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.

Broadband frequency comb generation through cascaded quadratic nonlinearity in thin-film lithium niobate microresonators.

Broadband frequency comb generation through cascaded quadratic nonlinearity remains experimentally untapped in free-space cavities with bulk χ(2) materials mainly due to the high threshold power and restricted ability of dispersion engineering. Thin-film lithium niobate (LN) is a good platform for nonlinear optics due to the tight mode confinement in a nano-dimensional waveguide, the ease of dispersion engineering, large quadratic nonlinearities, and flexible phase matching via periodic poling. Here we demonstrate broadband frequency comb generation through dispersion engineering in a thin-film LN microresonator. Bandwidths of 150 nm (80 nm) and 25 nm (12 nm) for center wavelengths at 1560 and 780 nm are achieved, respectively, in a cavity-enhanced second-harmonic generation (doubly resonant optical parametric oscillator). Our demonstration paves the way for pure quadratic soliton generation, which is a great complement to dissipative Kerr soliton frequency combs for extended interesting nonlinear applications.

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.

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.

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.

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.

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.

Cr2+: CdSe passively Q-switched Ho: YAG laser.

We first demonstrate the laser performance of a Cr2+:CdSe passively Q-switched (PQS) 2.09 µm Ho: YAG laser resonantly pumped by a thulium-doped fiber laser. The maximum output pulse energy of 1.766 mJ, corresponding to a repetition frequency of 685 Hz, was obtained with a pulse duration of 15.4 ns. The pulse peak power was 114.7 kW, while the PQS efficiency was 21.45% against the continuous-wave output. The laser wavelength in the PQS operation was precisely measured to be 2090.2 nm.

Active pulse shaping for end-pumped Nd:YVO4 amplifier with high gain.

We demonstrated the active shaping for a solid-state Nd:YVO4 amplifier with a high average gain of 39.2 dB. The average output power was 8.3 W with respect to the input power of 1 mW. A range of common and useful pulse shapes was generated at the final output. In addition, a very flat square pulse was produced with a root-mean-square less than 3% in amplitude. A numerical method was proposed to realize active shaping without an experimental test for the Nd:YVO4 amplifier, showing great potential for the design of lasers with both high peak power (>100 kW) and a desired pulse shape.

High peak power hybrid MOPA laser with tunable pulse repetition frequency and pulse duration.

In this paper, we demonstrated a hybrid master oscillator power amplifier (MOPA) laser with high peak power and widely tunable pulse repetition frequency (PRF) and pulse duration. The first-stage solid-state amplifier was carefully designed to keep good beam quality and supply high gain simultaneously. The maximum peak power of 760 kW was achieved with average power of 42 W, PRF of 50 kHz, pulse duration of 1.1 ns, and near-diffraction limited beam quality. The MOPA laser covers a broad tunable temporal range with 1-100 ns for pulse duration and 50 kHz-1 MHz for PRF. Moreover, we experimentally and numerically figure out that Nd:YVO4 crystal behaves as if continuous-wave (CW) amplification takes place when PRF is larger than 30 kHz.

High-slope-efficiency 2.06 µm Ho: YLF laser in-band pumped by a fiber-coupled broadband diode.

We first demonstrate the laser performance of a compact 2.06 µm Ho: YLF laser resonantly pumped by a broadband fiber-coupled diode. In continuous-wave (CW) operation, maximum output power of 1.63 W, corresponding to a slope efficiency of 89.2%, was obtained with a near diffraction-limited beam quality. In actively Q-switched operation, maximum pulse energy of 1.1 mJ was achieved at the repetition frequency of 100 Hz. The minimum pulse duration was 43 ns. The performance in both the CW and Q-switched regimes indicates that the current fiber-coupled diode in-band pumped Ho: YLF laser has great potential in certain conditions that require several watts of output power or several millijoules of short pulse energy.

Clinicopathologic characteristics and prognostic of gastric cancer in young patients.

OBJECTIVES: Gastric cancer (GC) in young patients is thought to exhibit a worse prognosis due to specific clinicopathologic characteristics and delayed diagnosis; however, the data are controversial. This study aimed to analyse the clinicopathologic characteristics and prognostic factors of GC in young patients and to determine whether GC is a different clinical entity in younger vs. older patients. PATIENTS AND METHODS: Clinical data of 3930 gastric cancer patients who underwent radical gastrectomy were retrospectively analysed and divided into two age groups. The younger group consisted of 342 cases of patients aged 40 years or younger at the time of surgery, and the older group included 3588 cases of patients older than 40 years. Clinicopathologic characteristics were compared using Pearson's χ(2) or Fisher's exact tests, and survival curves were constructed using the Kaplan-Meier method. RESULTS: Clinicopathologic characteristics of the younger group exhibited a predominance of females (p < 0.001), diffuse stomach lesions (p = 0.014), signet-ring cell type (p < 0.001), poorly differentiated histological tumours (p < 0.001), Borrmann type IV (p < 0.001), mixed Lauren's classification types (p = 0.004), and recurrence rate in the gastric remnant (p < 0.001). The overall 5-year survival rates in the younger group and older group were 60.8% and 53.7%, respectively (p = 0.017). When stratified by TNM stage, the younger group exhibited enhanced 5-year survival at stage IV compared with the older group (26.9% VS. 10.3%, p = 0.003). CONCLUSION: Although younger patients with GC exhibit more aggressive cancer patterns and higher recurrence rate in the gastric remnant, the overall 5-year survival rate may be better than older patients.

Gain change by adjusting the pumping wavelength in an end-pumped Nd:YVO4 amplifier.

In this paper, the performance of an end-pumped laser amplifier was experimentally studied by adjusting the pumping wavelength of a laser diode. An interesting phenomenon was observed: that the gain would decrease with an increase in absorbed pump power. The scaled output power of 0.3 at. % doped 20 mm long Nd:YVO4 crystal decreased from 0.48 to 0.2 W when the absorbed pump power increased from 17.5 to 17.8 W. Theoretical analysis was demonstrated according to our previous model. The long crystal length is the main reason for the observed phenomenon. This phenomenon could be utilized to enhance amplifier gain and improve thermal performance, including the maximal temperature and thermal stress of the crystal.

Theoretical and experimental analysis of high-power frequency-stabilized semiconductor master oscillator power-amplifier system.

We present a compact high-power 780 nm frequency-stabilized diode laser with a power of as high as 2.825 W, corresponding to an estimated overall efficiency of 38.5%. The tapered amplifier (TPA) gain was about 24.5 dB, which was basically consistent with the simulation results. The beam quality factor was M2<1.72. The core feature of the system was stabilizing the frequency of the narrowband semiconductor TPA system with the matured saturated absorption spectrum technique. The laser frequency was stabilized against mode hops for a period of >4200 s with a frequency fluctuation around 6.7×10-10 within 1 s of the observation period, and the linewidth was no more than 0.95 MHz. The laser performance indicates that the current frequency-stabilized semiconductor laser has great potential in certain conditions that require several watts of output power.

End-pumped temperature-dependent passively Q-switched lasers.

In this paper, we compare pulse parameters in two end-pumped passively Q-switched lasers by increasing the boundary temperature of the laser crystal. For the Nd:YAG/Cr:YAG laser, the pulse energy at 1 kHz increased from 12.4 to 21 µJ when the boundary temperature increased from 20°C to 120°C, while the pulse width decreased by 1.2 times. For the Nd:YVO4 passively Q-switched laser using Cr:YAG as the saturable absorber, the pulse energy at 100 Hz increased from 5.45 to 24.5 µJ when the boundary temperature increased from 26°C to 113°C, while the pulse width decreased by 2.4 times. An improved model based on the rate equations was introduced to analyze the large variation of pulse energy when heating the Nd:YVO4 crystal.

Influence of ERCC1 and ERCC4 polymorphisms on response to prognosis in gastric cancer treated with FOLFOX-based chemotherapy.

Polymorphisms in the excision repair cross-complimentary group 1 (ERCC1)-excision repair cross-complimentary group 4 (ERCC4) genes have been implicated in the prognosis of various cancers. We conducted a cohort study to investigate the role of ERCC1-ERCC4 gene polymorphisms on the response to chemotherapy and the role of these two gene polymorphisms on the clinical outcomes of gastric cancer. Four hundred forty-seven patients with newly diagnosed and histopathologically confirmed primary gastric cancer were collected in our study and were followed up until March 2012. ERCC1 (rs11615, rs3212986C>A, and rs2298881) and ERCC4 (rs226466C>G, rs2276465, and rs6498486) were selected and genotyped. The overall chemotherapy response rate for treatment was 68 %. Carriers of the rs11615 TT and T allele and ERCC1 rs2298881 CC and C allele had a marginally significantly higher response rate to the chemotherapy. In the Cox proportional hazard model, the hazard ratios (HRs) for overall survival (OS) in patients carrying ERCC1 rs11615 TT genotype and T allele were 0.53 (0.29-0.95) and 0.63 (0.42-0.94), respectively. Similarly, we found a significant decreased risk of death from gastric cancer among patients carrying ERCC1 rs2298881 CC genotype and C allele when compared with CC genotype, and HRs (95% confidence interval (CI)) of OS were 0.50 (0.24-0.98) and 0.62 (0.40-0.96), respectively. Moreover, individuals carrying ERCC1 rs11615 T allele and rs2298881 C allele could decrease a 0.62-fold risk of death from gastric cancer. This study reported a carriage of ERCC1 rs11615, and rs2298881 polymorphism can be used as a predictor of response to folinic acid/5-fluorouracil (5-FU)/oxaliplatin (FOLFOX)-based chemotherapy in gastric cancer patients.