Anlotinib may enhance the efficacy of anti-PD1 therapy by inhibiting the AKT pathway and promoting the apoptosis of CAFs in lung adenocarcinoma.

Although PD-1 inhibitors have revolutionized the treatment paradigm of non-small cell lung cancer (NSCLC), their efficacy in treating NSCLC has remained unsatisfactory. Targeting cancer-associated fibroblasts (CAFs) is a potential approach for improving the immunotherapy response. Multitarget antiangiogenic tyrosine kinase receptor inhibitors (TKIs) can enhance the efficacy of PD-1 inhibitors in NSCLC patients. However, the effects and mechanisms of antiangiogenic TKIs on CAFs have not been elucidated. In this study, we first compared anlotinib with other antiangiogenic TKIs and confirmed the superior efficacy of anlotinib. Furthermore, we established NSCLC-associated CAF models and found that anlotinib impaired CAF viability and migration capacity and contributed to CAF apoptosis and cell cycle arrest in the G2/M phase. Moreover, anlotinib treatment attenuated the capacity of CAFs to recruit lung cancer cells and macrophages. Experiments in animal models suggested that anlotinib could enhance the efficacy of anti-PD1 therapy in NSCLC and affect CAF proliferation and apoptosis. Anlotinib increased the abundance of tumor-infiltrating CD8 + T cells, and PD-1 inhibitor-induced cytotoxicity to tumor cells was achieved through the transformation of the tumor microenvironment (TME) caused by anlotinib, which may partly explain the synergistic antitumor effect of anlotinib and PD-1 inhibitors. Mechanistically, anlotinib affects CAF apoptosis and cell viability at least in part by inhibiting the AKT pathway. In conclusion, our study suggested that anlotinib could regulate the TME, inhibit the AKT pathway and promote CAF apoptosis, providing new insights into the antitumor effect of anlotinib and improving the efficacy of immunotherapy.

Research status and challenges of plant-derived exosome-like nanoparticles.

In recent years, there has been an increasing number of related studies on exosomes. Most studies have focused on exosomes derived from mammals, confirming the important role that exosomes play in cell communication. Plants, as a natural ingredient, plant-derived exosomes have been confirmed to have similar structures and functions to mammalian-derived exosomes. Plant-derived exosome-like nanoparticles (PELNs) are lipid bilayer membrane nanovesicles containing bioactive constituents such as miRNA, mRNA, protein, and lipids obtained from plant cells, that can participate in intercellular communication and mediate transboundary communication, have high bioavailability and low immunogenicity, are relatively safe, and have been shown to play an important role in maintaining cell homeostasis and preventing, and treating a variety of diseases. In this review, we describe the biogenesis, isolation and purification methods, structural composition, stability, safety, function of PELNs and challenges. The functions of PELNs in anti-inflammatory, antioxidant, antitumor and drug delivery are mainly described, and the status of research on exosome nanoparticles of Chinese herbal medicines is outlined. Overall, we summarized the importance of PELNs and the latest research results in this field and provided a theoretical basis for the future research and clinical application of PELNs.

Revealing the specific regulations of nitric oxide on the postharvest ripening and senescence of bitter melon fruit.

Bitter melon fruit is susceptible to yellowing, softening, and rotting under room-temperature storage conditions, resulting in reduced commercial value. Nitric oxide (NO) is an important signaling molecule and plays a crucial role in regulating the fruit postharvest quality. In this study, we investigated the effects of NO treatment on changes in sensory and firmness of bitter melon fruit during postharvest storage. Moreover, transcriptomic, metabolomic, and proteomic analyses were performed to elucidate the regulatory mechanisms through which NO treatment delays the ripening and senescence of bitter melon fruit. Our results show that differentially expressed genes (DEGs) were involved in fruit texture (CSLE, ß-Gal, and PME), plant hormone signal transduction (ACS, JAR4, and AUX28), and fruit flavor and aroma (SUS2, LOX, and GDH2). In addition, proteins differentially abundant were associated with fruit texture (PLY, PME, and PGA) and plant hormone signal transduction (PBL15, JAR1, and PYL9). Moreover, NO significantly increased the abundance of key enzymes involved in the phenylpropanoid biosynthetic pathway, thus enhancing the disease resistance and alleviating softening of bitter melon fruit. Finally, differential metabolites mainly included phenolic acids, terpenoids, and flavonoids. These results provide a theoretical basis for further studies on the physiological changes associated with postharvest ripening and senescence of bitter melon fruit. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-023-00110-y.

Gallium-68 labeled somatostatin receptor antagonist PET/CT in over 500 patients with neuroendocrine neoplasms: experience from a single center in China.

PURPOSE: Somatostatin receptor antagonists have shown promising performance for imaging neuroendocrine neoplasms. However, there is a lack of studies exploring the diagnostic performance of SSTR antagonists or comparing them with agonists in a large cohort of patients with NENs. This study aimed to retrospectively review all SSTR antagonist PET/CT scans conducted at Peking Union Medical College Hospital since November 2018 in patients with confirmed or suspected NENs. METHODS: Four types of SSTR antagonists were utilized, including [68Ga]Ga-NODAGA-LM3, [68Ga]Ga-DOTA-LM3, [68Ga]Ga-NODAGA-JR11, and [68Ga]Ga-DOTA-JR11. The reference standard was based on a combination of histopathology, clinical evaluation, imaging results, and follow-up. Patient-based sensitivity, specificity, and accuracy were evaluated. The SUVmax and tumor-to-liver ratio (TLR) of the hottest lesions was recorded and compared between antagonists and [68Ga]Ga-DOTATATE. RESULTS: A total of 622 antagonist scans from 549 patients were included in the analysis. The patient-level sensitivity, specificity, and accuracy of antagonist imaging (all tracers combined) were 91.0% (443/487), 91.9% (57/62), and 91.1% (500/549), respectively. In 181 patients with a comparative [68Ga]Ga-DOTATATE PET/CT scan, the patient-level sensitivity, specificity, and accuracy were 87.5% (147/168), 76.9% (10/13), and 86.7% (157/181), respectively. For the hottest lesions, SSTR antagonists all tracers combined demonstrated an overall comparable SUVmax to [68Ga]Ga-DOTATATE (40.1 ± 32.5 vs. 39.4 ± 23.8, p = 0.772). While [68Ga]Ga-NODAGA-LM3 showed significantly higher uptake than [68Ga]Ga-DOTATATE (57.4 ± 38.5 vs. 40.0 ± 22.8, p<0.001), [68Ga]Ga-NODAGA-JR11 (39.7 ± 26.5 vs. 34.3 ± 23.9, p = 0.108) and [68Ga]Ga-DOTA-LM3 (38.9 ± 32.1 vs. 37.2 ± 22.1, p = 0.858) showed comparable uptake to [68Ga]Ga-DOTATATE, and [68Ga]Ga-DOTA-JR11 showed lower uptake (28.9 ± 26.1 vs. 44.0 ± 25.7, p = 0.001). All antagonists exhibited significantly higher TLR than [68Ga]Ga-DOTATATE (12.1 ± 10.8 vs. 5.2 ± 4.5, p<0.001). CONCLUSION: Gallium-68 labeled SSTR antagonists could serve as alternatives to SSTR agonists for imaging of NENs. Among various antagonists, [68Ga]Ga-NODAGA-LM3 seems to have the best imaging profile.

Dissection of mRNA ac4C acetylation modifications in AC and Nr fruits: insights into the regulation of fruit ripening by ethylene.

N4-acetylcytidine (ac4C) modification of mRNA has been shown to be present in plant RNAs, but its regulatory function in plant remains largely unexplored. In this study, we investigated the differentially expressed mRNAs, lncRNAs and acetylation modifications of mRNAs in tomato fruits from both genotypes. By comparing wild-type (AC) tomato and the ethylene receptor-mutant (Nr) tomato from mature green (MG) to six days after the breaker (Br6) stage, we identified differences in numerous key genes related to fruit ripening and observed the corresponding lncRNAs positively regulated the target genes expression. At the post-transcriptional level, the acetylation level decreased and increased in AC and Nr tomatoes from MG to Br6 stage, respectively. The integrated analysis of RNA-seq and ac4C-seq data revealed the potential positive role of acetylation modification in regulating gene expression. Furthermore, we found differential acetylation modifications of certain transcripts (ACO, ETR, ERF, PG, CesA, ß-Gal, GAD, AMY, and SUS) in AC and Nr fruits which may explain the differences in ethylene production, fruit texture, and flavor during their ripening processes. The present study provides new insights into the molecular mechanisms by which acetylation modification differentially regulates the ripening process of wild-type and mutant tomato fruits deficient in ethylene signaling.

Multiomics analyses of the effects of LED white light on the ripening of apricot fruits.

INTRODUCTION: Apricot (Prunus armeniaca L.) fruits are highly perishable and prone to quality deterioration during storage and transportation. OBJECTIVES: To investigate the effects of LED white light treatment on postharvest ripening of fruits using metabolomics, transcriptomics, and ATAC-Seq analysis. METHODS: Fruits were exposed to 5 µmol m-2 s-1 LED white light for 12 h followed by 12 h of darkness at 20 °C daily for 12 days. The effects of the treatments on the physiological and nutritional quality of the fruits were evaluated. These data were combined with transcriptomic, metabolomic, and ATAC-Seq data from fruits taken on 8 d of treatment to provide insight into the potential mechanism by which LED treatment delays ripening. RESULTS: LED treatment activated pathways involved in ascorbate and aldarate metabolism and flavonoid and phenylpropanoid biosynthesis. Specifically, LED treatment increased the expression of UDP-sugar pyrophosphorylase (USP), L-ascorbate peroxidase (AO), dihydroflavonol 4-reductase (DFR), chalcone synthase (CHS), and caffeoyl-CoA O-methyltransferase (CCOAOMT1), leading to the accumulation of caffeoyl quinic acid, epigallocatechin, and dihydroquercetin and the activation of anthocyanin biosynthesis. LED treatment also affected the expression of genes associated with plant hormone signal transduction, fruit texture and color transformation, and antioxidant activity. The notable genes affected by LED treatment included 1-aminocyclopropane-1-carboxylate synthase (ACS), 1-aminocyclopropane-1-carboxylate oxidase (ACO), hexokinase (HK), lipoxygenase (LOX), malate dehydrogenase (MDH), endoglucanase (CEL), various transcription factors (TCP, MYB, EFR), and peroxidase (POD). ATAC-Seq analysis further revealed that LED treatment primarily regulated phenylpropanoid biosynthesis. CONCLUSION: The results obtained in this study provide insights into the effects of LED light exposure on apricot fruits ripening. LEDs offer a promising approach for extending the shelf life of other fruits and vegetables.

Baseline radiologic features as predictors of efficacy in patients with pancreatic neuroendocrine tumors with liver metastases receiving surufatinib.

Objective: Currently, pre-treatment prediction of patients with pancreatic neuroendocrine tumors with liver metastases (PNELM) receiving surufatinib treatment was unsatisfying. Our objective was to examine the association between radiological characteristics and efficacy/prognosis. Methods: We enrolled patients with liver metastases in the phase III, SANET-p trial (NCT02589821) and obtained contrast-enhanced computed tomography (CECT) images. Qualitative and quantitative parameters including hepatic tumor margins, lesion volumes, enhancement pattern, localization types, and enhancement ratios were evaluated. The progression-free survival (PFS) and hazard ratio (HR) were calculated using Cox's proportional hazard model. Efficacy was analyzed by logistic-regression models. Results: Among 152 patients who had baseline CECT assessments and were included in this analysis, the surufatinib group showed statistically superior efficacy in terms of median PFS compared to placebo across various qualitative and quantitative parameters. In the multivariable analysis of patients receiving surufatinib (N=100), those with higher arterial phase standardized enhancement ratio-peri-lesion (ASER-peri) exhibited longer PFS [HR=0.039; 95% confidence interval (95% CI): 0.003-0.483; P=0.012]. Furthermore, patients with a high enhancement pattern experienced an improvement in the objective response ratio [31.3% vs. 14.7%, odds ratio (OR)=3.488; 95% CI: 1.024-11.875; P=0.046], and well-defined tumor margins were associated with a higher disease control rate (DCR) (89.3% vs. 68.2%, OR=4.535; 95% CI: 1.285-16.011; P=0.019) compared to poorly-defined margins. Conclusions: These pre-treatment radiological features, namely high ASER-peri, high enhancement pattern, and well-defined tumor margins, have the potential to serve as predictive markers of efficacy in patients with PNELM receiving surufatinib.

Synthesis, molecular docking studies of formononetin derivatives as potent Bax agonists for anticancer activity.

Formononetin as a Bax agonist exhibits anticancer effects. To identify novel Bax agonist, 18 new structurally modified formononetin derivatives were synthesised and their anticancer activities were evaluated in the A549 and Beas-2b cell lines. The results indicated that 7a elicited the most potent inhibitory effect against the A549 cell line, with an IC50 value of 0.87 µM, and no obvious toxicity to Beas-2b cells. These results indicated that 7a was 40-fold and 6.94-fold more efficacious than Formononetin and Doxorubicin, respectively. Additionally, western blot and immunofluorescence assays demonstrated that 7a downregulated the protein expression of Bcl-2 and upregulated the expressions of Bax to promote A549 apoptosis, the obtained results also suggested that 7a had the potential to be developed into a lead compound that can be applied in the prevention and treatment of lung cancer.

Successful Treatment of Concurrent Follicular Lymphoma and Triple-Negative Breast Cancer Using Rituximab Plus Nab-Paclitaxel and Cisplatin: A Case Report and Literature Review.

Background: Co-occurrence of breast cancer and non-Hodgkin's lymphoma is a rare condition with diagnostic and therapeutic challenges. The coexistence of follicular lymphoma (FL) and triple-negative breast cancer (TNBC) has not been described previously. Case Presentation: A 46-year-old woman, already suffering a history of untreated, advanced-stage, high tumor burden FL, was admitted for a rapidly progressing right breast mass. Ultrasonography showed an 8.3 × 3.6 × 4.1 cm fungating mass in the right breast with enlarged lymph nodes (LNs) in bilateral axillae. PET-CT demonstrated increased 18F- FDG activity in right breast mass, LNs on both sides of the diaphragm, enlarged spleen, and bone marrow. Biopsy of the right breast mass revealed TNBC. The patient underwent neoadjuvant therapy with R-CHOP and achieved partial response of breast tumor. However, TNBC progressed after three cycles of R-CHOP. According to the next-generation sequencing (NGS) assay on breast mass showing a homologous recombination repair (HRR) deficiency (HRD) score of 72, the neoadjuvant regimen was changed to rituximab plus nab-paclitaxel and cisplatin (R-TP) and resulted in significant tumor regression. The patient then underwent right mastectomy with an axillary LN dissection. After the surgery, she was regularly monitored and given adjuvant therapy with R-TP and radiotherapy. Conclusion: The coexistence of FL and HRD-positive TNBC poses diagnostic and treatment challenges. Well-founded neoadjuvant strategy based on multidisciplinary team (MDT) discussion and NGS warranted a good outcome in this case.

A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma.

BACKGROUND: There are no standard third-line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC). Trametinib in combination with hydroxychloroquine (HCQ) or CDK4/6 inhibitors for pancreatic adenocarcinoma showed promising efficacy in preclinical studies. However, the regimens have not been well examined in patients with mPDAC. METHODS: Patients with mPDAC who received the combination of trametinib and HCQ or CDK4/6 inhibitors as third- or later-line therapy were reviewed. The efficacy and prognosis were further analyzed. RESULTS: A total of 13 mPDAC patients were enrolled, of whom 8 and 5 patients were treated with trametinib plus HCQ or a CDK4/6 inhibitor (palbociclib or abemaciclib), respectively. All enrolled patients had either KRAS G12D or G12V mutations and had received a median of 3 prior lines of therapy (range, 2-6). The median trametinib treatment duration was 1.4 months. Of the 10 patients with measurable disease, only 1 patient achieved stable disease, and the remaining patients had progressive disease. Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, respectively, and the median overall survival was 4.2 and 4.7 months, respectively. Moreover, 5 (50%) patients experienced grade 3-4 adverse events in 10 patients with available safety data. CONCLUSIONS: The combination of trametinib and HCQ or CDK4/6 inhibitors may not be an effective later-line treatment for mPDAC, and the current preliminary findings need to be confirmed by other studies with larger sample sizes.

Efficacy and safety of gemcitabine plus S-1 vs. gemcitabine plus nab-paclitaxel in treatment-naïve advanced pancreatic ductal adenocarcinoma.

OBJECTIVE: Gemcitabine plus nab-paclitaxel (GnP) is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC). S-1, an oral fluoropyrimidine derivative, as compared with gemcitabine, is non-inferior in terms of overall survival (OS) and is associated with lower hematologic toxicity. Accordingly, S-1 is a convenient oral alternative treatment for advanced PDAC. This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1 (GS) vs. GnP as first-line chemotherapy for advanced PDAC. METHODS: Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated. RESULTS: A total of 300 patients were assessed, of whom 84 received GS and 216 received GnP. The chemotherapy completion rate was higher with GS than GnP (50.0% vs. 30.3%, P = 0.0028). The objective response rate (ORR) was slightly higher (14.3% vs. 9.7%, P = 0.35), and the median OS was significantly longer (17.9 months vs. 13.3 months, P = 0.0078), in the GS group than the GnP group. However, the median progression-free survival (PFS) did not significantly differ between groups. Leukopenia risk was significantly lower in the GS group than the GnP group (14.9% vs. 28.1%, P = 0.049). CONCLUSIONS: As first-line chemotherapy for advanced PDAC, the GS regimen led to a significantly longer OS than the GnP regimen. The PFS, ORR, and incidence of severe adverse events were comparable between the GS and GnP groups.

Necroptosis-related signatures identify two distinct hepatocellular carcinoma subtypes: Implications for predicting drug sensitivity and prognosis.

Background: Necroptosis is associated with oncogenesis, tumor immunity and progression. This research aims to investigate the association of necroptosis-related genes with drug sensitivity and prognosis in hepatocellular carcinoma (HCC). Methods: Based on necroptosis-related signatures, HCC patients retrieved from the TCGA database were categorized. Survival outcomes, mutation profile, immune microenvironment, and drug sensitivity between HCC subtypes were further compared. Then, LASSO analysis was performed to construct a necroptosis-related prognostic signature, which was further evaluated using another independent cohort. Results: A total of 371 patients with HCC could be categorized into two necroptosis-related subtypes. About 36% of patients were allocated to subtype A, with worse survival, more mutant TP53, and a lower likelihood of immunotherapy response. In contrast, patients in subtype B had a favorable prognosis, with lower expression of immunosuppressive signatures but a lower abundance of B and CD8+ T-cell infiltration. The prognostic risk score calculated using the expression levels of nine genes involved in the necroptosis pathway (MLKL, FADD, XIAP, USP22, UHRF1, CASP8, RIPK3, ZBP1, and FAS) showed a significant association with tumor stage, histologic grade, and Child‒Pugh score. Additionally, the risk score model was proven to be accurate in both the training and independent external validation cohorts and performed better than the TNM staging system and three well-recognized risk score models. Conclusions: Based on necroptosis-related signatures, we identified two HCC subtypes with distinctive immune microenvironments, mutation profiles, drug sensitivities, and survival outcomes. A novel well-performing prognostic model was further constructed.

The prognostic role of WeChat-based instant doctor-patient communication in patients with advanced pancreatic cancer.

BACKGROUND: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) need timely medical assistance since the emergence of complications due to the disease and antitumor treatment. Studies have confirmed that instant messaging can improve the quality of life and compliance of cancer patients. However, the prognostic role of instant doctor-patient communication based on instant messaging applications in PDAC has not been studied. METHODS: Patients with PDAC who received first-line chemotherapy at Peking Union Medical College Hospital between January 2015 and October 2022 were reviewed. We categorized patients into two groups according to whether they received WeChat-based instant doctor-patient communication, and the prognosis and toxicity data between the two groups were compared. RESULTS: A total of 431 PDAC patients were enrolled, of whom 163 had long-term instant communication with their doctors based on WeChat, and 268 did not receive WeChat-based instant communication. There was no significant correlation between WeChat-based communication and first-line chemotherapy overall response rate (14.1% vs. 8.6%, p = 0.074), incidence of grade ≥ 3 adverse events (66.9% vs. 65.7%, p = 0.814) or overall survival (14.7 vs. 13.9 months, p = 0.170) in all enrolled patients. However, patients who received WeChat-based instant communication had a higher completion rate of first-line chemotherapy (42.0% vs. 30.7%, p = 0.023). Consistently, in the patients who developed grade ≥ 3 adverse events (n = 231), those who received WeChat-based instant communication had significantly longer overall survival (17.3 vs. 15.3 months, p = 0.018), even after adjustment for biases. CONCLUSIONS: WeChat-based instant doctor-patient communication demonstrated no superiority in improving the efficacy of chemotherapy or preventing chemotherapy toxicity in PDAC patients, but it may contribute to improving the completion rate of chemotherapy and the prognosis in patients who experienced severe adverse events. IMPLICATIONS FOR CANCER SURVIVORS: Instant doctor‒patient communication may help to timely and appropriately deal with adverse events and prolong the survival time of patients with PDAC, supporting the promotion of mobile technology in clinical practice.

Pancreatic ductal adenocarcinoma with synchronous and metachronous hepatic metastasis predicted by contrast-enhanced ultrasound.

Background: Contrast-enhanced ultrasound (CEUS) has proven valuable in diagnosing benign and malignant pancreatic diseases, but its value in evaluating hepatic metastasis remains to be further explored. This study investigated the relationship between CEUS features of pancreatic ductal adenocarcinoma (PDAC) and concomitant or recurrent liver metastases after treatment. Methods: This retrospective study included 133 participants with PDAC who were diagnosed with pancreatic lesions with CEUS at Peking Union Medical College Hospital from January 2017 to November 2020. According to the CEUS classification methods in our center, all the pancreatic lesions were classified as either with rich or poor blood supply. Additionally, quantitative ultrasonographic parameters were measured in the center and periphery of all pancreatic lesions. CEUS modes and parameters of the different hepatic metastasis groups were compared. The diagnostic performance of CEUS was calculated for diagnosing synchronous and metachronous hepatic metastasis. Results: The proportions of rich blood supply and poor blood supply were 46% (32/69) and 54% (37/69), respectively, in the no hepatic metastasis group; 42% (14/33) and 58% (19/33), respectively, in the metachronous hepatic metastasis (MHM) group; and 19% (6/31) and 81% (25/31), respectively, in the synchronous hepatic metastasis (SHM) group. The wash-in slope ratio (WIS ratio) between the center of the lesion and around the lesion and peak intensity ratio (PI ratio) between the center of the lesion and around the lesion had higher values in the negative hepatic metastasis group (P<0.05). In predicting synchronous and metachronous hepatic metastasis, the WIS ratio had the best diagnostic performance. The sensitivity (SEN), specificity (SPE), accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) were 81.8%, 95.7%, 91.2%, 90.0%, and 91.7%, respectively, for MHM; and 87.1%, 95.7%, 93.0%, 90.0%, and 94.3%, respectively, for SHM. Conclusions: CEUS would be helpful in image surveillance for synchronous or metachronous hepatic metastasis of PDAC.

Prognostic and predictive significance of circulating biomarkers in patients with advanced upper gastrointestinal cancer undergoing systemic chemotherapy.

Objective: The prognosis of patients with advanced cancers of the upper gastrointestinal (UGI) tract is poor. Systemic chemotherapy forms the basis for their treatment, with limited efficacy. Biomarkers have been introduced into clinical practice for cancer management. This study aimed to investigate the predictive and prognostic values of circulating biomarkers in patients with advanced esophageal and gastric cancers receiving chemotherapy. Design: Overall, 92 patients with advanced esophageal squamous cell carcinoma (ESCC; n = 38) and gastric adenocarcinoma (GAC; n = 54) were enrolled. We analyzed the association of circulating lymphocyte subsets, inflammatory markers, and blood cell counts with treatment efficacy and patient survival. Results: Significant differences were identified in peripheral blood parameters between the groups with different clinicopathological features. Hemoglobin (Hb, p = 0.014), eosinophil counts (p = 0.028), CD4+CD28+T/CD4+T percentage (p = 0.049), CD8+CD38+T/CD8+T percentage (p = 0.044), memory CD4+T (p = 0.007), and CD4+CD28+T (p = 0.007) were determined as predictors for achieving non-PD (progression disease) in the ESCC cohort. High levels of eosinophils (p = 0.030) and memory CD4+T cells (p = 0.026) and high eosinophil-to-lymphocyte ratio (ELR, p = 0.013) were predictors of non-PD in patients with GAC. The combined detection models exhibited good ability to distinguish between partial response (PR)/non-PR and PD/non-PD in patients with ESCC and GAC, respectively. Using the multivariate Cox model, the Eastern Cooperative Oncology Group (ECOG) score status (hazard ratio [HR]: 4.818, 95% confidence intervals [CI]: 2.076-11.184, p < 0.001) and eosinophil count (HR: 0.276, 95% CI: 0.120-0.636, p = 0.003) were independent prognostic factors of progression-free survival (PFS) in patients with ESCC. Metastatic sites (HR: 2.092, 95% CI: 1.307-3.351, p = 0.002) and eosinophil-to-lymphocyte ratio (ELR; HR: 0.379, 95% CI: 0.161-0.893, p = 0.027) were independent prognostic factors for overall survival (OS) in patients with ESCC. Differentiation (HR: 0.041, 95% CI: 0.200-0.803, p = 0.010), memory CD4+T (HR: 0.304, 95% CI: 0.137-0.675, p = 0.003), NK cells (HR: 2.302, 95% CI: 1.044-3.953, p = 0.037), and C-reactive protein-to-lymphocyte ratio (CLR; HR: 2.070, 95% CI: 1.024-4.186, p = 0.043) were independent prognostic factors for PFS in patients with GAC. Total lymphocyte counts (HR: 0.260, 95% CI: 0.086-0.783, p = 0.017), CD8+T (HR: 0.405, 95% CI: 0.165-0.997, p = 0.049), NK cells (HR: 3.395, 95% CI: 1.592-7.238, p = 0.002), and monocyte-to-lymphocyte ratio (MLR; HR: 3.076, 95% CI: 1.488-6.360, p = 0.002) were identified as independent prognostic factors associated with OS of GAC. Conclusion: Lymphocyte subsets, blood cell counts, and inflammatory parameters may predict the chemotherapeutic response and prognosis in ESCC and GAC. A combination of these markers can be used to stratify patients into risk groups, which could improve treatment strategies.

Clinical features and prognosis of lung cancer in patients with connective tissue diseases: a retrospective cohort study.

Background: Studies have demonstrated a close association between connective tissue diseases (CTDs) and lung cancer (LC). Evidence supports that poor survival may be associated with the presence of CTDs in patients with LC. Methods: This retrospective cohort study investigated 29 patients with LC with CTDs, and 116 patients with LC without CTDs were enrolled as case-matched control cohorts. Medical records, therapeutic efficacy of cancer, and outcomes were analyzed. Results: The median duration from the diagnosis of CTDs to LC was 17 years. The Eastern Cooperative Oncology Group (ECOG) performance score for LC-CTD patients was worse than that for matched non-CTD LC patients. The median progression-free survival (mPFS) and overall survival (mOS) of first-line chemotherapy did not differ between patients with lung adenocarcinoma (AC) with and without CTDs. A significant difference was observed in mPFS [4 months vs. 17 months; hazard ratio (HR), 9.987; p = 0.004] and mOS (6 months vs. 35 months; HR, 26.009; p < 0.001) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment between patients with AC with and without CTDs. The presence of CTD, sex, ECOG performance status, and tumor-node-metastasis clinical stage were the independent prognostic factors in all patients with non-small cell LC (NSCLC). ECOG performance status was determined to be an independent prognostic factor in patients with LC-CTD. In patients with NSCLC with CTD (n = 26), sex (male) and worse ECOG score were the independent poor prognostic factors. Conclusions: CTDs were associated with poor survival in patients with LC. The therapeutic efficacy of first-line EGFR-TKI therapy was significantly worse in patients with lung AC with CTDs than in those without CTDs. ECOG performance status was determined as an independent prognostic factor for patients with LC and CTDs.

POSTN Secretion by Extracellular Matrix Cancer-Associated Fibroblasts (eCAFs) Correlates with Poor ICB Response via Macrophage Chemotaxis Activation of Akt Signaling Pathway in Gastric Cancer.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy.

Preclinical and pilot clinical evaluation of a small-molecule carbonic anhydrase IX targeting PET tracer in clear cell renal cell carcinoma.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) highly expresses carbonic anhydrase IX (CAIX). The purpose of this study was to evaluate 68Ga-NY104, a small-molecule CAIX-targeting PET agent, in tumor models of ccRCC and patients diagnosed with confirmed, or suspicious, ccRCC. METHODS: The in vivo and ex vivo biodistribution of 68Ga-NY104 was investigated in CAIX-positive OS-RC-2 xenograft-bearing models. The binding of the tracer was further validated using autoradiography for human ccRCC samples. In addition, three patients with confirmed or suspicious ccRCC were studied. RESULTS: NY104 can be labeled with high radiochemical yield and purity. It quickly cleared through kidney with α-half-life of 0.15 h. Discernible uptake is noted in the heart, lung, liver, stomach, and kidney. The OS-RC-2 xenograft demonstrated intense uptake 5 min after injection and gradually increased until 3 h after injection with ID%/g of 29.29 ± 6.82. Significant binding was detected using autoradiography on sections of human ccRCC tumor. In the three patients studied, 68Ga-NY104 was well-tolerated and no adverse events were reported. Substantial accumulation was observed in both primary and metastatic lesions in patient 1 and 2 with SUVmax of 42.3. Uptake in the stomach, pancreas, intestine, and choroid plexus was noted. The lesion in third patient was correctly diagnosed as non-metastatic for negative 68Ga-NY104 uptake. CONCLUSION: 68Ga-NY104 can efficiently and specifically bind to CAIX. Given the pilot nature of our study, future clinical studies are warranted to evaluate 68Ga-NY104 for detection of CAIX-positive lesions in patients with ccRCC. TRIAL REGISTRATION: The clinical evaluation part of this study was retrospectively registered at ClinicalTrial.gov (NCT05728515) as NYPILOT on 6 Feb, 2023.

Effect of age on the risk of immune-related adverse events in patients receiving immune checkpoint inhibitors.

Identifying patients at increased risk of immune-related adverse events (irAEs) facilitates safe application of immune checkpoint inhibitors (ICIs). This retrospective study aimed to determine the effect of age on the risk of irAEs in patients receiving ICIs and to identify potential mechanisms underlying age-related irAE risk differences. We analyzed reports of FDA Adverse Event Reporting System from July 1, 2014, to September 30, 2021. The information component ratio (ICΔ) was used to compare the irAE risk between older adults (> 65 years) and younger adults (25-65 years), of which the 95% confidential interval lower limit (ICΔ025) exceeding zero indicated significantly increased risk. We found that older adults had a significantly higher overall irAE risk than younger adults (ICΔ025 0.38), which was observed in almost all organ systems. We further analyzed the correlation between age-related irAE risks and age-related transcriptional changes to identify potential genes and pathways underlying age-related irAE risk differences. We found that genes significantly correlated with ICΔ were enriched in processes including extracellular matrix organization, regulation of myeloid leukocyte mediated immunity, and regulation of c-Jun N-terminal kinase (JNK) cascade. In addition, single-cell RNA sequencing analysis confirmed that genes involved in collagen-containing extracellular matrix and JNK cascade were significantly upregulated in myeloid cells from ICI-associated colitis tissues compared with ICI-treated colon tissues without colitis. In conclusion, older adults receiving ICIs have higher irAE risks than younger adults. Upregulation of genes involved in JNK cascade and collagen-containing extracellular matrix in myeloid cells may contribute to increased irAE risks in older adults.

Transcriptomic, metabolomic, and ATAC-seq analysis reveal the regulatory mechanism of senescence of post-harvest tomato fruit.

Several physiological changes occur during fruit storage, which include the regulation of genes, metabolisms and transcription factors. In this study, we compared 'JF308' (a normal tomato cultivar) and 'YS006' (a storable tomato cultivar) to determine the difference in accumulated metabolites, gene expression, and accessible chromatin regions through metabolome, transcriptome, and ATAC-seq analysis. A total of 1006 metabolites were identified in two cultivars. During storage time, sugars, alcohols and flavonoids were found to be more abundant in 'YS006' compared to 'JF308' on day 7, 14, and 21, respectively. Differentially expressed genes, which involved in starch and sucrose biosynthesis were observed higher in 'YS006'. 'YS006' had lower expression levels of CesA (cellulose synthase), PL (pectate lyase), EXPA (expansin) and XTH (xyglucan endoglutransglucosylase/hydrolase) than 'JF308'. The results showed that phenylpropanoid pathway, carbohydrate metabolism and cell wall metabolism play important roles in prolonging the shelf life of tomato (Solanum lycopersicum) fruit. The ATAC-seq analysis revealed that the most significantly up-regulated transcription factors during storage were TCP 2,3,4,5, and 24 in 'YS006' compared to 'JF308' on day 21. This information on the molecular regulatory mechanisms and metabolic pathways of post-harvest quality changes in tomato fruit provides a theoretical foundation for slowing post-harvest decay and loss, and has theoretical importance and application value in breeding for longer shelf life cultivars.