Co-targeting CD47 and VEGF elicited potent anti-tumor effects in gastric cancer.

BACKGROUND: CD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear. METHODS: The expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells. Flow cytometry analyses were employed to evaluate the rate of phagocytosis. Humanized patient-derived xenografts (Hu-PDXs) models were established to assess the efficacy of anti-CD47 immunotherapy or the combination of anti-CD47 and anti-VEGF therapy in treating gastric cancer. The infiltrated immune cells in the xenograft were analyzed by immunohistochemistry. RESULTS: In this study, we have substantiated the high expression of CD47 in gastric cancer tissues, establishing a strong association with unfavorable prognosis. Through the utilization of SIRPα-Fc to target CD47, we have effectively enhanced macrophage phagocytosis of PDCs in vitro and impeded the growth of Hu-PDXs. It is noteworthy that anti-CD47 immunotherapy has been observed to sustain tumor angiogenic vasculature, with a positive correlation between the expression of VEGF and CD47 in gastric cancer. Furthermore, the successful implementation of anti-angiogenic treatment has further augmented the anti-tumor efficacy of anti-CD47 therapy. In addition, the potent suppression of tumor growth, prevention of cancer recurrence after surgery, and significant prolongation of overall survival in Hu-PDX models can be achieved through the simultaneous targeting of CD47 and VEGF using the bispecific fusion protein SIRPα-VEGFR1 or by combining the two single-targeted agents. CONCLUSIONS: Our preclinical studies collectively offer substantiation that CD47 holds promise as a prospective target for gastric cancer, while also highlighting the potential of anti-angiogenic therapy to enhance tumor responsiveness to anti-CD47 immunotherapy.

Turnkey photonic flywheel in a microresonator-filtered laser.

Dissipative Kerr soliton (DKS) microcomb has emerged as an enabling technology that revolutionizes a wide range of applications in both basic science and technological innovation. Reliable turnkey operation with sub-optical-cycle and sub-femtosecond timing jitter is key to the success of many intriguing microcomb applications at the intersection of ultrafast optics and microwave electronics. Here we propose an approach and demonstrate the first turnkey Brillouin-DKS frequency comb to the best of our knowledge. Our microresonator-filtered laser design offers essential benefits, including phase insensitivity, self-healing capability, deterministic selection of the DKS state, and access to the ultralow noise comb state. The demonstrated turnkey Brillouin-DKS frequency comb achieves a fundamental comb linewidth of 100 mHz and DKS timing jitter of 1 femtosecond for averaging times up to 56 µs. The approach is universal and generalizable to various device platforms for user-friendly and field-deployable comb devices.

The correlation between the margin of resection and prognosis in esophagogastric junction adenocarcinoma.

Adenocarcinoma of the gastroesophageal junction (AEG) has become increasingly common in Western and Asian populations. Surgical resection is the mainstay of treatment for AEG; however, determining the distance from the upper edge of the tumor to the esophageal margin (PM) is essential for accurate prognosis. Despite the relevance of these studies, most have been retrospective and vary widely in their conclusions. The PM is now widely accepted to have an impact on patient outcomes but can be masked by TNM at later stages. Extended PM is associated with improved outcomes, but the optimal PM is uncertain. Academics continue to debate the surgical route, extent of lymphadenectomy, preoperative tumor size assessment, intraoperative cryosection, neoadjuvant therapy, and other aspects to further ensure a negative margin in patients with gastroesophageal adenocarcinoma. This review summarizes and evaluates the findings from these studies and suggests that the choice of approach for patients with adenocarcinoma of the esophagogastric junction should take into account the extent of esophagectomy and lymphadenectomy. Although several guidelines and reviews recommend the routine use of intraoperative cryosections to evaluate surgical margins, its generalizability is limited. Furthermore, neoadjuvant chemotherapy and radiotherapy are more likely to increase the R0 resection rate. In particular, intraoperative cryosections and neoadjuvant chemoradiotherapy were found to be more effective for achieving negative resection margins in signet ring cell carcinoma.

Anti-CD47 Antibody Enhances the Efficacy of Chemotherapy in Patients with Gastric Cancer Liver Metastasis.

Patients with gastric cancer liver metastasis (GCLM) are often treated with palliative care, and they show a poor prognosis. In gastric cancer, high CD47 expression has been shown to indicate a poor prognosis. CD47, expressed on the cell surface, prevents the cells from being phagocytosed by macrophages. Anti-CD47 antibodies have been shown to be effective in the treatment of metastatic leiomyosarcoma. Nonetheless, the role of CD47 in GCLM has not yet been elucidated. Here, we showed that CD47 expression in GCLM tissues was higher than that in situ. Moreover, we demonstrated that high CD47 expression correlated with an adverse prognosis. Accordingly, we investigated the role of CD47 in the development of GCLM in mouse liver. Knockdown of CD47 inhibited GCLM development. Furthermore, in vitro engulfment assays showed that decreased CD47 expression led to an increased phagocytic activity of Kupffer cells (KCs). Using enzyme-linked immunosorbent assay, we determined that CD47 knockdown promoted cytokine secretion by macrophages. Furthermore, we found that tumor-derived exosomes decreased KC-mediated phagocytosis of gastric cancer cells. Finally, in a heterotopic xenograft model, the administration of anti-CD47 antibodies inhibited tumor growth. In addition, as 5-fluorouracil (5-Fu)-based chemotherapy is the cornerstone in GCLM treatment, we administered a combination of anti-CD47 antibodies and 5-Fu, which acted synergistically to suppress the tumor. Overall, we demonstrated that tumor-derived exosomes are involved in GCLM progression, targeting CD47 inhibits gastric cancer tumorigenesis, and a combination of anti-CD47 antibodies and 5-Fu shows potential for treating GCLM.

Turnkey photonic flywheel in a Chimera cavity.

Dissipative Kerr soliton (DKS) microcomb has emerged as an enabling technology that revolutionizes a wide range of applications in both basic science and technological innovation. Reliable turnkey operation with sub-optical-cycle and sub-femtosecond timing jitter is key to the success of many intriguing microcomb applications at the intersection of ultrafast optics and microwave electronics. Here we propose a novel approach to demonstrate the first turnkey Brillouin-DKS frequency comb. Our approach with a Chimera cavity offers essential benefits that are not attainable previously, including phase insensitivity, self-healing capability, deterministic selection of DKS state, and access to the ultralow noise comb state. The demonstrated turnkey Brillouin-DKS frequency comb achieves a fundamental comb linewidth of 100 mHz and DKS timing jitter of 1 femtosecond for averaging times up to 56 µs. The approach is universal and generalizable to various device platforms for user-friendly and field-deployable comb devices.

Synthesized spatiotemporal mode-locking and photonic flywheel in multimode mesoresonators.

Dissipative Kerr soliton (DKS) frequency combs-also known as microcombs-have arguably created a new field in cavity nonlinear photonics, with a strong cross-fertilization between theoretical, experimental, and technological research. Spatiotemporal mode-locking (STML) not only adds new degrees of freedom to ultrafast laser technology, but also provides new insights for implementing analogue computers and heuristic optimizers with photonics. Here, we combine the principles of DKS and STML to demonstrate the STML DKS by developing an unexplored ultrahigh-quality-factor Fabry-Pérot (FP) mesoresonator based on graded index multimode fiber (GRIN-MMF). Complementing the two-step pumping scheme with a cavity stress tuning method, we can selectively excite either the eigenmode DKS or the STML DKS. Furthermore, we demonstrate an ultralow noise microcomb that enhances the photonic flywheel performance in both the fundamental comb linewidth and DKS timing jitter. The demonstrated fundamental comb linewidth of 400 mHz and DKS timing jitter of 500 attosecond (averaging times up to 25 µs) represent improvements of 25× and 2.5×, respectively, from the state-of-the-art. Our results show the potential of GRIN-MMF FP mesoresonators as an ideal testbed for high-dimensional nonlinear cavity dynamics and photonic flywheel with ultrahigh coherence and ultralow timing jitter.

Dissipative soliton generation and real-time dynamics in microresonator-filtered fiber lasers.

Optical frequency combs in microresonators (microcombs) have a wide range of applications in science and technology, due to its compact size and access to considerably larger comb spacing. Despite recent successes, the problems of self-starting, high mode efficiency as well as high output power have not been fully addressed for conventional soliton microcombs. Recent demonstration of laser cavity soliton microcombs by nesting a microresonator into a fiber cavity, shows great potential to solve the problems. Here we study the dissipative soliton generation and interaction dynamics in a microresonator-filtered fiber laser in both theory and experiment. We bring theoretical insight into the mode-locking principle, discuss the parameters effect on soliton properties, and provide experimental guidelines for broadband soliton generation. We predict chirped bright dissipative soliton with flat-top spectral envelope in microresonators with normal dispersion, which is fundamentally forbidden for the externally driven case. Furthermore, we experimentally achieve soliton microcombs with large bandwidth of ~10 nm and high mode efficiency of 90.7%. Finally, by taking advantage of an ultrahigh-speed time magnifier, we study the real-time soliton formation and interaction dynamics and experimentally observe soliton Newton's cradle. Our study will benefit the design of the novel, high-efficiency and self-starting microcombs for real-world applications.

Monostable dissipative Kerr solitons.

Kerr microcombs hold the promise of bringing frequency combs onto the chip and into a variety of applications requiring low size, weight, power, and cost. However, reliable Kerr microcomb generation is hindered by the thermal effect and multistability of dissipative Kerr solitons (DKSs). Past approaches toward Kerr microcomb reliability include either deterministic single-soliton generation or self-starting soliton behavior but not both. Here we describe a regime of DKSs that is both deterministic and self-starting, in which only a single soliton can stably exist. We term this new DKS regime "monostable DKSs" (MS-DKSs) as all other optical behaviors, such as continuous-wave-only and multiple solitons, are fundamentally forbidden by the design. We establish a graphical model to describe MS-DKSs and discuss the design principles of MS-DKSs. We numerically demonstrate the MS-DKS behavior in an example periodically poled lithium niobate microring resonator.

Delayed bowel perforation after instilling over warmed peritoneal dialysate.

BACKGROUND: Peritoneal dialysis (PD) is a safe and home-based treatment for end-stage renal disease (ESRD) patients. The direct thermal damage of abdominal organs is very rare. CASE PRESENTATION: We report a peritoneal dialysis patient presented abdominal pain and feculent effluent 3 weeks after he instilled hot dialysis solution. In spite of emergency exploratory laparotomy and active treatment, the patient died of septic shock. Biopsy revealed necrosis and perforation of the intestines. CONCLUSIONS: Delayed bowel perforation by hot fluid is very rare. Standardized performance is of the first importance for peritoneal dialysis patients.

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment.

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-γ (IFN-γ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities.

Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer.

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently.

Analysis of risk factors and prevention strategies for functional delayed gastric emptying in 1243 patients with distal gastric cancer.

BACKGROUND: Analysis of the risk factors associated with functional delayed gastric emptying after distal gastric cancer surgery to provide a basis for further reduction of the incidence of this complication. METHODS: Total of 1382 patients with distal gastric cancer from January 2016 to October 2018 were enrolled. Correlation analysis was performed in 53 patients with FDGE by logistic regression. Subgroup risk analysis was performed in 114 patients with preoperative pyloric obstruction. A Pearson Chi-square analysis was used to compare categorical variables between normal distribution groups. Meanwhile, a t test was used to compare continuous variables between groups. Odds ratio (OR) was used for comparison of the two groups, and it was summarized with its 95% confidence interval (CI) and p value using logistic regression. RESULT: In multivariable analysis, age (OR 1.081, 95% CI, 1.047-1.117), BMI (OR 1.233, 95% CI, 1.116-1.363), preoperative pyloric obstruction (OR 3.831, 95% CI, 1.829-8.023), smaller volume of residual stomach (OR 1.838, 95% CI, 1.325-6.080), and anastomosis in greater curvature perpendicular (OR 3.385, 95% CI, 1.632-7.019) and in greater curvature parallel (OR 2.375, 95% CI, 0.963-5.861) were independent risk factors of FDGE. In the preoperative pyloric obstruction group, higher BMI (OR 1.309, 95% CI, 1.086-1.579) and preoperative obstruction time (OR 1.054, 95% CI, 1.003-1.108) were independent risk factors of FDGE and preoperative gastrointestinal decompression (OR 0.231, 95% CI, 0.068-0.785) was independent protective factor of FDGE. CONCLUSION: Adequate gastrointestinal decompression should be performed before the operation to reduce the incidence of postoperative gastroparesis in patients with preoperative pyloric obstruction. We also could improve the surgical methods to reduce the occurrence of FDGE, such as controlling the size of the residual stomach, ensuring blood supply. Especially selecting an appropriate stapler and anastomosis during the anastomosis process, the occurrence of FDGE can be reduced.

Symbiotic quadratic soliton mode-locked non-degenerate optical parametric oscillators.

We analytically and numerically unveil the existence condition of symbiotic solitons in doubly resonant non-degenerate optical parametric oscillators. Resonant signal and idler with terahertz comb bandwidth and femtosecond pulse duration in the mid-infrared are attainable through this symbiotic soliton mode-locking technique. The group velocity mismatches between the three interacting waves are the dominant cause of the symbiotic soliton perturbation, and their effects are numerically investigated in detail. The principle can be applied to commonly used mid-infrared material platforms, making it a competitive ultrashort pulse and broadband comb source architecture.

Quadratic soliton mode-locked degenerate optical parametric oscillator.

We examine the existence condition of the quadratic soliton mode-locked degenerate optical parametric oscillator in the previously unexplored parameter space. We study the nature of the quadratic solitons and divide their dynamics into two distinctive branches, depending on the system parameters. Origin of the quadratic soliton perturbation is identified, and strategy to mitigate its detrimental effect is developed. Frequency comb with terahertz bandwidth and femtosecond pulse duration are attainable in an example periodically poled lithium niobate waveguide resonator. Design rules of the quadratic soliton mode-locking are summarized. The principle can be further extended to other material platforms, making it a competitive ultrashort pulse and broadband comb source architecture at the mid-infrared.

Cancer-associated fibroblasts promote malignancy of gastric cancer cells via Nodal signalling.

The roles of cancer-associated fibroblasts (CAFs) in progression of gastric cancer (GC) are far from well illustration. Here, we show that CAFs can trigger the proliferation and decrease the doxorubicin (Dox) sensitivity of GC cells via secretion of Nodal, one embryonic morphogen that can promote malignancy of various cancers. The neutralization antibody of Nodal can attenuate CAFs-induced cell proliferation. Further, CAFs can activate the Smad2/3 signal, which further increase the phosphorylation and nuclear localization of Akt, in GC cells. While anti-Nodal can abolish the CAFs-induced activation of Smad2/3/Akt signals. Further, both inhibitors of Smad2/3 and Akt can attenuate CAFs-induced proliferation of GC cells. All these data suggest that CAFs can increase the malignancy of GC cells via Nodal-induced activation of Smad2/3/Akt signals. It indicates that CAFs/Nodal signals might be a potential new target of clinical interventions for GC patients. SIGNIFICANCE OF THE STUDY: The roles about CAFs in progression of GC are not well illustrated. Our present study reveals that CAFs can increase the proliferation and decrease the Dox sensitivity of GC cells via secretion of Nodal. The secreted Nodal further activated Samd2/3/Akt signals to trigger the GC progression. It suggests that targeted inhibition CAFs/Nodal might be a potential approach for GC therapy.

Mutational landscape of gastric cancer and clinical application of genomic profiling based on target next-generation sequencing.

BACKGROUND: Gastric cancer (GC) is a leading cause of cancer deaths, and an increased number of GC patients adopt to next-generation sequencing (NGS) to identify tumor genomic alterations for precision medicine. METHODS: In this study, we established a hybridization capture-based NGS panel including 612 cancer-associated genes, and collected sequencing data of tumors and matched bloods from 153 gastric cancer patients. We performed comprehensive analysis of these sequencing and clinical data. RESULTS: 35 significantly mutated genes were identified such as TP53, AKAP9, DRD2, PTEN, CDH1, LRP2 et al. Among them, 29 genes were novel significantly mutated genes compared with TCGA study. TP53 is the top frequently mutated gene, and tends to mutate in male (p = 0.025) patients and patients whose tumor located in cardia (p = 0.011). High tumor mutation burden (TMB) gathered in TP53 wild-type tumors (p = 0.045). TMB was also significantly associated with DNA damage repair (DDR) genes genotype (p = 0.047), Lauren classification (p = 1.5e-5), differentiation (1.9e-7), and HER2 status (p = 0.023). 38.31% of gastric cancer patients harbored at least one actionable alteration according to OncoKB database. CONCLUSIONS: We drew a comprehensive mutational landscape of 153 gastric tumors and demonstrated utility of target next-generation sequencing to guide clinical management.

Short pulse close to round-trip time generated by cavity-less high-gain Nd:GdVO4 bounce geometry.

In this paper, pulsed output with pulse-widths approaching the round-trip time were generated by utilizing a cavity-less high-gain Nd:GdVO4 bounce geometry. By adopting an EOQ (electro-optics Q-switch) device, pulse-widths of 1.36 ns, 1.82 ns, and 2.39 ns were achieved at three effective cavity lengths, respectively. All these pulse-widths were close to the round-trip time of corresponding effective cavity lengths. Moreover, watt-level output power at kHz-level repetition rate was achieved, as well as the good beam quality with M2 factor less than 1.3. The output had a time-averaged continuous spectrum with 10 dB linewidth of 0.2 nm.

Cytoreductive surgery for metastatic gastrointestinal stromal tumors followed by sunitinib compared to followed by imatinib-a multi-center cohort study.

BACKGROUND: The progression-free survival (PFS) is not optimal when imatinib was recommended for treatment of gastrointestinal stromal tumor (GIST) undergoing surgery after tumor local or multifocal progression. METHODS: We evaluate PFS of patients undergoing R0 resection or optimal cytoreductive surgery followed by sunitinib therapy compared with imatinib after tumor unifocal or multifocal progression. RESULTS: From January 2006 to June 2017, ninety-seven patients from thirteen medical centers were enrolled. Fifty-six patients continued imatinib therapy and 41 patients switched sunitinib treatment directly after R0 resection or optimal cytoreductive surgery. The PFS of sunitinib group was longer than that of imatinib group (30.0 months vs 12.0 months, p = 0.009). In subgroup analysis, the PFS of the sunitinib and imatinib groups were 25.5 months and 12.0 months in patients with tumor multifocal progression (p = 0.008), and 39.0 months and 13.0 months in patients with unifocal progression (p = 0.156), respectively. PFS of postoperative sunitinib group was also superior to the total PFS of postoperative imatinib group (PFS of postoperative imatinib plus PFS of subsequent sunitinib therapy (30.0 months vs 21.0 months, p = 0.012). The overall survival in the sunitinib and imatinib groups were 37.0 months and 33.0 months, respectively (p = 0.794). CONCLUSIONS: Surgery followed by sunitinib in GIST patients with unifocal or multifocal progression on imatinib may improve PFS, compared with surgery followed by imatinib.

Pathway- and clinical-factor-based risk model predicts the prognosis of patients with gastric cancer.

Gastric cancer (GC) has a high incidence and mortality rate. If discovered late, GC tends to have a poor prognosis. Improvements in the prognostic accuracy of GC through combined analysis of multiple relevant genes and clinical factors may solve this problem. In the present study, GSE62254 (including 300 GC tissues), obtained from the Gene Expression Omnibus database, was used as a training set, and the mRNA­sequencing data of GC (including 384 GC tissues) downloaded from the Cancer Genome Atlas database served as a validation set. Based on the t­test and Wilcoxon test, the significantly differentially expressed genes (DEGs) were obtained by screening the intersecting DEGs. The prognosis-associated genes and clinical factors were identified using Cox regression analysis in the R survival package. The optimal prognosis­associated pathways were examined using the Cox­proportional hazards (Cox­PH) model in the R penalized package. Finally, risk prediction models were constructed and validated using the Cox­PH model and the Kaplan­Meier method, respectively. There were a total of 382 significant DEGs, including 268 upregulated genes and 114 downregulated genes. A total of 50 prognosis­associated genes were identified, 16 optimal prognosis­associated pathways (including mitochondrial pathway and the tyrosine­protein kinase JAK­signal transducer and activator of transcription signaling pathway, which involve caspase 7, phosphoinositide­3­kinase regulatory subunit 3, peroxisome proliferator­activated receptor γ and collagen triple helix repeat containing 1) and four prognosis­associated clinical factors [including Pathologic_N, Pathologic_stage, mutL homolog 1 (MLH1) mutation and recurrence]. The pathway­ and clinical­factor­based risk prediction model exhibited marked prognostic accuracy. The clinical­factor­based risk prediction model with improved P­values for prognosis prediction may be superior to the pathway­based risk prediction model in predicting the prognosis of GC patients.