Cáncer Gástrico Bifocal con Linfonodos Negativos en un Paciente con Cirrosis Hepática / Bifocal Gastric Cancer with Negative Lymph Nodes in a Hepatic Cirrhosis Patient

El cáncer gástrico (CG), es la primera causa de muerte por cáncer, en hombres, y la tercera en mujeres, en Chile. No obstante ello, el CG bifocal (CGB) es una situación poco frecuente. El objetivo de este manuscrito fue reportar un caso de CGB, con linfonodos negativos en un paciente con cirrosis hepática, que fue intervenido quirúrgicamente; y revisar la evidencia existente respecto de sus características morfológicas, terapéuticas y pronósticas. Caso clínico: Hombre de 74 años diabético, hipertenso, insuficiente cardíaco y cirrótico; portador de CGB (subcardial y antro-pilórico), diagnosticado por endoscopia y con confirmación histológica de ambas lesiones; operado en Clínica RedSalud Mayor Temuco en septiembre de 2023. En el intraoperatorio se verificó además la coexistencia de una lesión de aspecto metastásico en el segmento III del hígado, y adhesión de la región antro-pilórica a la vesícula biliar. Se realizó gastrectomía total, linfadenectomía D2, esófago-yeyuno anastomosis término-lateral, resección segmentaria hepática (segmento III) y colecistectomía. El paciente permaneció 6 días en la UCI debido a que desarrolló insuficiencia hepática (encefalopatía leve y ascitis). Se alimentó vía enteral por sonda naso-yeyunal. Posteriormente inició alimentación oral progresiva, la que fue bien tolerada. Completó 11 días de hospitalización en servicio médico-quirúrgico, donde mejoró actividad neurológica, hasta su alta domiciliaria. Actualmente, lleva dos meses desde su operación, se encuentra en buenas condiciones generales, y el Comité Oncológico decidió no dar quimioterapia adyuvante. Se presenta un caso inusual de CG de tipo bifocal, respecto de lo cual hay escasa información disponible. Se logró realizar cirugía con intención curativa en un paciente de alto riesgo, con un resultado exitoso.

SUMMARY: Gastric cancer (GC) is the first cause of death from cancer in men, and the third one in women, in Chile. However, a bifocal GC (BGC) is uncommon. The aim of this study was to report a case of CGB, with negative-lymph nodes in a patient with liver cirrhosis, who underwent surgery; and review the existing evidence regarding its morphological, therapeutic and prognostic characteristics. Clinical case: A 74-year-old male patient with a medical history of diabetes, hypertension, congestive heart failure, and cirrhosis underwent surgical intervention for GC located in subcardial and antro- pyloric regions. The diagnosis was established via endoscopy and confirmed histologically. Surgery was performed at the RedSalud Mayor Temuco Clinic in September 2023. During intraoperative assessment, the coexistence of a lesion with metastatic-like characteristics in segment III of the liver was also verified, along with adhesions between the antro-pyloric region and the gallbladder. Surgical approach encompassed total gastrectomy, D2 lymphadenectomy, esophago-jejunostomy, segmental hepatic resection, and cholecystectomy. Subsequently, the patient required a six-day stay in ICU due to the development of hepatic insufficiency, characterized by mild encephalopathy and ascites. Enteral nutrition was administered via a naso-jejunal tube, followed by a gradual transition to oral feeding, which was well-tolerated. The patient completed an 11-day hospitalization period in the medical-surgical ward, during which his neurological function improved significantly, resulting in his discharge. At present, 2 months post-surgery, the patient remains in satisfactory general health, and the Oncology Committee decided not to proceed with adjuvant chemotherapy. This case represents a rare instance of bifocal GC, for which there is limited available literature. Surgical intervention with curative intent was successfully carried out in a high-risk patient, yielding a positive outcome.

Effects of the proliferation, migration and apoptosis of AHVAC - on gastric cancer MKN-28 cells / 中国临床药理学与治疗学

AIM: To investigate the effects of agkis-trodon halys venom anti-tumor component (AHVAC-) on the biological behavior of gastric cancer MKN-28 cells. METHODS: Gastric cancer MKN-28 cells were treated with the experimental concentrations (5, 10, 15 μg/mL) of AHAVC- for 24 h. Cell proliferation and toxicity assay (cell counting kit-8, CCK-8) was used to detect the inhibition rates of the cells in different concentrations of AHVAC-. The migration ability of the cells was evaluated by wound-healing and Transwell assay. The apoptosis were observed by laser confocal microscopy with annexin V-mCherry/DAPI double staining, and the apoptosis rates were analyzed by flow cytometry with annexin V-FITC/PI double fluorescence staining. The protein level of Caspease-3 was determined by Western blot. RESULTS: Compared with normal control group, the results of AHVAC- concentration groups showed that with the increase of AHVAC- concentration, the proliferative activity of MN-28 cells decreased gradually (P<0.01), the cell migration ability decreased gradually (P<0.01), and the cell apoptosis rate increased (P<0.05). The expression of apoptosis-related protein Caspease-3 was up-regulated (P<0.01). CONCLUSION: AHVAC- inhibits proliferation and migration of gastric cancer MSN-28 cells and induces apoptosis.

Diallyl disulfide augments sensitivity of DJ-1 overexpressed human gastric cells to 5-FU / 中国药理学通报

Aim To investigate whether diallyl disul-fide (DADS) augments the sensitivity of DJ-1 (protein/ nucleic acid deglycase) overexpressed human gastric SGC7901 cells to 5-FU (5-fluorouracil). Methods The experimental groups include control group, DADS group, VCR (vincristine) group, VCR + DADS group, DJ-1 group, DJ-1 + DADS group. MTT was used to analyze the effect of DADS on 5 -FU (5 -fluorou- racil) induced proliferation inhibition. Flow cytometry was performed to examine the effect of DADS on cell apoptosis. RT-PCR, Western blot, and immunofluo-rescence were used for determine the effect of DADS on the drug resistance associated gene expression. Results DADS enhanced the proliferation inhibitory effect of 5-FU on DJ-1 overexpressed cells and VCR resistant cells. DADS could induce apoptosis in VCR-resistant cells. DADS downregulated the expression of DJ-1 while inducing apoptosis in DJ-1 overexpressed cells. DJ-1 overexpression upregulated the expression of P-gp (P-glycoprotein), Bcl-2, and XIAP (X-linked inhibitor of apoptosis protein), downregulated the expression of caspase-3. DADS decreased the expression of P-gp, Bcl-2, and XIAP, while increased the expression of caspase-3 in DJ-1 overexpressed cells and VCR-resistant cells. Conclusions DADS can augment the sensitivity of DJ-1 overexpressed cells to 5-FU, which is related to its antagonism against DJ-1 mediated upregula- tion of P-gp, Bcl-2, XIAP, and downregulation of caspase-3.

Literature analysis of ADR after the listing of apatinib / 中国药房

OBJECTIVE To explore the characteristics and regulations of adverse drug reactions （ADR） caused by apatinib， and to provide a reference for the safe use of apatinib in clinic. METHODS Case and group reports on ADR and safety evaluation of apatinib were retrieved from Chinese and English databases such as CNKI， Wanfang medical network， VIP and PubMed since its listing in 2014， literature data were extracted and statistically analyzed after screening. RESULTS Totally 101 cases were included， involving 221 ADR. In the above cases， the male-to-female ratio was 1.24∶1， with the highest proportion of patients aged 51 to 70 years， most of the patients were given a dose of 500 mg or more， and the patients given low dose of apatinib combined with other antitumor drugs were also likely to have ADR. One to two types of adverse reaction were the most common， while the types could reach up to six. Most ADR occurred within 30 days after medication， and the systems/organs involved were mainly the cardiovascular system damage，skin and its accessories damage， gastrointestinal system damage and urinary system damage； the main clinical manifestations were hypertension/aggravation，hand-foot syndrome，abdominal pain diarrhea and albuminuria， etc. Hypertension/aggravation， hand-foot syndrome and myelosuppression were the most common serious ADR. Most ADR could be improved/cured by suspension of administration， dose downregulation and symptomatic treatment. All 4 patients who died had underlying diseases， and their ECOG scores all ≥2 points. Special ADR （such as reversible posterior encephalopathy syndrome， psychiatric disorders， and cognitive impairment） were mostly caused by apatinib itself， or may be caused by apatinib in combination with the primary or underlying disease. CONCLUSIONS Advanced age， large dose， combination medication， underlying diseases and poor physical condition might be the high risks for ADR caused by apatinib. It is recommended to monitor the blood pressure，urine protein and skin of hands and feet of all patients with medication on a daily basis，pay attention to the occurrence of special ADR， and timely detect abnormal states and give effective intervention，so as to avoid the aggravation of ADR and other secondary ADR.

Research Progress on Association Between Oral Bacteria and Gastric Cancer / 肿瘤防治研究

Gastric cancer is one of the major types of cancer threatening human health worldwide. Its pathogenesis has not been fully elucidated, and patients are often diagnosed at an advanced stage. The oral cavity is the second largest microbial pool after the intestine in the human body, and thus the relationship between oral bacteria and human health is attracting increasing interest. Oral bacteria are closely related to gastric cancer and potentially serve as noninvasive diagnostic screening biomarkers for the disease. Imbalance in and displacement of these bacteria can promote the occurrence and development of gastric cancer. Hence, this article reviews the association between oral bacteria and gastric cancer, aiming to provide a basis for further elucidating the pathogenesis of gastric cancer and screening it early through noninvasive methods and serve as a reference for subsequent related research.

GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer

Glutamate-ammonia ligase (GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

Research progress about traditional Chinese medicine in the intervention of gastric cancer by regulating Th17/Treg balance / 中国药房

Gastric cancer （GC） is a common malignant tumor of the digestive tract. T helper cells 17 （Th17） and T regulatory cells （Treg） are differentiated subsets of CD4+T cells. Th17/Treg imbalance has been shown to be closely related to the progression of GC. Traditional Chinese medicine （TCM） can not only improve the survival prognosis of GC patients， but also play a role in enhancing the efficacy and reducing the toxicity of postoperative chemotherapy for GC. This paper systematically sorted out the action rules of TCM in the intervention of GC by regulating Th17/Treg balance. The results showed that the TCM compound could regulate the balance of GC Th17/Treg by invigorating the spleen and invigorating Qi， warming Yang， removing blood stasis and detoxifying. The mechanism of regulating Th17/Treg balance in the intervention of GC is mainly to inhibit the excessive differentiation of Th17 and Treg and the overexpression of transcription factors and cytokines， reverse the excessive drift of GC Th17/Treg balance to Th17 or Treg， and thus restore the immune balance of GC Th17/Treg.

Mechanism on Banxia Xiexintang Inducing Ferroptosis in Gastric Cancer Cells Based on Nrf2/GPX4 Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo observe the effect of Banxia Xiexintang （BXT） on the proliferation of human gastric cancer HGC-27， MKN-45， and AGS cells and its mechanism. MethodCell counting kit-8 （CCK-8） was used to detect the effects of different concentrations of BXT-containing serum （5%， 10%， and 20%） on the proliferation of HGC-27， MKN-45， and AGS cells. A mitochondrial membrane potential probe （TMRE） was used to detect the expression of mitochondrial membrane potential in cells. A kit was used to detect iron ion （Fe2+） content， lipid peroxide （LPO）， and superoxide dismutase （SOD） activity. Western blot was used to detect the protein expression levels of glycogen synthase3β （GSK3β）， phosphorylated GSK3β （p-GSK3β）， nuclear factor E2 related factor 2 （Nrf2）， and glutathione peroxidase 4 （GPX4）. The real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of member 11 of the cystine/glutamic acid reverse transporter solute vector family 7 （SLC7A11）， member 2 of the heavy chain solute vector family 3 （SLC3A2）， transferrin receptor 3 （TFRC）， and tumor protein （TP）53. ResultCCK-8 results showed that BXT and capecitabine could significantly reduce the survival rate of three kinds of gastric cancer cells after treatment with drug-containing serum for 24 h （P<0.01）. After 48 h of intervention with drug-containing serum， the survival rate of three kinds of gastric cancer cells was significantly decreased in both the capecitabine group and the BXT group compared with the blank group. The BXT group was dose-dependent， with 20% BXT having the most significant effect （P<0.01）. In terms of biochemical indicators of ferroptosis， compared with the blank group， BXT and capecitabine significantly decreased the expression of mitochondrial membrane potential （P<0.01） and SOD activity （P<0.01） and significantly increased the contents of LPO and Fe2+ （P<0.01）， so as to improve the sensitivity of gastric cancer cells to ferroptosis. In terms of the Nrf2/GPX4 pathway， compared with the blank group， the BXT group could reduce the protein expressions of p-GSK3β， Nrf2， and GPX4 （P<0.01） in gastric cancer cells and increase mRNA expressions of SLC7A11 and SLC3A2 （P<0.05）. It could also increase the protein expression of GSK3β （P<0.01） and mRNA expression of TP53 and TFRC （P<0.05， P<0.01） in gastric cancer cells. Inhibition of the Nrf2/GPX4 pathway induces ferroptosis in gastric cancer cells. Compared with the capecitabine group， the 20% BXT group showed a more obvious effect. ConclusionBanxia Xiexintang can induce ferroptosis in gastric cancer cells HGC-27， MKN-45， and AGS by inhibiting the Nrf2/GPX4 pathway.

Papel da biópsia da incisura angular no estadiamento da gastrite e na avaliação de risco do câncer gástrico / Role of incisura angularis biopsy in gastritis staging and risk assessment of gastric câncer

ABSTRACT Background: Gastric atrophy (GA) and intestinal metaplasia (IM) are early stages in the development of gastric cancer. Evaluations are based on the Updated Sydney System, which includes a biopsy of the incisura angularis (IA), and the Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastritis Assessment using Intestinal Metaplasia (OLGIM) gastric cancer risk staging systems. Objective: To compare the OLGA and OLGIM classifications with and without IA biopsy. In addition, to determine the prevalence of Helicobacter pylori (HP) and pre-neoplastic changes (GA and IM) in different biopsied regions and to identify the exclusive findings of IA. Methods: Observational, prospective, descriptive, unicentric study with 350 patients without a diagnosis of gastric cancer, who underwent upper digestive endoscopy with biopsies at Gastroclínica Itajaí, from March 2020 to May 2022. The histopathological classification of gastritis followed the Updated Sydney System, and the gastric cancer risk assessment followed the OLGA and OLGIM systems. The methodology applied evaluated the scores of the OLGA and OLGIM systems with and without the assessment of the IA biopsy. Statistical analysis was performed using descriptive measures (frequencies, percentages, mean, standard deviation, 95% confidence interval). Ranks were compared using the Kruskal-Wallis or Wilcoxon tests. To analyze the relationship between the frequencies, the bilateral Fisher's exact test was used. Wilson's score with continuity correction was applied to the confidence interval. Results: The median age was 54.7 years, with 52.57% female and 47.43% male patients. The comparison between the used biopsies protocol (corpus + antrum [CA] vs corpus + antrum + incisura angularis [CAI]) and the OLGA and OLGIM stages showed a significant decrease in both staging systems when the biopsy protocol restricted to the corpus and antrum was applied (OLGA CAI vs CA; P=0.008 / OLGIM CAI vs CA; P=0.002). The prevalence of pre-malignant lesions (GA, IM and dysplasia) of the gastric mucosa was (33.4%, 34% and 1.1%, respectively) in the total sample. The antrum region exhibited significantly higher numbers of alteration (P<0.001), except for HP infection, which was present in 24.8% of the patients. Conclusion: Incisura angularis biopsy is important because it increased the number of cases diagnosed in more advanced stages of intestinal metaplasia and atrophy. The study had limitations, with the main one being the relatively small sample size, consisting mostly of healthy individuals, although mostly elderly.

RESUMO Contexto: A atrofia gástrica (AG) e a metaplasia intestinal (MI) são estágios iniciais do desenvolvimento do câncer gástrico. As avaliações são baseadas no Sistema de Sydney Atualizado, que inclui uma biópsia da incisura angular (IA), e nos sistemas de estadiamento de risco de câncer gástrico Operative Link on Gastritis Assessment (OLGA) e Operative Link on Gastritis Assessment using Intestinal Metaplasia (OLGIM). Objetivo: Comparar as classificações OLGA e OLGIM com e sem biópsia da IA. Além disso, determinar a prevalência de Helicobacter pylori (HP) e alterações pré-neoplásicas (AG e MI) em diferentes regiões biopsiadas e identificar os achados exclusivos da IA. Métodos: Estudo observacional, prospectivo, descritivo, unicêntrico, com 350 pacientes sem diagnóstico de câncer gástrico, submetidos à endoscopia digestiva alta com biópsias na Gastroclínica Itajaí, no período de março de 2020 a maio de 2022. A classificação histopatológica da gastrite seguiu o Sistema de Sydney Atualizado, e a avaliação do risco de câncer gástrico seguiu os sistemas OLGA e OLGIM. A metodologia aplicada avaliou os escores dos sistemas OLGA e OLGIM com e sem a avaliação da biópsia da IA. A análise estatística foi realizada por meio de medidas descritivas (frequências, porcentagens, média, desvio padrão, intervalo de confiança de 95%). As classificações foram comparadas usando os testes de Kruskal-Wallis ou Wilcoxon. Para analisar a relação entre as frequências, foi usado o teste exato de Fisher bilateral. O escore de Wilson com correção de continuidade foi aplicado ao intervalo de confiança. Resultados: A idade média foi de 54.7 anos, com 52.57% de pacientes do sexo feminino e 47.43% do sexo masculino. A comparação entre o protocolo de biópsias utilizado (corpo + antro [CA] vs corpo + antro + incisura angular [CAI]) e os estágios OLGA e OLGIM mostrou uma diminuição significativa em ambos os sistemas de estadiamento quando o protocolo de biópsia restrito ao corpo e ao antro foi aplicado (OLGA CAI vs CA; P=0.008 / OLGIM CAI vs CA; P=0.002). A prevalência de lesões pré-malignas (GA, MI e displasia) da mucosa gástrica foi de (33.4%, 34% e 1.1%, respectivamente) na amostra total. A região do antro exibiu um número significativamente maior de alterações (P<0.001), com exceção da infecção por HP, que estava presente em 24.8% dos pacientes. Conclusão: A biópsia de IA é importante porque aumentou o número de casos diagnosticados em estágios mais avançados de MI e AG. O estudo teve limitações, sendo a principal delas o tamanho relativamente pequeno da amostra, composta principalmente por indivíduos saudáveis, embora em sua maioria idosos.

Efficacy of Neoadjuvant Chemotherapy on Locally Advanced Gastric Adenocarcinoma in Terms of Downstaging and Resectability in a Tertiary Cancer Hospital

Background: Neoadjuvant chemotherapy (NACT) in carcinoma stomach was introduced in an effort to eliminate micro-metastasis and to improve resectablity before surgery which improves R0 resection rates. The aim of the current study was to evaluate the effect of neoadjuvant chemotherapy on downstaging and resectability rate in locally advanced gastric cancer. Material & Methods: This was a single-center quasi-experimental study conducted in the Department of Surgical Oncology in collaboration with the Departments of Medical Oncology, Radiation oncology, and Pathology at the National Institute of Cancer Research and hospital, Dhaka, which is a tertiary care cancer hospital in Bangladesh, between January 2021 and June 2022.Patients with locally advanced adenocarcinoma stomach staged by contrast-enhanced computed tomography (CECT) were randomly included in this study by purposive sampling. Patients in Group I underwent upfront surgery Patients in Group II were started on neoadjuvant chemotherapy, either XELOX or FLOT regimen. Surgery was done following the response assessment CECT. We assessed R0 resection rate, age, sex, comorbidities, tumour size, TNM stage and complications were compared between the two groups. Response to NACT was assessed in Group II. Results: The mean age of patients in groups 1 & 2 was 56 ± 11.06 and 55.70 ± 10.46 years of age respectively (p > 0.05). Majority of the respondents (55/74) were male and 19 patients (26%) were female. Male to female ratio was (24/37 &31/37) in group 1 and (31/37 & 6/37) groups respectively (p > 0.05). Out of 37 patients who received NACT, in 9 patients (24.32%) complete response was noted. Partial response was found in 20 cases (54.05%), p-value (<.0001) while a stable disease was reported in three (8.1%) cases. 5 patients (13.51%) had progressive disease. In the upfront surgery group, R0 resection was feasible in 16 (43.2%) cases, and in the NACT plus surgery group, R0 resection was done in 29 (78.4%) cases. In group 1, R1 resection was done in considerable numbers (19/37) compared to group 2 (5/37), P=0.001. Three patients (8.1%) in group 2 and one (2.7) in group 1 had irresectable lesions. Conclusion: In this study it can be concluded that neoadjuvant chemotherapy could downstage tumour and increase tumor resectability rate in patients with locally-advanced gastric adenocarcinoma. However, further studies are necessary to confirm the effect of this modality on patients’ overall survival. We await survival analysis to further validate the role of NACT.

The Burden of Gastric Cancer Disease from 2010 to 2019 in Tunja, Boyacá, Colombia

Introduction: Gastric cancer (GC) is the first cause of death by neoplasm in Colombia, with 6,451 deaths in 2020. This pathology and its chronic manifestations pose a public health challenge. The objective is to estimate the disease burden of GC in Tunja, Boyacá, from 2010 to 2019. Materials and methods: An exploratory ecological study was conducted using disability-adjusted life years (DALYs) as the unit of measurement. The National Administrative Department of Statistics (DANE) mortality databases and prevalence information from the Integrated Social Protection Information System (SISPRO) records were used. Deaths and GC cases were pooled and then adjusted to control for bias. Results: In 2010-2019, 34.2 DALYs were lost for every 1,000 people secondary to GC in Tunja, 30.5 were due to years lost due to premature death, and 3.72 were due to years lived with disability. DALYs due to premature death were found to exceed DALYs due to disability. Conclusion: The morbidity burden of GC from 2010 to 2019 for Tunja was similar to that of other cancers because of years of life lost due to premature death, so public health efforts should be made to increase early detection.

Introducción: el cáncer gástrico (CG) es la primera causa de muerte por neoplasia en Colombia, con 6451 muertes durante el 2020. Esta patología y sus manifestaciones crónicas plantean un desafío en la salud pública. El objetivo fue estimar la carga de enfermedad por CG en Tunja, Boyacá, durante los años 2010 a 2019. Metodología: se realizó un estudio ecológico exploratorio en el que se utilizó como unidad de medida los años de vida ajustados por discapacidad (AVAD). Se emplearon las bases de datos de mortalidad del Departamento Administrativo Nacional de Estadística (DANE) e información de la prevalencia desde los registros del Sistema Integrado de Información de la Protección Social (SISPRO). Las muertes y los casos de CG se agruparon y luego se ajustaron para controlar sesgos. Resultados: en el período 2010-2019 se perdieron 34,2 AVAD por cada 1000 personas secundarios a CG en Tunja, de los cuales 30,5 fueron debido a años perdidos por muerte prematura y 3,72 por años vividos con discapacidad. Se encontró que los AVAD por muerte prematura superan a los AVAD por discapacidad. Conclusión: la carga de morbilidad por CG en el período 2010 a 2019 para la ciudad de Tunja fue similar a la carga de otros cánceres y fue debido a años de vida perdidos por muerte prematura, motivo por el cual se deben realizar esfuerzos de salud pública para aumentar la detección temprana.

Over-expression of gastrin inhibits apoptosis of gastric cancer cells via reactive oxygen species and annexin A2-mediated mitochondrial dysfunction / La sobreexpresión de gastrina inhibe la apoptosis de las células de cáncer gástrico a través de especies reactivas de oxígeno y disfunción mitocondrial mediada por anexina A2

SUMMARY: Gastrin plays a vital role in the development and progression of gastric cancer (GC). Its expression is up-regulated in GC tissues and several GC cell lines. Yet, the underlying mechanism remains to be investigated. Here, we aim to investigate the role and mechanism of gastrin in GC proliferation. Gastrin-overexpressing GC cell model was constructed using SGC7901 cells. Then the differentially expressed proteins were identified by iTRAQ analysis. Next, we use flow cytometry and immunofluorescence to study the effect of gastrin on the mitochondrial potential and mitochondria-derived ROS production. Finally, we studied the underlying mechanism of gastrin regulating mitochondrial function using Co-IP, mass spectrometry and immunofluorescence. Overexpression of gastrin promoted GC cell proliferation in vitro and in vivo. A total of 173 proteins were expressed differently between the controls and gastrin- overexpression cells and most of these proteins were involved in tumorigenesis and cell proliferation. Among them, Cox17, Cox5B and ATP5J that were all localized to the mitochondrial respiratory chain were down-regulated in gastrin-overexpression cells. Furthermore, gastrin overexpression led to mitochondrial potential decrease and mitochondria-derived ROS increase. Additionally, gastrin-induced ROS generation resulted in the inhibition of cell apoptosis via activating NF-kB, inhibiting Bax expression and promoting Bcl-2 expression. Finally, we found gastrin interacted with mitochondrial membrane protein Annexin A2 using Co-IP and mass spectrometry. Overexpr ession of gastrin inhibits GC cell apoptosis by inducing mitochondrial dysfunction through interacting with mitochondrial protein Annexin A2, then up-regulating ROS production to activate NF-kB and further leading to Bax/Bcl-2 ratio decrease.

La gastrina juega un papel vital en el desarrollo y progresión del cáncer gástrico (CG). Su expresión está regulada al alza en tejidos de CG y en varias líneas celulares de CG. Sin embargo, el mecanismo subyacente aun no se ha investigado. El objetivo de este estudio fue investigar el papel y el mecanismo de la gastrina en la proliferación de CG. El modelo de células CG que sobre expresan gastrina se construyó usando células SGC7901. Luego, las proteínas expresadas diferencialmente se identificaron mediante análisis iTRAQ. A continuación, utilizamos la citometría de flujo y la inmunofluorescencia para estudiar el efecto de la gastrina en el potencial mitocondrial y la producción de ROS derivada de las mitocondrias. Finalmente, estudiamos el mecanismo subyacente de la gastrina que regula la función mitocondrial utilizando Co-IP, espectrometría de masas e inmunofluorescencia. La sobreexpresión de gastrina promovió la proliferación de células CG in vitro e in vivo. Un total de 173 proteínas se expresaron de manera diferente entre los controles y las células con sobreexpresión de gastrina y la mayoría de estas proteínas estaban implicadas en la tumorigenesis y la proliferación celular. Entre estas, Cox17, Cox5B y ATP5J, todas localizadas en la cadena respiratoria mitocondrial, estaban reguladas a la baja en las células con sobreexpresión de gastrina. Además, la sobreexpresión de gastrina provocó una disminución del potencial mitocondrial y un aumento de las ROS derivadas de las mitocondrias. Por otra parte, la generación de ROS inducida por gastrina resultó en la inhibición de la apoptosis celular mediante la activación de NF-kB, inhibiendo la expresión de Bax y promoviendo la expresión de Bcl-2. Finalmente, encontramos que la gastrina interactuaba con la proteína de membrana mitocondrial Anexina A2 usando Co-IP y espectrometría de masas. La sobreexpresión de gastrina inhibe la apoptosis de las células CG al inducir la disfunción mitocondrial a través de la interacción con la proteína mitocondrial Anexina A2, luego regula el aumento de la producción de ROS para activar NF-kB y conduce aún más a la disminución de la relación Bax/Bcl-2.

Low Expression of E-Cadherin and Cdh1 Variants Associated with Diffuse Gastric Cancer

ABSTRACT Background Reduced or null expression of E-cadherin protein is a frequent cause of diffuse gastric cancer (DGC). More than 50% of patients with DGC present somatic variants in CDH1 gene. Objectives The objectives of this study were to study E-cadherin expression and identify variants in the CDH1 gene in gastric tumors of patients with DGC. Methods We studied 18 Mexican DGC patients who attended a hospital of the Mexican Social Security Institute; E-cadherin expression was determined by immunohistochemistry, and variants were identified by Sanger sequencing in promoter and coding regions. Predictive analysis was performed using PolyPhen-2 and HOPE software. Results We found that 56% of DGC patients showed reduced expression of E-cadherin. All patients carried CDH1 variants; overall, 12 different CDH1 variants were identified. Predictive analysis revealed that the rs114265540 variant was probably damaging, with a value of 0.985, indicating a functional impact on the E-cadherin protein. Variants rs34939176 and rs33964119 were identified as risk factors for DGC (odds' ratios [OR] = 31.3, 95% CI 6.3-154.0, p < 0.001; OR = 6.1, 95% CI 2.0-19.0, p < 0.001, respectively) given their elevated frequency and by comparing it with those reported for MXL population in the 1000 Genomes Project database. Conclusions In this Mexican population, the percentage of diffuse gastric tumors with reduced expression of E-cadherin was similar to that reported in other populations. All gastric tumors of DGC patients studied had somatic CDH1 gene variants; however, the rs114265540, rs34939176, and rs33964119 variants were importantly related to DGC.

Estenosis gastroduodenal: una complicación infrecuente del carcinoma gástrico de células en anillo de sello / Upper gastrointestinal stenosis: a rare complication of gastric-signet ring cell carcinoma / Estenose gastroduodenal: uma complicação rara do carcinoma gástrico de células em anel de sinete

El carcinoma de células en anillo de sello es una variante histopatológica de cáncer gástrico que se encuentra en aumento, se caracteriza por un mal pronóstico. Se presenta el caso de un hombre joven al que se le hizo este diagnóstico en el contexto de una complicación rara como es el síndrome de estenosis gastroduodenal.

Signet ring cell carcinoma is a histopathological variant of gastric cancer that is increasing and is characterized by a poor prognosis. We present the case of a young man who underwent this diagnosis in the context of a rare complication such as upper gastrointestinal stenosis syndrome.

O carcinoma de células em anel de sinete é uma variante histopatológica do câncer gástrico que está aumentando e é caracterizado por um mau prognóstico. É apresentado o caso de um jovem que recebeu este diagnóstico no contexto de uma complicação rara como a síndrome de estenose gastroduodenal.

Oncogenic transmembrane protein 158 drives the PI3K/Akt signaling pathway to accelerate gastric cancer cell growth

Gastric cancer (GC) is a serious threat to human health and an important cause of cancer-related death. Herein, we evaluated the influence of transmembrane protein 158 (TMEM158) on GC cell growth. According to Genomic Spatial Event (GSE) and The Cancer Genome Atlas (TCGA) databases, TMEM158 content is amplified in GC tissues. The diagnostic value of TMEM158 expression in GC is huge. GC sufferers with high expression of TMEM158 were associated with poor overall survival. In addition, TMEM158 content was increased in GC cells. TMEM158 promoted GC cell proliferation by modulating the PI3K/Akt signaling pathway. Lack of TMEM158 reduced GC tumor growth. Collectively, TMEM158 accelerated GC cell proliferation by modulating the PI3K/Akt signaling pathway, making it a prospective biomarker for survival in GC patients.

Virus de Epstein-Barr: más que una mononucleosis infecciosa / Epstein-Barr virus: more than infectious mononucleosis

El virus de Epstein-Barr (VEB) fue el primer virus asociado a neoplasias en humanos. Infecta el 95 % de la población mundial, y aunque usualmente es asintomático, puede causar mononucleosis infecciosa y se relaciona con más de 200.000 casos de neoplasias al año. De igual forma, se asocia con esclerosis múltiple y otras enfermedades autoinmunes. A pesar de ser catalogado como un virus oncogénico, solo un pequeño porcentaje de los individuos infectados desarrollan neoplasias asociadas a VEB. Su persistencia involucra la capacidad de alternar entre una serie de programas de latencia, y de reactivarse cuando tiene la necesidad de colonizar nuevas células B de memoria, con el fin de sostener una infección de por vida y poder transmitirse a nuevos hospederos. En esta revisión se presentan las generalidades del VEB, además de su asociación con varios tipos de neoplasias, como son el carcinoma nasofaríngeo, el carcinoma gástrico, el linfoma de Hodgkin y el linfoma de Burkitt, y la esclerosis múltiple. Adicionalmente, se describen los mecanismos fisiopatológicos de las diferentes entidades, algunos de ellos no completamente dilucidados

Epstein-Barr virus (EBV) was the first virus associated with human cancer. It infects 95% of the world's population, and although it is usually asymptomatic, it causes infectious mononucleosis. It is related to more than 200,000 cases of cancer per year, and is also associated with multiple sclerosis and other autoimmune diseases. Despite being classified as an oncogenic virus, only a small percentage of infected individuals develop EBV-associated cancer. Its persistence involves the ability to alternate between a series of latency programs, and the ability to reactivate itself when it needs to colonize new memory B cells, in order to sustain a lifelong infection and be able to transmit to new hosts. In this review, the general characteristics of EBV are presented, in addition to its association with various types of cancers, such as nasopharyngeal carcinoma, gastric carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma, and multiple sclerosis. Additionally, the pathophysiological mechanisms of the different entities are described, some of them not completely elucidated yet

Guiqi Baizhu Prescription Combined with Oxaliplatin Protects Intestinal Barrier of Tumor-bearing Mice with Gastric Cancer by Regulation of VIP/cAMP/PKA/AQP Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the protective effect of Guiqi Baizhu prescription combined with oxaliplatin on the intestinal barrier of tumor-bearing mice with gastric cancer by regulating downstream aquaporin 3 （AQP3） and aquaporin 4 （AQP4） through the vasoactive intestinal peptide （VIP）/cyclic adenosine monophosphate （cAMP）/protein kinase A （PKA） signaling pathway. MethodThe gastric cancer cell lines MFC with a density of 1×107/mL were prepared into cell suspension. The tumor-bearing mouse model of gastric cancer was established by inoculating 0.2 mL cell suspension under the right axilla of mice. After successful modeling， mice were randomly divided into 5 groups， namely， model group， oxaliplatin group （10 mg·kg-1）， and high， medium， and low-dose oxaliplatin + Guiqi Baizhu prescription groups （17.68， 8.84， 4.42 g·kg-1）， with 10 mice in each group， and the remaining 10 mice were set as a blank group. Mice in each group were treated with Chinese medicine， oxaliplatin， or normal saline by gavage or intraperitoneal injection for 14 d. The next day after the last dose， blood was taken from the eyeball to separate serum and take colonic samples. Hematoxylin-eosin （HE） staining was used to observe the changes in tissue morphology. The content of D-lactate acid （D-LA） and diamine oxidase （DAO） in the serum was determined by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein expressions of VIP， cAMP， PKA， AQP3， and AQP4 were detected by Real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. ResultCompared with the blank group， the model group showed edema in the colonic submucosa， disordered arrangement of intestinal glands in the mucosal layer， loss of goblet cells， infiltration of inflammatory cells， and villus shedding. However， there were different degrees of improvement in each administration group. As compared with the blank group， the serum levels of DAO and D-LA in the model group were significantly increased （P<0.01）. As compared with the model group， the levels of DAO and D-LA in the high-dose oxaliplatin + Guiqi Baizhu prescription group and the level of D-LA in the medium-dose oxaliplatin + Guiqi Baizhu prescription group were decreased （P<0.05， P<0.01）. As compared with the oxaliplatin group， the levels of D-LA in the high and medium-dose oxaliplatin + Guiqi Baizhu prescription groups were decreased （P<0.05）， and the levels of DAO and D-LA in other administration groups were decreased as well， but the difference had no statistical significance. As compared with the blank group， the mRNA and protein expression levels of VIP， cAMP， PKA， AQP3， and AQP4 in the model group were significantly decreased （P<0.05， P<0.01）. As compared with the model group， the mRNA and protein expression levels of VIP， cAMP， PKA， AQP3， and AQP4 in each administration group were increased， and those in the high-dose oxaliplatin + Guiqi Baizhu prescription group were significantly increased （P<0.05， P<0.01）， while the protein expression level of cAMP in the medium-dose oxaliplatin + Guiqi Baizhu prescription group were increased （P<0.05）. As compared with the oxaliplatin group， the protein expression levels of cAMP in the high-dose oxaliplatin + Guiqi Baizhu prescription group were increased （P<0.05）， and the mRNA and protein expressions of these indexes in the other groups were also increased but the differences were not statistically significant. ConclusionGuiqi Baizhu prescription combined with oxaliplatin can regulate AQP3 and AQP4 through the VIP/cAMP/PKA signaling pathway to protect the intestinal barrier of tumor-bearing mice with gastric cancer.

Baicalin Induces Ferroptosis in Gastric Cancer Cells via p53-mediated SLC7A11 Down-regulation / 中国实验方剂学杂志

ObjectiveTo explore the inhibitory effect of different concentration of baicalin （0， 100， 200， 400 μmol·L-1） on the proliferation of human gastric cancer SGC-7901 cells and the underlying mechanism. MethodSGC-7901 cells were treated with baicalin. Then methyl thiazolyl tetrazolium （MTT） assay was employed to examine the inhibitory effect of baicalin on the cells. At the same time， ferrostatin-1 （Fer-1） was added to observe the viability of cells after baicalin treatment. The expression of ferroptosis-related genes was detected by Real-time polymerase chain reaction （Real-time PCR） and Western blot. The content of malondialdehyde （MDA） and the level of glutathione （GSH） were detected respectively by MTT assay and enzyme-linked immunosorbent assay. The role of tumor protein 53 （p53）/solute carrier family 7 member 11 （SLC7A11） pathway in the regulation of ferroptosis was investigated respectively via overexpression and small interfering RNA （siRNA） methods. ResultCompared with the blank group， baicalin decreased the viability of SGC-7901 （P<0.05， P<0.01） in a dose- and time-dependent manner. The intervention of Fer-1 significantly alleviated the decrease of SGC-7901 cell viability caused by baicalin （P<0.01）. In addition， compared with the baicalin group， Fer-1+baicalin group showed decrease in MDA content and the mRNA and protein levels of prostaglandin-endoperoxide synthase 2 （PTGS2） in the cells （P<0.01）， and increase in GSH activity and mRNA and protein levels of glutathione peroxidase 4 （GPX4） （P<0.01）. The protein level of SLC7A11 in the baicalin group was decreased compared with that in the blank group （P<0.05， P<0.01） in a dose-dependent manner. Compared with the baicalin group， the reactive oxygen species （ROS） level and MDA content in SLC7A11-overexpressing cells were significantly decreased after baicalin treatment （P<0.01）， and the GSH activity was significantly increased （P<0.01）. The fluorescence intensity of p53 in the cells of the baicalin group was increased compared with that of the blank group （P<0.01）. Compared with the baicalin group， the expression level of p53 protein in the cells transfected with p53 siRNA was significantly decreased after baicalin treatment （P<0.01）， and the expression level of SLC7A11 was significantly increased （P<0.01）. ConclusionBaicalin can effectively inhibit the proliferation of SGC-7901 cells by regulating p53/SLC7A11-mediated ferroptosis.

High sodium diet on the prevalence and mortality of gastric cancer in Xi'an / 公共卫生与预防医学

Objective To investigate the effect of high sodium diet on the prevalence and mortality of gastric cancer in Xi'an , and to provide reference for its clinical treatment and prevention. Methods A questionnaire survey was conducted on 604 inpatients in tertiary hospitals in Xi'an from 2018 to 2020, and data including medical history, medication use, daily sodium intake and gastric cancer incidence were collected. A one-year follow-up was completed, and all-cause mortality was recorded during the follow-up period. Results A total of 604 cases , there were 81 cases of gastric cancer and 523 cases of non-gastric cancer, with a prevalence rate of 13.41%. Among patients with gastric cancer, 49 (8.11%) were male and 32 (5.30%) were female. There were 9 cases (1.49%) aged 30-40 years, 14 cases (2.32%) aged 41-50 years, 27 cases (4.47%) aged 51-60 years and 31 cases (5.13%) aged 60 years and above. The gastric cancer and non-gastric cancer patients yielded no statistical difference in terms of age, gender and medical history (P>0.05), while the proportion of sodium intake was significantly higher in gastric cancer patients than in non-gastric cancer patients (P<0.05). Logistics analysis showed that high sodium diet was a risk factor for the development of gastric cancer (P<0.05). The proportion of high sodium diets was 40.89% (247/604) in all selected individuals, 72.84% (59/81) in gastric cancer patients and 35.95% (188/523) in non-gastric cancer patients. The proportion of patients on a high sodium diet demonstrated statistical difference between gastric cancer and non-gastric cancer patients (P<0.05). One-year follow-up showed that 58 of 81 gastric cancer patients survived (71.60%) and 23 died (28.40%), including 20 survivors (34.48%) and 17 deaths (73.91%) on a high-sodium diet. Significant difference was found in the proportion of patients on high sodium diet between dead and surviving gastric cancer patients (P<0.05). Conclusion The prevalence and mortality rate of gastric cancer caused by high sodium diet is high among residents in Xi'an , clinical guidance on sodium intake is of great importance to patients.

Trends in incidence of malignant tumors in Yuyao City from 2011 to 2018 / 预防医学

Objective@#To investigate the trends in incidence of malignant tumors in Yuyao City, Zhejiang Province from 2011 to 2018, so as to provide insights into formulation of the malignant tumor control strategy.@*Methods@#Data pertaining to the incidence of malignant tumor in Yuyao City from 2011 to 2018 were captured from the Chronic Disease Surveillance Module of Ningbo Municipal Digital Disease Control and Prevention Platform. The crude incidence, Chinese population-standardized incidence, global population-standardized incidence, cumulative incidence (0 to 74 years of age), and truncated age-standardized incidence (35 to 64 years of age) of malignant tumors were estimated, and the trends in incidence of malignant tumors were analyzed in Yuyao City from 2011 to 2018 using average annual percentage change (AAPC).@*Results@#The crude incidence, Chinese population-standardized incidence, global population-standardized incidence, cumulative incidence (0 to 74 years of age), and truncated age-standardized incidence (35 to 64 years of age) of malignant tumors were 433.78/105, 289.37/105, 224.22/105, 25.83% and 83.34/105 in Yuyao City from 2011 to 2018, with AAPC of 5.90%, 3.31%, 3.31%, 2.84% and 4.24%, respectively (all P<0.05), and the incidence of malignant tumors appeared an overall tendency towards a rise. The incidence of malignant tumors increased with age in Yuyao City from 2011 to 2018, and the incidence of malignant tumors was significantly higher in women than in men at ages of 20 to 54 years, while higher incidence was seen in men than in women at ages of 55 years and older. The ten most common malignant tumors included lung cancer, gastric cancer, colorectal cancer, liver cancer, breast cancer, esophageal cancer, thyroid cancer, pancreatic cancer, prostate cancer and cervical cancer, accounting for 78.84% of all malignancies, and the the incidence of lung cancer, colorectal cancer, breast cancer, thyroid cancer, pancreatic cancer and prostate cancer appeared a tendency towards a rise year by year, with AAPC of 8.37%, 5.36%, 6.42%, 24.81%, 5.49% and 18.78%, respectively (all P<0.05). @*Conclusions@#The of malignant tumors appeared a tendency towards a rise in Yuyao City from 2011 to 2018, and lung cancer, thyroid cancer, specific female cancers, male gastrointestinal and prostate cancers should be given a high priority for cancer control in Yuyao City in the future. Early screening and early diagnosis of cancers should be facilitated among high-risk populations.