and median overall survival was 40.2 months (95% CI, 12.4–not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5–57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%). Conclusions Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals. Trial registration This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

Abstract Purpose of review Atherosclerosis, a highly pathogenic and lethal disease, is difficult to locate accurately via conventional imaging because of its scattered and deep lesions. However, second near-infrared (NIR-II) nanomaterials show great application potential in the tracing of atherosclerotic plaques due to their excellent penetration and angiographic capabilities. Recent findings With the development of nanotechnology, among many nanomaterials available for the visual diagnosis and treatment of cardiovascular diseases, optical nanomaterials provide strong support for various biomedical applications because of their advantages, such as noninvasive, nondestructive and molecular component imaging. Among optical nanomaterials of different wavelengths, NIR-II-range (900 ~ 1700 nm) nanomaterials have been gradually applied in the visual diagnosis and treatment of atherosclerosis and other vascular diseases because of their deep biological tissue penetration and limited background interference. Summary This review explored in detail the prospects and challenges of the biological imaging and clinical application of NIR-II nanomaterials in treating atherosclerosis. Graphical abstract

Abstract In the KEYNOTE-811 study, anti-HER2 and immunotherapy treatments resulted in longer survival in HER2-positive gastric cancer patients with CPS ≥ 1, whereas CPS

Abstract The sole use of single modality data often fails to capture the complex heterogeneity among patients, including the variability in resistance to anti-HER2 therapy and outcomes of combined treatment regimens, for the treatment of HER2-positive gastric cancer (GC). This modality deficit has not been fully considered in many studies. Furthermore, the application of artificial intelligence in predicting the treatment response, particularly in complex diseases such as GC, is still in its infancy. Therefore, this study aimed to use a comprehensive analytic approach to accurately predict treatment responses to anti-HER2 therapy or anti-HER2 combined immunotherapy in patients with HER2-positive GC. We collected multi-modal data, comprising radiology, pathology, and clinical information from a cohort of 429 patients: 310 treated with anti-HER2 therapy and 119 treated with a combination of anti-HER2 and anti-PD-1/PD-L1 inhibitors immunotherapy. We introduced a deep learning model, called the Multi-Modal model (MuMo), that integrates these data to make precise treatment response predictions. MuMo achieved an area under the curve score of 0.821 for anti-HER2 therapy and 0.914 for combined immunotherapy. Moreover, patients classified as low-risk by MuMo exhibited significantly prolonged progression-free survival and overall survival (log-rank test, P

Objective: This study evaluated the safety and efficacy of an anti-epidermal growth factor receptor (EGFR) antibody (SCT200) and an anti-programmed cell death 1 (PD-1) antibody (SCT-I10A) as third-line or subsequent therapies in patients with rat sarcoma viral oncogene (RAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type (wt) metastatic colorectal cancer (mCRC). Methods: We conducted a multicenter, open-label, phase Ib clinical trial. Patients with histologically confirmed RAS/BRAF wt mCRC with more than two lines of treatment were enrolled and treated with SCT-I10A and SCT200. The primary endpoints were the objective response rate (ORR) and safety. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-one patients were enrolled in the study through January 28, 2023. The ORR was 28.57% and the DCR was 85.71% (18/21). The median PFS and OS were 4.14 and 12.84 months, respectively. The treatment-related adverse events (TRAEs) were tolerable. Moreover, compared with the monotherapy cohort from our previous phase I study evaluating SCT200 for RAS/BRAF wt mCRC in a third-line setting, no significant improvements in PFS and OS were observed in the combination group. Conclusions: SCT200 combined with SCT-I10A demonstrated promising efficacy in previously treated RAS/BRAF wt mCRC patients with an acceptable safety profile. Further head-to-head studies with larger sample sizes are needed to validate whether the efficacy and safety of combined anti-EGFR and anti-PD-1 therapy are superior to anti-EGFR monotherapy in the third-line setting. (Registration No. NCT04229537).

In addition to the cardinal motor symptoms, pain is a major non-motor symptom of Parkinson's disease (PD). Neuroinflammation in the substantia nigra pars compacta and dorsal striatum is involved in neurodegeneration in PD. But the polarization of microglia and astrocytes in the dorsal striatum and their contribution to motor deficits and hyperalgesia in PD have not been characterized. In the present study, we observed that hemiparkinsonian mice established by unilateral 6-OHDA injection in the medial forebrain bundle exhibited motor deficits and mechanical allodynia. In these mice, both microglia and astrocytes in the dorsal striatum were activated and polarized to M1/M2 microglia and A1/A2 astrocytes as genes specific to these cells were upregulated. These effects peaked 7 days after 6-OHDA injection. Meanwhile, striatal astrocytes in parkinsonian mice also displayed hyperpolarized membrane potentials, enhanced voltage-gated potassium currents, and dysfunction in inwardly rectifying potassium channels and glutamate transporters. Systemic administration of minocycline, a microglia inhibitor, attenuated the expression of genes specific to M1 microglia and A1 astrocytes in the dorsal striatum (but not those specific to M2 microglia and A2 astrocytes), attenuated the damage in the nigrostriatal dopaminergic system, and alleviated the motor deficits and mechanical allodynia in parkinsonian mice. By contrast, local administration of minocycline into the dorsal striatum of parkinsonian mice mitigated only hyperalgesia. This study suggests that M1 microglia and A1 astrocytes in the dorsal striatum may play important roles in the development of pathophysiology underlying hyperalgesia in the early stages of PD.

Abstract Background Diabetes mellitus is generally accompanied by dyslipidaemia, but inconsistent relationships between lipid profiles and diabetes are noted. Moreover, genetic variations in insertion/deletion (I/D) polymorphisms at angiotensin-converting enzyme gene (ACE) and T/C polymorphisms in the angiotensin type 1 receptor gene (AGTR1) are related to diabetes and lipid levels, but the associations are controversial. Thus, the current research aimed to explore the effects of ACE I/D, AGTR1 rs5182 and diabetes mellitus on serum lipid profiles in 385 Chinese participants with an average age of 75.01 years. Methods The ACE I/D variant was identified using the polymerase chain reaction (PCR) method, whereas the AGTR1 rs5182 polymorphism was identified using the PCR-based restriction fragment length polymorphism (PCR-RFLP) method and verified with DNA sequencing. Total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured using routine methods, and the lipid ratios were calculated. Results ACE I/D, but not AGTR1 rs5182, was a predictor of TG/HDL-C for the whole study population. Both ACE I/D and AGTR1 rs5182 were predictors of HDL-C and LDL-C levels in females but not in males. Moreover, in females, diabetes mellitus and ACE I/D were identified as predictors of TG and TG/HDL-C, whereas AGTR1 rs5182 and diabetes mellitus were predictors of TG/HDL-C. Moreover, diabetes mellitus and the combination of ACE I/D and AGTR1 rs5182 variations were predictors of TG and TG/HDL-C exclusively in females. Conclusions The results demonstrated the potential for gender-dependent interactions of ACE I/D, AGTR1 rs5182, and diabetes on lipid profiles. These findings may serve as an additional explanation for the inconsistent changes of blood lipids in individuals with diabetes mellitus, thereby offering a novel perspective for the clinical management of blood lipid levels in diabetic patients.

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally. Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics, the management of gastric cancer calls for better-defined, biomarker-guided, molecular-based treatment strategies. MET is a receptor tyrosine kinase mediating important physiologic processes, such as embryogenesis, tissue regeneration, and wound healing. However, mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types, including gastric cancer, and is associated with poor patient outcomes. As such, MET-targeting therapies are being actively developed and promising progress has been demonstrated, especially with MET tyrosine kinase inhibitors. This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib, tepotinib, capmatinib, and crizotinib. Building on current knowledge, this review further discusses existing challenges in MET alterations testing, possible resistance mechanisms to MET inhibitors, and future directions of MET-targeting therapies.

Abstract Radiation‐induced heart disease (RIHD) is a heterogeneous, delayed, and potentially fatal adverse reaction to radiation that can damage all structures of the heart, including the pericardium, myocardium, coronary arteries, valves, and conduction system, leading to a series of diseases. Acute and chronic disease processes play a role in the development of RIHD, the onset times of which range from months to decades. However, the clinical manifestations of RIHD are usually insidious, overlap with several other diseases, and lack specificity. Cardiovascular imaging is essential for early diagnosis, follow‐up, and outcome assessment in patients with RIHD. This review first describes the pathogenesis and clinical manifestations of RIHD before providing an overview of the practical approaches and research advances in multimodal cardiovascular imaging in patients with RIHD, including echocardiography, cardiac magnetic resonance (CMR) and nuclear medicine, and cardiac computed tomography (CT). Then, the value of new cardiac imaging assessments for the early diagnosis of RIHD is described, particularly with relation to speckle‐tracking echocardiography, extracellular volume fraction assessment as a quantitative CMR technique, CMR myocardial strain assessment, positron emission tomography‐CT myocardial perfusion imaging, CT‐ECV, and CT strain assessment, amongst others. In addition, the advantages and disadvantages of each screening technique are compared with the aim of better guiding the follow‐up and diagnosis of subclinical RIHD and preventing cardiovascular events.

Abstract Purpose The objective of this study was to provide a comprehensive review of the existing literature regarding the treatment of osteochondral lesions of the talus (OLT) using autologous matrix-induced chondrogenesis (AMIC), while also discussing the mid-long term functional outcomes, complications, and surgical failure rate. Methods We searched Embase, PubMed, and Web of Science for studies on OLT treated with AMIC with an average follow-up of at least 2 years. Publication information, patient data, functional scores, surgical failure rate, and complications were extracted. Results A total of 15 studies were screened and included, with 12 case series selected for meta-analysis and 3 non-randomized controlled studies chosen for descriptive analysis. The improvements in the Visual Analog Scale (VAS), the American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot, and Tegner scores at the last follow-up were (SMD = − 2.825, 95% CI − 3.343 to − 2.306, P

Abstract Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal squamous cell carcinoma (ESCC) patients, but anti-EGFR treatments offer limited survival benefits. Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC. This proof-of-concept, phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients (n = 41) with EGFR overexpression (NCT03940976). The study met its primary endpoint, with a confirmed objective response rate (ORR) of 39% in 38 efficacy-evaluable patients and a median overall survival of 7.8 months, with a manageable toxicity profile. Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2 (NTRK2) was negatively associated with afatinib sensitivity and might serve as a predictive biomarker, irrespective of EGFR expression. Notably, knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment. Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

The World Health Organization (WHO) 2017 classifications for neuroendocrine neoplasms (NENs) subdivided grade 3 pancreatic neuroendocrine neoplasms (pNENs) into G3 well-differentiated pancreatic neuroendocrine tumors (G3 pNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), according to the mitotic count, Ki-67 index, and cell differentiation. As a new category, G3 pNETs remain a challenging group of tumors to manage by lacking large randomized trials and consensus to support its clinical practice. Therefore, the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association gathered experts in this field to formulate this consensus for the diagnosis and treatment of G3 pNETs.

Photoacoustic microscopy (PAM) leverages the photoacoustic effect to provide high-resolution structural and functional imaging. However, achieving high-speed imaging with high spatial resolution remains challenging. To address this, undersampling and deep learning have emerged as common techniques to enhance imaging speed. Yet, existing methods rarely achieve effective recovery of functional images. In this study, we propose Mask-enhanced U-net (MeU-net) for recovering sparsely sampled PAM structural and functional images. The model utilizes dual-channel input, processing photoacoustic data from 532 nm and 558 nm wavelengths. Additionally, we introduce an adaptive vascular attention mask module that focuses on vascular information recovery and design a vessel-specific loss function to enhance restoration accuracy. We simulate data from mouse brain and ear imaging under various levels of sparsity (4 ×, 8 ×, 12 ×) and conduct extensive experiments. The results demonstrate that MeU-net significantly outperforms traditional interpolation methods and other representative models in structural information and oxygen saturation recovery.