Immunoneoadjuvant therapy with immune checkpoint inhibitors of gastric cancer: an emerging exemplification : Immunoneoadjuvant therapy of gastric cancer.

Advances in immune checkpoint inhibitors (ICIs) have enabled more effective treatment for individuals with various types of solid tumors. Given the improved survival benefit and acceptable safety profile of ICIs in advanced gastric cancer, there is plenty of interest in the use of ICIs in the neoadjuvant setting with curative intent. Theoretically, immunoneoadjuvant with ICIs could boost the levels of endogenous tumor antigen present in the tumor to enhance T-cell priming and further enhance systemic immunity. This systemic immune response may improve the detection and elimination of the disseminated micrometastatic tumors beyond the resected tumor, which are sources of postsurgical relapse. Numerous clinical studies have begun to explore the application of ICIs in neoadjuvant treatment of gastric cancer. This article reviews the progress in the use of ICI monotherapy and in combination with alternative therapies for the treatment of gastric cancer to aid in the development of gastric cancer immunoneoadjuvant therapy and improve the overall therapeutic benefit.

Effective Combination of Targeted Therapies with Sonodynamic Treatment for Use in Exploring Differences in Therapeutic Efficacy across Organelle Targets.

Acoustic kinetic therapy systems that target specific organelles can improve the precision of a sonosensitizer, which is a perfect combination of targeted therapy and sonodynamic therapy (SDT) and plays an important role in current acoustic kinetic therapy. In this study, we loaded PpIX, a sonosensitizer, on targeted-functional carbon dots (CDs) via an amide reaction and then generated the mitochondria-targeted system (Mit-CDs-PpIX) and nucleus-targeted system (Nuc-CDs-PpIX), respectively, to deliver the sonosensitizer. Both systems exhibited minimal cytotoxicity in the absence of ultrasound stimulation. The efficacy of the targeted SDT systems was investigated using methylthiazol tetrazolium (MTT) assays, live/dead staining, flow cytometry, etc. Compared with the free PpIX and mitochondria-targeted system, the nucleus-targeted system is more potent in killing effect under ultrasound stimulation and induces apoptosis with higher intensity. To achieve the equal killing effect, the effective concentration of Nuc-CDs-PpIX is just one third of that of Mit-CDs-PpIX.

Gastrointestinal signet ring cell malignancy: current advancement and future prospects.

Globally, gastrointestinal cancer is the most widespread neoplastic disease and the primary contributor to cancer-associated fatalities. Gastrointestinal signet ring cell carcinoma (SRCC) exhibits unique distinguishing features in several aspects when compared to adenocarcinomas (ACs). The scarcity of signet ring cell carcinoma has resulted in a heightened significance of related clinical and molecular investigations. However, a comprehensive and systematic review of the clinical, molecular, therapeutic, and research aspects of this disease is currently absent. This review provides an overview of the latest developments in our understanding of the clinical and molecular features of gastrointestinal signet ring cell carcinoma (SRCC). Additionally, we have compiled a list of potential therapeutic targets or biomarkers, as well as an examination of the current treatment options and the possible mechanisms of formation.

3D printing to construct in vitro multicellular models of melanoma.

Currently, there is a lack of suitable models for in-vitro studies of malignant melanoma and traditional single cell culture models no longer reproduce tumor structure and physiological complexity well. The tumor microenvironment is closely related to carcinogenesis and it is particularly important to understand how tumor cells interact and communicate with surrounding nonmalignant cells. Three-dimensional (3D) in vitro multicellular culture models can better simulate the tumor microenvironment due to their excellent physicochemical properties. In this study, 3D composite hydrogel scaffolds were prepared from gelatin methacrylate and polyethylene glycol diacrylate hydrogels by 3D printing and light curing techniques, and 3D multicellular in vitro tumor culture models were established by inoculating human melanoma cells (A375) and human fibroblasts cells on them. The cell proliferation, migration, invasion, and drug resistance of the 3D multicellular in vitro model was evaluated. Compared with the single-cell model, the cells in the multicellular model had higher proliferation activity and migration ability, and were easy to form dense structures. Several tumor cell markers, such as matrix metalloproteinase-9 (MMP-9), MMP-2, and vascular endothelial growth factor, were highly expressed in the multicellular culture model, which were more favorable for tumor development. In addition, higher cell survival rate was observed after exposure to luteolin. The anticancer drug resistance result of the malignant melanoma cells in the 3D bioprinted construct demonstrated physiological properties, suggesting the promising potential of current 3D printed tumor model in the development of personalized therapy, especially for discovery of more conducive targeted drugs.

Sintilimab plus fluorouracil, leucovorin, oxaliplatin and docetaxel regimen as neoadjuvant therapy for resectable gastric cancer and biomarker exploration.

At present, preoperative chemotherapy is the standard of care for the neoadjuvant treatment of potentially resectable gastric cancer (GC). However, because the efficacy and prognosis are not ideal, curative effects for this population are unsatisfactory. With the development of immune checkpoint inhibitors, the results of a few encouraging early trials of immunotherapeutic agents as neoadjuvant therapies for resectable GC have been reported. However, markers of the efficacy of immune checkpoint inhibitors remain unclear. This prospective single-center, single-arm observational study was designed to evaluate the efficacy of sintilimab plus the fluorouracil, leucovorin, oxaliplatin and docetaxel regimen as a neoadjuvant treatment for localized GC. More importantly, this work assesses multiple dimensions and include ctDNA, the immune microenvironment and intestinal microbiome to explore correlations between biomarkers and neoadjuvant therapeutic efficacy. Clinical trial registration: ChiCTR2200061629 (www.chictr.org.cn/index.aspx).

Ba-modified peanut shell biochar (PSB): preparation and adsorption of Pb(II) from water.

The impact of Ba-modified peanut shell biochar (Ba-PSB) on Pb(II) removal was studied and BaCl2 was used as a modifier. It was shown that the PSB obtained at 750 °C had the best adsorption effect, and the Ba-PSB had a larger specific surface area and a good adsorption effect on Pb(II). At pH = 5, concentration was 400 mg/L, time was 14 h, and temperature was 55 °C, the loading amount of black peanut shell biochar (BPSB), red peanut shell biochar (RPSB), Ba-BPSB, and Ba-RPSB reached 128.050, 98.217, 379.330, and 364.910 mg/g, respectively. In addition, based on the non-linear fitting, it was found that the quasi-second-order kinetic model, and isothermal model could be applied to describe Pb(II) adsorption on PSB and Ba-PSB. The adsorption behavior of PSB unmodified and modified was a spontaneous process. Moreover, chemical modification of BPSB, RPSB, Ba-BPSB, and Ba-RPSB for hindering of -COOH and -OH groups revealed 81.81, 77.08, 86.90, and 83.65% removal of Pb(II), respectively, which was due to the participation of -COOH, while 17.61, 21.70, 12.77, and 15.06% was from -OH group, respectively. The increase of cation strength (Na+, K+, Ca2+, and Mg2+) will reduce the adsorption capacity of PSB for Pb(II).

Proteomics and Biochemical Analyses of Secreted Proteins Revealed a Novel Mechanism by Which ADAM12S Regulates the Migration of Gastric Cancer Cells.

Gastric cancer is one of the cancers with the highest morbidity and mortality. Although several therapeutic approaches have been developed to treat this disease, the overall survival rate is still very low due to metastasis, drug resistance, and so forth. Therefore, it is necessary to discover new regulatory molecules and signaling pathways that modulate the metastasis of gastric cancer cells. A Disintegrin And Metalloprotease 12 (ADAM12) was highly expressed in gastric cancer tissues and presented in the patient urine. However, it is unclear whether and how ADAM12 regulates the migration of gastric cancer cells. In this work, we used the secretome protein enrichment with click sugars (SPECS) method to purify the secreted glycosylated proteins and performed quantitative proteomics to identify the secreted proteins that were differentially regulated by ADAM12S, the short and secreted form of ADAM12. Our proteomic and biochemical analyses revealed that ADAM12S upregulated the cell surface glycoprotein CD146, a cell adhesion molecule and melanoma marker, which was dependent on the catalytic residue of ADAM12S. Furthermore, we discovered that the ADAM12S-enhanced migration of gastric cancer cells was, at least partially, mediated by CD146. This work may help to evaluate whether ADAM12 could be a potential therapeutic target for the treatment of gastric cancer patients.

A lung adenocarcinoma patient harboring MET c. 3028 + 2 T >A variant sensitive to crizotinib treatment.

Several studies have reported that patients harboring MET-ex14 skipping benefit from MET tyrosine kinase inhibitors (TKIs) such as crizotinib, however, the overall response of crizotinib was 32% in these patients. Therefore, the clinical outcome of patients harboring different MET 14 skipping subtypes are worthy to be concern. Based on NGS analysis, we described a lung adenocarcinoma patient harboring a MET c.3028 + 2 T > A mutation which was predicted to lead to MET-ex14 skipping. Moreover, we performed IHC and qPCR to verify this variant. Then the patient treated with crizotinib and achieved good therapeutic effect. This mutation is firstly verified not only by multiple methodologies, but also by clinical effect. Our finding expands the spectrum of MET 14 exon skipping variant and maybe offer available application basis of MET inhibitor to patients harboring MET c. 3028 + 2 T > A/C/G. Importantly, targeted NGS analysis could improve detection of MET alterations in routine practice.

Dramatic response to alectinib in a lung adenocarcinoma patient harboring a Novel SSFA2-ALK fusion.

ALK (anaplastic lymphoma kinase) gene rearrangements have been reported in 3-5% of NSCLC patients. Different ALK fusion forms can mediate different downstream signaling pathways and may exhibit different sensitivities to ALK tyrosine kinase inhibitors (TKIs). To identify more fusion partners that are sensitive to ALK-TKIs, we present a case of 46-year-old woman with stage IV lung adenocarcinoma. NGS panel analysis suggested that a novel SSFA2-ALK fusion was identified in this patient. Moreover, this fusion was validated through IHC (VENTANA ALK (D5F3) antibody) and FISH (ZytoLight ALK Break Apart FISH Probe). Importantly, to the best of our knowledge, there is no report about SSFA2-ALK fusion in solid cancers. Moreover, the patient achieved an admirable response to alectinib, with a clinical evaluation of complete response (CR). In summary, our findings expand the spectrum of ALK fusion patterns and provide robust evidence for the precise administration of alectinib in the future.

Photo-crosslinked hydrogels for tissue engineering of corneal epithelium.

The vast majority of patients with corneal blindness cannot recover their vision due to the serious shortage of donor cornea. However, the technology to construct a feasible corneal substitute is a promising treatment method for corneal blindness. In this paper, methacrylated gelatin (GelMA)-methacrylated hyaluronic acid (HAMA) double network (GHDN) hydrogels were prepared by modifying gelatin and hyaluronic acid with methacrylate anhydride (MA). GHDN hydrogel was compared with GelMA single network and HAMA single network hydrogels through characterization experiments of mechanical properties, optical properties, hydrophilicity and in-situ degradation in vitro. At the same time, the biocompatibility of hydrogel was tested by inoculating rabbit corneal epithelial cells (CEpCs) epidermal cells on hydrogels using CCK-8 test, live/dead staining, immunofluorescence staining and qRT-PCR. It was found that the GHDN hydrogel has optical transparency in the visible region, and its mechanical properties are better than those of GelMA and HAMA hydrogels, and its hydrophilicity is similar to that of normal human corneas. The results of in vitro hydrogel culture of CEpCs showed that the proliferation of CEpCs on GHDN hydrogel was two times higher than that of HAMA hydrogel, and the expression of specific marker Cytokeratin 3 (CK3) and Cytokeratin 12 (CK12) could be better maintained on GHDN hydrogel. All the experimental results proved that GHDN hydrogel has good physical properties and biocompatibility and is a potential candidate for corneal tissue engineering scaffolds.

A novel LRRFIP1-ALK fusion in inflammatory myofibroblastic tumor of hip and response to crizotinib.

An inflammatory myofibroblastic tumor (IMT) is a rare invasive soft tissue mass with intramuscular penetration that is primarily treated via a surgical procedure. However, with unclear boundaries and a high rate of relapse, there is no standard treatment for recurrence or unresectable tumors. It is noteworthy that approximately half of IMTs harbor genetic rearrangements of the anaplastic lymphoma kinase (ALK). ALK inhibitors have been used successfully in the treatment of IMTs with a variety of ALK fusions. Here, we present a case of a 15-year-old patient with IMT around the hip. Next-generation sequencing (NGS) revealed an LRRFIP1-ALK fusion, which has not yet been reported in the literature. Crizotinib, an ALK inhibitor, was effective in the treatment of this patient, indicating that ALK inhibitors may be effective for IMT with LRRFIP1-ALK fusions. This report expands the list of gene fusions in IMTs and highlights a new target for treatment.

SILAC Quantitative Proteomics and Biochemical Analyses Reveal a Novel Molecular Mechanism by Which ADAM12S Promotes the Proliferation, Migration, and Invasion of Small Cell Lung Cancer Cells through Upregulating Hexokinase 1.

Small cell lung cancer (SCLC) accounts for ∼14% of total lung cancer, which is the worldwide leading cause of morbidity and mortality in cancer. Although SCLC can be treated with chemotherapy and radiotherapy, its 5 year survival rate is still below 7%. Therefore, it is essential to discover new molecules and elucidate the underlying mechanisms modulating the tumorigenesis and metastasis of SCLC for the unmet medical needs. The secreted form of A Disintegrin And Metalloproteinase 12 (ADAM12S) is highly expressed in SCLC and promotes the proliferation, migration, and invasion of SCLC cells. However, the underlying molecular mechanism is still elusive. Using stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics, we identify 82 ADAM12S-regulated proteins in an SCLC cell line. Our proteomics and biochemical analyses discover that ADAM12S overexpression elevates while ADAM12 knockdown reduces the rate-limiting enzyme hexokinase 1 (HK1) in glycolysis. Through bioinformatics analyses, genetic manipulation, and in vitro assays, we further reveal that ADAM12S promotes the proliferation, colony formation, migration, and invasion of SCLC cells through upregulating HK1. This work links ADAM12S to glucose metabolic pathways in its attribution to the tumorigenesis and metastasis of SCLC cells and might provide valuable information for the exploration of therapeutic intervention for SCLC.

Rapid cancer diagnosis by highly fluorescent carbon nanodots-based imaging.

Carbon dots (Cdots) with bright green fluorescence were applied to the rapid and selective cell imaging for a variety of cell lines. Different labeling distributions of hepatoma cells (HepG2) and normal human liver cells (LO2) were achieved using Cdots as imaging agents. For HepG2 cells, the Cdots could rapidly permeate the cell membrane and diffuse into the cytoplasm and nucleus within 3 min, and retained their location in the targets for 24 h. However, the Cdots exhibited bright fluorescence only in the cytoplasm of LO2 cell lines. Moreover, the Cdots were almost non-cytotoxic and exhibited superior photostability over a wide range of pH. Therefore, these Cdots have great potential for rapid, luminous and selective bioimaging applications, and are expected to be used as a nucleus-staining agent in cancer diagnosis. Graphical abstract ᅟ.

A fluorometric method for mercury(II) detection based on the use of pyrophosphate-modified carbon quantum dots.

Pyrophosphate-modified carbon quantum dots (PP-CDs) are demonstrated to be a viable fluorescent nanoprobe for mercury(II) (Hg2+) detection. Hg2+ reacts with the pyrophosphate groups on the surface of PP-CDs to form a non-fluorescent complex. This results in quenching of the green fluorescence which has excitation/emission peaks at 400/513 nm. Static quenching is shown to be the dominant mechanism. The probe works in 0.1 µM to 1.4 µM Hg2+ concentration range, and the limit of detection is 2 nM. The PP-CDs were also used to visualize Hg2+ inside human hepatocyte LO2 cells. Graphical abstract Schematic representation of pyrophosphate-modified carbon quantum dots (CDs) for selective and sensitive fluorometric determination of mercury(II). Hg(II) quenches the blue fluorescence of the CDs, and glutathione restores it. The method was used to detect Hg(II) in spiked tap water and inside cells.

[Signal exchange between plants and Arbuscular Mycorrhizae fungi during the early stage of symbiosis - A review].

Much is known about Arbuscular Mycorrhizae (AM), an important component of the ecosystem, whereas little is known about the signal exchange that allows mutual recognition and reprograming for the anticipated physical interaction. This review addresses the latest advances of signal exchange between plants and AM, including signal substances and their function, related genes and regulation function in the early stage of plant-fungal symbiosis.

An approximation solution to refinery crude oil scheduling problem with demand uncertainty using joint constrained programming.

This paper is devoted to develop an approximation method for scheduling refinery crude oil operations by taking into consideration the demand uncertainty. In the stochastic model the demand uncertainty is modeled as random variables which follow a joint multivariate distribution with a specific correlation structure. Compared to deterministic models in existing works, the stochastic model can be more practical for optimizing crude oil operations. Using joint chance constraints, the demand uncertainty is treated by specifying proximity level on the satisfaction of product demands. However, the joint chance constraints usually hold strong nonlinearity and consequently, it is still hard to handle it directly. In this paper, an approximation method combines a relax-and-tight technique to approximately transform the joint chance constraints to a serial of parameterized linear constraints so that the complicated problem can be attacked iteratively. The basic idea behind this approach is to approximate, as much as possible, nonlinear constraints by a lot of easily handled linear constraints which will lead to a well balance between the problem complexity and tractability. Case studies are conducted to demonstrate the proposed methods. Results show that the operation cost can be reduced effectively compared with the case without considering the demand correlation.

A novel algorithm combining finite state method and genetic algorithm for solving crude oil scheduling problem.

A hybrid optimization algorithm combining finite state method (FSM) and genetic algorithm (GA) is proposed to solve the crude oil scheduling problem. The FSM and GA are combined to take the advantage of each method and compensate deficiencies of individual methods. In the proposed algorithm, the finite state method makes up for the weakness of GA which is poor at local searching ability. The heuristic returned by the FSM can guide the GA algorithm towards good solutions. The idea behind this is that we can generate promising substructure or partial solution by using FSM. Furthermore, the FSM can guarantee that the entire solution space is uniformly covered. Therefore, the combination of the two algorithms has better global performance than the existing GA or FSM which is operated individually. Finally, a real-life crude oil scheduling problem from the literature is used for conducting simulation. The experimental results validate that the proposed method outperforms the state-of-art GA method.

A rare case of primary central nervous system histiocytic sarcoma harboring a novel ARHGAP45::BRAF fusion: a case report and literature review.

INTRODUCTION: Patients with histiocytic sarcoma occurring in the central nervous system (CNS) are rare and have a very poor prognosis. The increased use of molecular diagnostic approaches in solid tumors has brought more opportunities for the diagnosis and treatment of central nervous system histiocytic sarcoma (CNSHS). CASE DESCRIPTION: A 9-year-old girl was admitted to the hospital with pain in her head and neck, as well as vomiting. Imaging scans showed a prominent abnormality in the anterior falciform region, and histopathology revealed the presence of CD68 (+) and CD163 (+) cells, leading to a preliminary diagnosis of primary intracerebral CNSHS. Molecular profiling tests identified a new variant of ARHGAP45::BRAF fusion in this case, which has not been reported in any other tumor. The patient underwent surgical removal of the tumor and will require long-term monitoring. CONCLUSION: The presence of the BRAF point mutation, predominantly BRAF p.V600E, has been documented in prior literature of CNSHS. This is the first case of pediatric histiocytic sarcoma in the anterior falciform region who has a unique ARHGAP45::BRAF fusion. The findings of our study indicate that a broader range of molecular assays should be employed in the diagnosis of CNSHS and opens up new possibilities for the treatment of the patient.